Cerebral Blood Flow, Autoregulation and Vascular Reactivity in Normal Pressure Hydrocephalus: a systematic review

Cerebral Blood Flow, Autoregulation and Vascular Reactivity in Normal Pressure Hydrocephalus: a systematic review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Cerebral Blood Flow, Autoregulation and Vascular Reactivity in Normal Pressure Hydrocephalus: a systematic review Afroditi Despoina Lalou, Marek Czosnyka, Zofia Helena Czosnyka, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6480393/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Dec, 2025 Read the published version in Fluids and Barriers of the CNS → Version 1 posted 10 You are reading this latest preprint version Abstract Normal pressure hydrocephalus is one of the few remediable causes of decline in gait and cognitive function in the ageing population. The roles of the cerebral circulation including haemodynamic reserve and cardiovascular co-morbidity in the pathogenesis, management and prognostication of NPH remain ill-defined. In this systematic review, we have updated Owler & Pickard’s review of 2001 1 to examine • whether there are changes in global and regional CBF that are specific to NPH and its clinical manifestations? • whether levels of global and regional CBF are appropriately coupled to cerebral metabolism and/or low enough to equate to ongoing cerebral ischaemia? • whether any changes in global or regional CBF are predictive of outcome after CSF drainage, both temporary and permanent (shunting)? • whether global and regional cerebrovascular autoregulation and reactivity are more sensitive predictors of outcome and reversibility of symptoms in response to both temporary and permanent CSF drainage than baseline rCBF? • whether changes in resistance to CSF outflow, whole brain compliance, local tissue stress and loss of brain tissue volume relate to CBF and disordered cerebrovascular autoregulation and reactivity? Whether any changes in global or regional CBF are the cause or effect (‘chicken and the egg’) of iNPH? • whether a trial is warranted that combines assessments of haemodynamic reserve, CSF outflow resistance and response to temporary CSF drainage? autoregulation cerebral autoregulation cerebrovascular reactivity cerebral blood flow hydrocephalus normal pressure hydrocephalus Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Reversible causes of dementia are crucially important to the individual, to their family and to society. It is almost 60 years since the symptoms of normal pressure hydrocephalus (‘Hakim’s triad’: gait disturbance, dementia and urinary incontinence with radiological hydrocephalus and normal baseline CSF pressure) and their response to CSF drainage were first described 2 , 3 and yet there remain many uncertainties around the pathogenesis, diagnosis and management of Normal Pressure Hydrocephalus (NPH). The prevalence of symptomatic iNPH is of the order of 1.5% at the age of 70 rising to 7.7% at 86 years of age 4 , 5 in parallel with the normal age-related increase in ventricular volume. 6 , 7 , 8 A further 3.7% at the age of 70 years have radiologically probable NPH, a proportion of whom progress to become symptomatic. 5 , 9 – 11 There remains a wide geographical disparity in the incidence of shunting for NPH 12 . Secondary NPH develops late after disease processes that are well known to obstruct the CSF circulation including, for example, subarachnoid and intraventricular haemorrhage, meningitis, traumatic brain injury, basilar artery ectasia or longstanding aqueduct stenosis. Such cases respond well to CSF diversion. By definition in idiopathic NPH, no such prior disease appears to have been present. A disturbance of the CSF circulation alone may not always be sufficient for developing the condition. Certainly, there is autopsy evidence of meningeal thickening, subependymal gliosis and periventricular white matter demyelination 13 – 15 and yet the relationship of CSF outflow resistance to post-drainage outcome, either temporary or permanent, is nonlinear 16 . MR studies have confirmed the presence of periventricular axonal stretch injury and, in some but not all studies, reduced volumes of the caudate, thalamus, putamen, pallidum, hippocampus and nucleus accumbens. 17 – 20 Reductions in volume of thalamus and caudate may also be part of normal ageing 8 . Co-morbidity and fragility are very common in iNPH. 21 – 23 There is a high incidence of vascular risk factors, cardio- or cerebro- vascular disease and white matter changes in many NPH subjects 24 – 31 . In iNPH with dementia, neuropathology often reveals evidence of Alzheimer change, cerebral small vessel disease (CSVD), multifocal infarcts, Parkinson’s disease or Parkinsonism (including Progressive Supranuclear Palsy, Corticobasal Degeneration and Multiple System Atrophy) 15 , 32 , 33 . CSF biomarker studies confirm that patients with iNPH and CSVD share common features of subcortical neuronal degeneration, demyelination, and astroglial response including the reduction in all APP-derived proteins 34 . Interestingly, it has been suggested that some cases of iNPH may have started with benign external hydrocephalus in infancy followed by deep white matter ischaemia in late adulthood. 35 , 36 Certainly, head size is statistically larger in NPH patients compared with normal subjects. 37 , 38 Hence, the cerebral vasculature may have a role in the pathogenesis of iNPH. However, such a role remains ill-defined, as does the ability of measurements of CBF and cerebrovascular autoregulation/reactivity to predict outcome after CSF diversion. The previous systematic review (2001 1 ) found that studies of CBF in iNPH had been inconsistent, not least in predicting the response to shunting. Studies had been hampered by heterogeneous patient groups of small size, incompatible definitions of clinical outcome, lack of longitudinal studies, and the resolving power of the then available technology to quantify periventricular regional CBF. Unresolved issues include Whether there are changes in global and regional CBF that are specific to NPH and its clinical manifestations? Whether levels of global and regional CBF are appropriately coupled to cerebral metabolism and/or low enough to equate to ongoing cerebral ischaemia? Whether any changes in global or regional CBF are predictive of outcome after CSF drainage, both temporary and permanent? Whether global and regional cerebrovascular autoregulation and reactivity are more sensitive predictors of outcome and reversibility of symptoms in response to both temporary and permanent CSF drainage than baseline rCBF? Whether changes in whole brain CSF pressure-volume compensation and circulation, local tissue stress and loss of brain tissue volume relate to CBF and cerebrovascular autoregulation and reactivity? Whether any changes in global or regional CBF are the cause or effect (‘chicken and the egg’) of iNPH? In this systematic review, we have updated the previous 2001 review and examined how far new knowledge has addressed these questions. Methods From February 2020 up until June 2024, we performed a detailed search on Scopus, Cochrane, PubMed, and Web of Knowledge, using the key phrases “(((cerebral autoregulation) OR (cerebrovascular reactivity) OR (cerebrovascular resistance))) AND (normal pressure hydrocephalus)”. We set out the timeline to include manuscripts after 2000 up until 30/06/2024, due to the fact that Owler & Pickard 1 performed a systematic review of the relevant literature up to year 2000. The language in which papers were written did not matter, since we had access to the vast majority of the world languages. The articles had to be published - unpublished work or work awaiting publication was not considered. Case reports were excluded as they do not contribute to the questions asked nor to the need for adequate numbers of patients with NPH. Articles had to involve idiopathic or secondary adult NPH patients with pre-shunting assessment of CBF or autoregulation at baseline and/or after CSF drainage or shunting; this was in order to investigate the different measurements of CBF at baseline and the previously found difference in rCBF as well as to examine their to date not clear outcome implications. We compared all papers for consistency of references, background, analytical reporting of methods as well as reasoning and drawing of conclusions in an unbiased manner, taking into account NPH literature and its pathophysiological considerations. Cerebral Autoregulation was assessed separately to Cerebrovascular Reactivity (CVR). The data from all the original articles was extracted using piloted data forms; the forms underwent some dynamic changes during the data extraction when new data or information arose. The RTI tool was used to assess bias in observational studies. The QUIPS tool was used for assessing risk of bias for study participation, prognostic factor measurement and outcome measurement. The GRADE tool was used to classify the diagnostic and prognostic level of evidence as High, Moderate and Low 39 . A high level of evidence consisted of high quality studies with consistency and low to moderate (unclear) risk of bias; moderate level consisted of high quality evidence but inconsistent and with low to moderate risk of bias. Finally, low level of evidence included either high-moderate quality of evidence with inconsistency and high risk of bias, or moderate-low quality with at least inconsistency and/or high risk of bias. In order to uphold a standardised definition of Normal Pressure Hydrocephalus, the following criteria had to be met in defining and selecting the NPH group, as reported in Owler & Pickard 1 : Full or incomplete clinical triad/primarily gait disorder; ventricular dilatation on CT without significant atrophy; absence of focal neurological deficit or focal pathology on CT; normal ICP/CSF pressure (< 15 mmHg) assessed using ICP monitoring or infusion study, objective, well documented follow-up. We reviewed and combined the findings prior to our 2001 review with the new research. This review design and protocol can be accessed in the PROSPERO register (registration number CRD42018090946). Results and Discussion Figure 1 maps out the number of records identified from the searched databases, including those included and excluded with the reasons for their exclusions. All results reported refer to statistically significant results, unless stated otherwise. Our risk of bias assessment for observational and prognostic factor studies are presented in Supplementary tables 1 and 2. Overview. This review should be read in conjunction with Owler & Pickard’s review of 2001 1 which matched the reports of global and regional CBF, autoregulation and reactivity to the methodology used. Unfortunately, very few studies since have included more than 50 patients and have not always included details of clinical presentation including duration of symptoms, or co-morbidity (frailty, Alzheimer’s, Parkinsons, cerebral small vessel disease (CSVD), systemic hypertension, diabetic status and other cardiovascular risk factors). It is now clear that there is much overlap in terms of patterns of CBF between CSVD and NPH. Few studies reported the scanning environment (eg quiet room, eyes closed) or what the patients were asked to think about during the CBF measurements. Such clinical and procedural heterogeneity renders statistical analysis challenging. Table 1 Global CBF studies at baseline : results of pre-2001 studies from Owler & Pickard (re-graded using updated GRADE tool) combined with later studies. Global CBF Reference Grade Method Number of NPH patients Main findings Comments 1.Greitz et al., 1969 (2 parts) 42 , 43 B Intracarotid 133Xe clearance during Angiography 28 (21 + 7) Reduced In cases without a vascular component, correlation between ventricular dilation and ↓CBF 2.Salmon & Timperman et al., 1971a (2 parts) 44 , 45 C As in 1 (Greitz et al) 12 (5 + 7) Reduced 4.Mathew et al., 1975 46 B As in 1 15 Reduced CBF unchanged between NPH&atrophy. No correlation between CBF &ventricular size 5.Hartmann et al., 1977 47 C As in 1 11 Same 6.Grubb et al., 1977 48 B H 2 O 15 PET Intracarotid 11 Reduced CBF unchanged between NPH&atrophy. No definite pattern of CBF could be identified in NPH patients 7.Lying-Tunnell et al., 1977 & 1981 49,50 C AV-Difference N 2 O 7 Reduced ↓CBF especially in the most demented patients 8.Hayashi et al., 1984 51 B As in 1 16 Reduced ↓CBF correlated with ↑ventricular size. 9.Kushner et al., 1984 52 B As in 1 19 Reduced No difference in CBF between NPH and non-NPH dementia patients 10.Meyer et al., 1984 53 B 133Xe inhalation 11 Reduced 11.Meyer et al., 1985a 54 C 133Xe inhalation & Xe contrast CT 8 Reduced Frontal, temporal and parietal cortex 12.Meyer et al., 1985b 55 B Xe contrast CT 10 Reduced 13.Brooks et al., 1986 56 C C15O2 PET inhalation 3 Reduced 14.Mamo et al., 1987 57 B 133Xe IV 25 Reduced ↓CBF compared to controls. No correlation between ventricular size and CBF reduction 15.Vorstrup et al., 1987 58 B 133Xe inhalation SPECT 17 Reduced In 14/17 cases there was correlation between ↓CBF and ↑ ventricular size. 16.Graff-Radford et al., 1987 & 89 25,37 C 133Xe inhalation SPECT 61 (26 + 35) Reduced No difference between CBF in AD and NPH patients. 17.Meixenberger et al., 1989 59 C 133Xe inhalation 31 Reduced Frontal cortex 18.Matsuda et al., 1990 60 B 133Xe inhalation 13 Reduced ↓CBF correlated with ventricular size. 19.Kimura et al., 1992 61 C Xe contrast CT 7 Reduced Generally ↓CBF in NPH 20.Waldemar et al., 1993 40 B 99m Tc-HMPAO SPECT & 133Xe inhalation SPECT 14 Same No difference in tCBF. 21.Maeder et al., 1995 62 C Xe contrast CT 4 Reduced 22.Kristensen et al., 1996 63 B 99m Tc-HMPAO SPECT 31 Reduced 23.Tanaka et al., 1997 64 A Xe contrast CT 21 Reduced 24.Klinge et al., 1998 65 B H2O15 bolus PET 21 Reduced Generally ↓CBF 25.Klinge et al., 1999 66 B H2O15 bolus PET 10 Reduced Generally ↓CBF 26.Owler et al 2004* 67 B H 2 15 O PET 17 Reduced 27.Bateman & Loiselle 2007 68 B PC MRI 32 Reduced Total blood inflow 20% ↓ Sagittal sinus outflow 35% ↓ 28.El Sankari et al 2011 69 B PC MRI 13 Reduced Total blood inflow 12% ↓ (NS); Venous outflow unchanged (-2%; NS) 29.Yamada et al (2013)* 70 B SPECT 25 Reduced Diffuse ↓ in global CBF pre-shunting similar to patients with ventriculomegaly due to age (no healthy controls). 30.Ziegelitz et al 2014 * 71 B Dynamic susceptibility contrast MRI 21 Reduced Preoperative CBF ↓ in the global parenchyma deep GM 31.Qvarlander et al 2017 41 B PC MRI 16 Same ↓Internal Carotid artery flow (Controls:519 ± 123, NPH: 461 ± 84ml/min,p = 0.04) 32.Huang et al 2022 72 C 3D pulsed ASL MRI 32 Reduced No healthy controls. Xe: Xenon, Tc-HMPAO: Technetium – Hexamethylpropylene Amine Oxime. PC: Phase Contrast. ASL: Arterial Spin-Labelling Global and Regional CBF (Table 1, Figure 2) Overall, the 25 studies reported prior to 2001 provided Grade B evidence for reduced global CBF in 23 studies of 382 NPH patients with only 2 studies of 25 NPH patients showing unchanged global CBF compared to controls. PC MRI and perfusion MRI have been introduced since 2001. In Waldemar’s study 40 , although global CBF was not reduced, the subcortical low flow area was enlarged. In the Qvarlander study 41 , internal carotid but not vertebral artery flow was reduced. Post-2001 CBF measurements have confirmed that global CBF is reduced by 15.2% (sd 14.0%) in iNPH at baseline compared to controls (Fig. 2 ). Various MR techniques (PC MRI, ASL MRI and DSC MRI), 15 O PET and SPECT have now confirmed the older literature that global CBF is modestly reduced in NPH compared with age-matched healthy controls (Table 1 and Fig. 2 ). Regional CBF and clinical correlations ( Table 2 ). Table 2 Regional Cerebral Blood Flow at baseline including clinical correlations Regional CBF Reference Grade Method Number of NPH patients Main findings Comments 1.Mathew et al., 1975 46 B Intracarotid 133Xe clearance during Angiography 15 Reduced Frontal lobe (grey & white matter) & ACA territories (parietal lobe, corpus callosum, basal ganglia) 2. Meyer et al., 1985a 54 C 133Xe inhalation & Xe contrast CT 8 Reduced Frontal, temporal and parietal cortex, thalamus &fronto-temporal WM 3,Meyer et al., 1985b 53 B Xe contrast CT 10 Reduced Frontal WM 4.Graff-Radford et al., 1987 & 89 25,37 C 133Xe inhalation SPECT 61 (26 + 35) Reduced Frontal “region” 5.Waldemar et al., 1993 40 B 99m Tc-HMPAO SPECT & 133Xe inhalation SPECT 14 Same * *Slight ↓ in the centrum semiovale. *NPH patients had lower frontal/parietal ratio CBF 6.Maeder et al., 1995 62 C Xe contrast CT 4 Reduced Frontal cortex & white matter 7.Kristensen et al., 1996 63 B 99m Tc-HMPAO SPECT 31 Reduced Inferior frontal &temporal cortex. frontal & parietal WM 8.Owler et al (2004a) 92 * B H2 15 O PET &3T MRI 17 Reduced Cerebellum, thalamus , head of caudate and putamen. 9.Momjian et al(2004) 93 B H 2 15 O PET & 3TMRI 12 Reduced Paraventricular borderzone regions. WM, with abnormal gradient from lateral ventricles towards the subcortical WM (PVWM). 10.Sasaki et al (2007) 94 B SPECT (voxel based analysis) 30 Reduced Corpus callosum. Either frontal dominant or diffuse pattern. Medial &lateral in urinary incontinence 11.Klinge et al (2008) 95 B H 2 15 O PET uptake 68 Reduced Greater impairment correlated with reduced tracer uptake in mesial frontal and anterior temporal areas. 12.Yoon et al (2009) 96 B SPECT 10 Reduced bilateral thalami , anterior and posterior cingulate gyri, right prefrontal area, right caudate nucleus and left parahippocampal gyrus 13.Takaya et al (2010) 97 B SPECT 14 Reduced parietal lobe, lateral &medial frontal cortex , lateral temporal &occipital cortex, cingulate gyrus, precuneus, frontal WM, semioval center,corpus callosum ; caudate, thalamus , pons, cerebellum 14. Ishii et al 2011 98 A N-isopropyl-p- 123 I iodoamphetamine SPECT. Relative CBF in each voxel was calculated by normalizing each voxel activity to the global brain activity. 84 Variable patterns: frontal perfusion predominantly reduced. The medial and lateral frontal, parietal, and occipital CBFs relatively increased at high convexity. Multicentre study in 26 centres; basal ganglia and thalamus not analysed. CBF in the peri-sylvian and ventricular areas, where the cerebrospinal fluid spaces are dilated, is also reduced – partial volume issue. 14. Ziegelitz et al 2014 71 B Dynamic susceptibility contrast MRI 21 Reduced basal medial frontal cortex, hippocampus, lentiform nucleus, PVWM & central GM 15.Virhammar et al (2017) 99 B pCASL perfusion MRI 21 Reduced PVWM , cerebellum and pons lentiform nucleus & thalamus 16. Takahashi et al (2019) 100 B CBF SPECT & MRI 30 Reduced ↑rCBF in the lower part of the high convexity area. ↓rCBF in medial frontal lobes, left lateral frontal lobe, and left parietotemporal region 17. Azuma et al (2019) 79 B 123 I-IMP SPECT MRI 39 (15 - iNPH/AD+ 24 - iNPH/AD−) The putamen was the only region in which rCBF was significantly lower in iNPH/AD − patients than in iNPH/AD + patients No controls No significant correlation between gait and rCBF in any region. 18. Agerskov et al (2020)* 101 B DSC MR perfusion 20 Same ROIs in upper mesencephalon and lower pons only. 19. Huang et al 2022 72 B 3D pulsed ASL MRI 32 Reduced high convexity, temporal lobe, precuneus, and thalamus. 20. Kang et al 2023 102 B 18 F-florbetaben (E-FBB) PET FDG PET MRI 39 Mixed patterns ↑rCBF in the high convexity of frontal and parietal cortical regions ↓rCBF in ventrolateral frontal cortex, supramarginal gyrus and temporal cortical regions. *Owler et al (2004) & Momjian et al (2004) analysed the same cohort of patients using different voxel analyses. With regard to regional CBF, the new consistent findings since 2001 are that, in addition to the frontal lobe, rCBF in the periventricular white matter and deep grey matter (thalamus and, more variably, caudate, hippocampus and lentiform nucleus) are reduced. One important methodological finding was that cerebellar CBF is modestly reduced which suggests that the use of the cerebellum as a control for SPECT studies is problematic. The reductions in rCBF in the deep WM and GM are in accord with reductions in volumes of these structures (but see below for discussion of the ‘chicken and egg’ conundrum) 73 , 74 . All the post-2001 studies that have investigated the frontal cortex confirmed the pre-2001 findings of frontal hypoperfusion but with less consistent findings in the lateral and medial frontal cortices and frontal white matter. Studies that included the periventricular white matter, thalamus, basal ganglia and cerebellum as ROIs demonstrated hypoperfusion. There were also reports of hypoperfusion of the cingulate gyrus, corpus callosum, pons and temporo-parietal areas. Frontal hypoperfusion (lateral, medial and basal) accords with the loss of both executive and motor function in NPH. Cognitive functions depend upon efficient functioning of distributed brain networks connected by white matter tracts. In the case of CSVD, such frontal hypoperfusion has been related to a regional predominance of WMH and white matter tract disruption in the frontal lobes, consistent with cortical disconnection, that would provide a plausible structural basis for selective loss of executive function [ 29 , 75 – 78 ). Regarding neurocognitive symptoms, impaired wakefulness was associated with decreased rCBF in the anterior cingulate gyrus and anterior periventricular white matter in two out of the three studies of neurocognitive results. Of the 12 studies on rCBF, 4 described the relationship between gait and rCBF. Whilst different regions were investigated, the thalamus as well as frontal and periventricular structures demonstrated a correlation with gait impairment in 3 studies. In contrast, Azuma’s study 79 did not find any significant correlation between gait and rCBF in any regions. White matter surrounding the lateral ventricles, especially in the frontal lobes, is key to gait function. Fibres in these areas connect brain regions likely involved in iNPH, such as the supplementary motor cortex, basal ganglia, and thalamus, and in elderly people without iNPH, WM hyperintensities in the frontal lobe and periventricular WM have the strongest relationship with impairments in balance and gait 80 , 81 . Akai et al 13 reported that the most prominent post-mortem finding in NPH was demyelination of the white matter supplied by the anterior and middle cerebral arteries. While the peripheral arcuate region of the white matter region was reasonably maintained, the deep white matter demonstrated a marked reduction in the number of myelinated axons. The number of axons themselves was also reduced. Whether this is a cause or effect of reduced blood flow in periventricular regions is not clear. Such changes may also have distant effects due to deafferentation and thereby reduction in CBF in those regions affected. Such functional deafferentation is consistent with recent studies of Resting State Networks 82 – 85 . Axons may only need to be stretched across the dilated ventricles to influence functioning. As early as 1947 Yakovlev had proposed that gait disorder was due to stretching of axons responsible for gait 86 . Of course, periventricular stretch and compression impacts on blood vessels as well as axons (see below; 13 , 87 – 90 ) There is some intriguing disagreement over whether rCBF is increased in the high convexity area (Table 2 ). Such increases are counter-intuitive and yet have also been identified in longitudinal studies of normal aging without dementia where extensive bilateral regions showed greater relative increases in rCBF in the group with progressive WM abnormalities compared with the stable WM group over time. Kraut et al 91 suggested that ‘these increases in rCBF associated with WM pathology might relate to changes in resting cerebral cortical activity (and thus metabolic requirements), as accommodations are made for less efficient interregional WM connections. That is, regions of brain that are interconnected by deficient WM would have to maintain activity for longer periods or at a higher level to communicate with one another even in the resting state, either through the deteriorating pathways that had been used before WM degeneration had begun, or through less efficient indirect pathways. This prolonged cortical neural activity would require increased blood flow to meet the increased metabolic demands.” The authors accepted that this idea runs counter to several studies of the relationship between cerebral glucose metabolism and WM abnormalities, where in general it has been found that increased severity of WM disease correlates with reduced regional rates of cerebral glucose metabolism. Table 3 Results of Cerebral Metabolism studied either separately or simultaneously with Cerebral Blood Flow. Reference Grade Method Significant findings Baseline Significant post-shunt changes Comments Cerebral oxygen consumption 1. Lying-Tunnell 1981 49 C Kety-Schmidt N 2 O ↓CBF (-33%) ↓CMRGlu ↓oxygen uptake All parameters improved 2.Brooks 1986 56 B 15 O PET ↓CBF ↓CMRO 2 OEF no change No change Cortical CBF only reported; only CMRO 2 changes were significant 3.Miyamoto 2007a/b 111,112 C 15 O PET ↑CMRO 2 4. Zhuang 2023 113 B 3D multi- gradient echo to assess ventricular CSF volumes with OEF mapping (MRI QQ-CCTV algorithm); ASL Significant negative correlation between OEF and normalised ventricular volume, cortical and deep GM. No clinical data. No WM data. No significant finding with CBF or CMRO 2 . QQ-CCTV and ASL are complex techniques. A fall in OEF would suggest true ischaemia rather than oligemia but CBF would be expected to be low which was not found 105 , 106 . Cerebral glucose metabolism 6.Jagust 1985 114 C 18 F-FDG PET Global hypometabolism in 3 patients 2 Idio; 1 post SAH No CMRGlu calculation 4.George 1986 115 C 18 F-FDG PET 3 chronic HC patients: ↑CMRGlu post-shunt 5.Kaye 1990 116 C 18 F-FDG PET Global ↓CMRGlu Early ↑CMRGlu with return to near normal by 2 years with maintained clinical improvement Case report 7.Tedeschi 1995 117 B 18 F-FDG PET Global hypometabolism – very heterogenous patterns 18 patients; 7 improved post-shunt; frontal biopsy: heterogeneous findings 8.Calcagni 2013 118 C 18 F-FDG PET CMRGlu increased in all cortical regions post shunt; no correlation with symptoms; no specific regional variation N = 20 9.Townley 2018 119 B 18 F-FDG PET Co registered MRI - partial volume correction No specific pattern of significant cortical hypometabolism. Significant striatal hypometabolism. N = 7; healthy controls 10.Miyazaki 2019 120 A 18 F-FDG PET Cerebellar cortex used for ratio calculation ↓frontal and temporal ratios in prodromal and iNPH. ↓ratio in thalamus and striatum in iNPH 12 iNPH 33 with DESH only 32 asymptomatic with ventriculomegly and DESH 11.Chiaravalloti 2020 121 B 18 F-FDG PET Significant ↑ left frontal and parietal regions; ↓right frontal 10 patients No CMRGlu analysis Intracerebral microdialysis 12.Agren-Wilsson 2003 124 B Right frontal 10mm catheter; 0-7mm from the frontal horn Brain tissue oxygen tension PtiO 2 Pre and 2–4 hours post CSF infusion study and drainage to zero CSF pressure Lactate and pyruvate increased; no change in Lac/Pyr ratio PtiO 2 increased in 5 of 8 patients (~ 3 mmHg) 10 patients 13.Eide 2010 122 Left frontal (20mm catheter) extending from cortical surface to 20mms below; controls using normal frontal cortex. Modest changes: ↑Lac (63% of patients) ↓Pyr (60% of Patients) L/P: no change (↑8% of patients) ↑Glut (38% of patients) Modest changes during Extended lumbar drainage ↓Lac (29% of patients) ↑Pyr (82% of patients) ↓L/P (43% of patients) ↓Glut (75% of patients) No differences in baseline or during EDT between reponers and non-reponders. Magnetic Resonance Spectroscopy 14. Kizu et al 2001 125 1 H-CSI intraventricular lactate peaks in NPH (n = 9) not in controls or Alzheimer’s/Picks. 15.Braun 2003 126 C 1 H MRS – ratio analysis WM; NAA/Cr no change 18 adults 40. WM lateral to lateral ventricle 16.Shiino 2004 127 B 1 H MRS – ratio analysis No controls High NAA/Cr – favourable outcome Secondary NPH only; WM lateral to lateral ventricle 17.Kubas 2006 128 B 1 H MRS – ratio analysis NAA/Cr ↓8% Not done Left frontal VOI 18.Del Mar Matarin 2007 129 B 1 H MRS – ratio analysis NAA/Cr ↑ 6% No controls Medial frontal 19.Lenfeldt 2008a 130 A 1 H MRS – ratio analysis NAA/Cr ↓13% Higher in improved patients Frontal WM ELD for 3 days 20.Algin 2010 131 B 1 H MRS – ratio analysis NAA/CR ↓11% NAA/Cho ↓13% No change; no correlation with outcome (n = 18) Frontal lobe 21.Lundin 2011/2013 132,133 A 1 H MRS – absolute quantification Thalamus – NAA ↓10% Frontal deep WM – Cho ↓7.9% Thalamus: No change Frontal deep WM: Cho ↑4.5% Evidence for and against borderline cerebral ischaemia (Table 3) It is a matter of some debate whether changes in the cerebral circulation are a cause or effect of NPH. There is strong evidence of decreased vascular density in ageing animals including humans, 103 – 106 . As noted above, cerebrovascular hypertensive changes are common in NPH. White matter hyperintensities are very common in NPH 29 , 30 . The normal-appearing white matter surrounding white matter hyperintensities is associated with decreased structural integrity and perfusion and increased risk of their growth 107 , 108 . However, CBF reduction may also be the consequence of ventricular dilatation, reduced metabolism and other secondary changes. Unfortunately, there have been no longitudinal studies comparing the time course of changes in rCBF with tissue volume nor of comparative recovery after shunting. However, it is well established that, at least in MCI, hypoperfusion may be dissociated from atrophy 73 , 74 . The use of positron emission tomography (PET) in cerebrovascular disorders has greatly improved our understanding of the clinical pathophysiology of cerebral ischaemia 109 , 110 . The measurement of regional cerebral blood flow (CBF), oxygen consumption (CMRO 2 ), oxygen extraction (OEF) and blood volume (CBV) has permitted the identification of three successive stages of severity which are characterized by (1) an isolated rise of CBV (reflecting a vasodilatation that largely underlies the mechanism of CBF autoregulation); (2) a moderate fall in CBF with normal CMRO 2 and increased OEF (a fully compensated stage defining oligaemia); (3) a depression of CMRO 2 as CBF falls further (denoting true ischaemia). In NPH, both cerebral oxygen and glucose metabolism were reduced to a similar degree to CBF with no change in oxygen extraction fraction (OEF) 49 , 56 , 111 , 112 . The majority of studies reported reduced glucose metabolism in the frontal region, thalamus, caudate and subcortical periventricular white matter 113 – 121 . Hence, the reduction in global/cortical CBF was coupled to the reduction in oxidative brain metabolism and therefore there was no evidence of significant cerebral ischaemia. Despite this preservation of OEF, there is some evidence of low-grade, covert / impending / borderline / chronic ischaemia / misery perfusion in NPH (Table 3 ). Despite significant, modest baseline changes in lactate (increase) and pyruvate (decrease), there was no significant change in lactate/pyruvate ratio. 122 . These changes do not meet the strict microdialysis definition of cerebral ischaemia - increased L/P ratio with reduced pyruvate 123 . However, extended lumbar drainage resulted in modest falls in lactate, increase in pyruvate and fall in L/P ratio in some patients 124 . Neither baseline values nor changes with ELD differed between responders and non-responders. Brain tissue oxygen tension increased modestly (by 3mmHg) in 5 of 8 patients after the combination of a constant pressure CSF infusion study and CSF drainage down to zero pressure 124 . Magnetic Resonance Spectroscopy studies of N-Acetylaspartate/Creatine (NAA/Cr) ratio in the frontal lobe have demonstrated no change or falls of 8–13% which increased after shunting 125 – 133 . Absolute quantification of NAA revealed a significant fall in NAA in the thalamus (↓10%) and in choline, but not NAA, in the deep frontal WM (↓7.9%). Thalamic NAA did not normalise after shunting 132 . Low NAA may be an indicator of neuronal loss that may be reversible. Changes in NAA are not an early indicator of cerebral ischaemia. Reduction in NAA occurs more slowly than increases in lactate after focal ischaemia and is greater in the core of an infarct than in peripheral areas 134 . The thalamic findings are in accord with the reduction in thalamic volume in NPH. Effect of CSF drainage (tap test and shunting) on global and regional CBF ( Tables 4 – 5 ) Table 4 CBF before and after temporary CSF withdrawal. Ref Grade NPH I and/or 2 0 Method Main Findings Comments and correlations Owler et al 2002 - Summary of previous evidence Systematic review of literature ↑ in CBF equally likely as ↓after CSF withdrawal 1.Mori et al (2002) 137 A 22(I3 2 0 post SAH; 9 I) Regional CBF pre & 10 minutes post CSF drainage in shunt responders vs non-responders (no controls; prospective) CSF removal (30–50 mls); [ 123 I]IMP SPECT with arterial sampling and arterial blood gas/MAP monitoring Baseline clinical characteristics & CBF values were not significantly different between responders (15) & non-responders (7). 10 Minutes post-drainage, CBF significantly more in all regions in responders (101+/-39%) than in non-responders (46 +/- 40%). > 80% increase in CBF after CSF removal was predictive of response to shunt surgery with 77% accuracy. Corrected CBF change of < 20% indicated nonresponse to shunting (see Table X). 2.Hertel, Walter et al (2003) 138 B 27(I) Correlation of preoperative STT with CBF/CBV changes and response to subsequent shunt (retrospective) STT (> 40mls); 99 m Tc -bicisate SPECT (normalisation to cerebellum); pwMRI (Gad) 33% of patients showed clinical and regional perfusion improvement post-STT; 33% showed increases in regional perfusion but no post-STT improvement; 33% showed no clinical improvement post-STT and no increases in cerebral perfusion. There were no differences between regions. It was not possible to distinguish white matter from grey matter on SPECT. Both groups who showed increases in post-STT cerebral perfusion variably improved post shunt. The group who were imaging negative and did not improve post-STT clinically were not shunted (see Table X). 3.Walter, Hertel et al (2005) 139 B 28(I) 9 patients common with Hertel, Walter et al 2003. Correlation of preoperative STT with CBF/CBV changes and response to subsequent shunt (prospective) STT (> 40mls); Pw -MRI (Gad) pre and 24 hours post-STT (with analysis by visual inspection) 7/28 patients: rCBV and gait improved post-STT (all improved post-shunt). 9/28 patients: rCBV but not gait improved post-STT (7/9 shunted and improved to some degree). 12/28 patients: no improvement in either rCBV or gait post-STT (none of this group were shunted). Improved brain perfusion after STT is more sensitive than clinical assessment alone in predicting improvement after a shunt (see Table 5 ). 4.Dumarey et al (2005) 140 B 40(I&2 o x 8) Regional CBF & gait measurements pre & post STT (retrospective) STT (> 30mls); 99 m Tc HMPAO SPECT (with SPM analysis) No significant difference between pre- and post-STT SPECT images. Gait improvement after STT was associated with ↑rCBF in the middle frontal gyrus & left parahippocampal gyrus. Only 14 patients shunted. No data on WM v GM. 5.Virhammar et al (2014) 141 A 20(I) rCBF before & 30mins, 4hrs and 24 hrs after STT; comparison with gait improvement after STT (prospective) STT; pCASL-MRI Overall, no significant increase in rCBF in any region after CSF removal compared with baseline. In patients with ↑ CBF in the periventricular lateral and frontal white matter after the CSF STT, gait function improved more than in patients with↓ CBF in these regions. Table 5 Global and regional CBF before & after shunting including correlation with outcome after shunting Reference Grade Method No of shunted patients Main findings Comments Post-CBF correlation to improvement • Global CBF 1. Greitz et al, 1969 142 C Intracarotid 133Xe clearance during Angiography 7 Increase No 2. Salmon & Timperman et al., 1971b 45 C As in 1. 12 Increase Grey matter more than white matter. Variable change in white matter NA 3. Lying-Tunnell et al., 1977 & 1981 49,50 C AV-Difference N 2 O 7 Increase Temporary NA 4. Kushner et al., 1984 52 B As in 1. 19 Increase No 5. Meyer et al., 1984 53 C 133Xe inhalation 10 Increase Inconclusive Inconclusive 6. Brooks et al., 1986 56 C C15O2 PET inhalation 8 No change NA 7. Mamo et al., 1987 57 B 133Xe IV 25 Increase No region or pattern. Also temporary vs sustained No 8. Vorstrup et al., 1987 58 B 133Xe inhalation, SPECT 17 No change No pattern No 9. Graff-Radford et al., 1987 143 C 133Xe inhalation, SPECT 30 No change No region or pattern No 10. Meixensberger et al., 1989 59 C 133Xe inhalation No change Frontal regions NA 11. Matsuda et al., 1990 144 B 133Xe inhalation 13 No change NA 12. Klinge et al., 1998 65 B H2O15 bolus PET 21 No change NA 13. Klinge et al., 1999 66 B H2O15 bolus PET 10 No change NA 14. Matsuda et al., 1999 145 B Xe contrast CT 16 Increase No pattern yes 15. Bakker et al 34(2002) 146 C TCD 10 No change NA 16. Klinge et al (2002) 147 B 15-O-H2O PET 59 No change Same patients, both global and regional studies (see below) No 17. Bateman & Loiselle (2007) 68 C MRI (1.5T) with flow sequences 32 No change No 18. Ziegelitz et al (2016) 148 B Dynamic susceptibility contrast MRI 20 Increase Yes 19. Virhammar et al (2020) 149 B pCASL perfusion MRI 18 No change Potential methodological limitation w ASL No • Regional CBF 20. Meyer et al., 1985a 53 C 133Xe inhalation 10 Increase Cortices, basal ganglia, frontal WM Inconclusive 21. Meyer et al., 1985b 54 B 133Xe inhalation 7 Increase Cortices, basal ganglia, frontal WM Yes 22. Waldemar et al., 1993 40 B 99m Tc-HMPAO SPECT & 133Xe inhalation 13 Increase Subcortical structures, some cortical Yes 23. Kimura et al., 1992 61 C Xe contrast CT 7 post SAH rCBF returned to within normal limits in the. white matter of the frontal and temporo-parieto-occipital lobes CBF restoration closely correlated with clinical improvement and reduction in ventricular dilation and periventricular lucency. 24. Shimoda et al., 1994 150 B Xe contrast CT 22 Increase Some subcortical, not basal ganglia Yes 25. Maeder et al., 1995 62 C Xe contrast CT 2 Increase Frontal cortex and WM NA 26. Tanaka et al., 1997 64 B Xe contrast CT 21 Increase WM more than grey Yes 27. Klinge et al (2002) 151 B 15-O-H2O PET 11 Increase Frontal inferior, frontal rostral, temporal inferior, temporal dorsal, cingulum, parietal yes 28. Mataró et al (2003) 152 C HMPAO-SPECT with SPM analysis 15 Increase prefrontal dorsolateral areas, frontal premotor, medial prefrontal, frontal WM , inferior parietal lobule & basal ganglia NA 29. Tullberg et al (2004) 153 A HMPAO SPECT – relative regional CBF (rrCBF) using cerebellum as the reference 28 (16 with impaired wakefulness) Increase thalamic, frontal and hippocampal grey matter. Yes (impaired awareness only, no other symptom studied) 30. Murakami et al (2007) 154 B IMP SPECT + MRI with 3D-SSP 24 Increase frontal base and the anterior part of limbic areas . NA 31. Klinge et al (2008) 155 B 15-O-H2O PET 47 Increase superior mesial frontal areas Yes 32. Ishii et al (2011) 98 A IMP SPECT rCBF relative to global brain activity. 84 Increase 3 different patterns of reduction in rCBF identified (anterior, posterior and mixed) NA 33. Ziegelitz et al (2014) 71 C DSC MRI with Gd-DTPA using the occipital lobe as reference 20 Increase PVWM Yes 34. Ziegelitz et al (2015) 156 B DSC MRI with Gd-DTPA 20 Increase hippocampus, PVWM, and in the cingulum, thalamus & basal ganglia Yes 35. Nocun et al 2015 157 B HMPAO SPECT 16 Increase 3–6 days post-shunt Variable between patients – predominantly in frontal lobes NA 36. Ziegelitz et al (2016) 148 C CT perfusion 17 CBF in responders increased postoperatively in all anatomical regions by 2.5–32%; Significant increase in caudate head, normal appearing WM and periventricular WM. Postoperative perfusion in the periventricular WM regions showed positive correlations with the gait score, continence score and total iNPH scale score. 37. Tuniz et al (2017) 158 B Diffusion and DSC MRI (3T) with gadobutrol using the occipital lobe as reference 13 Increase basal ganglia and PVWM area. Yes . 38. Azuma et al (2019) 79 C IMP SPECT MRI 39 Increase putamen, amygdala, hippocampus, and parahippocampal gyrus. White matter not analysed (not sure why) No 39. Agerskov et al (2020)* 101 B DSC MR perfusion 20 Increase Mesencephalon & pons ↓rCBF in the mesencephalon of non-responders Yes 40. Huang et al 2022 72 B 3D pulsed arterial-spin labelling (PASL) MRI 32 No change Very weak correlations No Overall, global CBF assessed using TCD, 15 O PET, PC MRI and ASL MRI does not appear to increase after spinal tap test or shunting (Tables 4 & 5 ). Interestingly, one study using DSC MRI in 20 subjects did report an increase in global perfusion. Surprisingly, there have been no reports of combining ELD with global CBF studies. Most studies have confirmed that rCBF increases after shunting in the frontal lobe, periventricular white matter and deep grey matter. Importantly, there is some evidence that such increases correlate with gait improvement after shunting, even when there has been no clinical improvement after a spinal tap test. In a landmark study, the Umea group have demonstrated enhanced activity in the SMA accompanying improved finger motor performance after extended CSF drainage consistent with changes in subcortical connections 135 . In hydrocephalus, periventricular stretch of axons is probably greatest frontally. In NPH, such axonal stretch may be compounded by CSVD but, unlike CVSD, is more likely to be reversible after shunting 87 , 90 , 136 . However, functional improvement is not associated with restoration of ventricular size. Lenfeldt et al surmised that CSF withdrawal “improved neuronal operational ability, possibly by reversing a subcortical chronic ischaemia related to cerebrovascular disease in periventricular pathways to and from SMA 25 – 27 . This would result in improved signalling in these circuits, normalizing the motor planning process, giving further support for the view of INPH as a hypokinetic condition caused by malfunction in cortico-basal ganglia-thalamo-cortical circuits with special involvement of frontal areas”. This notion is also supported by correlations between motor function and blood flow changes in frontal subcortical regions after shunting, and deficiencies in neuronal integrity in the same area ( 95 ). Cerebrovascular Reactivity and Autoregulation before and after shunting (Tables 6 & 7) Table 6 Cerebrovascular reactivity & autoregulation: baseline Reference Grade Method No of Patients Main findings Comments Cerebrovascular reactivity 1. Hartmann et al., 1977 47 B CO2 11 Impaired CVR 2. Meyer et al., 1984 53 C CO2 7 Impaired CVR 3. Lee et al., 1998 163 B CO2 11 Impaired CVR 4. Miyake et al, 1999 164 B ACZ 41 5. Klinge et al 1999, 2002a 66 , 165 C/B 15 O-H 2 O PET; ACZ 10/33 Impaired CVR Baseline CVR lower in responders than non-responders (NS) 6. Chang et al., 2000 166 B ACZ 41 Impaired CVR 7. Chang et al (2003) 167 B 99 m Tc HMPAO & ACZ 48 ↓ CVR in 30 shunt responders compared to normals. 4 non-responders with ↓ CBF but preserved CVR. 8. Jarus-Dziedzic et al (2005) 168 C TCD; ACZ 13 Preserved CVR (not different to controls) CVR better in NPH compared to atrophy . ↓ CVR in atrophic group (n = 10) vs controls 9. Yamada et al (2013) 70 B 99 m Tc-ECD SPECT + ACZ 25 Impaired CVR Autoregulation 10. 1.Mathew et al., 1975 46 B NPH (10 2 0 ; 5 I) Intracarotid 133Xe clearance during Angiography rCBF and rCBV increased after CSF removal (?volume) The greater the increase in CBF in the upper frontal and postcentral areas after CSF removal, the better the post-shunting outcome. 11. Schmidt et al., 1990a 169 B Kety-Schmidt Captopril and CO2 14 Preserved autoregulation 12. Czosnyka et al (2002) 170 B TCD (Mx) & CSF infusion test; CT/MRI 35 Preserved global autoregulation Correlation with Rout. Autoregulation tended to be worse in patients with ischaemic changes on CT/MRI 13. Owler et al (2004b) 171 B H 2 15 O PET and MRI; CSF infusion study; finite element analysis 15 With increases in CSF pressure, global CBF was reduced. Regional CBF decreased in the thalamus and basal ganglia, and in white matter regions in proximity to the ventricles. 14. Momjian et al (2004) 93 B H 2 15 O PET and MRI T1&T2-weighted; CSF infusion study. 12 White matter CBF reduced in NPH compared with controls with an abnormal gradient from the lateral ventricles towards the subcortical WM. Reduction in CPP and raised CSF pressure reduce CBF which is maximal in the paraventricular watershed region. 15. Czosnyka et al (2005) 172 B CSF infusion test & non-invasive MAP 68 Preserved global autoregulation Better global autoregulation associated with high Rout. 16. Lalou et al (2018) 173 B CSF infusion test (PRx) & non-invasive MAP 131 Preserved global autoregulation Better autoregulation correlated with increased Rout ** No Healthy controls. Patients with NPH symptoms that were not selected for shunting were used as comparison, together with CSF dynamics parameters. CVR: cerebrovascular reactivity, TCD: Transcranial Doppler, Mx:Mean Flow velocity Index, PRx: Pressure Reactivity Index, MAP: Mean arterial Blood Pressure, CPP: Cerebral perfusion Pressure Table 7 Cerebrovascular reactivity pre and post shunt including correlation with outcome after shunting. Ref GRADE Method No of patients Main findings Post-shunt CVR: correlation with improvement 1. Meyer et al 1984 53 C Xe-CT + 5%CO2 + 100%O2 7 Global increase yes 2. Lee et al., 1998 163 C TCD response to 5% CO2; 11 Global increase NA 3. Klinge et al., 1999 66 B 15-O-H2O PET + ACZ 10 Global increase yes 4. Chang et al., 2000 166 B 99mTc-HMPAO + ACZ 41 Global increase NA 5. Bakker et al (2002) 180 C TCD response to 5% CO2; 10 Global increase NA 6. Klinge et al (2002a-d) 148 , 152 , 165 , 181 A 15 O-H 2 O PET; ACZ 53 Global increase in responders at 7d & 7m; in both high and low vascular risk groups; No increase in CVR in non-responders. Yes. Increase in global CVR at 7d correlated with improved gait; Increase in global CVR at 7m correlated with improvement in visual attention and verbal memory 7. Chang et al (2003) 167 B tec99m HCMP & ACZ 48 Global increase yes 8. Chang et al (2003, 2009) 167 , 182 B SPECT and Xe-CT, ACZ 162 Global increase yes 9. Yamada et al (2013) 70 B SPECT + ACZ 25 NPH 30 controls Global decrease pre-shunt compared with controls that improved post-shunt yes Studies of CVR and Autoregulation might be expected to be more sensitive than baseline measurements of CBF by quantifying haemodynamic reserve, both global and regional 159 – 162 . Global CVR to either ACZ or hypercapnia was generally reduced in NPH patients and increased after shunting (Tables 6 & 7 ). This reduction in cerebrovascular reactivity is consistent with the arterioles being already maximally dilated as a result of local ischaemia. Unfortunately, there are no published studies of CVR before and after temporary CSF drainage. In contrast, very few studies of cerebral autoregulation have been reported and all recent studies are from one centre using CSF infusion studies to manipulate cerebral perfusion pressure. With increases in CSF pressure, there was a variable increase in arterial blood pressure between individuals and global CBF was reduced. This change in arterial blood pressure, with more modest changes in CSF pressure than the conventional end-stage Cushing response, has subsequently been attributed to the existence of an intracranial baroreceptor 174 – 176 . Crucially, during the plateau of an CSF infusion study, CBF decreased in the basal ganglia, thalamus and periventricular WM. The strength of cerebral autoregulation reached a minimum in the white matter close to the periventricular watershed area. The integrity of AR also depends on cardiovascular comorbidity and abnormalities within the cerebral mantle. In Lalou’s study 177 , the relationship between the global autoregulation pressure reactivity index (PRx) and the profile of disturbed CSF circulation and pressure-volume compensation in relation to outcome after surgery was examined. The PRx was negatively correlated with resistance to CSF outflow: patients with normal CSF circulation tended to have worse autoregulation. Given the importance of co-morbidities to the diagnosis and outcome of shunting in iNPH, it is important to note that AR is intact in Alzheimer’s disease but variably impaired in CSVD 178 , 179 . Surprisingly, there are no reported studies of autoregulation before and after temporary CSF drainage or shunting. Prediction of outcome: Baseline global & regional CBF, Cerebrovascular Reactivity and Autoregulation ( Tables 8 & 9 , Figs. 5 –7 ) Table 8 Predictive value of baseline global and regional CBF for outcome after shunting Reference GRADE Method No of patients Predictive Yes/No Comments Global CBF 1. Mathew et al., 1975 + 1977 46 C Intracarotid 133Xe clearance during Angiography 21 Yes Higher gCBF related to better clinical outcome 2. Hayashi et al., 1984 51 B Intracarotid 133Xe clearance during Angiography 16 Yes Poor outcome if reduced gCBF 20 ml/100 g/min 4. Klinge et al., 1998 65 B H2O15 bolus PET 21 Yes Improvement with lower gCBF 33 vs. 45 ml/1 00 ml per min responders vs non-responders 5. Klinge et al., 1999 66 B H2O15 bolus PET 10 Yes Improvement with lower gCBF Global. 36 vs 44 ml/100 ml/min responders vs non-responders 6. Bateman et al (2007) 68 C MRI (1.5T) with flow sequences 32 No 20 responders vs 12 non-responders Global & Regional CBF 7. Grubb et al 1977 48 C H2O15 PET Intracarotid 5 No 8. Lying-Tunnel 49 C AV-Difference NO2 7 No 9. Graff-Radford et al., 1987 + 1989 25,37 B 133Xe inhalation SPECT 56 Yes Improvement with increased Anterior/Posterior rCBF 10. Kushner et al 1984 52 C As in 1. 19 No 11. Mamo et al 1987 57 B 133Xe IV 25 No 12. Meixensberger et al., 1989 59 C 133Xe inhalation 31 No 13. Granado et al., 1991 183 B 99m Tc-HMPAO SPECT 14 Yes Improvement with increased Anterior/Posterior rCBF Regional CBF 14. Morretti et al., 1988 184 C 123BAMP IV SPECT 12 No Cortical rCBF, PVWM and basal ganglia examined 15. Ishii et al (2011) 98 A IMP SPECT rCBF relative to global brain activity. 84 Yes In non-responders, 3 different patterns of reduction in rCBF identified (anterior, posterior and mixed) Table 9 Baseline cerebrovascular reactivity and autoregulation: predictive value Ref GRADE Method No of patients CVR predictive Comments 1. Meyer et al., 1984 53 C CO2 7 Yes Impaired CVR associated with better outcome 2. Shimoda et al 1994 150 C glycerol 22 Yes More widespread increases in CBF post glycerol in shunt responders ( preserved CVR). 3. Lee et al., 1998 163 C CO2 11 No 4. Klinge et al., 1999, 2002a, 2002b (patient series) 5. 66 , 165 , 181 B 15 O-H 2 O PET; ACZ Low and high vascular risk factor groups 53 Yes in low risk group and no in high risk group Baseline CVR was lower in responders than in non-responders (NS). Increase in CVR at 7d after shunting was predictive of a good outcome. 6. Chang et al (2003) 185 B Tc 99 m HCMP & ACZ 48 Yes ↓ CVR in 30 shunt responders compared to normals. 4 non-responders with preserved CVR. 7. Chen et al 2008) 186 C Xe-CT, MRI and MRSI 28 Yes Preserved CVR ◊improved .23 responders vs 5 non-responders 8. Chang et al (2009) 182 B SPECT and Xe-CT 162 Yes Impaired CVR predictive. Responders w incomplete triad: ↓preop CVR than controls. Full triad:↓ preop CVR than in incomplete. 9. Yamada et al (2013)* 70 B 99 m Tc-ECD SPECT + ACZ 25 Yes MMSE as improvement marker. < 20% ↑ in preoperative CBF response to ACZ predicted improvement ( impaired ) Global Autoregulation 10. Lalou et al (2018) 173 B CSF infusion test (PRx) & non-invasive MAP 131 There was a trend towards higher values for PRx (greater global AR derangement) in non-responders v responders. The product MAPx(1 + PRx) – a measure of combined arterial hypertension and deranged AR, showed a significant association with outcome. None of the post-2001 studies have related global or regional CBF to outcome. Such measurements prior to 2001 were not entirely consistent in their findings with no strong evidence for using global or regional CBF before surgery as a useful prognostic factor for shunt response. The studies reporting the role of baseline CBF in predicting outcome post shunting were not based on secure statistical power analyses and the number of patients recruited overall was small (average of 20–30 patients with only 2 studies including > 50 patients). There was grade C evidence of the predictive value of CBF in NPH. 5 studies of 89 patients’ global CBF showed different thresholds for positive and negative predictive value of CBF. The other 5 studies of 99 patients showed no correlation. rCBF was investigated in 3 studies or 82 patients, 2 of which reported that the ratio of the anterior and posterior CBF was high in improvers (70 patients total). Overall, there was very little evidence that either global CBF or the pattern of rCBF at baseline was correlated with outcome post shunting. In contrast, studies of CVR are more promising. Although there is some inconsistency between studies, overall, it appears that impaired CVR in NPH patients was a favourable prognostic factor. 4 studies report that worse rather than good reactivity to ACZ predicts a favourable outcome 70 , 151 , 165 . One of them 151 interestingly stratified the patients into different groups depending on cardiovascular burden: worse reactivity predicted shunt responsiveness for high cardiovascular risk; better reactivity was related to shunt responsiveness in those with low cardiovascular risk. This interesting finding again highlights the importance of consideration of the degree of cerebrovascular disease in iNPH. 5 out of 5 studies that measured CVR post-operatively agree that it is significantly increased compared to pre-operatively and that restoration of CVR is a hallmark of shunt responsiveness 181 . Early detection of a CVR/CA problem may precede falls in global and rCBF, and white matter hyperintensities unlike in CSVD . There has been only one study of global AR in relation to outcome after shunting 173 . There was a trend towards higher values for PRx (greater global AR derangement) in non-responders v responders associated with higher MAP values. The product MAP x (1 + PRx) was proposed as a measure that combined arterial hypertension with deranged AR – this measure revealed a significant association with outcome. Relationship between CBF, CSF dynamics and the mechanical properties of the cerebral mantle There is considerable evidence that the normal interrelationships between the cerebral circulation, the circulation of CSF and interstitial fluid and the mechanical properties of the cerebral mantle are altered in NPH. Ventricular reflux and convexity block NPH is characterised by ventricular reflux of CSF and convexity block 2 , 3 , 187 , 188 . Intrathecal gadolinium tracer MR studies have confirmed these earlier findings with reduced clearance of gadobutrol and delayed tracer distribution over the external brain surface arteries compared with reference subjects 189 . The combination of DESH (Disproportionately enlarged subarachnoid space hydrocephalus) and FES (focally enlarged sulci) may prove to be a surrogate marker for convexity block. It has recently been suggested that focally enlarged sulci are not the result of atrophy but of CSF entrapment that reduce in size after shunting 190 , 191 . Experimentally, convexity block can induce ventriculomegaly 192 . In NPH, ventricular reflux of CSF and convexity block is accompanied by increased MR mean diffusivity within the white matter indicative of raised extracellular water content manifesting as periventricular lucencies (PVLs), particularly around the frontal and occipital horns 193 – 195 However, ventricular reflux and convexity block may occur in a minority of normal people and other conditions without hydrocephalus 196 . Findings of an abnormal CSF circulation on cisternography correlate to some degree with shunt responsiveness in NPH but neither are robust standalone predictors of outcome. Hence, other factors apart from partial or complete reversal of the CSF circulation must be at play, including changes in brain biomechanics, to explain why an individual’s ventriculomegaly progresses and becomes symptomatic. Ageing and ventricular size As described previously, ventricular size in healthy people increases very rapidly after the age of 50 years 6 , 7 , 10 , 11 . Longitudinal studies confirm that there is a presymptomatic stage to NPH when ventriculomegaly is present 6 – 9 . Graff-Radford and colleagues 37 , 38 have suggested that some patients with NPH have head circumferences greater than in controls and suggested that the cause of the NPH was arrested congenital hydrocephalus becoming symptomatic later in life. Many patients with NPH have intracranial volumes significantly larger than normal, suggesting that the initial insult occurs before the sutures fuse at 1 year of age. Bradley et al 35 , 36 also suggested that NPH may be a ‘two hit’ disease: benign external hydrocephalus in infancy followed by deep white matter ischaemia in late adulthood (see below). Ageing, Hypertension and CSVD As noted earlier, CBF and vascular density in the brain decreases and the stiffness of the large elastic arteries increases with normal ageing.. These ageing changes are compounded by chronic hypertension which induces remodelling and stenosis of the arteries and fibrinoid necrosis of the arterioles, attenuates cerebrovascular reactivity and functional hyperaemia, and shifts autoregulation to the right, thereby increasing vulnerability to hypotension and chronic, borderline ischaemia 197 – 203 . The human periventricular arterial blood supply is at particular risk 93 , 204 . The increase in arterial stiffness is associated with elevated pulse pressure and blood flow pulsatility in the cerebral vasculature thereby releasing more pulsatile energy into the brain and leading to white matter hyperintensities and tissue damage which is associated with cerebrovascular/cognitive impairments. It is likely that NPH patients will be susceptible to episodes of reduced cerebral perfusion pressure particularly when cardiovascular disease, both systemic and CSVD, is present and autoregulation is impaired. As described earlier, many NPH patients have both systemic hypertension and white matter vascular disease 24 – 31 . In Earnest’s original cases 24 , autopsy showed extensive hypertensive cerebrovascular disease with multiple small infarcts of the deep cerebral and cerebellar grey and white matter but normal leptomeninges and arachnoid villi. One case improved with a shunt. Earnest proposed that hypertensive cerebrovascular disease, by causing multiple infarcts in the periventricular white matter and basal ganglia, may reduce periventricular tissue tensile strength and elastic properties permitting the ventricles to enlarge under the stress of the intraventricular pulse pressure when increased by hypertension. Some evidence for this concept has come from magnetic resonance elastography studies but the results are not consistent 205 – 210 . One confounding factor is the change in CSF outflow resistance and mechanical properties of the cerebral mantle as an individual’s NPH evolves 211 , 212 . Interestingly, SHR rats, but not the more hypertensive SHRSP rats, develop chronic hydrocephalus with ventricular reflux 213 – 215 . The ventricular enlargement in SHRs does not develop as a direct consequence of the concomitant elevation in blood pressure - pharmacological blood pressure reduction failed to attenuate the ventricular enlargement in SHRs and experimentally induced hypertension was insufficient to cause ventricular enlargement in naïve rats. A meticulous study in the SHR rat by Macaulay’s group 216 has revealed that, although brain water does increase with ventriculomegaly, neither CSF production rate, ICP, nor CSF outflow resistance appear to be elevated when compared to WKY rats. They concluded that ‘SHR hydrocephalus represents a type of hydrocephalus that is not life threatening and occurs by unknown disturbances to the CSF dynamics’. Both subcortical (eg increased ventricular volume) and cortical (eg thinning and sulcal widening) atrophy can result from CSVD and Cadasil in the human 217 – 220 . Hence, although CSVD is very common in NPH, CSVD alone does not appear to be sufficient to induce NPH as opposed to atrophy. Compliance, resistance to CSF outflow and cerebral autoregulation Global intracranial compliance is reduced in NPH despite, by definition, normal CSF pressure (mean 9–12 mm Hg). Pulsatile ICP, reflecting impairment of pressure-volume reserve capacity, increases as intracranial compliance is reduced 221 . Lundberg’s B waves occur more frequently and are increased in amplitude during sleep in NPH 222 , 223 . However, such rises in ICP may not in general indicate ischaemia but are synchronised with rhythmical increases in cerebral blood volume 224 – 226 . As highlighted above, it has been suggested that such reduced intracranial compliance and increased intracranial pulse pressure might lead to local ‘‘barotrauma’’ or ‘‘tangential shear stress’’ 174 – 176 , 227 – 230 . Increased intracranial and microvascular pulsatility might increase pulsatile stress forces and activate potent vasoactive factors, damage the cerebral microcirculation and even cause cognitive decline in elderly individuals (“pulse-wave encephalopathy”). Leukoaraiosis might reflect an arteriosclerotic and/or resistive pulse wave encephalopathy in mild cognitive impairment. Intriguingly, the Umea group have shown that elderly subjects with high intracranial pulsatility display smaller brain volume and larger ventricles, supporting the notion that excessive cerebral arterial pulsatility harms the brain 231 . However, In healthy older adults, the expression of white matter lesions and enlarged perivascular spaces precedes increases in cerebral arterial PI - elevated PI may be a relatively late manifestation, rather than a risk factor, for CSVD 232 . Using MR flow- quantification technology, Bateman has shown that intracranial arterial and sagittal sinus pulsatility was increased in NPH whereas CSF pulse was reduced 233 . Elevated CSF flow pulsation through the cerebral aqueduct have been widely described in communicating hydrocephalus but has not proven to be widely accepted as a good predictor of outcome after shunting 234 – 236 . Moreover, such enhanced pulsatility does not extend, at least in the adult rat with induced communicating hydrocephalus, to the entire cerebral vasculature including the cortical capillaries. Rashid et al 237 concluded that, even in the presence of markedly elevated pulsatile CSF flow in the aqueduct, there was no concurrent increase in microvascular pulsatile flow. A shunt may help in NPH, not by greatly decreasing CSF pressure or/and its dynamics but by increasing both compliance and perfusion. Global intracranial compliance should be distinguished from intracranial arterial compliance. In the majority of patients with iNPH, there was a low correlation between intracranial and vascular pressure pulsatility. During moderate rises in ICP (eg up to 40 mmHg during an infusion test), TCD mean blood flow velocity does not change, although the pulsatility index rises. This reflects changes in compliance of the cerebral arterial walls, with autoregulation efficient enough to keep CBF constant. However, the ability of arteries in the subarachnoid space to expand, including during autoregulatory responses to changes in cerebral perfusion pressure, may be restricted when intracranial compliance is reduced 238 , 239 . The cerebral periarterial spaces are dilated in NPH compared with controls 240 . In rodents, arterial hypertension reduces both arterial wall pulsatility and periarterial tracer movement 213 , 216 , 241 . It has been proposed that impaired intracranial compliance restricts cerebral arterial pumping, which in turn hampers the driving forces of perivascular molecular transport. As noted above, intrathecal gadolinium tracer MR studies in NPH subjects have demonstrated reduced clearance of gadobutrol and delayed tracer distribution over the external brain surface arteries compared with reference subjects (‘impaired glymphatic tracer clearance’). The study of CSF dynamics and pressure-volume compensation combined with assessment of CBF provides an opportunity to assess the state of autoregulation using a variety of techniques including TCD and MRI 242 – 245 . For example, TCD enables the study of changes in CBF and global autoregulation continuously over time including overnight and during an infusion study 245 .The shape of the TCD pulse waveform is able to differentiate between hydrocephalus and normal subjects 246 Unfortunately, relevant measurements using MRI have been limited by the strong magnetic field which excludes using invasive ICP instrumentation but Unnerbäck et al 247 have overcome this problem for patients in neurointensive care. Hence MR studies equivalent to PET studies 92 , 93 , 172 to assess autoregulation are feasible. Despite such limitations, the global and local biomechanical response of the brain to changes in CSF pressure may be studied using MRI to map CBF – stress/strain relationships and phase contrast MRI to characterize the CNS elastance coefficient during CSF infusion studies. A significant association between the CNS elastance coefficient, frailty and age has been reported, results that were independent of CSF dynamics and not specific to NPH 23 . Unpublished data from a large series using PC MRI suggests that there is a negative correlation between CBF, Rout and the baseline pulse amplitude of the ICP pulse waveform. Lastly, studies of global autoregulation in NPH during CSF infusion studies using both the PRx index derived from continuous blood pressure monitoring and TCD-derived autoregulation (Mx index), have confirmed that there is an negative correlation between Rout and autoregulation 174 . This negative relationship at first seems counterintuitive. It might simply reflect the likelihood that global measurements of autoregulation do not detect dysautoregulation restricted to the periventricular zone in uncomplicated NPH. A high Rout and preserved global autoregulation might indicate that there is salvageable tissue which might be helped with a shunt. In contrast, global dysautoregulation would indicate more global cerebrovascular disease and ischaemia that has not affected resistance to CSF outflow. These links between CBF, CSF pressure-volume compensation, the CSF circulation and periarterial fluid flow are very interesting but require further study in patients. Stress, Stretch, Compression and Intramantle pressure gradients It has long been postulated that ventriculomegaly creates regions of stress within the cerebral mantle, and thereby the interplay between mechanical and vascular factors 2 , 3 , 66 , 230 , 247 , 248 , Such stresses result in stretch and compression of both vascular and neural tissue, changes that may mirror the symptoms of NPH. Such effects have been successfully modelled for neural tissue using poroelastic theory 86 , 87 . Crucially, Earnest’s hypothesis paved the way for subsequent studies of the biomechanics of the cerebral mantle in communicating hydrocephalus. The concept of a transmantle pressure gradient including differential pulse pressures, however small, between ventricle and subarachnoid space to explain ventricular dilatation in communicating hydrocephalus has not been demonstrated 249 However, finite element studies have demonstrated that both ventricular expansion induced by CSF infusion and brain deformation are accompanied by heterogeneous stress concentrations within the cerebral mantle. 67 , 87 , 88 , 172 Mean stress, indicating compression, was distributed throughout the brain during CSF infusion and maximal in the thalamus and corpus callosum. The white matter surrounding the ventricular horns was the site of maximal shear stress. Subsequent to brain deformation, one would expect some distortion to local arterial trees and thus a compromise to rCBF. In an instructive case report, brain deformation caused by a cyst was accompanied by large shear stresses and moderate compressive stresses consistent with areas of hypoperfusion on PET rCBF maps and specific cognitive deficits. 87 Only small interstitial fluid pressure changes were present. Ventricular dilatation has often been taken as evidence that the brain is being compressed and that an increase in intra-parenchymal pressure results 250 . However, there is no direct evidence to suggest that the intra-parenchymal pressure is increased, quite the reverse. Pena et al have proposed, based on a finite element analysis of a poroelastic model, that ventricular expansion may result from a relative reduction in interstitial fluid pressure in the periventricular area leading to the formation of a ventricle - parenchymal rather than ventricle – subarachnoid pressure gradient 251 . This concept has received experimental and modelling support by Johnston’s group 252 , 253 . It will be fascinating to see what the impact of the recently described genetic risk variants for NPH have on paraventricular biomechanics and ISF flow, and whether they overlap with those for CSVD 254 , 255 . Bias assessment There was frequently a moderate to high risk of selection and prognostic factor measurement bias in the current evidence, mainly due to the absence of unified criteria that include comorbidities for defining and selecting the study participants. Furthermore, there are no randomized trials specifically designed to assess outcome in the current literature, utilising CBF as a prognostic factor. Future directions As noted in the 2001 systematic review, large multicentre platforms are required to provide the infrastructure for producing higher level evidence with reduced risk of bias based on a general consensus over definitions including clinical heterogeneity, inclusion/exclusion criteria, comorbidities including frailty, and outcome measures. Significant progress has been made in building such platforms as exemplified by the publication and adoption of International NPH Guidelines 256 – 258 , multinational RCTs 259 , 260 , FinnGen Cohort 254 , 255 , Registries (UK, Sweden & Australasia 5 , 12 , 261 and NPH Special Interest Groups (eg Hydrocephalus Society, Association of British Neurologists UK). The mechanism(s) governing normal autoregulation are complex 160 , 161 . Similarly, the mechanisms underlying impaired cerebrovascular reactivity and autoregulation in NPH remain an enigma. Future studies should include mapping of regional variations in haemodynamic reserve onto intracerebal water content, state of myelination, resting state networks, CSF periarterial inflow and outflow pathways, vascular co-morbidity and CSVD. A holy grail of NPH research is to identify accurate predictive biomarkers, alone or in combination, of outcome after shunting. The relationship between response to a tap test and outcome after shunting is capricious. The interpretation of CSF outflow resistance depends on age, duration of symptoms and co-morbidities. The higher the Rout, the greater the probability of a favourable outcome after a shunt but a minority of patients with a normal Rout still improve after shunting. Interestingly, cerebrovascular reactivity tests have predictive value. One possibility would be an RCT that explores the predictive accuracy of the combination of a tap test/EDLT with CVR. Apart from shunting, there are no other proven treatments apart from conventional management of frailty, vascular risk factors and comorbidities including, for example, PD and CSVD. Blood pressure control may help to prevent white matter hyperintensities in CSVD 262 . ACZ was discovered in the 1940’s as an inhibitor of carbonic anhydrase. ACZ has well known effects on CSF production by the choroid plexus and as a cerebral vasodilator. In a pioneering French pilot study 263 , ACZ was found to clinically improve 10 out of 15 NPH patients examined over 2 years. Tolerance was excellent with a daily dose of 250 to 500 mg. The benefit remained stable after 1 year follow-up in 8 cases. Low-dose ACZ was later shown to reverse white matter lesions in NPH within a few months 193 , 264 . The results of the Uppsala DRAIN RCT are keenly awaited (EudraCT Number 2020-004132-22). Conclusions Both baseline rCBF and borderline ischaemia approximate to the cortical and subcortical circuitry that contribute to the clinical features of NPH but are not predictive of the response to shunting. Impaired cerebrovascular reactivity has predictive value for the clinical response to shunting. In addition to RCTs of carbonic anhydrase inhibitors, consideration should be given to an RCT that explores the predictive accuracy of the combination of the clinical response to temporary CSF drainage with changes in CVR. Abbreviations CBF Cerebral Blood Flow rCBF regional Cerebral Blood Flow tCBF total Cerebral Blood Flow CVR Cerebrovascular reactivity GRAD Grading of Recommendations Assessment, Development, and Evaluation (i)NPH (idiopathic) Normal Pressure Hydrocephalus RTI from RTI international, no acronym clarification provided. https://www.rti.org/about-us STT Spinal Tap Test TCD Transcranial Doppler Declarations Acknowledgements We would like to acknowledge the invaluable help and support of the Umeå Hydrocephalus Group during the last phase of this review. Funding We received no funding for this review JDP: NIHR Senior Investigator award 2009-2014; EC Interreg-4 (Amiens) Dynamic MR project 2008-11; NIHR Healthcare Technology Cooperative for Brain Injury 2013-2017; NIHR Brain Injury MedTech 2018-2023. MC and ZC: Have received departmental funding for the REVERT project, part of the European programme Interreg France (Channel Manche) England. The project is co-financed by ERDF (European Regional Development Fund) and also EC Interreg-4 (Amiens) Dynamic MR project 2008-11 Disclosure MC has partial financial interest from licensing the ICM+ software (Cambridge Enterprise) for Multimodality Brain Monitoring. Author Contribution ADL performed the systematic review of the literature, synthesised and analysed the review results and drafted the manuscript. JDP was the second reviewer of the literature and decided independently whether to include the articles or not. He also contributed significantly to the design and finalisation of the manuscript and oversaw the entire process.MC and ZC dealt with agreements and disagreements about which articles to include, and contributed to the review and interpreation of the results, as well as to the writing and discussion for the review. All authors reviewed the manuscript several times (more than one can even count at this point) and agreed to this final version for submission. 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Brain hydrodynamics study by phase-contrast magnetic resonance imaging and transcranial color Doppler. J Magn Reson IMAGING. 2006;24:995–1004. Czosnyka Z, Lalou A, Pelah AI et al. Cerebral hemodynamic monitoring combined with infusion test in hydrocephalus. BRAIN AND SPINE ; 3. Epub ahead of print 2023. 10.1016/j.bas.2023.102705 Ziolkowski A, Pudelko A, Kazimierska A et al. Analysis of relative changes in pulse shapes of intracranial pressure and cerebral blood flow velocity. Physiol Meas ; 42. Epub ahead of print 2021. 10.1088/1361-6579/ac38bf Unnerbäck M, Ottesen JT, Reinstrup P. ICP curve morphology and intracranial flow-volume changes: a simultaneous ICP and cine phase contrast MRI study in humans. Acta Neurochir (Wien). 2018;160:219–24. Hladky SB, Barrand MA. Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence. Fluids Barriers CNS ; 11. Epub ahead of print 2014. 10.1186/2045-8118-11-26 Eide PK, Saehle T. Is ventriculomegaly in idiopathic normal pressure hydrocephalus associated with a transmantle gradient in pulsatile intracranial pressure? Acta Neurochir (Wien). 2010;152:989–95. Hakim S, Venegas JG, Burton JD. The physics of the cranial cavity, hydrocephalus and normal pressure hydrocephalus: mechanical interpretation and mathematical model. Surg Neurol. 1976;5:187–210. Pena A, Harris NG, Bolton MD, et al. Communicating hydrocephalus: the biomechanics of progressive ventricular enlargement revisited. Acta Neurochir Suppl. 2002;81:59–63. Nagra G, Koh L, Aubert I, et al. Intraventricular injection of antibodies to beta1-integrins generates pressure gradients in the brain favoring hydrocephalus development in rats. Am J Physiol Regul Integr Comp Physiol. 2009;297:R1312–21. Wilkie KP, Nagra G, Johnston M, A MATHEMATICAL ANALYSIS OF PHYSIOLOGICAL, AND MOLECULAR MECHANISMS THAT MODULATE PRESSURE GRADIENTS AND FACILITATE VENTRICULAR EXPANSION IN HYDROCEPHALUS. Int J Numer Anal Model Ser B. 2012;316:65–81. Räsänen J, Heikkinen S, Mäklin K, et al. Risk Variants Associated With Normal Pressure Hydrocephalus: Genome-Wide Association Study in the FinnGen Cohort. Neurology. 2024;103:e209694. Räsänen J, Helisalmi S, Heikkinen S, et al. Low prevalence of CWH43 variants among Finnish and Norwegian idiopathic normal pressure hydrocephalus patients: a cohort-based observational study. Fluids Barriers CNS. 2025;22:17. Marmarou A, Black P, Bergsneider M, et al. Guidelines for management of idiopathic normal pressure hydrocephalus: progress to date. Acta Neurochir Suppl. 2005;95:237–40. Nakajima M, Yamada S, Miyajima M, et al. Guidelines for Management of Idiopathic Normal Pressure Hydrocephalus (Third Edition): Endorsed by the Japanese Society of Normal Pressure Hydrocephalus. Neurol Med Chir (Tokyo). 2021;61:63–97. Hamilton MG, Williams MA, Edwards S, et al. Guidelines for Diagnosis and Management of Idiopathic Normal Pressure Hydrocephalus. Neurosurg Clin N Am. 2025;36:199–205. EudraCT Number 2020-004132-22. DRAIN RCT. Luciano M, Holubkov R, Williams MA, et al. Placebo-Controlled Effectiveness of Idiopathic Normal Pressure Hydrocephalus Shunting: A Randomized Pilot Trial. Neurosurgery. 2023;92:481–9. Stuart MJ, Wray A, Dexter M, et al. Validation of data capture in the Australasian shunt registry with a prospectively maintained institutional database. J Clin Neurosci. 2025;135:111179. Lai Y, Jiang C, Du X, et al. Effect of intensive blood pressure control on the prevention of white matter hyperintensity: Systematic review and meta-analysis of randomized trials. J Clin Hypertens (Greenwich). 2020;22:1968–73. Aimard G, Vighetto A, Gabet JY, et al. [Acetazolamide: an alternative to shunting in normal pressure hydrocephalus? Preliminary results]. Rev Neurol (Paris). 1990;146:437–9. Alperin N, Oliu CJ, Bagci AM, et al. Low-dose acetazolamide reverses periventricular white matter hyperintensities in iNPH. Neurology. 2014;82:1347–51. Additional Declarations Competing interest reported. MC has partial financial interesting in licencing the ICM+software (Cambridge enterprise), a research software for multi-modality physiological monitoring Supplementary Files biasassessment04.25.docx Cite Share Download PDF Status: Published Journal Publication published 16 Dec, 2025 Read the published version in Fluids and Barriers of the CNS → Version 1 posted Editorial decision: Revision requested 29 Aug, 2025 Reviews received at journal 22 Aug, 2025 Reviewers agreed at journal 16 Aug, 2025 Reviews received at journal 15 Aug, 2025 Reviewers agreed at journal 14 Aug, 2025 Reviewers agreed at journal 13 Aug, 2025 Reviewers invited by journal 13 Aug, 2025 Editor assigned by journal 27 Apr, 2025 Submission checks completed at journal 21 Apr, 2025 First submitted to journal 18 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6480393","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":458698144,"identity":"5312b1d8-1265-4108-be3e-a03813abbed6","order_by":0,"name":"Afroditi Despoina Lalou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4ElEQVRIie3PrQ7CMBDA8VuatKYEyzI+XqFklsCrjJCgUWhUMTzASHgFBGZ6y5JhyLAkCDo/UYJBTNCRLXNlEtG/OvPL3QGYTP8YCgEoAwoELDVOWhDslYRRQACKLNsSYFCR+Lfo8k4m8lXRB4RE+OTX+dH3kJQa0kuIOz58D8Ms2vP7PLh52PZ1ax4cO9UvLO5UBFGNGCW4JkQqkpYEvQoNYQ2h5ZawJODo7honGKlfXKqOWUV+unCDS8btnYYME2yJvBjOumR7EnI9HQTnRSzfujV1uBmtTRtgMplMJk0f/bxHUFouNQwAAAAASUVORK5CYII=","orcid":"","institution":"Umeå University","correspondingAuthor":true,"prefix":"","firstName":"Afroditi","middleName":"Despoina","lastName":"Lalou","suffix":""},{"id":458698145,"identity":"818ac6db-035e-48ea-8efe-0785a08dabf7","order_by":1,"name":"Marek Czosnyka","email":"","orcid":"","institution":"University of Cambridge","correspondingAuthor":false,"prefix":"","firstName":"Marek","middleName":"","lastName":"Czosnyka","suffix":""},{"id":458698146,"identity":"828604d8-08bd-40f7-a034-fcc3d7348ef9","order_by":2,"name":"Zofia Helena Czosnyka","email":"","orcid":"","institution":"University of Cambridge","correspondingAuthor":false,"prefix":"","firstName":"Zofia","middleName":"Helena","lastName":"Czosnyka","suffix":""},{"id":458698147,"identity":"49b185f4-b50a-4777-9c3c-e394350f156f","order_by":3,"name":"John Douglas Pickard","email":"","orcid":"","institution":"University of Cambridge","correspondingAuthor":false,"prefix":"","firstName":"John","middleName":"Douglas","lastName":"Pickard","suffix":""}],"badges":[],"createdAt":"2025-04-18 16:23:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6480393/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6480393/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12987-025-00720-2","type":"published","date":"2025-12-16T15:57:40+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":88562895,"identity":"42903e02-e9e4-4751-8f77-2260c6c58bd1","added_by":"auto","created_at":"2025-08-07 18:36:49","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":332961,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eFrom: \u003c/em\u003eMoher D, Liverati A, Tetzlaff J, Altman \u0026nbsp;DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviws and Metal-Analyses: The PRISMA Statement. PLoS Med 6(7): \u0026nbsp;e1000097. doi:10.1371/journal.pmen1000097 \u003cstrong\u003eFor more information, visit\u003c/strong\u003e\u003ca href=\"http://www.consort-statement.org/\"\u003e\u003cstrong\u003e \u003c/strong\u003e\u003c/a\u003e\u003ca href=\"http://www.consort-statement.org/\"\u003e\u003cstrong\u003ewww.prisma-statement.org\u003c/strong\u003e\u003c/a\u003e\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6480393/v1/6236df092079593fad06e430.jpeg"},{"id":88562520,"identity":"98b0bbc7-4860-4945-b49a-050898aff7c4","added_by":"auto","created_at":"2025-08-07 18:28:49","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":493672,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGlobal Cerebral Blood flow in Normal Pressure Hydrocephalus versus age-matched controls at baseline (post-2001 studies). \u003c/strong\u003eCBF values in mean and SD. Units are ml/(100g.min) for studies 1,2 \u0026amp;3 and ml/min for the Phase Contrast (PC) MRI studies 4-6.\u0026nbsp;\u003cem\u003eTau: estimated\u0026nbsp;standard deviation of underlying effects across studies (Tau\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e\u0026nbsp;is only displayed in the random model). Chi\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u0026nbsp;\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e(value of Chi-square for heterogeneity). Random: random analysis model (for meta-analysis). Standardised (Std.) mean difference: calculated as Cohen's delta, with Hedges' bias correction.\u0026nbsp;All studies have similar weight to the pooled estimate, as shown in the weight column and illustrated with the size of the green squares.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6480393/v1/b105d98f0e0a61ba4816f137.jpeg"},{"id":88563338,"identity":"3154468d-6b60-47da-8e05-84b5309792ca","added_by":"auto","created_at":"2025-08-07 18:44:49","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":152269,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGlobal Cerebral Blood Flow changes in improvers versus non-improvers. \u003c/strong\u003eThe odds ratio (OR) represents whether shunting likely resulted in CBF increase (OR \u0026gt;1) or no change/decrease (OR\u0026lt;1) in responders vs non-responders.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6480393/v1/5f170c5c1e6bbd8096b67d4d.jpeg"},{"id":88562897,"identity":"ce197a3e-529e-4951-9e5d-bef9914c9130","added_by":"auto","created_at":"2025-08-07 18:36:49","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":261117,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePredictive Value of Cerebral Blood Flow. \u003c/strong\u003eThe odds ratio (OR) represents the probability of baseline CBF measurements to predict improvement after shunting and is based on the number of patients in each study.\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6480393/v1/a9d17bdb808b0a048febaf29.jpeg"},{"id":88562525,"identity":"a6c07cab-958f-42c1-95eb-efa6bab93f00","added_by":"auto","created_at":"2025-08-07 18:28:49","extension":"jpeg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":137588,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePredictive value of changes in CBF before and after temporary CSF withdrawal (Spinal Tap Test -STT). \u003c/strong\u003eThe odds ratio (OR) reflects the number of patients in whom an increase in CBF after a spinal tap test predicted improvement after shunting or not.\u003c/p\u003e","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6480393/v1/06dd8b39a5ef8a678fba758a.jpeg"},{"id":88562900,"identity":"d7c62df2-7e79-48f3-8e6f-c19a99a2281e","added_by":"auto","created_at":"2025-08-07 18:36:49","extension":"jpeg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":220333,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe predictive value of baseline Cerebrovascular Reactivity . \u003c/strong\u003eThe odds ratio (OR) reflects the likelihood of baseline CVR to successfully differentiate between shunt responders and non-responders. All the studies except for Chen indicated that impaired preoperative CVR leads to a favourable outcome post-shunting.\u003c/p\u003e","description":"","filename":"floatimage6.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6480393/v1/325ef2c43ae2ea2cd71197d3.jpeg"},{"id":98814317,"identity":"dfa63cc4-2f10-4a47-afc2-579f04d1c50f","added_by":"auto","created_at":"2025-12-22 16:12:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5780249,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6480393/v1/9b093fc2-7a66-4cd5-a4ce-0dc1c9963bf8.pdf"},{"id":88563337,"identity":"7210b906-ecb1-4fba-9256-d0b9de9f03be","added_by":"auto","created_at":"2025-08-07 18:44:49","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":22631,"visible":true,"origin":"","legend":"","description":"","filename":"biasassessment04.25.docx","url":"https://assets-eu.researchsquare.com/files/rs-6480393/v1/fc295b87c92356aa5777f56d.docx"}],"financialInterests":"Competing interest reported. MC has partial financial interesting in licencing the ICM+software (Cambridge enterprise), a research software for multi-modality physiological monitoring","formattedTitle":"Cerebral Blood Flow, Autoregulation and Vascular Reactivity in Normal Pressure Hydrocephalus: a systematic review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eReversible causes of dementia are crucially important to the individual, to their family and to society. It is almost 60 years since the symptoms of normal pressure hydrocephalus (\u0026lsquo;Hakim\u0026rsquo;s triad\u0026rsquo;: gait disturbance, dementia and urinary incontinence with radiological hydrocephalus and normal baseline CSF pressure) and their response to CSF drainage were first described\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e and yet there remain many uncertainties around the pathogenesis, diagnosis and management of Normal Pressure Hydrocephalus (NPH). The prevalence of symptomatic iNPH is of the order of 1.5% at the age of 70 rising to 7.7% at 86 years of age\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e in parallel with the normal age-related increase in ventricular volume. \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003eA further 3.7% at the age of 70 years have radiologically probable NPH, a proportion of whom progress to become symptomatic. \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e There remains a wide geographical disparity in the incidence of shunting for NPH\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eSecondary NPH develops late after disease processes that are well known to obstruct the CSF circulation including, for example, subarachnoid and intraventricular haemorrhage, meningitis, traumatic brain injury, basilar artery ectasia or longstanding aqueduct stenosis. Such cases respond well to CSF diversion. By definition in idiopathic NPH, no such prior disease appears to have been present. A disturbance of the CSF circulation alone may not always be sufficient for developing the condition. Certainly, there is autopsy evidence of meningeal thickening, subependymal gliosis and periventricular white matter demyelination \u003csup\u003e\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e and yet the relationship of CSF outflow resistance to post-drainage outcome, either temporary or permanent, is nonlinear \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. MR studies have confirmed the presence of periventricular axonal stretch injury and, in some but not all studies, reduced volumes of the caudate, thalamus, putamen, pallidum, hippocampus and nucleus accumbens. \u003csup\u003e\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e Reductions in volume of thalamus and caudate may also be part of normal ageing\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Co-morbidity and fragility are very common in iNPH.\u003csup\u003e\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e There is a high incidence of vascular risk factors, cardio- or cerebro- vascular disease and white matter changes in many NPH subjects \u003csup\u003e\u003cspan additionalcitationids=\"CR25 CR26 CR27 CR28 CR29 CR30\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. In iNPH with dementia, neuropathology often reveals evidence of Alzheimer change, cerebral small vessel disease (CSVD), multifocal infarcts, Parkinson\u0026rsquo;s disease or Parkinsonism (including Progressive Supranuclear Palsy, Corticobasal Degeneration and Multiple System Atrophy)\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. CSF biomarker studies confirm that patients with iNPH and CSVD share common features of subcortical neuronal degeneration, demyelination, and astroglial response including the reduction in all APP-derived proteins\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. Interestingly, it has been suggested that some cases of iNPH may have started with benign external hydrocephalus in infancy followed by deep white matter ischaemia in late adulthood.\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e Certainly, head size is statistically larger in NPH patients compared with normal subjects.\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eHence, the cerebral vasculature may have a role in the pathogenesis of iNPH. However, such a role remains ill-defined, as does the ability of measurements of CBF and cerebrovascular autoregulation/reactivity to predict outcome after CSF diversion. The previous systematic review (2001\u003csup\u003e1\u003c/sup\u003e) found that studies of CBF in iNPH had been inconsistent, not least in predicting the response to shunting. Studies had been hampered by heterogeneous patient groups of small size, incompatible definitions of clinical outcome, lack of longitudinal studies, and the resolving power of the then available technology to quantify periventricular regional CBF.\u003c/p\u003e\u003cp\u003eUnresolved issues include\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eWhether there are changes in global and regional CBF that are specific to NPH and its clinical manifestations?\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eWhether levels of global and regional CBF are appropriately coupled to cerebral metabolism and/or low enough to equate to ongoing cerebral ischaemia?\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eWhether any changes in global or regional CBF are predictive of outcome after CSF drainage, both temporary and permanent?\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eWhether global and regional cerebrovascular autoregulation and reactivity are more sensitive predictors of outcome and reversibility of symptoms in response to both temporary and permanent CSF drainage than baseline rCBF?\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eWhether changes in whole brain CSF pressure-volume compensation and circulation, local tissue stress and loss of brain tissue volume relate to CBF and cerebrovascular autoregulation and reactivity? Whether any changes in global or regional CBF are the cause or effect (\u0026lsquo;chicken and the egg\u0026rsquo;) of iNPH?\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eIn this systematic review, we have updated the previous 2001 review and examined how far new knowledge has addressed these questions.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eFrom February 2020 up until June 2024, we performed a detailed search on Scopus, Cochrane, PubMed, and Web of Knowledge, using the key phrases \u0026ldquo;(((cerebral autoregulation) OR (cerebrovascular reactivity) OR (cerebrovascular resistance))) AND (normal pressure hydrocephalus)\u0026rdquo;. We set out the timeline to include manuscripts after 2000 up until 30/06/2024, due to the fact that Owler \u0026amp; Pickard \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e performed a systematic review of the relevant literature up to year 2000. The language in which papers were written did not matter, since we had access to the vast majority of the world languages. The articles had to be published - unpublished work or work awaiting publication was not considered. Case reports were excluded as they do not contribute to the questions asked nor to the need for adequate numbers of patients with NPH.\u003c/p\u003e\u003cp\u003eArticles had to involve idiopathic or secondary adult NPH patients with pre-shunting assessment of CBF or autoregulation at baseline and/or after CSF drainage or shunting; this was in order to investigate the different measurements of CBF at baseline and the previously found difference in rCBF as well as to examine their to date not clear outcome implications. We compared all papers for consistency of references, background, analytical reporting of methods as well as reasoning and drawing of conclusions in an unbiased manner, taking into account NPH literature and its pathophysiological considerations. Cerebral Autoregulation was assessed separately to Cerebrovascular Reactivity (CVR).\u003c/p\u003e\u003cp\u003eThe data from all the original articles was extracted using piloted data forms; the forms underwent some dynamic changes during the data extraction when new data or information arose. The RTI tool was used to assess bias in observational studies. The QUIPS tool was used for assessing risk of bias for study participation, prognostic factor measurement and outcome measurement.\u003c/p\u003e\u003cp\u003eThe GRADE tool was used to classify the diagnostic and prognostic level of evidence as High, Moderate and Low \u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. A high level of evidence consisted of high quality studies with consistency and low to moderate (unclear) risk of bias; moderate level consisted of high quality evidence but inconsistent and with low to moderate risk of bias. Finally, low level of evidence included either high-moderate quality of evidence with inconsistency and high risk of bias, or moderate-low quality with at least inconsistency and/or high risk of bias. In order to uphold a standardised definition of Normal Pressure Hydrocephalus, the following criteria had to be met in defining and selecting the NPH group, as reported in Owler \u0026amp; Pickard\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e:\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eFull or incomplete clinical triad/primarily gait disorder;\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eventricular dilatation on CT without significant atrophy;\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eabsence of focal neurological deficit or focal pathology on CT;\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003enormal ICP/CSF pressure (\u0026lt;\u0026thinsp;15 mmHg) assessed using ICP monitoring or infusion study,\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eobjective, well documented follow-up.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003cp\u003eWe reviewed and combined the findings prior to our 2001 review with the new research. This review design and protocol can be accessed in the PROSPERO register (registration number CRD42018090946).\u003c/p\u003e"},{"header":"Results and Discussion","content":"\u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e maps out the number of records identified from the searched databases, including those included and excluded with the reasons for their exclusions. All results reported refer to statistically significant results, unless stated otherwise. Our risk of bias assessment for observational and prognostic factor studies are presented in Supplementary tables 1 and 2.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eOverview.\u003c/span\u003e\u003c/p\u003e\u003cp\u003eThis review should be read in conjunction with Owler \u0026amp; Pickard\u0026rsquo;s review of 2001 \u003csup\u003e1\u003c/sup\u003e which matched the reports of global and regional CBF, autoregulation and reactivity to the methodology used. Unfortunately, very few studies since have included more than 50 patients and have not always included details of clinical presentation including duration of symptoms, or co-morbidity (frailty, Alzheimer\u0026rsquo;s, Parkinsons, cerebral small vessel disease (CSVD), systemic hypertension, diabetic status and other cardiovascular risk factors). It is now clear that there is much overlap in terms of patterns of CBF between CSVD and NPH. Few studies reported the scanning environment (eg quiet room, eyes closed) or what the patients were asked to think about during the CBF measurements. Such clinical and procedural heterogeneity renders statistical analysis challenging.\u003c/p\u003e\n\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cb\u003eGlobal CBF studies at baseline\u003c/b\u003e: \u003cb\u003eresults of pre-2001 studies from Owler \u0026amp; Pickard (re-graded using updated GRADE tool) combined with later studies.\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGlobal CBF\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGrade\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMethod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNumber of\u003c/p\u003e\u003cp\u003eNPH patients\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMain\u003c/p\u003e\u003cp\u003efindings\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eComments\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1.Greitz et al., 1969 (2 parts)\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIntracarotid 133Xe clearance during Angiography\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e28 (21\u0026thinsp;+\u0026thinsp;7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIn cases without a vascular component, correlation\u003c/p\u003e\u003cp\u003ebetween ventricular dilation and \u0026darr;CBF\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2.Salmon \u0026amp; Timperman et al., 1971a (2 parts)\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e,\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAs in 1 (Greitz et al)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12 (5\u0026thinsp;+\u0026thinsp;7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4.Mathew et al., 1975 \u003csup\u003e46\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAs in 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCBF unchanged between NPH\u0026amp;atrophy.\u003c/p\u003e\u003cp\u003eNo correlation between CBF \u0026amp;ventricular size\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5.Hartmann et al., 1977 \u003csup\u003e47\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAs in 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSame\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6.Grubb et al., 1977 \u003csup\u003e48\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eH\u003csub\u003e2\u003c/sub\u003eO\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e PET Intracarotid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCBF unchanged between NPH\u0026amp;atrophy.\u003c/p\u003e\u003cp\u003eNo definite pattern of CBF could be identified in\u003c/p\u003e\u003cp\u003eNPH patients\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7.Lying-Tunnell et al., 1977 \u0026amp; 1981 \u003csup\u003e49,50\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAV-Difference N\u003csub\u003e2\u003c/sub\u003eO\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;CBF especially in the most demented patients\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e8.Hayashi et al., 1984\u003csup\u003e51\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAs in 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;CBF correlated with \u0026uarr;ventricular size.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9.Kushner et al., 1984 \u003csup\u003e52\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAs in 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo difference in CBF between NPH and non-NPH\u003c/p\u003e\u003cp\u003edementia patients\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e10.Meyer et al., 1984 \u003csup\u003e53\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e133Xe inhalation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e11.Meyer et al., 1985a\u003csup\u003e\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e133Xe inhalation \u0026amp; Xe contrast CT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFrontal, temporal and parietal cortex\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12.Meyer et al., 1985b \u003csup\u003e\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eXe contrast CT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e13.Brooks et al., 1986 \u003csup\u003e56\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eC15O2 PET inhalation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14.Mamo et al., 1987 \u003csup\u003e57\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e133Xe IV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;CBF compared to controls. No correlation\u003c/p\u003e\u003cp\u003ebetween ventricular size and CBF reduction\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e15.Vorstrup et al., 1987 \u003csup\u003e58\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e133Xe inhalation SPECT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIn 14/17 cases there was correlation between \u0026darr;CBF\u003c/p\u003e\u003cp\u003eand \u0026uarr; ventricular size.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e16.Graff-Radford et al., 1987 \u0026amp; 89 \u003csup\u003e25,37\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e133Xe inhalation SPECT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e61 (26\u0026thinsp;+\u0026thinsp;35)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo difference between CBF in AD and NPH\u003c/p\u003e\u003cp\u003epatients.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e17.Meixenberger et al., 1989\u003csup\u003e59\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e133Xe inhalation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFrontal cortex\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e18.Matsuda et al., 1990 \u003csup\u003e60\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e133Xe inhalation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;CBF correlated with ventricular size.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e19.Kimura et al., 1992 \u003csup\u003e61\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eXe contrast CT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eGenerally \u0026darr;CBF in NPH\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e20.Waldemar et al., 1993\u003csup\u003e40\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99m Tc-HMPAO SPECT \u0026amp; 133Xe inhalation SPECT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSame\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo difference in tCBF.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e21.Maeder et al., 1995 \u003csup\u003e62\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eXe contrast CT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e22.Kristensen et al., 1996 \u003csup\u003e63\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99m Tc-HMPAO SPECT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e23.Tanaka et al., 1997\u003csup\u003e64\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eXe contrast CT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e24.Klinge et al., 1998 \u003csup\u003e65\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eH2O15 bolus PET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eGenerally \u0026darr;CBF\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e25.Klinge et al., 1999 \u003csup\u003e66\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eH2O15 bolus PET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eGenerally \u0026darr;CBF\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e26.Owler et al 2004*\u003csup\u003e\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eH\u003csub\u003e2\u003c/sub\u003e \u003csup\u003e15\u003c/sup\u003eO PET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e27.Bateman \u0026amp; Loiselle 2007\u003csup\u003e68\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePC MRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTotal blood inflow 20% \u0026darr;\u003c/p\u003e\u003cp\u003eSagittal sinus outflow\u003c/p\u003e\u003cp\u003e35% \u0026darr;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e28.El Sankari et al 2011\u003csup\u003e69\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePC MRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTotal blood inflow 12% \u0026darr; (NS); Venous outflow\u003c/p\u003e\u003cp\u003eunchanged (-2%; NS)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e29.Yamada et al (2013)*\u003csup\u003e70\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSPECT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eDiffuse \u0026darr; in global CBF pre-shunting similar to\u003c/p\u003e\u003cp\u003epatients with ventriculomegaly due to age\u003c/p\u003e\u003cp\u003e(no healthy controls).\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e30.Ziegelitz et al 2014 *\u003csup\u003e\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDynamic susceptibility contrast MRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePreoperative CBF \u0026darr; in the global parenchyma deep\u003c/p\u003e\u003cp\u003eGM\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e31.Qvarlander et al 2017\u003csup\u003e41\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePC MRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSame\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;Internal Carotid artery flow (Controls:519\u0026thinsp;\u0026plusmn;\u0026thinsp;123,\u003c/p\u003e\u003cp\u003eNPH: 461\u0026thinsp;\u0026plusmn;\u0026thinsp;84ml/min,p\u0026thinsp;=\u0026thinsp;0.04)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e32.Huang et al 2022\u003csup\u003e72\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3D pulsed ASL MRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo healthy controls.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cem\u003eXe: Xenon, Tc-HMPAO: Technetium \u0026ndash; Hexamethylpropylene Amine Oxime. PC: Phase Contrast. ASL: Arterial Spin-Labelling\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eGlobal and Regional CBF (Table 1, Figure 2)\u003c/p\u003e\u003cp\u003eOverall, the 25 studies reported prior to 2001 provided Grade B evidence for reduced global CBF in 23 studies of 382 NPH patients with only 2 studies of 25 NPH patients showing unchanged global CBF compared to controls. PC MRI and perfusion MRI have been introduced since 2001. In Waldemar\u0026rsquo;s study\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e, although global CBF was not reduced, the subcortical low flow area was enlarged. In the Qvarlander study\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, internal carotid but not vertebral artery flow was reduced. Post-2001 CBF measurements have confirmed that global CBF is reduced by 15.2% (sd 14.0%) in iNPH at baseline compared to controls (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eVarious MR techniques (PC MRI, ASL MRI and DSC MRI), \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003eO PET and SPECT have now confirmed the older literature that global CBF is modestly reduced in NPH compared with age-matched healthy controls (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eRegional CBF and clinical correlations (\u003c/span\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e).\u003c/span\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eRegional Cerebral Blood Flow at baseline including clinical correlations\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRegional CBF\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eReference\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eGrade\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eMethod\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003eNumber of NPH patients\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eMain findings\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003eComments\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e1.Mathew et al., 1975\u003c/b\u003e\u003csup\u003e46\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eB\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIntracarotid 133Xe clearance during Angiography\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e15\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eReduced\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003eFrontal lobe (grey \u0026amp; white matter) \u0026amp;\u003c/b\u003e ACA territories (parietal lobe, corpus callosum, basal ganglia)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e2. Meyer et al., 1985a\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eC\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e133Xe inhalation \u0026amp; Xe contrast CT\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eReduced\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFrontal, temporal and parietal cortex, \u003cb\u003ethalamus\u003c/b\u003e \u0026amp;fronto-temporal WM\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e3,Meyer et al., 1985b\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eB\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eXe contrast CT\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eReduced\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFrontal WM\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e4.Graff-Radford et al., 1987 \u0026amp; 89\u003c/b\u003e \u003csup\u003e25,37\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eC\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e133Xe inhalation SPECT\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e61 (26\u0026thinsp;+\u0026thinsp;35)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eReduced\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003eFrontal \u0026ldquo;region\u0026rdquo;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e5.Waldemar et al., 1993\u003c/b\u003e \u003csup\u003e40\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99m Tc-HMPAO SPECT \u0026amp; 133Xe inhalation SPECT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSame *\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e*Slight \u0026darr; in the centrum semiovale.\u003c/p\u003e\u003cp\u003e*NPH patients had lower frontal/parietal ratio CBF\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e6.Maeder et al., 1995\u003c/b\u003e \u003csup\u003e62\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eC\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eXe contrast CT\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eReduced\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFrontal cortex \u0026amp; white matter\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7.Kristensen et al., 1996 \u003csup\u003e63\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99m Tc-HMPAO SPECT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eInferior frontal \u0026amp;temporal cortex. frontal \u0026amp; parietal WM\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e8.Owler et al (2004a)\u003c/b\u003e\u003csup\u003e92\u003cb\u003e*\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eH2\u003csup\u003e15\u003c/sup\u003eO PET \u0026amp;3T MRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCerebellum, \u003cb\u003ethalamus\u003c/b\u003e, head of caudate and putamen.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e9.Momjian et al(2004)\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR93\" class=\"CitationRef\"\u003e93\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eH\u003csub\u003e2\u003c/sub\u003e\u003csup\u003e15\u003c/sup\u003eO PET \u0026amp; 3TMRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eParaventricular borderzone regions.\u0026nbsp;WM, with abnormal gradient from lateral ventricles towards the subcortical WM\u003cb\u003e(PVWM).\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e10.Sasaki et al (2007)\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR94\" class=\"CitationRef\"\u003e94\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSPECT\u003c/p\u003e\u003cp\u003e(voxel based analysis)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCorpus callosum. Either frontal dominant or diffuse pattern. Medial \u0026amp;lateral in urinary incontinence\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e11.Klinge et al (2008)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR95\" class=\"CitationRef\"\u003e95\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eH\u003csub\u003e2\u003c/sub\u003e\u003csup\u003e15\u003c/sup\u003eO PET uptake\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eGreater impairment correlated with reduced tracer uptake in mesial frontal and anterior temporal areas.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e12.Yoon et al (2009)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR96\" class=\"CitationRef\"\u003e96\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSPECT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ebilateral \u003cb\u003ethalami\u003c/b\u003e, anterior and posterior cingulate gyri, right prefrontal area, right caudate nucleus and left parahippocampal gyrus\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e13.Takaya et al (2010)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR97\" class=\"CitationRef\"\u003e97\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSPECT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eparietal lobe, \u003cb\u003elateral \u0026amp;medial frontal cortex\u003c/b\u003e, lateral temporal \u0026amp;occipital cortex, cingulate gyrus, precuneus, frontal WM, semioval center,corpus callosum ; caudate, \u003cb\u003ethalamus\u003c/b\u003e, pons, cerebellum\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e14. Ishii et al 2011\u003c/b\u003e \u003csup\u003e98\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eN-isopropyl-p-\u003csup\u003e\u003cspan citationid=\"CR123\" class=\"CitationRef\"\u003e123\u003c/span\u003e\u003c/sup\u003eI iodoamphetamine SPECT.\u003c/p\u003e\u003cp\u003eRelative CBF in each voxel was calculated by normalizing each voxel activity to the global brain activity.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eVariable patterns: frontal perfusion predominantly reduced. The medial and lateral frontal, parietal, and occipital CBFs relatively increased at high convexity.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMulticentre study in 26 centres; basal ganglia and thalamus not analysed.\u003c/p\u003e\u003cp\u003eCBF in the peri-sylvian and ventricular areas, where the cerebrospinal fluid spaces are dilated, is also reduced \u0026ndash; partial volume issue.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e14. Ziegelitz et al 2014\u003c/b\u003e \u003csup\u003e71\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDynamic susceptibility contrast MRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ebasal medial frontal cortex, hippocampus, lentiform nucleus,\u0026nbsp;\u003cb\u003ePVWM\u003c/b\u003e \u0026amp;\u003c/p\u003e\u003cp\u003ecentral GM\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e15.Virhammar\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eet al (2017)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR99\" class=\"CitationRef\"\u003e99\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003epCASL perfusion MRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003ePVWM\u003c/b\u003e, cerebellum and pons\u003c/p\u003e\u003cp\u003elentiform nucleus \u0026amp; \u003cb\u003ethalamus\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e16. Takahashi et al (2019)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR100\" class=\"CitationRef\"\u003e100\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCBF SPECT \u0026amp; MRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026uarr;rCBF in the lower part of the high convexity area.\u003c/p\u003e\u003cp\u003e\u0026darr;rCBF in medial frontal lobes, left lateral frontal lobe, and left parietotemporal region\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e17. Azuma et al (2019)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR123\" class=\"CitationRef\"\u003e123\u003c/span\u003e\u003c/sup\u003e I-IMP SPECT\u003c/p\u003e \u003cp\u003eMRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e39\u003c/p\u003e\u003cp\u003e(15 - iNPH/AD+\u003c/p\u003e\u003cp\u003e24 - iNPH/AD\u0026minus;)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eThe putamen was the only region in which rCBF was significantly lower in iNPH/AD\u0026thinsp;\u0026minus;\u0026thinsp;patients than in iNPH/AD\u0026thinsp;+\u0026thinsp;patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo controls\u003c/p\u003e\u003cp\u003eNo significant correlation between gait and rCBF in any region.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e18. Agerskov et al (2020)*\u003c/b\u003e\u003csup\u003e101\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDSC MR perfusion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSame\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eROIs in upper mesencephalon and lower pons only.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e19. Huang et al 2022\u003c/b\u003e \u003csup\u003e72\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3D pulsed ASL MRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReduced\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ehigh convexity, temporal lobe, precuneus, and \u003cb\u003ethalamus.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e20. Kang et al 2023\u003c/b\u003e \u003csup\u003e102\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-florbetaben (E-FBB) PET\u003c/p\u003e\u003cp\u003eFDG PET\u003c/p\u003e\u003cp\u003eMRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMixed patterns\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026uarr;rCBF in the high convexity of frontal and parietal cortical regions\u003c/p\u003e\u003cp\u003e\u0026darr;rCBF in ventrolateral frontal cortex, supramarginal gyrus and temporal cortical regions.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cem\u003e*Owler et al (2004) \u0026amp; Momjian et al (2004) analysed the same cohort of patients using different voxel analyses.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eWith regard to regional CBF, the new consistent findings since 2001 are that, in addition to the frontal lobe, rCBF in the periventricular white matter and deep grey matter (thalamus and, more variably, caudate, hippocampus and lentiform nucleus) are reduced. One important methodological finding was that cerebellar CBF is modestly reduced which suggests that the use of the cerebellum as a control for SPECT studies is problematic. The reductions in rCBF in the deep WM and GM are in accord with reductions in volumes of these structures (but see below for discussion of the \u0026lsquo;chicken and egg\u0026rsquo; conundrum) \u003csup\u003e\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e,\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAll the post-2001 studies that have investigated the frontal cortex confirmed the pre-2001 findings of frontal hypoperfusion but with less consistent findings in the lateral and medial frontal cortices and frontal white matter. Studies that included the periventricular white matter, thalamus, basal ganglia and cerebellum as ROIs demonstrated hypoperfusion. There were also reports of hypoperfusion of the cingulate gyrus, corpus callosum, pons and temporo-parietal areas.\u003c/p\u003e\u003cp\u003eFrontal hypoperfusion (lateral, medial and basal) accords with the loss of both executive and motor function in NPH. Cognitive functions depend upon efficient functioning of distributed brain networks connected by white matter tracts. In the case of CSVD, such frontal hypoperfusion has been related to a regional predominance of WMH and white matter tract disruption in the frontal lobes, consistent with cortical disconnection, that would provide a plausible structural basis for selective loss of executive function [ \u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/b\u003e,\u003cspan additionalcitationids=\"CR76 CR77\" citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e\u003c/sup\u003e). Regarding neurocognitive symptoms, impaired wakefulness was associated with decreased rCBF in the anterior cingulate gyrus and anterior periventricular white matter in two out of the three studies of neurocognitive results.\u003c/p\u003e\u003cp\u003eOf the 12 studies on rCBF, 4 described the relationship between gait and rCBF. Whilst different regions were investigated, the thalamus as well as frontal and periventricular structures demonstrated a correlation with gait impairment in 3 studies. In contrast, Azuma\u0026rsquo;s study \u003csup\u003e\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e\u003c/sup\u003edid not find any significant correlation between gait and rCBF in any regions. White matter surrounding the lateral ventricles, especially in the frontal lobes, is key to gait function. Fibres in these areas connect brain regions likely involved in iNPH, such as the supplementary motor cortex, basal ganglia, and thalamus, and in elderly people without iNPH, WM hyperintensities in the frontal lobe and periventricular WM have the strongest relationship with impairments in balance and gait \u003csup\u003e\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e,\u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAkai et al \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003ereported that the most prominent post-mortem finding in NPH was demyelination of the white matter supplied by the anterior and middle cerebral arteries. While the peripheral arcuate region of the white matter region was reasonably maintained, the deep white matter demonstrated a marked reduction in the number of myelinated axons. The number of axons themselves was also reduced. Whether this is a cause or effect of reduced blood flow in periventricular regions is not clear. Such changes may also have distant effects due to deafferentation and thereby reduction in CBF in those regions affected. Such functional deafferentation is consistent with recent studies of Resting State Networks \u003csup\u003e\u003cspan additionalcitationids=\"CR83 CR84\" citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAxons may only need to be stretched across the dilated ventricles to influence functioning. As early as 1947 Yakovlev had proposed that gait disorder was due to stretching of axons responsible for gait \u003csup\u003e\u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e\u003c/sup\u003e. Of course, periventricular stretch and compression impacts on blood vessels as well as axons (see below; \u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/b\u003e,\u003cspan additionalcitationids=\"CR88 CR89\" citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e\u003c/sup\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThere is some intriguing disagreement over whether rCBF is \u003cem\u003eincreased\u003c/em\u003e in the high convexity area (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Such increases are counter-intuitive and yet have also been identified in longitudinal studies of normal aging without dementia where extensive bilateral regions showed greater relative increases in rCBF in the group with progressive WM abnormalities compared with the stable WM group over time. Kraut et al \u003csup\u003e\u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e\u003c/sup\u003esuggested that \u0026lsquo;these increases in rCBF associated with WM pathology might relate to changes in resting cerebral cortical activity (and thus metabolic requirements), as accommodations are made for less efficient interregional WM connections. That is, regions of brain that are interconnected by deficient WM would have to maintain activity for longer periods or at a higher level to communicate with one another even in the resting state, either through the deteriorating pathways that had been used before WM degeneration had begun, or through less efficient indirect pathways. This prolonged cortical neural activity would require increased blood flow to meet the increased metabolic demands.\u0026rdquo; The authors accepted that this idea runs counter to several studies of the relationship between cerebral glucose metabolism and WM abnormalities, where in general it has been found that increased severity of WM disease correlates with reduced regional rates of cerebral glucose metabolism.\u003c/p\u003e\n\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eResults of Cerebral Metabolism studied either separately or simultaneously with Cerebral Blood Flow.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGrade\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMethod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSignificant findings\u003c/p\u003e\u003cp\u003eBaseline\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSignificant post-shunt changes\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eComments\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eCerebral oxygen consumption\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1. Lying-Tunnell 1981 \u003csup\u003e49\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eKety-Schmidt N\u003csub\u003e2\u003c/sub\u003eO\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026darr;CBF (-33%)\u003c/p\u003e\u003cp\u003e\u0026darr;CMRGlu\u003c/p\u003e\u003cp\u003e\u0026darr;oxygen uptake\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAll parameters improved\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2.Brooks 1986\u003csup\u003e56\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003eO PET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026darr;CBF \u0026darr;CMRO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003cp\u003eOEF no change\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo change\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCortical CBF only reported; only CMRO\u003csub\u003e2\u003c/sub\u003e changes were significant\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3.Miyamoto 2007a/b\u003csup\u003e111,112\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003eO PET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr;CMRO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4. Zhuang 2023 \u003csup\u003e113\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3D multi-\u003c/p\u003e\u003cp\u003egradient echo to assess ventricular CSF volumes with OEF\u003c/p\u003e\u003cp\u003emapping (MRI QQ-CCTV\u003c/p\u003e\u003cp\u003ealgorithm); ASL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSignificant negative\u003c/p\u003e\u003cp\u003ecorrelation\u003c/p\u003e\u003cp\u003ebetween OEF and\u003c/p\u003e\u003cp\u003enormalised\u003c/p\u003e\u003cp\u003eventricular volume,\u003c/p\u003e\u003cp\u003ecortical and deep\u003c/p\u003e\u003cp\u003eGM.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo clinical data. No WM data. No significant\u003c/p\u003e\u003cp\u003efinding with CBF or\u003c/p\u003e\u003cp\u003eCMRO\u003csub\u003e2\u003c/sub\u003e .\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eQQ-CCTV and ASL are\u003c/p\u003e\u003cp\u003ecomplex techniques. A fall in OEF would suggest true\u003c/p\u003e\u003cp\u003eischaemia rather than\u003c/p\u003e\u003cp\u003eoligemia but CBF would be\u003c/p\u003e\u003cp\u003eexpected to be low which\u003c/p\u003e\u003cp\u003ewas not found \u003csup\u003e\u003cspan citationid=\"CR105\" class=\"CitationRef\"\u003e105\u003c/span\u003e,\u003cspan citationid=\"CR106\" class=\"CitationRef\"\u003e106\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCerebral glucose metabolism\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6.Jagust 1985\u003csup\u003e114\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-FDG PET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eGlobal hypometabolism in 3 patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2 Idio; 1 post SAH\u003c/p\u003e\u003cp\u003eNo CMRGlu calculation\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4.George 1986 \u003csup\u003e115\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-FDG PET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 chronic HC patients: \u0026uarr;CMRGlu post-shunt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5.Kaye 1990 \u003csup\u003e116\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-FDG PET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eGlobal \u0026darr;CMRGlu\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eEarly \u0026uarr;CMRGlu with return to near normal by 2 years with maintained clinical improvement\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCase report\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7.Tedeschi 1995 \u003csup\u003e117\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-FDG PET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eGlobal hypometabolism \u0026ndash; very heterogenous patterns\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e18 patients; 7 improved post-shunt; frontal biopsy: heterogeneous findings\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e8.Calcagni 2013 \u003csup\u003e118\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-FDG PET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCMRGlu increased in all cortical regions post shunt; no correlation with symptoms; no specific regional variation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;20\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9.Townley 2018 \u003csup\u003e119\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-FDG PET\u003c/p\u003e\u003cp\u003eCo registered MRI - partial volume correction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo specific pattern of significant cortical hypometabolism.\u003c/p\u003e\u003cp\u003eSignificant striatal hypometabolism.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;7; healthy controls\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e10.Miyazaki 2019 \u003csup\u003e120\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-FDG PET Cerebellar cortex used for ratio calculation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026darr;frontal and temporal ratios in prodromal and iNPH.\u003c/p\u003e\u003cp\u003e\u0026darr;ratio in thalamus and striatum in iNPH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e12 iNPH\u003c/p\u003e\u003cp\u003e33 with DESH only\u003c/p\u003e\u003cp\u003e32 asymptomatic with ventriculomegly and DESH\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e11.Chiaravalloti 2020 \u003csup\u003e121\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-FDG PET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSignificant \u0026uarr; left frontal and parietal regions;\u003c/p\u003e\u003cp\u003e\u0026darr;right frontal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e10 patients\u003c/p\u003e\u003cp\u003eNo CMRGlu analysis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eIntracerebral microdialysis\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12.Agren-Wilsson 2003 \u003csup\u003e124\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRight frontal 10mm catheter; 0-7mm from the frontal horn\u003c/p\u003e\u003cp\u003eBrain tissue oxygen tension PtiO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003cp\u003ePre and 2\u0026ndash;4 hours post CSF infusion study and drainage to zero CSF pressure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLactate and pyruvate increased; no change in Lac/Pyr ratio\u003c/p\u003e\u003cp\u003ePtiO\u003csub\u003e2\u003c/sub\u003e increased in 5 of 8 patients (~\u0026thinsp;3 mmHg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e10 patients\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e13.Eide 2010 \u003csup\u003e122\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLeft frontal (20mm catheter) extending from cortical surface to 20mms below; controls using normal frontal cortex.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eModest changes:\u003c/p\u003e\u003cp\u003e\u0026uarr;Lac (63% of patients)\u003c/p\u003e\u003cp\u003e\u0026darr;Pyr (60% of Patients)\u003c/p\u003e\u003cp\u003eL/P: no change (\u0026uarr;8% of patients)\u003c/p\u003e\u003cp\u003e\u0026uarr;Glut (38% of patients)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eModest changes during Extended lumbar drainage\u003c/p\u003e\u003cp\u003e\u0026darr;Lac (29% of patients)\u003c/p\u003e\u003cp\u003e\u0026uarr;Pyr (82% of patients)\u003c/p\u003e\u003cp\u003e\u0026darr;L/P (43% of patients)\u003c/p\u003e\u003cp\u003e\u0026darr;Glut (75% of patients)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo differences in baseline or during EDT between reponers and non-reponders.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMagnetic Resonance Spectroscopy\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14. Kizu et al 2001 \u003csup\u003e125\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003eH-CSI\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eintraventricular lactate peaks in NPH (n\u0026thinsp;=\u0026thinsp;9) not in controls or Alzheimer\u0026rsquo;s/Picks.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e15.Braun 2003 \u003csup\u003e126\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003eH MRS \u0026ndash; ratio analysis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eWM; NAA/Cr no change\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e18 adults\u0026thinsp;\u0026lt;\u0026thinsp;40 years, 14\u0026thinsp;\u0026gt;\u0026thinsp;40. WM lateral to lateral ventricle\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e16.Shiino 2004 \u003csup\u003e127\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003eH MRS \u0026ndash; ratio analysis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo controls\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eHigh NAA/Cr \u0026ndash; favourable outcome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSecondary NPH only; WM lateral to lateral ventricle\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e17.Kubas 2006 \u003csup\u003e128\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003eH MRS \u0026ndash; ratio analysis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNAA/Cr \u0026darr;8%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNot done\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLeft frontal VOI\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e18.Del Mar Matarin 2007 \u003csup\u003e129\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003eH MRS \u0026ndash; ratio analysis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNAA/Cr \u0026uarr; 6%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo controls\u003c/p\u003e\u003cp\u003eMedial frontal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e19.Lenfeldt 2008a \u003csup\u003e\u003cspan citationid=\"CR130\" class=\"CitationRef\"\u003e130\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003eH MRS \u0026ndash; ratio analysis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNAA/Cr \u0026darr;13%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eHigher in improved patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFrontal WM\u003c/p\u003e\u003cp\u003eELD for 3 days\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e20.Algin 2010 \u003csup\u003e131\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003eH MRS \u0026ndash; ratio analysis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNAA/CR \u0026darr;11%\u003c/p\u003e\u003cp\u003eNAA/Cho \u0026darr;13%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo change; no correlation with outcome (n\u0026thinsp;=\u0026thinsp;18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFrontal lobe\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e21.Lundin 2011/2013 \u003csup\u003e132,133\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003eH MRS \u0026ndash; absolute quantification\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eThalamus \u0026ndash; NAA \u0026darr;10%\u003c/p\u003e\u003cp\u003eFrontal deep WM \u0026ndash; Cho \u0026darr;7.9%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eThalamus: No change\u003c/p\u003e\u003cp\u003eFrontal deep WM: Cho \u0026uarr;4.5%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003ch3\u003eEvidence for and against borderline cerebral ischaemia (Table 3)\u003c/h3\u003e\u003cp\u003eIt is a matter of some debate whether changes in the cerebral circulation are a cause or effect of NPH. There is strong evidence of decreased vascular density in ageing animals including humans, \u003csup\u003e\u003cspan additionalcitationids=\"CR104 CR105\" citationid=\"CR103\" class=\"CitationRef\"\u003e103\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR106\" class=\"CitationRef\"\u003e106\u003c/span\u003e\u003c/sup\u003e. As noted above, cerebrovascular hypertensive changes are common in NPH. White matter hyperintensities are very common in NPH \u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e. The normal-appearing white matter surrounding white matter hyperintensities is associated with decreased structural integrity and perfusion and increased risk of their growth \u003csup\u003e\u003cspan citationid=\"CR107\" class=\"CitationRef\"\u003e107\u003c/span\u003e,\u003cspan citationid=\"CR108\" class=\"CitationRef\"\u003e108\u003c/span\u003e\u003c/sup\u003e. However, CBF reduction may also be the consequence of ventricular dilatation, reduced metabolism and other secondary changes. Unfortunately, there have been no longitudinal studies comparing the time course of changes in rCBF with tissue volume nor of comparative recovery after shunting. However, it is well established that, at least in MCI, hypoperfusion may be dissociated from atrophy \u003csup\u003e\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e,\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe use of positron emission tomography (PET) in cerebrovascular disorders has greatly improved our understanding of the clinical pathophysiology of cerebral ischaemia \u003csup\u003e\u003cspan citationid=\"CR109\" class=\"CitationRef\"\u003e109\u003c/span\u003e,\u003cspan citationid=\"CR110\" class=\"CitationRef\"\u003e110\u003c/span\u003e\u003c/sup\u003e. The measurement of regional cerebral blood flow (CBF), oxygen consumption (CMRO\u003csub\u003e2\u003c/sub\u003e), oxygen extraction (OEF) and blood volume (CBV) has permitted the identification of three successive stages of severity which are characterized by (1) an isolated rise of CBV (reflecting a vasodilatation that largely underlies the mechanism of CBF autoregulation); (2) a moderate fall in CBF with normal CMRO\u003csub\u003e2\u003c/sub\u003e and increased OEF (a fully compensated stage defining oligaemia); (3) a depression of CMRO\u003csub\u003e2\u003c/sub\u003e as CBF falls further (denoting true ischaemia).\u003c/p\u003e\u003cp\u003eIn NPH, both cerebral oxygen and glucose metabolism were reduced to a similar degree to CBF with no change in oxygen extraction fraction (OEF) \u003csup\u003e\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e,\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e,\u003cspan citationid=\"CR111\" class=\"CitationRef\"\u003e111\u003c/span\u003e,\u003cspan citationid=\"CR112\" class=\"CitationRef\"\u003e112\u003c/span\u003e\u003c/sup\u003e. The majority of studies reported reduced glucose metabolism in the frontal region, thalamus, caudate and subcortical periventricular white matter \u003csup\u003e\u003cspan additionalcitationids=\"CR114 CR115 CR116 CR117 CR118 CR119 CR120\" citationid=\"CR113\" class=\"CitationRef\"\u003e113\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR121\" class=\"CitationRef\"\u003e121\u003c/span\u003e\u003c/sup\u003e. Hence, the reduction in global/cortical CBF was coupled to the reduction in oxidative brain metabolism and therefore there was no evidence of significant cerebral ischaemia. Despite this preservation of OEF, there is some evidence of low-grade, covert / impending / borderline / chronic ischaemia / misery perfusion in NPH (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Despite significant, modest baseline changes in lactate (increase) and pyruvate (decrease), there was no significant change in lactate/pyruvate ratio. \u003csup\u003e\u003cspan citationid=\"CR122\" class=\"CitationRef\"\u003e122\u003c/span\u003e\u003c/sup\u003e. These changes do not meet the strict microdialysis definition of cerebral ischaemia - increased L/P ratio with reduced pyruvate \u003csup\u003e\u003cspan citationid=\"CR123\" class=\"CitationRef\"\u003e123\u003c/span\u003e\u003c/sup\u003e. However, extended lumbar drainage resulted in modest falls in lactate, increase in pyruvate and fall in L/P ratio in some patients \u003csup\u003e\u003cspan citationid=\"CR124\" class=\"CitationRef\"\u003e124\u003c/span\u003e\u003c/sup\u003e. Neither baseline values nor changes with ELD differed between responders and non-responders. Brain tissue oxygen tension increased modestly (by 3mmHg) in 5 of 8 patients after the combination of a constant pressure CSF infusion study and CSF drainage down to zero pressure \u003csup\u003e\u003cspan citationid=\"CR124\" class=\"CitationRef\"\u003e124\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eMagnetic Resonance Spectroscopy studies of N-Acetylaspartate/Creatine (NAA/Cr) ratio in the frontal lobe have demonstrated no change or falls of 8\u0026ndash;13% which increased after shunting \u003csup\u003e\u003cspan additionalcitationids=\"CR126 CR127 CR128 CR129 CR130 CR131 CR132\" citationid=\"CR125\" class=\"CitationRef\"\u003e125\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR133\" class=\"CitationRef\"\u003e133\u003c/span\u003e\u003c/sup\u003e. Absolute quantification of NAA revealed a significant fall in NAA in the thalamus (\u0026darr;10%) and in choline, but not NAA, in the deep frontal WM (\u0026darr;7.9%). Thalamic NAA did not normalise after shunting \u003csup\u003e\u003cspan citationid=\"CR132\" class=\"CitationRef\"\u003e132\u003c/span\u003e\u003c/sup\u003e. Low NAA may be an indicator of neuronal loss that may be reversible. Changes in NAA are not an early indicator of cerebral ischaemia. Reduction in NAA occurs more slowly than increases in lactate after focal ischaemia and is greater in the core of an infarct than in peripheral areas \u003csup\u003e\u003cspan citationid=\"CR134\" class=\"CitationRef\"\u003e134\u003c/span\u003e\u003c/sup\u003e. The thalamic findings are in accord with the reduction in thalamic volume in NPH.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eEffect of CSF drainage (tap test and shunting) on global and regional CBF (\u003c/span\u003eTables \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e)\u003c/span\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCBF before and after temporary CSF withdrawal.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRef\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGrade\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNPH I and/or 2\u003csup\u003e0\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMethod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMain Findings\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eComments and correlations\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOwler et al 2002\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSummary of previous evidence\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSystematic review of literature\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026uarr; in CBF equally likely as \u0026darr;after CSF withdrawal\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e1.Mori et al (2002)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR137\" class=\"CitationRef\"\u003e137\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22(I3 2\u003csup\u003e0\u003c/sup\u003e post SAH; 9 I)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRegional CBF pre \u0026amp; 10 minutes post CSF drainage in shunt responders vs non-responders (no controls; prospective)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCSF removal (30\u0026ndash;50 mls); [\u003csup\u003e\u003cspan citationid=\"CR123\" class=\"CitationRef\"\u003e123\u003c/span\u003e\u003c/sup\u003eI]IMP SPECT with arterial sampling and arterial blood gas/MAP monitoring\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eBaseline clinical characteristics \u0026amp; CBF values were not significantly different between responders (15) \u0026amp; non-responders (7). 10 Minutes post-drainage, CBF significantly more in all regions in responders (101+/-39%) than in non-responders (46 +/- 40%).\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;80% increase in CBF after CSF removal was predictive of response to shunt surgery with 77% accuracy. Corrected CBF change of \u0026lt;\u0026thinsp;20% indicated nonresponse to shunting (see Table X).\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e2.Hertel, Walter et al (2003)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR138\" class=\"CitationRef\"\u003e138\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27(I)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCorrelation of preoperative STT with CBF/CBV changes and response to subsequent shunt\u003c/p\u003e\u003cp\u003e(retrospective)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSTT (\u0026gt;\u0026thinsp;40mls); \u003csup\u003e\u003cspan citationid=\"CR99\" class=\"CitationRef\"\u003e99\u003c/span\u003em\u003c/sup\u003eTc -bicisate SPECT (normalisation to cerebellum);\u003c/p\u003e\u003cp\u003epwMRI (Gad)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e33% of patients showed clinical and regional perfusion improvement post-STT;\u003c/p\u003e\u003cp\u003e33% showed increases in regional perfusion but no post-STT improvement;\u003c/p\u003e\u003cp\u003e33% showed no clinical improvement post-STT and no increases in cerebral perfusion. There were no differences between regions.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eIt was not possible to distinguish white matter from grey matter on SPECT.\u003c/p\u003e\u003cp\u003eBoth groups who showed increases in post-STT cerebral perfusion variably improved post shunt.\u003c/p\u003e\u003cp\u003eThe group who were imaging negative and did not improve post-STT clinically were not shunted (see Table X).\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e3.Walter, Hertel et al (2005)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR139\" class=\"CitationRef\"\u003e139\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28(I)\u003c/p\u003e\u003cp\u003e9 patients common with Hertel, Walter et al 2003.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCorrelation of preoperative STT with CBF/CBV changes and response to subsequent shunt\u003c/p\u003e\u003cp\u003e(prospective)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSTT (\u0026gt;\u0026thinsp;40mls);\u003c/p\u003e\u003cp\u003ePw -MRI (Gad) pre and 24 hours post-STT\u003c/p\u003e\u003cp\u003e(with analysis by visual inspection)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e7/28 patients: rCBV and gait improved post-STT (all improved post-shunt).\u003c/p\u003e\u003cp\u003e9/28 patients: rCBV but not gait improved post-STT (7/9 shunted and improved to some degree).\u003c/p\u003e\u003cp\u003e12/28 patients: no improvement in either rCBV or gait post-STT (none of this group were shunted).\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eImproved brain perfusion after STT is more sensitive than clinical assessment alone in predicting improvement after a shunt (see Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e4.Dumarey et al (2005)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR140\" class=\"CitationRef\"\u003e140\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e40(I\u0026amp;2\u003csup\u003eo\u003c/sup\u003e x 8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRegional CBF \u0026amp; gait measurements pre \u0026amp; post STT (retrospective)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSTT (\u0026gt;\u0026thinsp;30mls);\u003c/p\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR99\" class=\"CitationRef\"\u003e99\u003c/span\u003em\u003c/sup\u003eTc HMPAO SPECT (with SPM analysis)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo significant difference between pre- and post-STT SPECT images. Gait improvement after STT was associated with \u0026uarr;rCBF in the middle frontal gyrus \u0026amp; left parahippocampal gyrus.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eOnly 14 patients shunted.\u003c/p\u003e\u003cp\u003eNo data on WM v GM.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e5.Virhammar et al (2014)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR141\" class=\"CitationRef\"\u003e141\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20(I)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003erCBF before \u0026amp; 30mins, 4hrs and 24 hrs after STT; comparison with gait improvement after STT\u003c/p\u003e\u003cp\u003e(prospective)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSTT; pCASL-MRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eOverall, no significant increase in rCBF in any region after CSF removal compared with baseline. In patients with \u0026uarr; CBF in the periventricular lateral and frontal white matter after the CSF STT, gait function improved more than in patients with\u0026darr; CBF in these regions.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eGlobal and regional CBF before \u0026amp; after shunting including correlation with outcome after shunting\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eGrade\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMethod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo of shunted patients\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMain findings\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eComments\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003ePost-CBF correlation to improvement\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u0026bull; Global CBF\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1. \u003cb\u003eGreitz et al, 1969\u003c/b\u003e \u003csup\u003e142\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIntracarotid 133Xe clearance during Angiography\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2. \u003cb\u003eSalmon \u0026amp; Timperman et al., 1971b\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAs in 1.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eGrey matter more than white matter. Variable change in white matter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3. \u003cb\u003eLying-Tunnell et al., 1977 \u0026amp; 1981\u003c/b\u003e \u003csup\u003e49,50\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAV-Difference\u003c/p\u003e\u003cp\u003eN\u003csub\u003e2\u003c/sub\u003eO\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eTemporary\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4. \u003cb\u003eKushner et al., 1984\u003c/b\u003e \u003csup\u003e52\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAs in 1.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5. \u003cb\u003eMeyer et al., 1984\u003c/b\u003e \u003csup\u003e53\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e133Xe inhalation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eInconclusive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eInconclusive\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6. \u003cb\u003eBrooks et al., 1986\u003c/b\u003e \u003csup\u003e56\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eC15O2 PET\u003c/p\u003e\u003cp\u003einhalation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo change\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7. \u003cb\u003eMamo et al., 1987\u003c/b\u003e \u003csup\u003e57\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e133Xe IV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNo region or pattern. Also temporary vs sustained\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e8. \u003cb\u003eVorstrup et al., 1987\u003c/b\u003e \u003csup\u003e58\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e133Xe inhalation, SPECT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo change\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNo pattern\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9. \u003cb\u003eGraff-Radford et al., 1987\u003c/b\u003e \u003csup\u003e143\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e133Xe inhalation, SPECT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo change\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNo region or pattern\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e10. \u003cb\u003eMeixensberger et al., 1989\u003c/b\u003e \u003csup\u003e59\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e133Xe inhalation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo change\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFrontal regions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e11. \u003cb\u003eMatsuda et al., 1990\u003c/b\u003e \u003csup\u003e144\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e133Xe inhalation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo change\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12. \u003cb\u003eKlinge et al., 1998\u003c/b\u003e \u003csup\u003e65\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eH2O15 bolus\u003c/p\u003e\u003cp\u003ePET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo change\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e13. \u003cb\u003eKlinge et al., 1999\u003c/b\u003e \u003csup\u003e66\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eH2O15 bolus\u003c/p\u003e\u003cp\u003ePET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo change\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14. \u003cb\u003eMatsuda et al., 1999\u003c/b\u003e \u003csup\u003e145\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eXe contrast CT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNo pattern\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eyes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e15. \u003cb\u003eBakker et al 34(2002)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR146\" class=\"CitationRef\"\u003e146\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTCD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo change\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e16. \u003cb\u003eKlinge et al (2002)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR147\" class=\"CitationRef\"\u003e147\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e15-O-H2O PET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo change\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSame patients, both global and regional studies (see below)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e17. \u003cb\u003eBateman \u0026amp; Loiselle (2007)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMRI (1.5T) with flow sequences\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo change\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e18. \u003cb\u003eZiegelitz et al (2016)\u003c/b\u003e\u0026nbsp;\u003csup\u003e\u003cspan citationid=\"CR148\" class=\"CitationRef\"\u003e148\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDynamic susceptibility contrast MRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e19. \u003cb\u003eVirhammar et al (2020)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR149\" class=\"CitationRef\"\u003e149\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003epCASL perfusion MRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo change\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePotential methodological limitation w ASL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u0026bull; \u003cb\u003eRegional CBF\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e20. \u003cb\u003eMeyer et al., 1985a\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e133Xe inhalation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCortices, basal ganglia, \u003cb\u003efrontal WM\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eInconclusive\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e21. \u003cb\u003eMeyer et al., 1985b\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e133Xe inhalation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCortices, basal ganglia, \u003cb\u003efrontal WM\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e22. \u003cb\u003eWaldemar et al., 1993\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e99m Tc-HMPAO\u003c/p\u003e\u003cp\u003eSPECT \u0026amp;\u003c/p\u003e\u003cp\u003e133Xe inhalation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSubcortical structures, some cortical\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e23. \u003cb\u003eKimura et al., 1992\u003c/b\u003e \u003csup\u003e61\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eXe contrast CT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7 post SAH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003erCBF returned to within normal limits in the.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ewhite matter of the frontal and temporo-parieto-occipital lobes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCBF restoration closely correlated with clinical improvement and reduction in ventricular dilation and periventricular lucency.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e24. \u003cb\u003eShimoda et al., 1994\u003c/b\u003e \u003csup\u003e150\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eXe contrast CT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSome subcortical, not basal ganglia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e25. \u003cb\u003eMaeder et al., 1995\u003c/b\u003e \u003csup\u003e62\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eXe contrast CT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFrontal cortex and WM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e26. \u003cb\u003eTanaka et al., 1997\u003c/b\u003e \u003csup\u003e64\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eXe contrast CT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eWM more than grey\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e27. \u003cb\u003eKlinge et al (2002)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR151\" class=\"CitationRef\"\u003e151\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e15-O-H2O PET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFrontal inferior, frontal rostral, temporal inferior, temporal dorsal, cingulum, parietal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eyes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e28. \u003cb\u003eMatar\u0026oacute; et al (2003)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR152\" class=\"CitationRef\"\u003e152\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHMPAO-SPECT with SPM analysis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eprefrontal dorsolateral areas, frontal premotor, medial prefrontal, \u003cb\u003efrontal WM\u003c/b\u003e, inferior parietal lobule \u0026amp; basal ganglia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e29. \u003cb\u003eTullberg et al (2004)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR153\" class=\"CitationRef\"\u003e153\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHMPAO SPECT \u0026ndash; relative regional CBF (rrCBF) using cerebellum as the reference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e28 (16 with impaired wakefulness)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ethalamic, frontal and hippocampal grey matter.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYes (impaired awareness only, no other symptom studied)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e30. \u003cb\u003eMurakami et al (2007)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR154\" class=\"CitationRef\"\u003e154\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIMP SPECT\u0026thinsp;+\u0026thinsp;MRI\u0026nbsp; with 3D-SSP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003efrontal base and the anterior part of limbic areas .\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e31. \u003cb\u003eKlinge et al (2008)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR155\" class=\"CitationRef\"\u003e155\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e15-O-H2O PET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003esuperior mesial frontal areas\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e32. \u003cb\u003eIshii et al (2011)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR98\" class=\"CitationRef\"\u003e98\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIMP SPECT\u003c/p\u003e\u003cp\u003erCBF relative to global brain activity.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e3 different patterns of reduction in rCBF identified (anterior, posterior and mixed)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e33. \u003cb\u003eZiegelitz et al (2014)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDSC MRI with Gd-DTPA using the occipital lobe as reference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePVWM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e34. \u003cb\u003eZiegelitz et al (2015)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR156\" class=\"CitationRef\"\u003e156\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDSC MRI with Gd-DTPA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ehippocampus, PVWM, and in the cingulum, thalamus \u0026amp; basal ganglia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e35. \u003cb\u003eNocun et al 2015\u003c/b\u003e \u003csup\u003e157\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHMPAO SPECT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease 3\u0026ndash;6 days post-shunt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eVariable between patients \u0026ndash; predominantly in frontal lobes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e36. \u003cb\u003eZiegelitz et al (2016)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR148\" class=\"CitationRef\"\u003e148\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCT perfusion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCBF in responders increased postoperatively in all anatomical regions by 2.5\u0026ndash;32%;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSignificant increase in caudate head, normal appearing WM and periventricular WM.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003ePostoperative perfusion in the periventricular WM regions showed positive correlations with the gait score, continence score and total iNPH scale score.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e37. \u003cb\u003eTuniz et al (2017)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR158\" class=\"CitationRef\"\u003e158\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDiffusion and DSC MRI (3T) with gadobutrol using the occipital lobe as reference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ebasal ganglia and PVWM area.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003cp\u003e.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e38. \u003cb\u003eAzuma et al (2019)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIMP SPECT\u003c/p\u003e\u003cp\u003eMRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eputamen, amygdala, hippocampus, and parahippocampal gyrus.\u003c/p\u003e\u003cp\u003eWhite matter not analysed (not sure why)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e39. \u003cb\u003eAgerskov et al (2020)*\u003c/b\u003e \u003csup\u003e101\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDSC MR perfusion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIncrease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMesencephalon \u0026amp; pons\u003c/p\u003e\u003cp\u003e\u0026darr;rCBF in the mesencephalon of non-responders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e40. \u003cb\u003eHuang et al 2022\u003c/b\u003e \u003csup\u003e72\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3D pulsed arterial-spin labelling (PASL) MRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo change\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eVery weak correlations\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eOverall, global CBF assessed using TCD, \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003eO PET, PC MRI and ASL MRI does not appear to increase after spinal tap test or shunting (Tables\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e \u0026amp; \u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Interestingly, one study using DSC MRI in 20 subjects did report an increase in global perfusion. Surprisingly, there have been no reports of combining ELD with global CBF studies.\u003c/p\u003e\u003cp\u003eMost studies have confirmed that rCBF increases after shunting in the frontal lobe, periventricular white matter and deep grey matter. Importantly, there is some evidence that such increases correlate with gait improvement after shunting, even when there has been no clinical improvement after a spinal tap test. In a landmark study, the Umea group have demonstrated enhanced activity in the SMA accompanying improved finger motor performance after extended CSF drainage consistent with changes in subcortical connections \u003csup\u003e\u003cspan citationid=\"CR135\" class=\"CitationRef\"\u003e135\u003c/span\u003e\u003c/sup\u003e. In hydrocephalus, periventricular stretch of axons is probably greatest frontally. In NPH, such axonal stretch may be compounded by CSVD but, unlike CVSD, is more likely to be reversible after shunting \u003csup\u003e\u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e,\u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e,\u003cspan citationid=\"CR136\" class=\"CitationRef\"\u003e136\u003c/span\u003e\u003c/sup\u003e. However, functional improvement is not associated with restoration of ventricular size. Lenfeldt et al surmised that CSF withdrawal \u0026ldquo;improved neuronal operational ability, possibly by reversing a subcortical chronic ischaemia related to cerebrovascular disease in periventricular pathways to and from SMA \u003csup\u003e\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. This would result in improved signalling in these circuits, normalizing the motor planning process, giving further support for the view of INPH as a hypokinetic condition caused by malfunction in cortico-basal ganglia-thalamo-cortical circuits with special involvement of frontal areas\u0026rdquo;. This notion is also supported by correlations between motor function and blood flow changes in frontal subcortical regions after shunting, and deficiencies in neuronal integrity in the same area (\u003csup\u003e\u003cspan citationid=\"CR95\" class=\"CitationRef\"\u003e95\u003c/span\u003e\u003c/sup\u003e).\u003c/p\u003e\n\u003ch3\u003eCerebrovascular Reactivity and Autoregulation before and after shunting (Tables 6 \u0026 7)\u003c/h3\u003e\n\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCerebrovascular reactivity \u0026amp; autoregulation: baseline\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGrade\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMethod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo of Patients\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMain findings\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eComments\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCerebrovascular reactivity\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1. \u003cb\u003eHartmann et al., 1977\u003c/b\u003e \u003csup\u003e47\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCO2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eImpaired CVR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2. \u003cb\u003eMeyer et al., 1984\u003c/b\u003e \u003csup\u003e53\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCO2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eImpaired CVR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3. \u003cb\u003eLee et al., 1998\u003c/b\u003e \u003csup\u003e163\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCO2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eImpaired CVR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4. \u003cb\u003eMiyake et al, 1999\u003c/b\u003e \u003csup\u003e164\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eACZ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5. \u003cb\u003eKlinge et al 1999, 2002a\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e,\u003cspan citationid=\"CR165\" class=\"CitationRef\"\u003e165\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC/B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003eO-H\u003csub\u003e2\u003c/sub\u003eO PET; ACZ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10/33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eImpaired CVR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eBaseline CVR lower in responders than non-responders (NS)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6. \u003cb\u003eChang et al., 2000\u003c/b\u003e \u003csup\u003e166\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eACZ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eImpaired CVR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7. \u003cb\u003eChang et al (2003)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR167\" class=\"CitationRef\"\u003e167\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eB\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR99\" class=\"CitationRef\"\u003e99\u003c/span\u003em\u003c/sup\u003eTc HMPAO \u0026amp; ACZ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e48\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026darr; CVR in 30 shunt responders compared to normals.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e4 non-responders with \u0026darr; CBF but preserved CVR.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e8. \u003cb\u003eJarus-Dziedzic\u0026nbsp; et al (2005)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR168\" class=\"CitationRef\"\u003e168\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTCD; ACZ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePreserved CVR (not different to controls)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCVR better in NPH compared to atrophy .\u003c/p\u003e\u003cp\u003e\u0026darr; CVR in atrophic group (n\u0026thinsp;=\u0026thinsp;10) vs controls\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9. \u003cb\u003eYamada et al (2013)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR99\" class=\"CitationRef\"\u003e99\u003c/span\u003em\u003c/sup\u003eTc-ECD SPECT\u0026thinsp;+\u0026thinsp;ACZ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eImpaired CVR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAutoregulation\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e10. \u003cb\u003e1.Mathew et al., 1975\u003c/b\u003e \u003csup\u003e46\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eB\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNPH\u003c/p\u003e\u003cp\u003e(10 2\u003csup\u003e0\u003c/sup\u003e;\u003c/p\u003e\u003cp\u003e5 I)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIntracarotid 133Xe clearance during Angiography\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003erCBF and rCBV increased after CSF removal (?volume)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eThe greater the increase in CBF in the upper frontal and postcentral areas after CSF removal, the better the post-shunting outcome.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e11. \u003cb\u003eSchmidt et al., 1990a\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR169\" class=\"CitationRef\"\u003e169\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eKety-Schmidt Captopril and CO2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePreserved autoregulation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12. \u003cb\u003eCzosnyka et al (2002)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR170\" class=\"CitationRef\"\u003e170\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTCD (Mx) \u0026amp; CSF infusion test; CT/MRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePreserved global autoregulation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCorrelation with Rout. Autoregulation tended to be worse in patients with ischaemic changes on CT/MRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e13. \u003cb\u003eOwler et al (2004b)\u003c/b\u003e\u0026nbsp;\u003csup\u003e\u003cspan citationid=\"CR171\" class=\"CitationRef\"\u003e171\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eH\u003csub\u003e2\u003c/sub\u003e\u003csup\u003e15\u003c/sup\u003eO PET and MRI; CSF infusion study; finite element analysis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWith increases in CSF pressure, global CBF was reduced. Regional CBF decreased in the thalamus and basal ganglia, and in white matter regions in proximity to the ventricles.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14. \u003cb\u003eMomjian et al (2004)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR93\" class=\"CitationRef\"\u003e93\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eH\u003csub\u003e2\u003c/sub\u003e\u003csup\u003e15\u003c/sup\u003eO PET and MRI\u0026nbsp; T1\u0026amp;T2-weighted; CSF infusion study.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWhite matter CBF reduced in NPH compared with controls with an abnormal gradient from the lateral ventricles towards the subcortical WM. Reduction in CPP and raised CSF pressure reduce CBF which is maximal in the paraventricular watershed region.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e15. \u003cb\u003eCzosnyka et al (2005)\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR172\" class=\"CitationRef\"\u003e172\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCSF infusion test \u0026amp; non-invasive MAP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePreserved global autoregulation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eBetter global autoregulation associated with high Rout.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e16. \u003cb\u003eLalou et al (2018)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR173\" class=\"CitationRef\"\u003e173\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCSF infusion test (PRx) \u0026amp; non-invasive MAP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e131\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePreserved global autoregulation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eBetter autoregulation correlated with increased Rout\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003e\u003cb\u003e**\u003c/b\u003e\u003c/sup\u003e \u003cem\u003eNo Healthy controls. Patients with NPH symptoms that were not selected for shunting were used as comparison, together with CSF dynamics parameters.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eCVR: cerebrovascular reactivity, TCD: Transcranial Doppler, Mx:Mean Flow velocity Index, PRx: Pressure Reactivity Index, MAP: Mean arterial Blood Pressure, CPP: Cerebral perfusion Pressure\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab7\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 7\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCerebrovascular reactivity pre and post shunt including correlation with outcome after shunting.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRef\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGRADE\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMethod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo of patients\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMain findings\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePost-shunt CVR: correlation with improvement\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1. Meyer et al 1984 \u003csup\u003e53\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eXe-CT\u0026thinsp;+\u0026thinsp;5%CO2\u0026thinsp;+\u0026thinsp;100%O2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eGlobal increase\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eyes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2. Lee et al., 1998 \u003csup\u003e163\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTCD response to 5% CO2;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eGlobal increase\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3. Klinge et al., 1999 \u003csup\u003e66\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15-O-H2O PET\u0026thinsp;+\u0026thinsp;ACZ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eGlobal increase\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eyes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4. Chang et al., 2000 \u003csup\u003e166\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99mTc-HMPAO\u0026thinsp;+\u0026thinsp;ACZ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eGlobal increase\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5. \u003cb\u003eBakker et al (2002)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR180\" class=\"CitationRef\"\u003e180\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTCD response to 5% CO2;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eGlobal increase\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6. \u003cb\u003eKlinge et al (2002a-d)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR148\" class=\"CitationRef\"\u003e148\u003c/span\u003e,\u003cspan citationid=\"CR152\" class=\"CitationRef\"\u003e152\u003c/span\u003e,\u003cspan citationid=\"CR165\" class=\"CitationRef\"\u003e165\u003c/span\u003e,\u003cspan citationid=\"CR181\" class=\"CitationRef\"\u003e181\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003eO-H\u003csub\u003e2\u003c/sub\u003eO PET; ACZ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eGlobal increase in responders at 7d \u0026amp; 7m; in both high and low\u003c/p\u003e\u003cp\u003evascular risk groups;\u003c/p\u003e\u003cp\u003eNo increase in CVR in\u003c/p\u003e\u003cp\u003enon-responders.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eYes. Increase in\u003c/p\u003e\u003cp\u003eglobal CVR at 7d\u003c/p\u003e\u003cp\u003ecorrelated with\u003c/p\u003e\u003cp\u003eimproved gait;\u003c/p\u003e\u003cp\u003eIncrease in\u003c/p\u003e\u003cp\u003eglobal CVR at\u003c/p\u003e\u003cp\u003e7m correlated\u003c/p\u003e\u003cp\u003ewith\u003c/p\u003e\u003cp\u003eimprovement in\u003c/p\u003e\u003cp\u003evisual attention\u003c/p\u003e\u003cp\u003eand verbal\u003c/p\u003e\u003cp\u003ememory\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7. \u003cb\u003eChang et al (2003)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR167\" class=\"CitationRef\"\u003e167\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003etec99m HCMP \u0026amp; ACZ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eGlobal increase\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eyes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e8. \u003cb\u003eChang et al (2003, 2009)\u003c/b\u003e\u0026nbsp; \u003csup\u003e\u003cspan citationid=\"CR167\" class=\"CitationRef\"\u003e167\u003c/span\u003e, \u003cspan citationid=\"CR182\" class=\"CitationRef\"\u003e182\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSPECT and Xe-CT, ACZ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e162\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eGlobal increase\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eyes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9. \u003cb\u003eYamada et al (2013)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSPECT\u0026thinsp;+\u0026thinsp;ACZ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e25 NPH\u003c/p\u003e\u003cp\u003e30 controls\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eGlobal decrease pre-shunt compared with controls that improved post-shunt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eyes\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eStudies of CVR and Autoregulation might be expected to be more sensitive than baseline measurements of CBF by quantifying haemodynamic reserve, both global and regional \u003csup\u003e\u003cspan additionalcitationids=\"CR160 CR161\" citationid=\"CR159\" class=\"CitationRef\"\u003e159\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR162\" class=\"CitationRef\"\u003e162\u003c/span\u003e\u003c/sup\u003e. Global CVR to either ACZ or hypercapnia was generally reduced in NPH patients and increased after shunting (Tables\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e \u0026amp; \u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). This reduction in\u003c/p\u003e\u003cp\u003ecerebrovascular reactivity is consistent with the arterioles being already maximally dilated as a result of local\u003c/p\u003e\u003cp\u003eischaemia. Unfortunately, there are no published studies of CVR before and after temporary CSF drainage.\u003c/p\u003e\u003cp\u003eIn contrast, very few studies of cerebral autoregulation have been reported and all recent studies are from one centre using CSF infusion studies to manipulate cerebral perfusion pressure. With increases in CSF pressure, there was a variable increase in arterial blood pressure between individuals and global CBF was reduced. This change in arterial blood pressure, with more modest changes in CSF pressure than the conventional end-stage Cushing response, has subsequently been attributed to the existence of an intracranial baroreceptor \u003csup\u003e\u003cspan additionalcitationids=\"CR175\" citationid=\"CR174\" class=\"CitationRef\"\u003e174\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR176\" class=\"CitationRef\"\u003e176\u003c/span\u003e\u003c/sup\u003e. Crucially, during the plateau of an CSF infusion study, CBF decreased in the basal ganglia, thalamus and periventricular WM. The strength of cerebral autoregulation reached a minimum in the white matter close to the periventricular watershed area.\u003c/p\u003e\u003cp\u003eThe integrity of AR also depends on cardiovascular comorbidity and abnormalities within the cerebral mantle. In Lalou\u0026rsquo;s study \u003csup\u003e\u003cspan citationid=\"CR177\" class=\"CitationRef\"\u003e177\u003c/span\u003e\u003c/sup\u003e, the relationship between the global autoregulation pressure reactivity index (PRx) and the profile of disturbed CSF circulation and pressure-volume compensation in relation to outcome after surgery was examined. The PRx was negatively correlated with resistance to CSF outflow: patients with normal CSF circulation tended to have worse autoregulation. Given the importance of co-morbidities to the diagnosis and outcome of shunting in iNPH, it is important to note that AR is intact in Alzheimer\u0026rsquo;s disease but variably impaired in CSVD\u003csup\u003e\u003cspan citationid=\"CR178\" class=\"CitationRef\"\u003e178\u003c/span\u003e,\u003cspan citationid=\"CR179\" class=\"CitationRef\"\u003e179\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eSurprisingly, there are no reported studies of autoregulation before and after temporary CSF drainage or shunting.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003ePrediction of outcome: Baseline global \u0026amp; regional CBF, Cerebrovascular Reactivity and Autoregulation (\u003c/span\u003eTables\u0026nbsp;\u003cspan refid=\"Tab8\" class=\"InternalRef\"\u003e8\u003c/span\u003e \u0026amp; \u003cspan refid=\"Tab9\" class=\"InternalRef\"\u003e9\u003c/span\u003e, Figs.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e\u0026ndash;7\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e)\u003c/span\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab8\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 8\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePredictive value of baseline global and regional CBF for outcome after shunting\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGRADE\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMethod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo of patients\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePredictive Yes/No\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eComments\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eGlobal CBF\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1. \u003cb\u003eMathew et al., 1975\u0026thinsp;+\u0026thinsp;1977\u003c/b\u003e \u003csup\u003e46\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eC\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIntracarotid 133Xe clearance during Angiography\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e21\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHigher gCBF related to better clinical outcome\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2. \u003cb\u003eHayashi et al., 1984\u003c/b\u003e \u003csup\u003e51\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eB\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIntracarotid 133Xe clearance during Angiography\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e16\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003ePoor outcome if reduced gCBF\u0026thinsp;\u0026lt;\u0026thinsp;25\u003c/b\u003e ml/100 g/min\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3. \u003cb\u003eTanaka et al., 1997\u003c/b\u003e \u003csup\u003e64\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eC\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eXe contrast CT\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e21\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003eImprovement with gCBF\u0026thinsp;\u0026gt;\u0026thinsp;20\u003c/b\u003e ml/100 g/min\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4. \u003cb\u003eKlinge et al., 1998\u003c/b\u003e \u003csup\u003e65\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eB\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eH2O15 bolus\u003c/p\u003e\u003cp\u003ePET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e21\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003eImprovement with lower gCBF\u003c/b\u003e 33 vs. 45 ml/1 00 ml per min responders vs non-responders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5. \u003cb\u003eKlinge et al., 1999\u003c/b\u003e \u003csup\u003e66\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eB\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eH2O15 bolus\u003c/p\u003e\u003cp\u003ePET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003eImprovement with lower gCBF\u003c/b\u003e Global. 36 vs 44 ml/100 ml/min responders vs non-responders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6. \u003cb\u003eBateman et al (2007)\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMRI (1.5T) with flow sequences\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eNo\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e20 responders vs 12 non-responders\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGlobal \u0026amp; Regional CBF\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7. \u003cb\u003eGrubb et al 1977\u003c/b\u003e \u003csup\u003e48\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eC\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eH2O15 PET Intracarotid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eNo\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e8. \u003cb\u003eLying-Tunnel\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eC\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAV-Difference\u003c/p\u003e\u003cp\u003eNO2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e7\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eNo\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9. \u003cb\u003eGraff-Radford et al., 1987\u0026thinsp;+\u0026thinsp;1989\u003c/b\u003e \u003csup\u003e25,37\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eB\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e133Xe inhalation\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eSPECT\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e56\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eImprovement with increased Anterior/Posterior rCBF\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e10. \u003cb\u003eKushner et al 1984\u003c/b\u003e \u003csup\u003e52\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eC\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAs in 1.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e19\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eNo\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e11. \u003cb\u003eMamo et al 1987\u003c/b\u003e \u003csup\u003e57\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eB\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e133Xe IV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e25\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eNo\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12. \u003cb\u003eMeixensberger et al., 1989\u003c/b\u003e \u003csup\u003e59\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eC\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e133Xe inhalation\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e31\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eNo\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e13. \u003cb\u003eGranado et al., 1991\u003c/b\u003e \u003csup\u003e183\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eB\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e99m Tc-HMPAO\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eSPECT\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e14\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003eImprovement with increased Anterior/Posterior rCBF\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRegional CBF\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14. \u003cb\u003eMorretti et al., 1988\u003c/b\u003e \u003csup\u003e184\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eC\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e123BAMP IV\u003c/p\u003e\u003cp\u003eSPECT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e12\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eNo\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCortical rCBF, PVWM and basal ganglia examined\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e15. \u003cb\u003eIshii et al (2011)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR98\" class=\"CitationRef\"\u003e98\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIMP SPECT\u003c/p\u003e\u003cp\u003erCBF relative to global brain activity.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIn non-responders, 3 different patterns of reduction in rCBF identified (anterior, posterior and mixed)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab9\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 9\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline cerebrovascular reactivity and autoregulation: predictive value\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRef\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGRADE\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMethod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo of patients\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCVR predictive\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eComments\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1. Meyer et al., 1984 \u003csup\u003e53\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eC\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eCO2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e7\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003eImpaired\u003c/b\u003e CVR associated with better outcome\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2. Shimoda et al 1994 \u003csup\u003e150\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eC\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eglycerol\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e22\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMore widespread increases in CBF post glycerol in shunt responders (\u003cb\u003epreserved\u003c/b\u003e CVR).\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3. Lee et al., 1998 \u003csup\u003e163\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eC\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eCO2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e11\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eNo\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4. Klinge et al., 1999, 2002a, 2002b \u003cb\u003e(patient series)\u003c/b\u003e\u003c/p\u003e\u003cp\u003e5. \u003csup\u003e\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e,\u003cspan citationid=\"CR165\" class=\"CitationRef\"\u003e165\u003c/span\u003e,\u003cspan citationid=\"CR181\" class=\"CitationRef\"\u003e181\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eB\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003eO-H\u003csub\u003e2\u003c/sub\u003eO PET; ACZ\u003c/p\u003e\u003cp\u003eLow and high vascular risk factor groups\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e53\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYes in low risk group and no in high risk group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eBaseline CVR was lower in responders than in non-responders (NS).\u003c/p\u003e\u003cp\u003eIncrease in CVR at 7d after shunting was predictive of a good outcome.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6. \u003cb\u003eChang et al (2003)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR185\" class=\"CitationRef\"\u003e185\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eTc\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR99\" class=\"CitationRef\"\u003e99\u003c/span\u003em\u003c/b\u003e\u003c/sup\u003eHCMP \u0026amp; ACZ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e\u0026darr; CVR\u003c/b\u003e in 30 shunt responders compared to normals.\u003c/p\u003e\u003cp\u003e4 non-responders with preserved CVR.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7. \u003cb\u003eChen et al 2008)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR186\" class=\"CitationRef\"\u003e186\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eXe-CT, MRI and MRSI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003ePreserved\u003c/b\u003e CVR \u0026loz;improved .23 responders vs 5 non-responders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e8. \u003cb\u003eChang et al (2009)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR182\" class=\"CitationRef\"\u003e182\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSPECT and Xe-CT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e162\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003eImpaired CVR\u003c/b\u003e predictive. Responders w incomplete triad: \u003cb\u003e\u0026darr;preop CVR\u003c/b\u003e than controls.\u003c/p\u003e\u003cp\u003eFull triad:\u0026darr; preop CVR than in incomplete.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9. \u003cb\u003eYamada et al (2013)*\u003c/b\u003e \u003csup\u003e70\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR99\" class=\"CitationRef\"\u003e99\u003c/span\u003em\u003c/sup\u003eTc-ECD SPECT\u0026thinsp;+\u0026thinsp;ACZ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMMSE as improvement marker.\u003c/p\u003e\u003cp\u003e\u0026lt;\u0026thinsp;20% \u0026uarr; in preoperative CBF response to ACZ predicted improvement (\u003cb\u003eimpaired\u003c/b\u003e)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGlobal Autoregulation\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e10. \u003cb\u003eLalou et al (2018)\u003c/b\u003e \u003csup\u003e\u003cspan citationid=\"CR173\" class=\"CitationRef\"\u003e173\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCSF infusion test (PRx) \u0026amp; non-invasive MAP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e131\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eThere was a trend towards higher values for PRx (greater global AR derangement) in non-responders v responders.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eThe product MAPx(1\u0026thinsp;+\u0026thinsp;PRx) \u0026ndash; a measure of combined arterial hypertension and deranged AR, showed a significant association with outcome.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eNone of the post-2001 studies have related global or regional CBF to outcome. Such measurements prior to 2001 were not entirely consistent in their findings with no strong evidence for using global or regional CBF before surgery as a useful prognostic factor for shunt response. The studies reporting the role of baseline CBF in predicting outcome post shunting were not based on secure statistical power analyses and the number of patients recruited overall was small (average of 20\u0026ndash;30 patients with only 2 studies including\u0026thinsp;\u0026gt;\u0026thinsp;50 patients). There was grade C evidence of the predictive value of CBF in NPH. 5 studies of 89 patients\u0026rsquo; global CBF showed different thresholds for positive and negative predictive value of CBF. The other 5 studies of 99 patients showed no correlation. rCBF was investigated in 3 studies or 82 patients, 2 of which reported that the ratio of the anterior and posterior CBF was high in improvers (70 patients total). Overall, there was very little evidence that either global CBF or the pattern of rCBF at baseline was correlated with outcome post shunting.\u003c/p\u003e\u003cp\u003eIn contrast, studies of CVR are more promising. Although there is some inconsistency between studies, overall, it appears that impaired CVR in NPH patients was a favourable prognostic factor. 4 studies report that worse rather than good reactivity to ACZ predicts a favourable outcome \u003csup\u003e\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e,\u003cspan citationid=\"CR151\" class=\"CitationRef\"\u003e151\u003c/span\u003e,\u003cspan citationid=\"CR165\" class=\"CitationRef\"\u003e165\u003c/span\u003e\u003c/sup\u003e. One of them \u003csup\u003e\u003cspan citationid=\"CR151\" class=\"CitationRef\"\u003e151\u003c/span\u003e\u003c/sup\u003e interestingly stratified the patients into different groups depending on cardiovascular burden: worse reactivity predicted shunt responsiveness for high cardiovascular risk; better reactivity was related to shunt responsiveness in those with low cardiovascular risk. This interesting finding again highlights the importance of consideration of the degree of cerebrovascular disease in iNPH. 5 out of 5 studies that measured CVR post-operatively agree that it is significantly increased compared to pre-operatively and that restoration of CVR is a hallmark of shunt responsiveness\u003csup\u003e\u003cspan citationid=\"CR181\" class=\"CitationRef\"\u003e181\u003c/span\u003e\u003c/sup\u003e. Early detection of a CVR/CA problem may precede falls in global and rCBF, and white matter hyperintensities unlike in CSVD .\u003c/p\u003e\u003cp\u003eThere has been only one study of global AR in relation to outcome after shunting\u003csup\u003e\u003cspan citationid=\"CR173\" class=\"CitationRef\"\u003e173\u003c/span\u003e\u003c/sup\u003e. There was a trend towards higher values for PRx (greater global AR derangement) in non-responders v responders associated with higher MAP values. The product MAP x (1\u0026thinsp;+\u0026thinsp;PRx) was proposed as a measure that combined arterial hypertension with deranged AR \u0026ndash; this measure revealed a significant association with outcome.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eRelationship between CBF, CSF dynamics and the mechanical properties of the cerebral mantle\u003c/span\u003e\u003c/p\u003e\u003cp\u003eThere is considerable evidence that the normal interrelationships between the cerebral circulation, the circulation of CSF and interstitial fluid and the mechanical properties of the cerebral mantle are altered in NPH.\u003c/p\u003e\u003cp\u003eVentricular reflux and convexity block\u003c/p\u003e\u003cp\u003eNPH is characterised by ventricular reflux of CSF and convexity block \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR187\" class=\"CitationRef\"\u003e187\u003c/span\u003e,\u003cspan citationid=\"CR188\" class=\"CitationRef\"\u003e188\u003c/span\u003e\u003c/sup\u003e. Intrathecal gadolinium tracer MR studies have confirmed these earlier findings with reduced clearance of gadobutrol and delayed tracer distribution over the external brain surface arteries compared with reference subjects \u003csup\u003e\u003cspan citationid=\"CR189\" class=\"CitationRef\"\u003e189\u003c/span\u003e\u003c/sup\u003e. The combination of DESH (Disproportionately enlarged subarachnoid space hydrocephalus) and FES (focally enlarged sulci) may prove to be a surrogate marker for convexity block. It has recently been suggested that focally enlarged sulci are not the result of atrophy but of CSF entrapment that reduce in size after shunting \u003csup\u003e\u003cspan citationid=\"CR190\" class=\"CitationRef\"\u003e190\u003c/span\u003e,\u003cspan citationid=\"CR191\" class=\"CitationRef\"\u003e191\u003c/span\u003e\u003c/sup\u003e. Experimentally, convexity block can induce ventriculomegaly\u003csup\u003e\u003cspan citationid=\"CR192\" class=\"CitationRef\"\u003e192\u003c/span\u003e\u003c/sup\u003e. In NPH, ventricular reflux of CSF and convexity block is accompanied by increased MR mean diffusivity within the white matter indicative of raised extracellular water content manifesting as periventricular lucencies (PVLs), particularly around the frontal and occipital horns\u003csup\u003e\u003cspan additionalcitationids=\"CR194\" citationid=\"CR193\" class=\"CitationRef\"\u003e193\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR195\" class=\"CitationRef\"\u003e195\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eHowever, ventricular reflux and convexity block may occur in a minority of normal people and other conditions without hydrocephalus\u003csup\u003e\u003cspan citationid=\"CR196\" class=\"CitationRef\"\u003e196\u003c/span\u003e\u003c/sup\u003e. Findings of an abnormal CSF circulation on cisternography correlate to some degree with shunt responsiveness in NPH but neither are robust standalone predictors of outcome.\u003c/p\u003e\u003cp\u003eHence, other factors apart from partial or complete reversal of the CSF circulation must be at play, including changes in brain biomechanics, to explain why an individual\u0026rsquo;s ventriculomegaly progresses and becomes symptomatic.\u003c/p\u003e\u003cp\u003eAgeing and ventricular size\u003c/p\u003e\u003cp\u003eAs described previously, ventricular size in healthy people increases very rapidly after the age of 50 years\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eLongitudinal studies confirm that there is a presymptomatic stage to NPH when ventriculomegaly is present\u003csup\u003e\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eGraff-Radford and colleagues \u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e have suggested that some patients with NPH have head circumferences\u003c/p\u003e\u003cp\u003egreater than in controls and suggested that the cause of the NPH was arrested congenital hydrocephalus becoming\u003c/p\u003e\u003cp\u003esymptomatic later in life. Many patients with NPH have intracranial volumes significantly larger than normal,\u003c/p\u003e\u003cp\u003esuggesting that the initial insult occurs before the sutures fuse at 1 year of age. Bradley et al \u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e also\u003c/p\u003e\u003cp\u003esuggested that NPH may be a \u0026lsquo;two hit\u0026rsquo; disease: benign external hydrocephalus in infancy followed by deep white\u003c/p\u003e\u003cp\u003ematter ischaemia in late adulthood (see below).\u003c/p\u003e\u003cp\u003eAgeing, Hypertension and CSVD\u003c/p\u003e\u003cp\u003eAs noted earlier, CBF and vascular density in the brain decreases and the stiffness of the large elastic arteries increases with normal ageing.. These ageing changes are compounded by chronic hypertension which induces remodelling and stenosis of the arteries and fibrinoid necrosis of the arterioles, attenuates cerebrovascular reactivity and functional hyperaemia, and shifts autoregulation to the right, thereby increasing vulnerability to hypotension and chronic, borderline ischaemia\u003csup\u003e\u003cspan additionalcitationids=\"CR198 CR199 CR200 CR201 CR202\" citationid=\"CR197\" class=\"CitationRef\"\u003e197\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR203\" class=\"CitationRef\"\u003e203\u003c/span\u003e\u003c/sup\u003e. The human periventricular arterial blood supply is at particular risk \u003csup\u003e\u003cspan citationid=\"CR93\" class=\"CitationRef\"\u003e93\u003c/span\u003e,\u003cspan citationid=\"CR204\" class=\"CitationRef\"\u003e204\u003c/span\u003e\u003c/sup\u003e. The increase in arterial stiffness is associated with elevated pulse pressure and blood flow pulsatility in the cerebral vasculature thereby releasing more pulsatile energy into the brain and leading to white matter hyperintensities and tissue damage which is associated with cerebrovascular/cognitive impairments. It is likely that NPH patients will be susceptible to episodes of reduced cerebral perfusion pressure particularly when cardiovascular disease, both systemic and CSVD, is present and autoregulation is impaired.\u003c/p\u003e\u003cp\u003eAs described earlier, many NPH patients have both systemic hypertension and white matter vascular disease\u003csup\u003e\u003cspan additionalcitationids=\"CR25 CR26 CR27 CR28 CR29 CR30\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. In Earnest\u0026rsquo;s original cases \u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e, autopsy showed extensive hypertensive cerebrovascular disease with multiple small infarcts of the deep cerebral and cerebellar grey and white matter but normal leptomeninges and arachnoid villi. One case improved with a shunt. Earnest proposed that hypertensive cerebrovascular disease, by causing multiple infarcts in the periventricular white matter and basal ganglia, may reduce periventricular tissue tensile strength and elastic properties permitting the ventricles to enlarge under the stress of the intraventricular pulse pressure when increased by hypertension. Some evidence for this concept has come from magnetic resonance elastography studies but the results are not consistent \u003csup\u003e\u003cspan additionalcitationids=\"CR206 CR207 CR208 CR209\" citationid=\"CR205\" class=\"CitationRef\"\u003e205\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR210\" class=\"CitationRef\"\u003e210\u003c/span\u003e\u003c/sup\u003e. One confounding factor is the change in CSF outflow resistance and mechanical properties of the cerebral mantle as an individual\u0026rsquo;s NPH evolves \u003csup\u003e\u003cspan citationid=\"CR211\" class=\"CitationRef\"\u003e211\u003c/span\u003e,\u003cspan citationid=\"CR212\" class=\"CitationRef\"\u003e212\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eInterestingly, SHR rats, but not the more hypertensive SHRSP rats, develop chronic hydrocephalus with ventricular reflux \u003csup\u003e\u003cspan additionalcitationids=\"CR214\" citationid=\"CR213\" class=\"CitationRef\"\u003e213\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR215\" class=\"CitationRef\"\u003e215\u003c/span\u003e\u003c/sup\u003e. The ventricular enlargement in SHRs does not develop as a direct consequence of the concomitant elevation in blood pressure - pharmacological blood pressure reduction failed to attenuate the ventricular enlargement in SHRs and experimentally induced hypertension was insufficient to cause ventricular enlargement in na\u0026iuml;ve rats. A meticulous study in the SHR rat by Macaulay\u0026rsquo;s group \u003csup\u003e\u003cspan citationid=\"CR216\" class=\"CitationRef\"\u003e216\u003c/span\u003e\u003c/sup\u003e has revealed that, although brain water does increase with ventriculomegaly, neither CSF production rate, ICP, nor CSF outflow resistance appear to be elevated when compared to WKY rats. They concluded that \u0026lsquo;SHR hydrocephalus represents a type of hydrocephalus that is not life threatening and occurs by unknown disturbances to the CSF dynamics\u0026rsquo;. Both subcortical (eg increased ventricular volume) and cortical (eg thinning and sulcal widening) atrophy can result from CSVD and Cadasil in the human \u003csup\u003e\u003cspan additionalcitationids=\"CR218 CR219\" citationid=\"CR217\" class=\"CitationRef\"\u003e217\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR220\" class=\"CitationRef\"\u003e220\u003c/span\u003e\u003c/sup\u003e. Hence, although CSVD is very common in NPH, CSVD alone does not appear to be sufficient to induce NPH as opposed to atrophy.\u003c/p\u003e\n\u003ch3\u003eCompliance, resistance to CSF outflow and cerebral autoregulation\u003c/h3\u003e\n\u003cp\u003eGlobal intracranial compliance is reduced in NPH despite, by definition, normal CSF pressure (mean 9\u0026ndash;12 mm Hg).\u003c/p\u003e\u003cp\u003ePulsatile ICP, reflecting impairment of pressure-volume reserve capacity, increases as intracranial compliance is\u003c/p\u003e\u003cp\u003ereduced \u003csup\u003e\u003cspan citationid=\"CR221\" class=\"CitationRef\"\u003e221\u003c/span\u003e\u003c/sup\u003e. Lundberg\u0026rsquo;s B waves occur more frequently and are increased in amplitude during sleep in NPH\u003c/p\u003e\u003cp\u003e\u003csup\u003e\u003cspan citationid=\"CR222\" class=\"CitationRef\"\u003e222\u003c/span\u003e,\u003cspan citationid=\"CR223\" class=\"CitationRef\"\u003e223\u003c/span\u003e\u003c/sup\u003e. However, such rises in ICP may not in general indicate ischaemia but are synchronised with\u003c/p\u003e\u003cp\u003erhythmical increases in cerebral blood volume \u003csup\u003e\u003cspan additionalcitationids=\"CR225\" citationid=\"CR224\" class=\"CitationRef\"\u003e224\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR226\" class=\"CitationRef\"\u003e226\u003c/span\u003e\u003c/sup\u003e. As highlighted above, it has been suggested that such reduced intracranial compliance and increased intracranial pulse pressure might lead to local \u0026lsquo;\u0026lsquo;barotrauma\u0026rsquo;\u0026rsquo; or \u0026lsquo;\u0026lsquo;tangential shear stress\u0026rsquo;\u0026rsquo; \u003csup\u003e\u003cspan additionalcitationids=\"CR175\" citationid=\"CR174\" class=\"CitationRef\"\u003e174\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR176\" class=\"CitationRef\"\u003e176\u003c/span\u003e,\u003cspan additionalcitationids=\"CR228 CR229\" citationid=\"CR227\" class=\"CitationRef\"\u003e227\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR230\" class=\"CitationRef\"\u003e230\u003c/span\u003e\u003c/sup\u003e. Increased intracranial and microvascular pulsatility might increase pulsatile stress forces and activate potent vasoactive factors, damage the cerebral microcirculation and even cause cognitive decline in elderly individuals (\u0026ldquo;pulse-wave encephalopathy\u0026rdquo;). Leukoaraiosis might reflect an arteriosclerotic and/or resistive pulse wave encephalopathy in mild cognitive impairment. Intriguingly, the Umea group have shown that elderly subjects with high intracranial pulsatility display smaller brain volume\u003c/p\u003e\u003cp\u003eand larger ventricles, supporting the notion that excessive cerebral arterial pulsatility harms the\u003c/p\u003e\u003cp\u003ebrain\u003csup\u003e\u003cspan citationid=\"CR231\" class=\"CitationRef\"\u003e231\u003c/span\u003e\u003c/sup\u003e. However, In healthy older adults, the expression of white matter lesions and\u003c/p\u003e\u003cp\u003eenlarged perivascular spaces precedes increases in cerebral arterial PI - elevated PI may be a\u003c/p\u003e\u003cp\u003erelatively late manifestation, rather than a risk factor, for CSVD\u003csup\u003e\u003cspan citationid=\"CR232\" class=\"CitationRef\"\u003e232\u003c/span\u003e\u003c/sup\u003e. Using MR flow-\u003c/p\u003e\u003cp\u003equantification technology, Bateman has shown that intracranial arterial and sagittal sinus\u003c/p\u003e\u003cp\u003epulsatility was increased in NPH whereas CSF pulse was reduced\u003csup\u003e\u003cspan citationid=\"CR233\" class=\"CitationRef\"\u003e233\u003c/span\u003e\u003c/sup\u003e. Elevated CSF flow pulsation through the\u003c/p\u003e\u003cp\u003ecerebral aqueduct have been widely described in communicating hydrocephalus but has not proven to be widely\u003c/p\u003e\u003cp\u003eaccepted as a good predictor of outcome after shunting\u003csup\u003e\u003cspan additionalcitationids=\"CR235\" citationid=\"CR234\" class=\"CitationRef\"\u003e234\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR236\" class=\"CitationRef\"\u003e236\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eMoreover, such enhanced pulsatility does not extend, at least in the adult rat with induced communicating hydrocephalus, to the entire cerebral vasculature including the cortical capillaries. Rashid et al \u003csup\u003e\u003cspan citationid=\"CR237\" class=\"CitationRef\"\u003e237\u003c/span\u003e\u003c/sup\u003econcluded that, even in the presence of markedly elevated pulsatile CSF flow in the aqueduct, there was no concurrent increase in\u003c/p\u003e\u003cp\u003emicrovascular pulsatile flow. A shunt may help in NPH, not by greatly decreasing CSF pressure or/and its dynamics but by increasing both compliance and perfusion.\u003c/p\u003e\u003cp\u003eGlobal intracranial compliance should be distinguished from intracranial arterial compliance. In the majority of\u003c/p\u003e\u003cp\u003epatients with iNPH, there was a low correlation between intracranial and vascular pressure pulsatility. During\u003c/p\u003e\u003cp\u003emoderate rises in ICP (eg up to 40 mmHg during an infusion test), TCD mean blood flow velocity does not change,\u003c/p\u003e\u003cp\u003ealthough the pulsatility index rises. This reflects changes in compliance of the cerebral arterial walls, with\u003c/p\u003e\u003cp\u003eautoregulation efficient enough to keep CBF constant. However, the ability of arteries in the subarachnoid space to\u003c/p\u003e\u003cp\u003eexpand, including during autoregulatory responses to changes in cerebral perfusion pressure, may be restricted\u003c/p\u003e\u003cp\u003ewhen intracranial compliance is reduced\u003csup\u003e\u003cspan citationid=\"CR238\" class=\"CitationRef\"\u003e238\u003c/span\u003e,\u003cspan citationid=\"CR239\" class=\"CitationRef\"\u003e239\u003c/span\u003e\u003c/sup\u003e. The cerebral periarterial spaces are dilated in NPH compared\u003c/p\u003e\u003cp\u003ewith controls\u003csup\u003e\u003cspan citationid=\"CR240\" class=\"CitationRef\"\u003e240\u003c/span\u003e\u003c/sup\u003e. In rodents, arterial hypertension reduces both arterial wall pulsatility and periarterial tracer\u003c/p\u003e\u003cp\u003emovement \u003csup\u003e\u003cspan citationid=\"CR213\" class=\"CitationRef\"\u003e213\u003c/span\u003e,\u003cspan citationid=\"CR216\" class=\"CitationRef\"\u003e216\u003c/span\u003e,\u003cspan citationid=\"CR241\" class=\"CitationRef\"\u003e241\u003c/span\u003e\u003c/sup\u003e. It has been proposed that impaired intracranial compliance restricts cerebral arterial pumping,\u003c/p\u003e\u003cp\u003ewhich in turn hampers the driving forces of perivascular molecular transport. As noted above, intrathecal\u003c/p\u003e\u003cp\u003egadolinium tracer MR studies in NPH subjects have demonstrated reduced clearance of gadobutrol and delayed\u003c/p\u003e\u003cp\u003etracer distribution over the external brain surface arteries compared with reference subjects (\u0026lsquo;impaired glymphatic\u003c/p\u003e\u003cp\u003etracer clearance\u0026rsquo;).\u003c/p\u003e\u003cp\u003eThe study of CSF dynamics and pressure-volume compensation combined with assessment of CBF provides an\u003c/p\u003e\u003cp\u003eopportunity to assess the state of autoregulation using a variety of techniques including TCD and MRI \u003csup\u003e\u003cspan additionalcitationids=\"CR243 CR244\" citationid=\"CR242\" class=\"CitationRef\"\u003e242\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR245\" class=\"CitationRef\"\u003e245\u003c/span\u003e\u003c/sup\u003e. For example, TCD enables the study of changes in CBF and global autoregulation continuously over time including overnight and during an infusion study \u003csup\u003e\u003cspan citationid=\"CR245\" class=\"CitationRef\"\u003e245\u003c/span\u003e\u003c/sup\u003e.The shape of the TCD pulse waveform is able to differentiate between hydrocephalus and normal subjects \u003csup\u003e\u003cspan citationid=\"CR246\" class=\"CitationRef\"\u003e246\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eUnfortunately, relevant measurements using MRI have been limited by the strong magnetic field which excludes\u003c/p\u003e\u003cp\u003eusing invasive ICP instrumentation but Unnerb\u0026auml;ck et al \u003csup\u003e\u003cspan citationid=\"CR247\" class=\"CitationRef\"\u003e247\u003c/span\u003e\u003c/sup\u003ehave overcome this problem for\u003c/p\u003e\u003cp\u003epatients in neurointensive care. Hence MR studies equivalent to PET studies \u003csup\u003e\u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e,\u003cspan citationid=\"CR93\" class=\"CitationRef\"\u003e93\u003c/span\u003e,\u003cspan citationid=\"CR172\" class=\"CitationRef\"\u003e172\u003c/span\u003e\u003c/sup\u003e to assess\u003c/p\u003e\u003cp\u003eautoregulation are feasible. Despite such limitations, the global and local biomechanical response of the brain to\u003c/p\u003e\u003cp\u003echanges in CSF pressure may be studied using MRI to map CBF \u0026ndash; stress/strain relationships and phase contrast\u003c/p\u003e\u003cp\u003eMRI to characterize the CNS elastance coefficient during CSF infusion studies. A significant association between\u003c/p\u003e\u003cp\u003ethe CNS elastance coefficient, frailty and age has been reported, results that were independent of CSF dynamics\u003c/p\u003e\u003cp\u003eand not specific to NPH\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Unpublished data from a large series using PC MRI suggests that there is a negative correlation between CBF, Rout and the baseline pulse amplitude of the ICP pulse waveform.\u003c/p\u003e\u003cp\u003eLastly, studies of global autoregulation in NPH during CSF infusion studies using both the PRx index\u003c/p\u003e\u003cp\u003ederived from continuous blood pressure monitoring and TCD-derived autoregulation (Mx index), have confirmed that there is an negative correlation between Rout and autoregulation\u003csup\u003e\u003cspan citationid=\"CR174\" class=\"CitationRef\"\u003e174\u003c/span\u003e\u003c/sup\u003e. This negative relationship at first seems counterintuitive. It might simply reflect the likelihood that global measurements of autoregulation do not detect dysautoregulation restricted to the periventricular zone in uncomplicated NPH. A high Rout and preserved global autoregulation might indicate that there is salvageable tissue which might be helped with a shunt. In contrast, global dysautoregulation would indicate more global cerebrovascular disease and ischaemia that has not affected resistance to CSF outflow.\u003c/p\u003e\u003cp\u003eThese links between CBF, CSF pressure-volume compensation, the CSF circulation and periarterial fluid flow are\u003c/p\u003e\u003cp\u003every interesting but require further study in patients.\u003c/p\u003e\u003cp\u003eStress, Stretch, Compression and Intramantle pressure gradients\u003c/p\u003e\u003cp\u003eIt has long been postulated that ventriculomegaly creates regions of stress within the cerebral mantle, and thereby the interplay between mechanical and vascular factors \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e,\u003cspan citationid=\"CR230\" class=\"CitationRef\"\u003e230\u003c/span\u003e,\u003cspan citationid=\"CR247\" class=\"CitationRef\"\u003e247\u003c/span\u003e,\u003cspan citationid=\"CR248\" class=\"CitationRef\"\u003e248\u003c/span\u003e\u003c/sup\u003e, Such stresses result in stretch and compression of both vascular and neural tissue, changes that may mirror the symptoms of NPH. Such effects have been successfully modelled for neural tissue using poroelastic theory \u003csup\u003e\u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e,\u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eCrucially, Earnest\u0026rsquo;s hypothesis paved the way for subsequent studies of the biomechanics of the cerebral mantle in communicating hydrocephalus. The concept of a transmantle pressure gradient including differential pulse pressures, however small, between ventricle and subarachnoid space to explain ventricular dilatation in communicating hydrocephalus has not been demonstrated \u003csup\u003e\u003cspan citationid=\"CR249\" class=\"CitationRef\"\u003e249\u003c/span\u003e\u003c/sup\u003e However, finite element studies have demonstrated that both ventricular expansion induced by CSF infusion and brain deformation are accompanied by heterogeneous stress concentrations within the cerebral mantle. \u003csup\u003e\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e,\u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e,\u003cspan citationid=\"CR88\" class=\"CitationRef\"\u003e88\u003c/span\u003e,\u003cspan citationid=\"CR172\" class=\"CitationRef\"\u003e172\u003c/span\u003e\u003c/sup\u003e Mean stress, indicating compression, was distributed throughout the brain during CSF infusion and maximal in the thalamus and corpus callosum. The white matter surrounding the ventricular horns was the site of maximal shear stress. Subsequent to brain deformation, one would expect some distortion to local arterial trees and thus a compromise to rCBF. In an instructive case report, brain deformation caused by a cyst was accompanied by large shear stresses and moderate compressive stresses consistent with areas of hypoperfusion on PET rCBF maps and specific cognitive deficits. \u003csup\u003e\u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e\u003c/sup\u003e Only small interstitial fluid pressure changes were present.\u003c/p\u003e\u003cp\u003eVentricular dilatation has often been taken as evidence that the brain is being compressed and that an increase in intra-parenchymal pressure results \u003csup\u003e\u003cspan citationid=\"CR250\" class=\"CitationRef\"\u003e250\u003c/span\u003e\u003c/sup\u003e. However, there is no direct evidence to suggest that the intra-parenchymal pressure is increased, quite the reverse. Pena et al have proposed, based on a finite element analysis of a poroelastic model, that ventricular expansion may result from a relative reduction in interstitial fluid pressure in the periventricular area leading to the formation of a ventricle - parenchymal rather than ventricle \u0026ndash; subarachnoid pressure gradient \u003csup\u003e\u003cspan citationid=\"CR251\" class=\"CitationRef\"\u003e251\u003c/span\u003e\u003c/sup\u003e. This concept has received experimental and modelling support by Johnston\u0026rsquo;s group \u003csup\u003e\u003cspan citationid=\"CR252\" class=\"CitationRef\"\u003e252\u003c/span\u003e,\u003cspan citationid=\"CR253\" class=\"CitationRef\"\u003e253\u003c/span\u003e\u003c/sup\u003e. It will be fascinating to see what the impact of the recently described genetic risk variants for NPH have on paraventricular biomechanics and ISF flow, and whether they overlap with those for CSVD\u003csup\u003e\u003cspan citationid=\"CR254\" class=\"CitationRef\"\u003e254\u003c/span\u003e,\u003cspan citationid=\"CR255\" class=\"CitationRef\"\u003e255\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eBias assessment\u003c/h2\u003e\u003cp\u003eThere was frequently a moderate to high risk of selection and prognostic factor measurement bias in the current evidence, mainly due to the absence of unified criteria that include comorbidities for defining and selecting the study participants. Furthermore, there are no randomized trials specifically designed to assess outcome in the current literature, utilising CBF as a prognostic factor.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eFuture directions\u003c/h3\u003e\n\u003cp\u003eAs noted in the 2001 systematic review, large multicentre platforms are required to provide the infrastructure for producing higher level evidence with reduced risk of bias based on a general consensus over definitions including clinical heterogeneity, inclusion/exclusion criteria, comorbidities including frailty, and outcome measures. Significant progress has been made in building such platforms as exemplified by the publication and adoption of International NPH Guidelines \u003csup\u003e\u003cspan additionalcitationids=\"CR257\" citationid=\"CR256\" class=\"CitationRef\"\u003e256\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR258\" class=\"CitationRef\"\u003e258\u003c/span\u003e\u003c/sup\u003e, multinational RCTs \u003csup\u003e\u003cspan citationid=\"CR259\" class=\"CitationRef\"\u003e259\u003c/span\u003e,\u003cspan citationid=\"CR260\" class=\"CitationRef\"\u003e260\u003c/span\u003e\u003c/sup\u003e, FinnGen Cohort \u003csup\u003e\u003cspan citationid=\"CR254\" class=\"CitationRef\"\u003e254\u003c/span\u003e,\u003cspan citationid=\"CR255\" class=\"CitationRef\"\u003e255\u003c/span\u003e\u003c/sup\u003e, Registries (UK, Sweden \u0026amp; Australasia \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR261\" class=\"CitationRef\"\u003e261\u003c/span\u003e\u003c/sup\u003e and NPH Special Interest Groups (eg Hydrocephalus Society, Association of British Neurologists UK).\u003c/p\u003e\u003cp\u003eThe mechanism(s) governing normal autoregulation are complex\u003csup\u003e\u003cspan citationid=\"CR160\" class=\"CitationRef\"\u003e160\u003c/span\u003e,\u003cspan citationid=\"CR161\" class=\"CitationRef\"\u003e161\u003c/span\u003e\u003c/sup\u003e. Similarly, the mechanisms underlying impaired cerebrovascular reactivity and autoregulation in NPH remain an enigma. Future studies should include mapping of regional variations in haemodynamic reserve onto intracerebal water content, state of myelination, resting state networks, CSF periarterial inflow and outflow pathways, vascular co-morbidity and CSVD.\u003c/p\u003e\u003cp\u003eA holy grail of NPH research is to identify accurate predictive biomarkers, alone or in combination, of outcome after shunting. The relationship between response to a tap test and outcome after shunting is capricious. The interpretation of CSF outflow resistance depends on age, duration of symptoms and co-morbidities. The higher the Rout, the greater the probability of a favourable outcome after a shunt but a minority of patients with a normal Rout still improve after shunting. Interestingly, cerebrovascular reactivity tests have predictive value. One possibility would be an RCT that explores the predictive accuracy of the combination of a tap test/EDLT with CVR.\u003c/p\u003e\u003cp\u003eApart from shunting, there are no other proven treatments apart from conventional management of frailty, vascular risk factors and comorbidities including, for example, PD and CSVD. Blood pressure control may help to prevent white matter hyperintensities in CSVD \u003csup\u003e\u003cspan citationid=\"CR262\" class=\"CitationRef\"\u003e262\u003c/span\u003e\u003c/sup\u003e. ACZ was discovered in the 1940\u0026rsquo;s as an inhibitor of carbonic anhydrase. ACZ has well known effects on CSF production by the choroid plexus and as a cerebral vasodilator. In a pioneering French pilot study \u003csup\u003e\u003cspan citationid=\"CR263\" class=\"CitationRef\"\u003e263\u003c/span\u003e\u003c/sup\u003e, ACZ was found to clinically improve 10 out of 15 NPH patients examined over 2 years. Tolerance was excellent with a daily dose of 250 to 500 mg. The benefit remained stable after 1 year follow-up in 8 cases. Low-dose ACZ was later shown to reverse white matter lesions in NPH within a few months \u003csup\u003e\u003cspan citationid=\"CR193\" class=\"CitationRef\"\u003e193\u003c/span\u003e,\u003cspan citationid=\"CR264\" class=\"CitationRef\"\u003e264\u003c/span\u003e\u003c/sup\u003e. The results of the Uppsala DRAIN RCT are keenly awaited (EudraCT Number 2020-004132-22).\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eBoth baseline rCBF and borderline ischaemia approximate to the cortical and subcortical circuitry that contribute to the clinical features of NPH but are not predictive of the response to shunting. Impaired cerebrovascular reactivity has predictive value for the clinical response to shunting. In addition to RCTs of carbonic anhydrase inhibitors, consideration should be given to an RCT that explores the predictive accuracy of the combination of the clinical response to temporary CSF drainage with changes in CVR.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCBF\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCerebral Blood Flow\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003erCBF\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eregional Cerebral Blood Flow\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003etCBF\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003etotal Cerebral Blood Flow\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCVR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCerebrovascular reactivity\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eGRAD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eGrading of Recommendations Assessment, Development, and Evaluation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e(i)NPH\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003e(idiopathic) Normal Pressure Hydrocephalus\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRTI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003efrom RTI international, no acronym clarification provided. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.rti.org/about-us\u003c/span\u003e\u003cspan address=\"https://www.rti.org/about-us\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSTT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSpinal Tap Test\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTCD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTranscranial Doppler\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cu\u003eAcknowledgements\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to acknowledge the invaluable help and support of the Ume\u0026aring; Hydrocephalus Group during the last phase of this review.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eFunding\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe received no funding for this review\u003c/p\u003e\n\u003cp\u003eJDP: NIHR Senior Investigator award 2009-2014; EC Interreg-4 (Amiens) Dynamic MR project 2008-11; NIHR Healthcare Technology Cooperative for Brain Injury 2013-2017; NIHR Brain Injury MedTech 2018-2023.\u003c/p\u003e\n\u003cp\u003eMC and ZC: Have received departmental funding for the REVERT project, part of the European programme Interreg France (Channel Manche) England. The project is co-financed by ERDF (European Regional Development Fund) and also EC Interreg-4 (Amiens) Dynamic MR project 2008-11\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eDisclosure\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMC has partial financial interest from licensing the ICM+ software (Cambridge Enterprise) for Multimodality Brain Monitoring.\u0026nbsp;\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eADL performed the systematic review of the literature, synthesised and analysed the review results and drafted the manuscript. JDP was the second reviewer of the literature and decided independently whether to include the articles or not. He also contributed significantly to the design and finalisation of the manuscript and oversaw the entire process.MC and ZC dealt with agreements and disagreements about which articles to include, and contributed to the review and interpreation of the results, as well as to the writing and discussion for the review. All authors reviewed the manuscript several times (more than one can even count at this point) and agreed to this final version for submission.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOwler BK, Pickard JD. Normal pressure hydrocephalus and cerebral blood flow: a review. Acta Neurol Scand. 2001;104:325\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAdams RD, Fisher CM, Hakim S, et al. Symptomatic Occult Hydrocephalus with Normal Cerebrospinal-Fluid Pressure. N Engl J Med. 1965;273:117\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHakim S, Adams RD. 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Neurology. 2014;82:1347\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"fluids-and-barriers-of-the-cns","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"fbcn","sideBox":"Learn more about [Fluids and Barriers of the CNS](http://fluidsbarrierscns.biomedcentral.com/)","snPcode":"12987","submissionUrl":"https://submission.nature.com/new-submission/12987/3","title":"Fluids and Barriers of the CNS","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"autoregulation, cerebral autoregulation, cerebrovascular reactivity, cerebral blood flow, hydrocephalus, normal pressure hydrocephalus","lastPublishedDoi":"10.21203/rs.3.rs-6480393/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6480393/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eNormal pressure hydrocephalus is one of the few remediable causes of decline in gait and cognitive function in the ageing population. The roles of the cerebral circulation including haemodynamic reserve and cardiovascular co-morbidity in the pathogenesis, management and prognostication of NPH remain ill-defined. In this systematic review, we have updated Owler \u0026amp; Pickard\u0026rsquo;s review of 2001\u003csup\u003e1\u003c/sup\u003e to examine\u003c/p\u003e\u003cp\u003e\u0026bull; whether there are changes in global and regional CBF that are specific to NPH and its clinical manifestations?\u003c/p\u003e\u003cp\u003e\u0026bull; whether levels of global and regional CBF are appropriately coupled to cerebral metabolism and/or low enough to equate to ongoing cerebral ischaemia?\u003c/p\u003e\u003cp\u003e\u0026bull; whether any changes in global or regional CBF are predictive of outcome after CSF drainage, both temporary and permanent (shunting)?\u003c/p\u003e\u003cp\u003e\u0026bull; whether global and regional cerebrovascular autoregulation and reactivity are more sensitive predictors of outcome and reversibility of symptoms in response to both temporary and permanent CSF drainage than baseline rCBF?\u003c/p\u003e\u003cp\u003e\u0026bull; whether changes in resistance to CSF outflow, whole brain compliance, local tissue stress and loss of brain tissue volume relate to CBF and disordered cerebrovascular autoregulation and reactivity? Whether any changes in global or regional CBF are the cause or effect (\u0026lsquo;chicken and the egg\u0026rsquo;) of iNPH?\u003c/p\u003e\u003cp\u003e\u0026bull; whether a trial is warranted that combines assessments of haemodynamic reserve, CSF outflow resistance and response to temporary CSF drainage?\u003c/p\u003e","manuscriptTitle":"Cerebral Blood Flow, Autoregulation and Vascular Reactivity in Normal Pressure Hydrocephalus: a systematic review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-07 18:28:44","doi":"10.21203/rs.3.rs-6480393/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-29T13:23:29+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-22T05:51:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"160480004000057384351874936041048596528","date":"2025-08-16T08:20:34+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-15T15:44:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"128547018662496828819571812864777080970","date":"2025-08-14T22:50:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"220667888311571963512156278075665202435","date":"2025-08-13T16:43:34+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-13T14:25:51+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-27T23:27:54+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-21T15:28:58+00:00","index":"","fulltext":""},{"type":"submitted","content":"Fluids and Barriers of the CNS","date":"2025-04-18T16:18:24+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"fluids-and-barriers-of-the-cns","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"fbcn","sideBox":"Learn more about [Fluids and Barriers of the CNS](http://fluidsbarrierscns.biomedcentral.com/)","snPcode":"12987","submissionUrl":"https://submission.nature.com/new-submission/12987/3","title":"Fluids and Barriers of the CNS","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"05d5a18d-2228-4f1a-890f-759287d0c213","owner":[],"postedDate":"August 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-22T16:07:51+00:00","versionOfRecord":{"articleIdentity":"rs-6480393","link":"https://doi.org/10.1186/s12987-025-00720-2","journal":{"identity":"fluids-and-barriers-of-the-cns","isVorOnly":false,"title":"Fluids and Barriers of the CNS"},"publishedOn":"2025-12-16 15:57:40","publishedOnDateReadable":"December 16th, 2025"},"versionCreatedAt":"2025-08-07 18:28:44","video":"","vorDoi":"10.1186/s12987-025-00720-2","vorDoiUrl":"https://doi.org/10.1186/s12987-025-00720-2","workflowStages":[]},"version":"v1","identity":"rs-6480393","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6480393","identity":"rs-6480393","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}