Cerebral small vessel disease may not critically influence familial Parkinson’s disease

Cerebral small vessel disease may not critically influence familial Parkinson’s disease | 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 Article Cerebral small vessel disease may not critically influence familial Parkinson’s disease Bigyan Marhat, Malla Bimala, Marco Foddis, Manuel Holtgrewe, Dieter Beule, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4518069/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Familial Parkinson’s disease (PD) and vascular parkinsonism (VP) overlap in their clinical, neuroradiologic and neuropathologic features. To investigate whether PD and VP may share a pathogenic link, we used the modified Scheltens scale and assessed the classic neuroradiological features of cerebral small vessel disease in the axial T2 MRI flair sequences in a cohort of 58 familial PD patients, 46 familial PD prodromal patients and 48 age-matched controls from the PPMI publicly available database. We next examined the protein coding variability in the main PD-causing genes and genetic risk factors in a cohort of 96 patients with familial cerebral small vessel disease (cSVD) and 243 elderly healthy individuals from the HEX database. Patients with familial and prodromal PD have a moderate but still significant burden of superficial white matter hyperintensities compared to age-matched controls (Wilcox Test p-value = 4.335e-07, OR = 4.1, 95% CI = 1.8–9.23), with moderate motor impairment and minimal and non-pathological cognitive decline (UPDRS and MoCa up to 25 and 26,respectively). In contrast, 100% of patients carrying SNCA p.A53T and 25% of patients carrying LRRK2 p.G2019S, p.R1441C or GBA p.N409S, p.E365K and p.L483P had moderate to very severe dementia (average MoCa Score = 21) and mild motor impairment (mean UPDRS III score = 20) and only very modest white matter lesions. Finally, we report no known pathogenic coding variant in the PD genes studied in cSVD patients. Our study shows that familial PD and small vessel disease likely have distinct not necessarily mutually exclusive, pathogenic mechanisms. Biological sciences/Genetics Biological sciences/Neuroscience Health sciences/Neurology Health sciences/Pathogenesis Parkinson’s disease (PD) vascular parkinsonism (VP) Parkinson Mendelian genes cerebral small vessel disease (cSVD) white matter hyperintensities (WMH) Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Familial Parkinson’s disease (PD) and vascular parkinsonism (VP) present overlapping clinical (rigidity and bradykinesia, cognitive impairment to severe dementia) and to a different extent neuroradiological (white matter hyperintensities, PET-Scan decreased fluorodopa uptake in the basal ganglia) and neuropathological (depigmentation of the substantia nigra, cortical atrophy) features. Both conditions may co-exist particularly in elderly patients and are frequently misdiagnosed 1–2 ( Table S1 ). Vascular Parkinsonism is often caused by sporadic, severe, diffuse progressive cerebral small vessel disease (cSVD). Other less common causes of VP include mendelian cSVDs, such as Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL), and retinal vasculopathy with cerebral leukodystrophy (RVCL). More rarely, mendelian leukodystrophies such as hereditary diffuse leukoencephalopathy with spheroids (HDLS) leading to a reduction of thalamo-cortical drive can also cause VP 3,2 ( https://www.omim.org/ ) ( Table S2 ). However, despite the comprehensive body of literature describing white matter macro- and microstructural changes in PD patients and correlating these to the progression of diverse clinical PD phenotypes, 4–5 , a potential common pathogenic ground between familial PD and cSVD has not been extensively and systematically investigated. Therefore, we used a modified Scheltens scale and screened the classical cSVD neuroradiological biomarkers (periventricular hyperintensities, lobar superficial white matter hyperintensities, lobar deep white matter hyperintensities, status cribrosus, lobar cortical small-microinfarcts, lacunar Infarcts) 6–7 , Table S3 ) in T2 MRI Flair sequences of 58 familial PD and 46 familial PD prodromal patients and 48 age-matched controls from the PPMI publicly available database ( www.ppmi-info.org/data ) (Table 1 , Table S4). Next, we performed exome sequencing on a cohort of 96 familial cSVD Caucasian patients from the US to investigate in this cohort protein coding variability in the most common PD mendelian genes ( VPS35 , DJ1 , PINK1 , ATP13A2 , PRKN , SNCA , LRRK2 ) and risk factors ( LRRK2, GBA , MAPT , LAMP3 , STK39 ) ( https://www.omim.org/ ) (Fig. 1 ). Table 1 PPMI MRI cohort used in this study . Pheno., phenotype; PD, Parkinson’s disease; Prod, prodromal; CTRLS, controls; N., number; pat, patients; AAO, age-at onset; SD, standard deviation; F, female; N, number; fam, familial; Hypert., hypertension; DMT 2, diabetes mellitus type 2; Hyperlipid, hyperlipidemia; AF, atrial fibrillation; CAD, coronary artery disease; PFO, pervium foramen ovale; Hypercoag., hypercoagulability; * Data available for 33/104 (32%) Parkinson’s disease and prodromal patients. Cardiovascular risk factors (%)* Pheno. N. pat/ CTRLS AAO (SD) F (%) N. fam. Cases (%) LRRK2 (%) GBA (%) SNCA (%) APOE ε2 (%) Hypert. (%) DMT 2 (%) Hyperlipid (%) AF (%) CAD (%) Valve prolapse/ regurgitation PFO Hypercoag. PD 58 60 (32–82) 22 (38) 58 (100%) 42/104 (40) 30/104 ( 29 ) 2/104 ( 2 ) 8/14 (57) 4/14 ( 28 ) 7/14 4/14 1/14 0/14 1/14 1/14 Prod. patients 46 63 (34–77) 27 (59) 46 (100%) 16/104 (15%) 11/33 (61) 4/18 ( 22 ) 14/18 1/18 1/18 0/18 0/18 0/18 CTRLS 48 61 (32–81) 17 ( 35 ) 0 4/48 (8%) 4/18 ( 22 ) 2/18 ( 11 ) 6/18 1/18 0/18 3/18 0/18 0/18 MATERIAL AND METHODS MRI Study MRI Study cohort Fifty-eight familial idiopathic Parkisnon’s disease patients (females = 22, mean age-at onset 60 years [range: 32–82]), 46 familial prodromal PD patients (females = 27, mean age-at of onset 63 years [range: 34–77]) and 48 age-matched healthy controls (females = 17, mean age-at onset 61 years [range: 32–81]) were obtained from the Parkinson Progression Marker Initiative (PPMI) database (Table 1 , Table S4 ). The PPMI study is well-described at ppmi-info.org. Briefly, PPMI is a comprehensive multi-center study designed to identify biomarkers of PD with the goal of improving evaluation of disease modifying therapeutics 8 . Healthy control subjects included in PPMI were above 30 years of age, had never been diagnosed with any major neurological disorder, had no first-degree relatives with idiopathic PD, and were not cognitively impaired based on a score of 26 or above on the Montreal Cognitive Assessment (MoCa). Familial PD and familial prodromal PD patients were defined as having at least one first-degree relative with idiopathic PD. Of the 104 PD and prodromal patients, 42 (40%) carried pathogenic LRRK2 mutations, with 40/42 (95%) being heterozygous carriers for LRRK2 p.G2019S, the most common risk factor for late-onset sporadic PD 9 . Thirty of the 104 patients (29%) carried pathogenic mutations in GBA in heterozygosity. A minority of patients 2/104 (2%) presented an autosomal dominant form of PD and carried the SNCA pathogenic mutation p.A53T in heterozygosity. Information regarding cardiovascular risk factors was available only for a minority of cases (at least 32/104 [31%]) and controls (18/48 [38%]). Among these, hyperlipidaemia was the most common risk factor, detected in 66% of cases and 33% of controls. 40% of cases and 22% of controls displayed hypertension and 16% of cases and 5% of controls presented atrial fibrillation. 16% of controls and none of the cases had a valve prolapse or regurgitation and a minority of cases (5%) and none of the controls presented coronary artery disease, patent foramen ovale (PFO) or hypercoagulability (Table 1 ) Among the clinical features of the cohort, the motor impairment was measured using the Unified Parkinson’s disease rating scale (UPDRS) III for motor skills, PD patients presented an average score of 28 (ranging from 5 to 64), prodromal patients an average score of 5 (ranging from 0 to 33) and the controls an average score of 4 (ranging from 0 to 4). Cognitive skills were measured using the MOCA Test and PD patients presented an average score of 26 (ranging from 9 to 30), the prodromal patients an average score of 28 (ranging from 20 to 30) and the controls an average score of 27 (ranging from 21 to 30). For the PPMI cohort, the ethical approvals and commettees have been already described ( https://www.ppmi-info.org/sites/default/files/docs/archives/Amendment-12.pdf ). Informed consent was obtained. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. MRI T2 Flair All the MRI scans were separately rated twice by two experienced neurologists (H-M.S and V.K) and by two trained experienced residents in neurology (B.M and C.S). All raters were experienced in grading white matter abnormalities on MRI. Each scan was rated using the modified Scheltens scale 10 , representing a complement of the classical Fazekas scale, with the possibility of describing lobar distribution and rating with a score cortical and subcortical white matter hyperintensities ( Table S3 ). Briefly, Scheltens and colleagues described 4 classes of white matter hyperintensities: periventricular hyperintensities, white matter hyperintensities, basal ganglia hyperintensities and infra-tentorial foci of hyperintensities. We implemented this scale selecting 6 neuroradiological hallmarks for cerebral small vessel disease, based on the previous literature: periventricular hyperintensities 6 , lobar superficial white matter hyperintensities, 11 , lobar deep white matter hyperintensities 6 , status cribrosus 12 , lacunar infarcts 7 and lobar cortical small-microinfarcts 13 ( Table S3 , Fig. 1 ). Moreover, ischemic lesions such as cortical small-microinfarcts and lobar lacunes are a common feature of cerebral amyloid angiopathy (CAA) 14,13 and were considered as CAA hallmark ( Figure S2 ). Our rating scale provides 7 sum scores in a semiquantitative way, as explained in Table S3 : periventricular hyperintensities (PVH), lobar superficial white matter hyperintensities (LSWMH), lobar deep white matter hyperintensities (LDWMH), deep white matter hyperintensities, status cribrosus, lobar cortical small-microinfarcts, lacunar infarcts. PVH were identified as continuous, confluent areas of high signal intensity adjacent to anterior or posterior horns of the lateral ventricles ("caps") and along the lateral ventricles ("bands"). LDWMH, located in the deep and subcortical white matter, were separately rated in the frontal, temporal, parietal and occipital regions; superficial white matter hyperintensities were defined as tracts originating within 5 mm of the cortical surface, as previously described 15 ; status cribrosus describes the diffusely widened perivascular spaces (Virchow-Robin spaces) in the basal ganglia, especially in the corpus striatum on MRI 16,17 ; cortical small and microinfarcts were defined as cortical hypointense lesions 15 mm and ≤ 4 mm in largest diameter respectively and distinct from perivascular spaces 13 ; lacunar Infarcts were defined as lesions from 3 mm to < 15 mm in the supratentorial region, without cortical gray matter involvement 18 . Manual segmentation on T2-MRI Flair images was conducted using the publicly available IMAIOS Atlas ( https://www.imaios.com/en/e-Anatomy/Brain/Brain-MRI-in-axial-slices ). Genetic Study Patient Cohort All the patients included in the genetic study were Caucasian non-Hispanic from the US (NINDS [National Institute of Neurological Disorders and Stroke]). DNA was extracted and collected at the NINDS Repository. All NINDS Repository Samples are collected only after an IRB-approved, signed informed consent is secured by the submitter. Inclusion criteria comprised cerebral small vessel ischemic disease diagnosis based on TOAST classification, early age at onset (< 65 years [only 2 cases, whose age-at onset was 68 and 71 years old have been included in the study because of a positive family history]), absence of known pathogenic mutations in Mendelian small vessel disease genes ( HTRA1 , NOTCH3 , ACTA2 and COL4A1 ) and no enrichment for vascular risk factors except for hypertension, which generally plays a critical role in elderly people 19 . The mean age at disease onset was 51.5 years (range 34–71 years). 82.3% of the cases were male and 44.8% of the cases were positive for a familial history of cerebrovascular disorders. Among the comorbidities and possible risk factors for cSVID, hypertension was reported in 60.4% of the patients, diabetes type 2 in 30.2%, and myocardial infarction in 7.3%. The majority of the patients (at least 88.54%) were negative for atrial fibrillation (AF), which is among the most important risk factors for embolic small vessel occlusion 20 . In 4.1% and 7.3% of the patients the presence of AF was reported and unknown, respectively. Given the prevalent role of hypertension and type 2 diabetes in cSVID in the elderly people 19 and the young age at onset of the cohort, these patients were considered enriched for genetic risk factors ( Table S5 ). Finally, 243 controls > 80 years of age were selected from ‘HEALTHY EXOMES’, HEX, a publicly available database, which collects exome sequencing data from elderly neuropathologically proven controls ( https://www.alzforum.org/exomes/hex ; 22 ). All methods were performed in accordance with the relevant guidelines and regulations. The experimental protocols were approved by the PPI licensing committee ( https://www.ppmi-info.org/sites/default/files/docs/archives/Amendment-12.pdf ). RESULTS cSVID neuroimaging hallmarks in familial PD and control patients To investigate the hypothesis that familial PD and cSVD may have shared pathogenic mechanisms we used a modified Scheltens Scale ( Table S3 ) and screened the main 7 cSVD neuroradiological hallmarks (periventricular hyperintensities, lobar superficial white matter hyperintensities, lobar deep white matter hyperintensities, status cribrosus, lobar cortical small-microinfarcts, lacunar Infarcts) 6–7 in the MRI T2 Flair sequences in a cohort of 58 familial PD and 46 familial prodromal PD patients and 48 age-matched controls from the PPMI database (Fig. 1 ). Cumulative cSVD neuroradiological biomarker analysis When we considered the cSVD neuroradiological biomarker cumulative score, we did not identify any statistically significant difference between familial PD patients, familial prodromal PD patients and controls (p-value = 0.53, 95% CI -1.95-1.02). We report a linear and age-dependent increase of the cSVD neuroradiological hallmark cumulative score, particularly driven by periventricular and deep white matter hyperintensities both for familial PD and familial prodromal PD patients as well as for controls and more marked in the frontal lobe, representing 45% of the hemisphere 13 (Fig. 2 A-C, Table S6 ) The white matter hyperintensity cumulative score (WMHCS) was associated to a parallel and directly proportional and not statistically significant increase in UPDRS score (from 14 to 25, corresponding to a 10% increase of the total UPDRS III score and to a mild increase of the motoric impairment), as already reported in PD patients 23 , and a to a very modest and not statistically significant decrease of MoCa score (from 28 to 26, corresponding to a 6% decrease of the total MoCa score, with no indications of cognitive impairment) (Fig. 4 A ) Single cSVD neuroradiological biomarker analysis Analyzing individual neuroradiological cSVD biomarkers, we found a statistically significant increased burden of superficial white matter hyperintensities in familial PD-prodromal PD patients (81/104, 77%) compared to age-matched controls (22/48, 45.8%) (Fig. 3 A-B) (p-value = 0.0001538, Fisher Test and, Wilcox Test p-value = 4.335e-07, OR = 4.1, 95% CI = 1.8–9.23) 19% and 6.5% of familial PD and familial prodromal PD patients, respectively, presented several (> 6) superficial white matter hyperintensities and more than 10% of the patients presented lesions in multiple lobes, affecting in > 60% of these cases the frontal lobe (Fig. 3 A-C). Superficial white matter lesions clustered mostly in the superior frontal and inferior frontal gyrus, harboring the Broadmann areas 6 and 8 (Fig. 3 C). Analogously to the WMHCS, the increase of superficial white matter hyperintensity cumulative score (WMHCS) was paralleled by a mild and not statistically significant increase of the UPDRS score (from 14 to 25), as already reported in PD 22 and a very modest and not statistically significant decrease of MoCa score with no indications of cognitive impairment (from 28 to 26) (Fig. 4 B) Influence of white matter hyperintensities on PD outcome Multiple bilateral lacunar infarcts in the basal ganglia, capsula interna and externa were detected both in elderly cases (familial PD patients [14/58, 24%] and prodromal patients [9/46, 19%]) and controls (14/48, 29%) without any statistically significant difference (Fisher Test, p-value = 0.41, 95% CI =-0.29-1.63). However, familial PD patients presented a burden of lacunar strokes particularly in the thalamus (relative frequency 9% in familial PD cases and 2% in age-matched controls), which were associated with typical basal ganglia symptoms such as moderate akinesia and rigidity (UPDRS average score 3 [Finger tapping] and 4 [rigidity of extremities], respectively) 24 (Fig. 3 D-E). We did not identify any lacunar infarct in the pons or mesencephalon. Influence of PD causative and main genetic risk factors ( SNCA , LRRK2 and GBA ) and small vessel disease neuroradiological biomarkers on PD motor and cognitive outcome Patients carrying pathogenic mutations in SNCA (p.A53T, 2/2 carriers) or significant risk factors in GBA (p.N409S, p.E365K and p.L483P, 7/29 [24%] carriers) and LRRK2 (p. G2019S and p.R1441C, 7/41 [17%] carriers) displayed the lowest MoCa scores depicting a mild to a very severe dementia (from 25 to 9) characterized both by executive and visuospatial function and memory impairment (Trail Making Test, Cube Copy, or clock drawing). Importantly, we report for all these variants only a very modest WMHCS (average 1 [ GBA p.L483P] to 14 [ LRRK2 p.R1441C]) (Fig. 4 C). The phenotypical difference among carriers of GBA and LRRK2 variants are likely due to a penetrance factor 25–26 . The carriers of SNCA p.A53T presented a very early onset (32y and 53y) and were characterized by very severe dementia (MoCa score 17 and 9, respectively) and marked motor impairment (UPDRS III 37 and 46, respectively) whereas the WMHCS was very mild (10 and 6, respectively). A rapidly progressive dementia was also associated to 6/33 (18%) of LRRK2 p.G2019S carriers, and particularly in homozygous state associated to a statistically significant motor impairment (MoCa 18, UPDRS III 29). Analogously, LRRK2 p.R1441C carriers displayed a mild dementia and severe motor impairment (MoCa 23 and UPDRS 33). Moreover, 7/22 (32%) carriers of GBA coding variants (p.N409S, p.E365K and p.L483P) presented a mild dementia (MoCa average 23.4) and only 4/29 (14%) GBA mutation carriers were characterized by very severe motor impairment (UPDRS 39) (Fig. 4 C, Table S4 ). Finally, APOE ε2 allele has been associated to increased severity of small vessel disease 27,28 however, we have not detected a statistically significant difference between PD and prodromal PD patients and controls as in our cohort 16/104 (15%) of patients and 4/48 (8%) of controls carried this allele in heterozygosity (Fisher Test p-value = 0.3059, 95% CI = 0.59–8.67, OR 1.9)(Table 1 ). PD Mendelian genes and main GWAS loci genetic screening in familial SVID patients To further investigate the hypothesis that PD Mendelian genes and main common risk factors are associated with cSVD, we screened protein coding variability in 11 PD causative genes ( VPS35 , DJ1 , PINK1 , ATP13A2 , PRKN , SNCA , LRRK2 ) and genetic risk factors ( LRRK2, GBA , MAPT , LAMP3 , STK39 ) in 96 early-onset unrelated cerebral small-vessel disease cases and 243 elderly controls neuropathologically proven, from the UK ( Table S5 ). We did not identify any known pathogenic variant in the studied genes in our cSVD cohort ( Table S7 ). None of the detected variants in heterozygosity has been reported as pathogenic or likely pathogenic in ClinVar database ( https://www.ncbi.nlm.nih.gov/clinvar ). Six variants ( ATP13A2 p.Q377R and p.G372R, PINK1 p.R326C, LRRK2 p.D41Y, p.M167L and p.P1661T) are not present in the ClinVar database. PRKN p.G430D was found in heterozygosity in a male patient with very early-onset (41y) familial cSVD with a positive familial history (grand-mother affected) and hypertension treated with medications. Importantly, PRKN p.G430D in homozygosity causes autosomal recessive juvenile Parkinson whereas in heterozygosity it has not been associated to increased risk for PD 29 . Overall elderly controls displayed an higher relative frequency of variants in the studied genes ( Figure S1 ). The only exception was in SNCA , presenting a relative frequency of 1% (1/96) and 0.4% (1/243) in cSVD patients and elderly controls, respectively. Moreover, 10/96 (10%) early-onset cSVD cases and 82/243 (34%) elderly controls carried at least 1 rare coding variant in the studied genes. All the variants detected in the cSVD cohort were singletons. None of the cSVD patients carried any variant in homozygosity or compound heterozygosity. Moreover, in this cSVD cases we have not identified any rare coding variants in GBA , LAMP3 , MAPT , DJ1 , STK39 and VPS35 and we detected a total of 9 rare coding variants in ATP13A2 , PINK1, SNCA , PRKN and LRRK2 , absent in controls ( Table S7 and Table S8 ) ATP13A2 and PRKN , PINK1 and SNCA harbor the lowest and highest relative frequency of low-frequency and rare coding variants (mean 0.5 and 0.3 low-frequency-rare variants per kb of coding sequence) respectively. 90% of the variants were described as probably-damaging or possibly-damaging by in-silico prediction software (PolyPhen2). Additionally, LRRK2 p.G2019S, the most common cause of familial PD (5–6%) and a risk factor for sporadic PD (1%) was detected with a frequency of 4e-4 in the elderly controls and none of the cSVD familial cases 30 ( Table S8 and Table S7 ). DISCUSSION Using neuroradiology and genetics, we explored the hypothesis that familial PD, VP, and its hallmark, cSVD, which exhibit varying degrees of overlapping phenotype, may have been linked by a shared pathophysiology. To this end, we selected a cohort of 104 familial PD and familial PD prodromal patients from the PPMI database and used a modified Scheltens Scale to screen MRI T2 Flair sequences for the main cSVD neuroradiological biomarkers (ie, periventricular hyperintensities, lobar superficial white matter hyperintensities, lobar deep white matter hyperintensities, status cribrosus, lobar cortical small-microinfarcts, lacunar Infarcts) (Fig. 1 ). Familial PD and prodromal PD patients presented a statistically significant enrichment for superficial white matter hyperintensities particularly in the frontal superior and inferior gyrus and to a lesser extent in the parietal lobe, mainly corresponding to the Brodmann area 8 and to the premotor cortex (Brodmann area 6) (Fig. 3 A-C). Importantly, superficial white matter represents a very vulnerable area, located beneath the infragranular layer of the cerebral cortex, containing the last fibers to myelinate and extensive cortico-cortical connections 15 and has been already associated to ischemic and hemorragic damage during Covid-19 infection and cititoxic lesions that are due deposition of Aẞ plaques, and may trigger epileptic seizures in patients with small vessel disease 11,31 – 32 . Although statistically significant, this white matter hyperintensity burden did not present a clinical correlate and was not associated with a parallel statistically significant worsening of the cognitive or motoric function and may likely be interpreted as a global neurodegenerative process. In line with this hypothesis and in concert with our findings, a growing body of evidence described microstructural damages in the frontal cortex patients involving Broadmann area 6 and 8 (premotor cortex, supplementary motor area, the presupplementary motor area) in the early stages of PD 33,34 . Accordingly, a burden of superficial white matter hyperintensity has been associated to different neurodegenerative disorders such as AD 35 In addition, we report an enrichment for lacunar infarcts in the basal ganglia and especially in thalamus in the elderly familial PD patients, corresponding to a mild although not statistically significant increase of the UPDRS scores. Importantly, white matter hyperintensities in the frontal and parietal lobe and lacunar infarcts in the basal ganglia and particularly in the thalamus have been linked to an increased risk for mild parkinsonism, likely driven by the interruption of the basal ganglia–thalamofrontal cortical circuits leading to a reduction in the thalamocortical drive 3 . Thus suggesting that the statistically significant enrichment for superficial white matter hyperintensities particularly clustering in the frontal lobe and lacunar infarcts in the thalamus may shape familial PD endophenotypes mostly influencing the progression of classical basal ganglia symptoms such as akinesia and rigidity. By contrast, mutations in PD genes were associated to a severe and rapidly progressive dementia and moderate worsening of the motoric function. We next tested the hypothesis that the main PD genetic causative and risk factors may have explained the enrichment for cSVD neuroradiological biomarkers such as superficial white matter hyperintensities and lacunar infarcts in familial PD and prodromal patients, screening protein coding variability in VPS35 , DJ1 , PINK1 , ATP13A2 , PRKN , SNCA , GBA , MAPT , LAMP3 , STK39 in a cohort of familial 96 small vessel disease patients. We did not report any pathogenic variant in the studied genes in this cohort, arguing for a non-critical role of the main PD genes for the development and progression of cSVD. The burden of superficial white matter as well as white matter cumulative score were not associated to a parallel clinical motoric and cognitive worsening and, on the contrary, Mendelian mutations corresponded to a severe dementia and to a lesser extent motoric impairment, suggesting that white matter degeneration may shape the familial PD phenotype and likely influence the variant penetrance but do not play a critical role for the progression of PD. Moreover, PD Mendelian mutations were associated to modest increase of white matter hyperintensity cumulative scores implying that these genes are not likely to influence white matter burden. On the other hand, cSVD may facilitate the penetrance of some pathogenic mutations such as LRRK2 p.G2019S 30 and prime the α-synuclein protein misfolding and lead to Lewy body formation, as already described for other neurodegenerative disorders such Alzheimer’s disease 36 . We conclude that small vessel disease may not crucially influence familial PD severity and progression and are not critically linked to PD genetic main causative and risk factors. Our findings should foster a validation in a bigger cohort of familial PD and cSVD patients. Declarations Acknowledgements Prof. Ulrich Dirnagl from the Center for Stroke Research Berlin (CSB), Charité , Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität and Berlin Institute of Health, for the supervision, Dr. Zocholl Dario from Institute of Biometry and Clinical Epidemiology, Berlin, who provided the statistical advice. Data used in the preparation of this article were obtained [22 nd December 2021] from the Parkinson’s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/access-data-specimens/download-data), RRID:SCR_006431. For up-to-date information on the study, visit www.ppmi-info.org. Funding: PPMI – a public-private partnership – is funded by the Michael J. Fox Foundation for Parkinson’s Research and funding partners, including 4D Pharma, Abbvie, AcureX, Allergan, Amathus Therapeutics, Aligning Science Across Parkinson's, AskBio, Avid Radiopharmaceuticals, BIAL, Biogen, Biohaven, BioLegend, BlueRock Therapeutics, Bristol-Myers Squibb, Calico Labs, Celgene, Cerevel Therapeutics, Coave Therapeutics, DaCapo Brainscience, Denali, Edmond J. Safra Foundation, Eli Lilly, Gain Therapeutics, GE HealthCare, Genentech, GSK, Golub Capital, Handl Therapeutics, Insitro, Janssen Neuroscience, Lundbeck, Merck, Meso Scale Discovery, Mission Therapeutics, Neurocrine Biosciences, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi, Servier, Sun Pharma Advanced Research Company, Takeda, Teva, UCB, Vanqua Bio, Verily, Voyager Therapeutics, the Weston Family Foundation and Yumanity Therapeutics.” DNA panels from the NINDS Repository were used in this study, as well as clinical data. Data used in the preparation of this article were obtained from the Parkinson’s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data). For up-to-date information on the study, visit www.ppmi-info.org. PPMI, a public private partnership, was funded by the Michael J. Fox Foundation (MJFF) for Parkinson’s Research and funding partners, including Abbvie, Avid Radiopharmaceuticals, Biogen, Britsol-Myers Squibb, Covance, GE Healthcare, Genetech, GlaxoSmithKline, Lilly, Lundbeck, Merck, Meso Scale Discovery,Pfizer, Piramal, Roche, Servier, and UCB. Neither the funding agency nor any of the sponsors of the PPMI were involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. DISCLOSURES FUNDING SOURCES AND CONFLICT OF INTEREST This study was supported by NeuroCure, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Alexander von Humboldt Fellowship (to Celeste Sassi). All the authors declare that there are no conflicts of interest relevant to this work. DATA AVAILABILITY All data generated or analysed during this study are included in this published article (and its Supplementary Information files). References Kalra, S., Grosset, D. G. & Benamer, H. T. S. Differentiating vascular parkinsonism from idiopathic Parkinson’s disease: a systematic review. Mov Disord 25, 149–156 (2010). Peralta, C. et al. Parkinsonism following striatal infarcts: incidence in a prospective stroke unit cohort. J Neural Transm (Vienna) 111, 1473–1483 (2004). de Laat, K. F. et al. Cerebral white matter lesions and lacunar infarcts contribute to the presence of mild parkinsonian signs. Stroke 43, 2574–2579 (2012). Bohnen, N. I. & Albin, R. L. White matter lesions in Parkinson disease. Nat Rev Neurol 7, 229–236 (2011). Gattellaro, G. et al. White matter involvement in idiopathic Parkinson disease: a diffusion tensor imaging study. AJNR Am J Neuroradiol 30, 1222–1226 (2009). Fazekas, F., Chawluk, J. B., Alavi, A., Hurtig, H. I. & Zimmerman, R. A. MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. AJR Am J Roentgenol 149, 351–356 (1987). Wardlaw, J. M., Smith, C. & Dichgans, M. Small vessel disease: mechanisms and clinical implications. The Lancet Neurology 18, 684–696 (2019). Parkinson Progression Marker Initiative. The Parkinson Progression Marker Initiative (PPMI). Prog Neurobiol 95, 629–635 (2011). Paisán-Ruiz, C., Lewis, P. A. & Singleton, A. B. LRRK2: Cause, Risk, and Mechanism. J Parkinsons Dis 3, 85–103 (2013). Scheltens, P. et al. A semiquantative rating scale for the assessment of signal hyperintensities on magnetic resonance imaging. J Neurol Sci 114, 7–12 (1993). Wang, S. et al. Superficial white matter microstructure affects processing speed in cerebral small vessel disease. 2021.12.30.474604 Preprint at https://doi.org/10.1101/2021.12.30.474604 (2022). Ferrer, I., Bella, R., Serrano, M. T., Martí, E. & Guionnet, N. Arteriolosclerotic leucoencephalopathy in the elderly and its relation to white matter lesions in Binswanger’s disease, multi-infarct encephalopathy and Alzheimer’s disease. J Neurol Sci 98, 37–50 (1990). Xiong, L. et al. Cerebral Cortical Microinfarcts on Magnetic Resonance Imaging and Their Association With Cognition in Cerebral Amyloid Angiopathy. Stroke 49, 2330–2336 (2018). Reijmer, Y. D., van Veluw, S. J. & Greenberg, S. M. Ischemic brain injury in cerebral amyloid angiopathy. J Cereb Blood Flow Metab 36, 40–54 (2016). Reginold, W. et al. Altered Superficial White Matter on Tractography MRI in Alzheimer’s Disease. Dement Geriatr Cogn Dis Extra 6, 233–241 (2016). de Reuck, J., Sieben, G., de Coster, W. & vander Ecken, H. Parkinsonism in patients with cerebral infarcts. Clin Neurol Neurosurg 82, 177–185 (1980). Poirier, J. & Derouesné, C. [The concept of cerebral lacunae from 1838 to the present]. Rev Neurol (Paris) 141, 3–17 (1985). Riba-Llena, I. et al. Small cortical infarcts: prevalence, determinants, and cognitive correlates in the general population. Int J Stroke 10 Suppl A100, 18–24 (2015). Abraham, H. M. A. et al. Cardiovascular risk factors and small vessel disease of the brain: Blood pressure, white matter lesions, and functional decline in older persons. J. Cereb. Blood Flow Metab. 36, 132–142 (2016). de Leeuw, F. E. et al. Atrial fibrillation and the risk of cerebral white matter lesions. Neurology 54, 1795–1801 (2000). Guerreiro, R. et al. A comprehensive assessment of benign genetic variability for neurodegenerative disorders. bioRxiv 270686 (2018) doi: 10.1101/270686 . Jeong, S. H. et al. White Matter Hyperintensities, Dopamine Loss, and Motor Deficits in De Novo Parkinson’s Disease. Mov Disord 36, 1411–1419 (2021). Shulman, L. M. et al. The clinically important difference on the unified Parkinson’s disease rating scale. Arch Neurol 67, 64–70 (2010). Lalvay, L. et al. Quantitative Measurement of Akinesia in Parkinson’s Disease. Mov Disord Clin Pract 4, 316–322 (2017). Blauwendraat, C. et al. Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia. Brain 143, 234–248 (2020). Lee, A. J. et al. Penetrance estimate of LRRK2 p.G2019S mutation in individuals of non-Ashkenazi Jewish ancestry. Mov Disord 32, 1432–1438 (2017). Groot, C. et al. Clinical phenotype, atrophy, and small vessel disease in APOEε2 carriers with Alzheimer disease. Neurology 91, e1851–e1859 (2018). Gesierich, B. et al. APOE ɛ2 is associated with white matter hyperintensity volume in CADASIL. J. Cereb. Blood Flow Metab. 36, 199–203 (2016). Kay, D. M. et al. Heterozygous parkin point mutations are as common in control subjects as in Parkinson’s patients. Ann Neurol 61, 47–54 (2007). Tan, M. M. X. et al. Genetic analysis of Mendelian mutations in a large UK population-based Parkinson’s disease study. Brain 142, 2828–2844 (2019). Kirschenbaum, D. et al. Intracerebral endotheliitis and microbleeds are neuropathological features of COVID-19. Neuropathol Appl Neurobiol 47, 454–459 (2021). Stösser, S., Böckler, S., Ludolph, A. C., Kassubek, J. & Neugebauer, H. Juxtacortical lesions are associated with seizures in cerebral small vessel disease. J Neurol 266, 1230–1235 (2019). Karagulle Kendi, A. T., Lehericy, S., Luciana, M., Ugurbil, K. & Tuite, P. Altered diffusion in the frontal lobe in Parkinson disease. AJNR Am J Neuroradiol 29, 501–505 (2008). Yoshikawa, K., Nakata, Y., Yamada, K. & Nakagawa, M. Early pathological changes in the parkinsonian brain demonstrated by diffusion tensor MRI. J Neurol Neurosurg Psychiatry 75, 481–484 (2004). Veale, T. et al. Loss and dispersion of superficial white matter in Alzheimer’s disease: a diffusion MRI study. Brain Commun 3, fcab272 (2021). Raz, L., Knoefel, J. & Bhaskar, K. The neuropathology and cerebrovascular mechanisms of dementia. J Cereb Blood Flow Metab 36, 172–186 (2016). Additional Declarations No competing interests reported. Supplementary Files FigureS1.jpg S1 Relative frequency of rare protein coding variants in the most common PD causative genes ( VPS35 , DJ1 , PINK1 , ATP13A2 , PRKN , SNCA , LRRK2 ) or genetic risk factors ( LRRK2, GBA , MAPT , LAMP3 , STK39 ) detected in 96 familial early-onset cerebral small vessel disease patients and 243 elderly neuropathologically proven controls ( href="https://www.alzforum.org/exomes/hex">https://www.alzforum.org/exomes/hex; 22 ). CSVD, cerebral small vessel disease; CTRLS, controls. FigureS2.jpg S2 AI-III. Examples of cortical microinfarcts detected in controls (CTRLS), familial Parkinson’s disease patients (PD) and familial Parkinson’s disease prodromal patients, framed within a dashed line. SVDPDSupplementaryTables02.06.xlsx SuppelmentaryMaterialsandMethodsTables.05.06.pdf SupplementaryTableslegends.docx Cite Share Download PDF Status: Posted Version 1 posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-4518069","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":315086981,"identity":"dc3c210f-cca5-41fc-a5b5-b520acf9539b","order_by":0,"name":"Bigyan Marhat","email":"","orcid":"","institution":"Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt- Universität zu Berlin, Berlin Institute of Health","correspondingAuthor":false,"prefix":"","firstName":"Bigyan","middleName":"","lastName":"Marhat","suffix":""},{"id":315086982,"identity":"bd2bd4cc-459a-44fc-886f-d57da266078e","order_by":1,"name":"Malla Bimala","email":"","orcid":"","institution":"Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt- Universität zu Berlin, Berlin Institute of Health","correspondingAuthor":false,"prefix":"","firstName":"Malla","middleName":"","lastName":"Bimala","suffix":""},{"id":315086983,"identity":"40420907-5fc4-4512-8934-84992ba9de12","order_by":2,"name":"Marco Foddis","email":"","orcid":"","institution":"Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health","correspondingAuthor":false,"prefix":"","firstName":"Marco","middleName":"","lastName":"Foddis","suffix":""},{"id":315086984,"identity":"fcdaca78-0e8b-4bad-b313-e58796eec749","order_by":3,"name":"Manuel Holtgrewe","email":"","orcid":"","institution":"Berlin Institute of Health, BIH","correspondingAuthor":false,"prefix":"","firstName":"Manuel","middleName":"","lastName":"Holtgrewe","suffix":""},{"id":315086986,"identity":"09573392-98fe-476b-afca-e6ea173cd3bc","order_by":4,"name":"Dieter Beule","email":"","orcid":"","institution":"Berlin Institute of Health, BIH","correspondingAuthor":false,"prefix":"","firstName":"Dieter","middleName":"","lastName":"Beule","suffix":""},{"id":315086988,"identity":"216c2761-a41f-4d9c-b1d8-4c3615dbf79f","order_by":5,"name":"Jose Bras","email":"","orcid":"","institution":"Michigan State University College of Human Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jose","middleName":"","lastName":"Bras","suffix":""},{"id":315086990,"identity":"c70e118d-dde3-4194-8b0b-6f34534a0865","order_by":6,"name":"Rita Guerreiro","email":"","orcid":"","institution":"Michigan State University College of Human Medicine","correspondingAuthor":false,"prefix":"","firstName":"Rita","middleName":"","lastName":"Guerreiro","suffix":""},{"id":315086993,"identity":"da1bbfb2-98fe-4dce-a647-b5ddf251dd0d","order_by":7,"name":"Vasilis Kola","email":"","orcid":"","institution":"Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health","correspondingAuthor":false,"prefix":"","firstName":"Vasilis","middleName":"","lastName":"Kola","suffix":""},{"id":315086995,"identity":"dd504412-35e2-4820-ab67-9e23c1abdd0b","order_by":8,"name":"Hans-Michael Schmitt","email":"","orcid":"","institution":"Werner Forsmann Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hans-Michael","middleName":"","lastName":"Schmitt","suffix":""},{"id":315086997,"identity":"ab8bdea3-2ec9-4da4-a2dc-ad02f71a8d76","order_by":9,"name":"Matthias Endres","email":"","orcid":"","institution":"Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health","correspondingAuthor":false,"prefix":"","firstName":"Matthias","middleName":"","lastName":"Endres","suffix":""},{"id":315086999,"identity":"8c8d1e8b-b852-48db-aebf-55c48a144942","order_by":10,"name":"Celeste Sassi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDUlEQVRIie3PMUsDMRTA8XcUdAncGig0XyFS6NJynyWPg95SXFw6CCYcNEuhq6LUr6BL5ysBXYJzxx43uDhctysIelcogpCzo0P+0yPkx0sAfL5/WUf+zGIKAiBoTjotpLkgjsQeiJKnk2B2GINWEmql8n01AqZfizJfRpfhvdHbEoY9F6F2nfaJGAO3kwHFVXxF31CpW0j6LsIpzrogDHCYnAGuMpQ2UCkBg9JFWK73lfgCtngvSnzI8LEhn2BunITWXyYiA9iIeqPM8KkhAEY4RP0XTLtkHBO++RhQ8RLjc03u5jy5cG0JtVnvqlHUY4uk2FXXES7t+baspkPm2nKM/H7wX8Dn8/l8bX0D5iVc1Rj3vt8AAAAASUVORK5CYII=","orcid":"","institution":"Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health","correspondingAuthor":true,"prefix":"","firstName":"Celeste","middleName":"","lastName":"Sassi","suffix":""}],"badges":[],"createdAt":"2024-06-02 18:38:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4518069/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4518069/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":59119207,"identity":"2ba5aa2c-5193-46ee-8265-90bc966cf91b","added_by":"auto","created_at":"2024-06-26 14:36:46","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":160364,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy pipeline\u003c/strong\u003e. T2 MRI Flair scans of a cohort of 152 individuals (58 familial PD patients, 46 familial prodromal PD patients and 48 age-matched controls) from the Parkinson’s Progression Markers Initiative (PPMI) database, were screened for the main cerebral small vessel disease neuroradiological hallmarks: PVH, peri-ventricular hyperintensities; lobar SWMH, superficial white matter hyperintensities; lobar DWMH, deep white matter hyperintensities; status cribrosus; lobar cortical Si and Mi, small-and micro-infarcts and lacunar infarcts. Familial PD patients and familial PD prodromal patients displayed a statistically significant burden of cortical frontal superficial white matter hyperintensities (p-value = 0.0001538, Fisher Test and, Wilcox Test p-value= 4.335e-07, OR = 4.1, 95% CI = 1.8-9.23) compared to controls. To investigate the hypothesis that PD main genetic causative and risk factors may have played a critical role for the development of these SWMH and likely in cSVD, we performed exome sequencing on a cohort of 96 early-onset familial small vessel disease Caucasian from the US and in 243 elderly and neuropathologically proven controls from the publicly available HEX Database (https://www.alzforum.org/exomes/hex) and screened protein coding rare genetic variability in the main PD causative genes and GWAS loci.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4518069/v1/a208ae147b3a2a4706d1309a.jpg"},{"id":59119850,"identity":"ce5e2d21-0748-4c29-abca-1f3c9d2ad317","added_by":"auto","created_at":"2024-06-26 14:44:46","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":156109,"visible":true,"origin":"","legend":"\u003cp\u003eModified cumulative Scheltens score obtained from the sum of the 7 cSVD neuroradiological hallmarks, showing a strongly linear and age-dependent increase, both for controls (\u003cstrong\u003e2A\u003c/strong\u003e) and PD and prodromal PD patients (\u003cstrong\u003e2B\u003c/strong\u003e) particularly driven by periventricular and deep white matter scores (\u003cstrong\u003e2AI \u003c/strong\u003eand\u003cstrong\u003e 2BI\u003c/strong\u003e) and with a predilection for the frontal lobe, representing 45% of the whole lobar hemisphere (\u003cstrong\u003e2C\u003c/strong\u003e). PD, familial Parkinson’s disease patients.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4518069/v1/3a4b5ad22391b8ead068006b.jpg"},{"id":59119849,"identity":"23a1c005-47f0-4346-aa16-f86365be5b7e","added_by":"auto","created_at":"2024-06-26 14:44:46","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":372048,"visible":true,"origin":"","legend":"\u003cp\u003eSuperficial white matter hyperintensities in PD and prodromal PD patients particularly clustering in the superior frontal gyrus and framed within a dashed line (\u003cstrong\u003e3A I\u003c/strong\u003e,\u003cstrong\u003e II\u003c/strong\u003e,\u003cstrong\u003e III\u003c/strong\u003e)\u003cstrong\u003e. 3B \u003c/strong\u003eFamilial PD patients and familial PD prodromal patients displayed a statistically significant burden of cortical frontal superficial white matter hyperintensities (p-value = 0.0001538, Fisher Test and, Wilcox Test p-value= 4.335e-07, OR = 4.1, 95% CI = 1.8-9.23).\u003cstrong\u003e 3C\u003c/strong\u003e Collective representation of the superficial white matter hyperintensities in the 104 PD and prodromal PD patients analysed in the study, clustering in the frontal superior and to a lesser extent inferior gyrus, corresponding to the Brodmann area 8 (in yellow) and Brodmann area 6 (in light blue) . Each blue dot represents a single superficial white matter hyperintensity. PD, familial Parkinson’s disease patients; PR, familial prodromal Parkinson’s disease patients; CTRLS, controls; **, p-value \u0026gt; 0.00005.\u003cstrong\u003e 3 D-E. \u003c/strong\u003eLacunar infarcts detected in 58 familial\u003cstrong\u003e \u003c/strong\u003ePD patients, 46 familial PD prodromal patients and 48 age-matched controls. \u003cstrong\u003e3D I-V\u003c/strong\u003e, Thalamus infarcts detected in 5 late-onset familial PD patients, framed within a dashed line. \u003cstrong\u003e3E. \u003c/strong\u003eRelative frequency of\u003cstrong\u003e \u003c/strong\u003edifferent lacunar infarcts (thalamus, basal ganglia, capsula interna and capsula externa) detected in our cohort. PD, familial Parkinson’s disease patients; PR, familial prodromal Parkinson’s disease patients; CTRLS, controls.\u003c/p\u003e","description":"","filename":"Figure3AC.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4518069/v1/f259cc383c957b8d60588602.jpg"},{"id":59119209,"identity":"c55fb3bf-4262-4849-8164-dd833bbc3cc0","added_by":"auto","created_at":"2024-06-26 14:36:46","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":113333,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e4A-C\u003c/strong\u003e. Effect of white matter hyperintensities and \u003cem\u003eSNCA\u003c/em\u003e, \u003cem\u003eGBA\u003c/em\u003e and \u003cem\u003eLRRK2\u003c/em\u003e mutations on Parkinson’s disease outcome. \u003cstrong\u003eA-B \u003c/strong\u003eBar plot\u003cstrong\u003e \u003c/strong\u003eshowing an increasing white matter hyperintensity cumulative score (\u003cstrong\u003eA\u003c/strong\u003e) and superficial white matter cumulative score (\u003cstrong\u003eB\u003c/strong\u003e) and a parallel progressive mild decrease of MoCa scores and marked increase of UPDRS III scores.\u003cstrong\u003e C \u003c/strong\u003eBar plot describing a mild to very severe dementia triggered by \u003cem\u003eGBA\u003c/em\u003e, \u003cem\u003eLRRK2\u003c/em\u003e and particularly \u003cem\u003eSNCA\u003c/em\u003e mutations and a concomitant increase of UPDRS motoric scores, paralleled by only a modest increase of white matter cumulative scores. WMHCS, white matter hyperintensity cumulative score.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4518069/v1/34fc5018d98f887298d4bbbf.jpg"},{"id":62017125,"identity":"1426b5e1-f9d6-4340-a5e1-8dc9f9517d89","added_by":"auto","created_at":"2024-08-08 08:55:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1465528,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4518069/v1/e36260c6-2164-43fb-ad7c-04b20c13a2f3.pdf"},{"id":59119204,"identity":"947c3e2e-5f54-4f6a-9e0f-75c4b20d96d3","added_by":"auto","created_at":"2024-06-26 14:36:46","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":103220,"visible":true,"origin":"","legend":"\u003cp\u003eS1 Relative frequency of rare protein coding variants\u003cstrong\u003e \u003c/strong\u003ein the most common PD causative\u0026nbsp; genes (\u003cem\u003eVPS35\u003c/em\u003e, \u003cem\u003eDJ1\u003c/em\u003e, \u003cem\u003ePINK1\u003c/em\u003e, \u003cem\u003eATP13A2\u003c/em\u003e, \u003cem\u003ePRKN\u003c/em\u003e, \u003cem\u003eSNCA\u003c/em\u003e, \u003cem\u003eLRRK2\u003c/em\u003e) or genetic risk factors (\u003cem\u003eLRRK2, GBA\u003c/em\u003e, \u003cem\u003eMAPT\u003c/em\u003e, \u003cem\u003eLAMP3\u003c/em\u003e, \u003cem\u003eSTK39\u003c/em\u003e)\u003cstrong\u003e \u003c/strong\u003edetected in 96 familial early-onset cerebral small vessel disease patients and 243 elderly neuropathologically proven controls (\u003ca href=\"https://www.alzforum.org/exomes/hex\"\u003ehttps://www.alzforum.org/exomes/hex\u003c/a\u003e; \u003csup\u003e22\u003c/sup\u003e). CSVD, cerebral small vessel disease; CTRLS, controls.\u003c/p\u003e","description":"","filename":"FigureS1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4518069/v1/212e717a153a6b458a6b7773.jpg"},{"id":59121281,"identity":"40f4af6c-68bb-4ef0-92bd-d1807f17c9eb","added_by":"auto","created_at":"2024-06-26 14:52:46","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":70094,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eS2 AI-III. \u003c/strong\u003eExamples of cortical microinfarcts detected in controls (CTRLS), familial Parkinson’s disease patients (PD) and familial Parkinson’s disease prodromal patients, framed within a dashed line.\u003c/p\u003e","description":"","filename":"FigureS2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4518069/v1/6be84811841f6b7d9239da6a.jpg"},{"id":59119205,"identity":"5fd8a3eb-4f22-4fdb-b0f5-14c6053ab8ce","added_by":"auto","created_at":"2024-06-26 14:36:46","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":41185,"visible":true,"origin":"","legend":"","description":"","filename":"SVDPDSupplementaryTables02.06.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4518069/v1/b598226692a0a3cdf8da6bae.xlsx"},{"id":59119211,"identity":"42cdea10-015b-4b92-ac94-2b8d7af2e9bb","added_by":"auto","created_at":"2024-06-26 14:36:46","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":825539,"visible":true,"origin":"","legend":"","description":"","filename":"SuppelmentaryMaterialsandMethodsTables.05.06.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4518069/v1/d7cdcb8452fe7571dbb690ad.pdf"},{"id":59119206,"identity":"b032555e-832d-40ca-828d-c8694b82a14c","added_by":"auto","created_at":"2024-06-26 14:36:46","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":14505,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableslegends.docx","url":"https://assets-eu.researchsquare.com/files/rs-4518069/v1/b433f93ae1a30c3c93e8fd36.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cerebral small vessel disease may not critically influence familial Parkinson’s disease","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eFamilial Parkinson\u0026rsquo;s disease (PD) and vascular parkinsonism (VP) present overlapping clinical (rigidity and bradykinesia, cognitive impairment to severe dementia) and to a different extent neuroradiological (white matter hyperintensities, PET-Scan decreased fluorodopa uptake in the basal ganglia) and neuropathological (depigmentation of the substantia nigra, cortical atrophy) features. Both conditions may co-exist particularly in elderly patients and are frequently misdiagnosed \u003csup\u003e1\u0026ndash;2\u003c/sup\u003e (\u003cb\u003eTable \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eVascular Parkinsonism is often caused by sporadic, severe, diffuse progressive cerebral small vessel disease (cSVD). Other less common causes of VP include mendelian cSVDs, such as Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL), and retinal vasculopathy with cerebral leukodystrophy (RVCL). More rarely, mendelian leukodystrophies such as hereditary diffuse leukoencephalopathy with spheroids (HDLS) leading to a reduction of thalamo-cortical drive can also cause VP \u003csup\u003e3,2\u003c/sup\u003e (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.omim.org/\u003c/span\u003e\u003cspan address=\"https://www.omim.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) (\u003cb\u003eTable \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eHowever, despite the comprehensive body of literature describing white matter macro- and microstructural changes in PD patients and correlating these to the progression of diverse clinical PD phenotypes, \u003csup\u003e4\u0026ndash;5\u003c/sup\u003e, a potential common pathogenic ground between familial PD and cSVD has not been extensively and systematically investigated.\u003c/p\u003e \u003cp\u003eTherefore, we used a modified Scheltens scale and screened the classical cSVD neuroradiological biomarkers (periventricular hyperintensities, lobar superficial white matter hyperintensities, lobar deep white matter hyperintensities, status cribrosus, lobar cortical small-microinfarcts, lacunar Infarcts) \u003csup\u003e6\u0026ndash;7\u003c/sup\u003e, \u003cb\u003eTable S3\u003c/b\u003e) in T2 MRI Flair sequences of 58 familial PD and 46 familial PD prodromal patients and 48 age-matched controls from the PPMI publicly available database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.ppmi-info.org/data\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.ppmi-info.org/data\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cb\u003eTable S4).\u003c/b\u003e Next, we performed exome sequencing on a cohort of 96 familial cSVD Caucasian patients from the US to investigate in this cohort protein coding variability in the most common PD mendelian genes (\u003cem\u003eVPS35\u003c/em\u003e, \u003cem\u003eDJ1\u003c/em\u003e, \u003cem\u003ePINK1\u003c/em\u003e, \u003cem\u003eATP13A2\u003c/em\u003e, \u003cem\u003ePRKN\u003c/em\u003e, \u003cem\u003eSNCA\u003c/em\u003e, \u003cem\u003eLRRK2\u003c/em\u003e) and risk factors (\u003cem\u003eLRRK2, GBA\u003c/em\u003e, \u003cem\u003eMAPT\u003c/em\u003e, \u003cem\u003eLAMP3\u003c/em\u003e, \u003cem\u003eSTK39\u003c/em\u003e) (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.omim.org/\u003c/span\u003e\u003cspan address=\"https://www.omim.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \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\u003ePPMI MRI cohort used in this study\u003c/b\u003e. Pheno., phenotype; PD, Parkinson\u0026rsquo;s disease; Prod, prodromal; CTRLS, controls; N., number; pat, patients; AAO, age-at onset; SD, standard deviation; F, female; N, number; fam, familial; Hypert., hypertension; DMT 2, diabetes mellitus type 2; Hyperlipid, hyperlipidemia; AF, atrial fibrillation; CAD, coronary artery disease; PFO, pervium foramen ovale; Hypercoag., hypercoagulability; * Data available for 33/104 (32%) Parkinson\u0026rsquo;s disease and prodromal patients.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"18\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" 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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c15\" colnum=\"15\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c16\" colnum=\"16\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c17\" colnum=\"17\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c18\" colnum=\"18\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\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\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"9\" nameend=\"c18\" namest=\"c10\"\u003e \u003cp\u003eCardiovascular risk factors (%)*\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePheno.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN. pat/\u003c/p\u003e \u003cp\u003eCTRLS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAAO\u003c/p\u003e \u003cp\u003e(SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eF (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN.\u003c/p\u003e \u003cp\u003efam.\u003c/p\u003e \u003cp\u003eCases\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLRRK2 (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eGBA\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eSNCA\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cem\u003eAPOE\u003c/em\u003e ε2\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eHypert.\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eDMT 2 (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003eHyperlipid\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c13\"\u003e \u003cp\u003eAF\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c14\"\u003e \u003cp\u003eCAD\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c15\"\u003e \u003cp\u003eValve\u003c/p\u003e \u003cp\u003eprolapse/\u003c/p\u003e \u003cp\u003eregurgitation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c16\"\u003e \u003cp\u003ePFO\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c17\"\u003e \u003cp\u003eHypercoag.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c18\" namest=\"c18\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e60\u003c/p\u003e \u003cp\u003e(32\u0026ndash;82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e58 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e42/104 (40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e30/104 (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e2/104 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e8/14 (57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e4/14\u003c/p\u003e \u003cp\u003e(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e7/14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e4/14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1/14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e0/14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e1/14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003e1/14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c18\" namest=\"c18\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProd.\u003c/p\u003e \u003cp\u003epatients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e63\u003c/p\u003e \u003cp\u003e(34\u0026ndash;77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27 (59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e46 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e16/104\u003c/p\u003e \u003cp\u003e(15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e11/33 (61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e4/18\u003c/p\u003e \u003cp\u003e(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e14/18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1/18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1/18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e0/18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e0/18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003e0/18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c18\" namest=\"c18\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCTRLS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e61\u003c/p\u003e \u003cp\u003e(32\u0026ndash;81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \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 \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4/48 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4/18 (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2/18\u003c/p\u003e \u003cp\u003e(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e6/18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1/18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0/18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e3/18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e0/18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003e0/18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c18\" namest=\"c18\"\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 \u003c/p\u003e"},{"header":"MATERIAL AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eMRI Study\u003c/h2\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003eMRI Study cohort\u003c/h2\u003e \u003cp\u003eFifty-eight familial idiopathic Parkisnon\u0026rsquo;s disease patients (females\u0026thinsp;=\u0026thinsp;22, mean age-at onset 60 years [range: 32\u0026ndash;82]), 46 familial prodromal PD patients (females\u0026thinsp;=\u0026thinsp;27, mean age-at of onset 63 years [range: 34\u0026ndash;77]) and 48 age-matched healthy controls (females\u0026thinsp;=\u0026thinsp;17, mean age-at onset 61 years [range: 32\u0026ndash;81]) were obtained from the Parkinson Progression Marker Initiative (PPMI) database (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cb\u003eTable S4\u003c/b\u003e). The PPMI study is well-described at ppmi-info.org. Briefly, PPMI is a comprehensive multi-center study designed to identify biomarkers of PD with the goal of improving evaluation of disease modifying therapeutics \u003csup\u003e8\u003c/sup\u003e. Healthy control subjects included in PPMI were above 30 years of age, had never been diagnosed with any major neurological disorder, had no first-degree relatives with idiopathic PD, and were not cognitively impaired based on a score of 26 or above on the Montreal Cognitive Assessment (MoCa). Familial PD and familial prodromal PD patients were defined as having at least one first-degree relative with idiopathic PD.\u003c/p\u003e \u003cp\u003eOf the 104 PD and prodromal patients, 42 (40%) carried pathogenic \u003cem\u003eLRRK2\u003c/em\u003e mutations, with 40/42 (95%) being heterozygous carriers for \u003cem\u003eLRRK2\u003c/em\u003e p.G2019S, the most common risk factor for late-onset sporadic PD \u003csup\u003e9\u003c/sup\u003e. Thirty of the 104 patients (29%) carried pathogenic mutations in \u003cem\u003eGBA\u003c/em\u003e in heterozygosity. A minority of patients 2/104 (2%) presented an autosomal dominant form of PD and carried the \u003cem\u003eSNCA\u003c/em\u003e pathogenic mutation p.A53T in heterozygosity.\u003c/p\u003e \u003cp\u003eInformation regarding cardiovascular risk factors was available only for a minority of cases (at least 32/104 [31%]) and controls (18/48 [38%]).\u003c/p\u003e \u003cp\u003eAmong these, hyperlipidaemia was the most common risk factor, detected in 66% of cases and 33% of controls. 40% of cases and 22% of controls displayed hypertension and 16% of cases and 5% of controls presented atrial fibrillation. 16% of controls and none of the cases had a valve prolapse or regurgitation and a minority of cases (5%) and none of the controls presented coronary artery disease, patent foramen ovale (PFO) or hypercoagulability (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eAmong the clinical features of the cohort, the motor impairment was measured using the Unified Parkinson\u0026rsquo;s disease rating scale (UPDRS) III for motor skills, PD patients presented an average score of 28 (ranging from 5 to 64), prodromal patients an average score of 5 (ranging from 0 to 33) and the controls an average score of 4 (ranging from 0 to 4). Cognitive skills were measured using the MOCA Test and PD patients presented an average score of 26 (ranging from 9 to 30), the prodromal patients an average score of 28 (ranging from 20 to 30) and the controls an average score of 27 (ranging from 21 to 30).\u003c/p\u003e \u003cp\u003eFor the PPMI cohort, the ethical approvals and commettees have been already described (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ppmi-info.org/sites/default/files/docs/archives/Amendment-12.pdf\u003c/span\u003e\u003cspan address=\"https://www.ppmi-info.org/sites/default/files/docs/archives/Amendment-12.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Informed consent was obtained. We confirm that we have read the Journal\u0026rsquo;s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eMRI T2 Flair\u003c/h2\u003e \u003cp\u003eAll the MRI scans were separately rated twice by two experienced neurologists (H-M.S and V.K) and by two trained experienced residents in neurology (B.M and C.S). All raters were experienced in grading white matter abnormalities on MRI. Each scan was rated using the modified Scheltens scale \u003csup\u003e10\u003c/sup\u003e, representing a complement of the classical Fazekas scale, with the possibility of describing lobar distribution and rating with a score cortical and subcortical white matter hyperintensities (\u003cb\u003eTable S3\u003c/b\u003e). Briefly, Scheltens and colleagues described 4 classes of white matter hyperintensities: periventricular hyperintensities, white matter hyperintensities, basal ganglia hyperintensities and infra-tentorial foci of hyperintensities.\u003c/p\u003e \u003cp\u003eWe implemented this scale selecting 6 neuroradiological hallmarks for cerebral small vessel disease, based on the previous literature: periventricular hyperintensities \u003csup\u003e6\u003c/sup\u003e, lobar superficial white matter hyperintensities, \u003csup\u003e11\u003c/sup\u003e, lobar deep white matter hyperintensities \u003csup\u003e6\u003c/sup\u003e, status cribrosus \u003csup\u003e12\u003c/sup\u003e, lacunar infarcts \u003csup\u003e7\u003c/sup\u003e and lobar cortical small-microinfarcts \u003csup\u003e13\u003c/sup\u003e (\u003cb\u003eTable S3\u003c/b\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Moreover, ischemic lesions such as cortical small-microinfarcts and lobar lacunes are a common feature of cerebral amyloid angiopathy (CAA) \u003csup\u003e14,13\u003c/sup\u003e and were considered as CAA hallmark (\u003cb\u003eFigure \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e\u003c/b\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOur rating scale provides 7 sum scores in a semiquantitative way, as explained in \u003cb\u003eTable S3\u003c/b\u003e: periventricular hyperintensities (PVH), lobar superficial white matter hyperintensities (LSWMH), lobar deep white matter hyperintensities (LDWMH), deep white matter hyperintensities, status cribrosus, lobar cortical small-microinfarcts, lacunar infarcts. PVH were identified as continuous, confluent areas of high signal intensity adjacent to anterior or posterior horns of the lateral ventricles (\"caps\") and along the lateral ventricles (\"bands\"). LDWMH, located in the deep and subcortical white matter, were separately rated in the frontal, temporal, parietal and occipital regions; superficial white matter hyperintensities were defined as tracts originating within 5 mm of the cortical surface, as previously described \u003csup\u003e15\u003c/sup\u003e; status cribrosus describes the diffusely widened perivascular spaces (Virchow-Robin spaces) in the basal ganglia, especially in the corpus striatum on MRI \u003csup\u003e16,17\u003c/sup\u003e; cortical small and microinfarcts were defined as cortical hypointense lesions 15 mm and \u0026le;\u0026thinsp;4 mm in largest diameter respectively and distinct from perivascular spaces \u003csup\u003e13\u003c/sup\u003e; lacunar Infarcts were defined as lesions from 3 mm to \u0026lt;\u0026thinsp;15 mm in the supratentorial region, without cortical gray matter involvement \u003csup\u003e18\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eManual segmentation on T2-MRI Flair images was conducted using the publicly available IMAIOS Atlas (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.imaios.com/en/e-Anatomy/Brain/Brain-MRI-in-axial-slices\u003c/span\u003e\u003cspan address=\"https://www.imaios.com/en/e-Anatomy/Brain/Brain-MRI-in-axial-slices\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eGenetic Study\u003c/h2\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003ePatient Cohort\u003c/h2\u003e \u003cp\u003eAll the patients included in the genetic study were Caucasian non-Hispanic from the US (NINDS [National Institute of Neurological Disorders and Stroke]). DNA was extracted and collected at the NINDS Repository. All NINDS Repository Samples are collected only after an IRB-approved, signed informed consent is secured by the submitter.\u003c/p\u003e \u003cp\u003eInclusion criteria comprised cerebral small vessel ischemic disease diagnosis based on TOAST classification, early age at onset (\u0026lt;\u0026thinsp;65 years [only 2 cases, whose age-at onset was 68 and 71 years old have been included in the study because of a positive family history]), absence of known pathogenic mutations in Mendelian small vessel disease genes (\u003cem\u003eHTRA1\u003c/em\u003e, \u003cem\u003eNOTCH3\u003c/em\u003e, \u003cem\u003eACTA2\u003c/em\u003e and \u003cem\u003eCOL4A1\u003c/em\u003e) and no enrichment for vascular risk factors except for hypertension, which generally plays a critical role in elderly people \u003csup\u003e19\u003c/sup\u003e. The mean age at disease onset was 51.5 years (range 34\u0026ndash;71 years). 82.3% of the cases were male and 44.8% of the cases were positive for a familial history of cerebrovascular disorders. Among the comorbidities and possible risk factors for cSVID, hypertension was reported in 60.4% of the patients, diabetes type 2 in 30.2%, and myocardial infarction in 7.3%. The majority of the patients (at least 88.54%) were negative for atrial fibrillation (AF), which is among the most important risk factors for embolic small vessel occlusion \u003csup\u003e20\u003c/sup\u003e. In 4.1% and 7.3% of the patients the presence of AF was reported and unknown, respectively. Given the prevalent role of hypertension and type 2 diabetes in cSVID in the elderly people \u003csup\u003e19\u003c/sup\u003e and the young age at onset of the cohort, these patients were considered enriched for genetic risk factors (\u003cb\u003eTable S5\u003c/b\u003e). Finally, 243 controls\u0026thinsp;\u0026gt;\u0026thinsp;80 years of age were selected from \u0026lsquo;HEALTHY EXOMES\u0026rsquo;, HEX, a publicly available database, which collects exome sequencing data from elderly neuropathologically proven controls (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.alzforum.org/exomes/hex\u003c/span\u003e\u003cspan address=\"https://www.alzforum.org/exomes/hex\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e; \u003csup\u003e22\u003c/sup\u003e).\u003c/p\u003e \u003cp\u003e All methods were performed in accordance with the relevant guidelines and regulations.\u003c/p\u003e \u003cp\u003eThe experimental protocols were approved by the PPI licensing committee (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ppmi-info.org/sites/default/files/docs/archives/Amendment-12.pdf\u003c/span\u003e\u003cspan address=\"https://www.ppmi-info.org/sites/default/files/docs/archives/Amendment-12.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ecSVID neuroimaging hallmarks in familial PD and control patients\u003c/h2\u003e \u003cp\u003eTo investigate the hypothesis that familial PD and cSVD may have shared pathogenic mechanisms we used a modified Scheltens Scale (\u003cb\u003eTable S3\u003c/b\u003e) and screened the main 7 cSVD neuroradiological hallmarks (periventricular hyperintensities, lobar superficial white matter hyperintensities, lobar deep white matter hyperintensities, status cribrosus, lobar cortical small-microinfarcts, lacunar Infarcts) \u003csup\u003e6\u0026ndash;7\u003c/sup\u003e in the MRI T2 Flair sequences in a cohort of 58 familial PD and 46 familial prodromal PD patients and 48 age-matched controls from the PPMI database (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eCumulative cSVD neuroradiological biomarker analysis\u003c/h2\u003e \u003cp\u003eWhen we considered the cSVD neuroradiological biomarker cumulative score, we did not identify any statistically significant difference between familial PD patients, familial prodromal PD patients and controls (p-value\u0026thinsp;=\u0026thinsp;0.53, 95% CI -1.95-1.02). We report a linear and age-dependent increase of the cSVD neuroradiological hallmark cumulative score, particularly driven by periventricular and deep white matter hyperintensities both for familial PD and familial prodromal PD patients as well as for controls and more marked in the frontal lobe, representing 45% of the hemisphere \u003csup\u003e13\u003c/sup\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003eA-C, \u003cb\u003eTable S6\u003c/b\u003e)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe white matter hyperintensity cumulative score (WMHCS) was associated to a parallel and directly proportional and not statistically significant increase in UPDRS score (from 14 to 25, corresponding to a 10% increase of the total UPDRS III score and to a mild increase of the motoric impairment), as already reported in PD patients \u003csup\u003e23\u003c/sup\u003e, and a to a very modest and not statistically significant decrease of MoCa score (from 28 to 26, corresponding to a 6% decrease of the total MoCa score, with no indications of cognitive impairment) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA )\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSingle cSVD neuroradiological biomarker analysis\u003c/h2\u003e \u003cp\u003eAnalyzing individual neuroradiological cSVD biomarkers, we found a statistically significant increased burden of superficial white matter hyperintensities in familial PD-prodromal PD patients (81/104, 77%) compared to age-matched controls (22/48, 45.8%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e3\u003c/span\u003eA-B) (p-value\u0026thinsp;=\u0026thinsp;0.0001538, Fisher Test and, Wilcox Test p-value\u0026thinsp;=\u0026thinsp;4.335e-07, OR\u0026thinsp;=\u0026thinsp;4.1, 95% CI\u0026thinsp;=\u0026thinsp;1.8\u0026ndash;9.23)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e19% and 6.5% of familial PD and familial prodromal PD patients, respectively, presented several (\u0026gt;\u0026thinsp;6) superficial white matter hyperintensities and more than 10% of the patients presented lesions in multiple lobes, affecting in \u0026gt;\u0026thinsp;60% of these cases the frontal lobe (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e3\u003c/span\u003eA-C).\u003c/p\u003e \u003cp\u003eSuperficial white matter lesions clustered mostly in the superior frontal and inferior frontal gyrus, harboring the Broadmann areas 6 and 8 (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e3\u003c/span\u003eC).\u003c/p\u003e \u003cp\u003eAnalogously to the WMHCS, the increase of superficial white matter hyperintensity cumulative score (WMHCS) was paralleled by a mild and not statistically significant increase of the UPDRS score (from 14 to 25), as already reported in PD \u003csup\u003e22\u003c/sup\u003e and a very modest and not statistically significant decrease of MoCa score with no indications of cognitive impairment (from 28 to 26) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eInfluence of white matter hyperintensities on PD outcome\u003c/h2\u003e \u003cp\u003eMultiple bilateral lacunar infarcts in the basal ganglia, capsula interna and externa were detected both in elderly cases (familial PD patients [14/58, 24%] and prodromal patients [9/46, 19%]) and controls (14/48, 29%) without any statistically significant difference (Fisher Test, p-value\u0026thinsp;=\u0026thinsp;0.41, 95% CI =-0.29-1.63). However, familial PD patients presented a burden of lacunar strokes particularly in the thalamus (relative frequency 9% in familial PD cases and 2% in age-matched controls), which were associated with typical basal ganglia symptoms such as moderate akinesia and rigidity (UPDRS average score 3 [Finger tapping] and 4 [rigidity of extremities], respectively) \u003csup\u003e24\u003c/sup\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e3\u003c/span\u003eD-E).\u003c/p\u003e \u003cp\u003eWe did not identify any lacunar infarct in the pons or mesencephalon.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eInfluence of PD causative and main genetic risk factors (\u003c/span\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eSNCA\u003c/span\u003e, \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eLRRK2\u003c/span\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eand\u003c/span\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eGBA\u003c/span\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e) and small vessel disease neuroradiological biomarkers on PD motor and cognitive outcome\u003c/span\u003e\u003c/p\u003e \u003cp\u003ePatients carrying pathogenic mutations in \u003cem\u003eSNCA\u003c/em\u003e (p.A53T, 2/2 carriers) or significant risk factors in \u003cem\u003eGBA\u003c/em\u003e (p.N409S, p.E365K and p.L483P, 7/29 [24%] carriers) and \u003cem\u003eLRRK2\u003c/em\u003e (p. G2019S and p.R1441C, 7/41 [17%] carriers) displayed the lowest MoCa scores depicting a mild to a very severe dementia (from 25 to 9) characterized both by executive and visuospatial function and memory impairment (Trail Making Test, Cube Copy, or clock drawing). Importantly, we report for all these variants only a very modest WMHCS (average 1 [\u003cem\u003eGBA\u003c/em\u003e p.L483P] to 14 [\u003cem\u003eLRRK2\u003c/em\u003e p.R1441C]) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC). The phenotypical difference among carriers of \u003cem\u003eGBA\u003c/em\u003e and \u003cem\u003eLRRK2\u003c/em\u003e variants are likely due to a penetrance factor \u003csup\u003e25\u0026ndash;26\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe carriers of \u003cem\u003eSNCA\u003c/em\u003e p.A53T presented a very early onset (32y and 53y) and were characterized by very severe dementia (MoCa score 17 and 9, respectively) and marked motor impairment (UPDRS III 37 and 46, respectively) whereas the WMHCS was very mild (10 and 6, respectively). A rapidly progressive dementia was also associated to 6/33 (18%) of \u003cem\u003eLRRK2\u003c/em\u003e p.G2019S carriers, and particularly in homozygous state associated to a statistically significant motor impairment (MoCa 18, UPDRS III 29). Analogously, \u003cem\u003eLRRK2\u003c/em\u003e p.R1441C carriers displayed a mild dementia and severe motor impairment (MoCa 23 and UPDRS 33). Moreover, 7/22 (32%) carriers of \u003cem\u003eGBA\u003c/em\u003e coding variants (p.N409S, p.E365K and p.L483P) presented a mild dementia (MoCa average 23.4) and only 4/29 (14%) \u003cem\u003eGBA\u003c/em\u003e mutation carriers were characterized by very severe motor impairment (UPDRS 39) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC, \u003cb\u003eTable S4\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eFinally, \u003cem\u003eAPOE ε2\u003c/em\u003e allele has been associated to increased severity of small vessel disease \u003csup\u003e27,28\u003c/sup\u003e however, we have not detected a statistically significant difference between PD and prodromal PD patients and controls as in our cohort 16/104 (15%) of patients and 4/48 (8%) of controls carried this allele in heterozygosity (Fisher Test p-value\u0026thinsp;=\u0026thinsp;0.3059, 95% CI\u0026thinsp;=\u0026thinsp;0.59\u0026ndash;8.67, OR 1.9)(Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003ePD Mendelian genes and main GWAS loci genetic screening in familial SVID patients\u003c/h2\u003e \u003cp\u003eTo further investigate the hypothesis that PD Mendelian genes and main common risk factors are associated with cSVD, we screened protein coding variability in 11 PD causative genes (\u003cem\u003eVPS35\u003c/em\u003e, \u003cem\u003eDJ1\u003c/em\u003e, \u003cem\u003ePINK1\u003c/em\u003e, \u003cem\u003eATP13A2\u003c/em\u003e, \u003cem\u003ePRKN\u003c/em\u003e, \u003cem\u003eSNCA\u003c/em\u003e, \u003cem\u003eLRRK2\u003c/em\u003e) and genetic risk factors (\u003cem\u003eLRRK2, GBA\u003c/em\u003e, \u003cem\u003eMAPT\u003c/em\u003e, \u003cem\u003eLAMP3\u003c/em\u003e, \u003cem\u003eSTK39\u003c/em\u003e) in 96 early-onset unrelated cerebral small-vessel disease cases and 243 elderly controls neuropathologically proven, from the UK (\u003cb\u003eTable S5\u003c/b\u003e). We did not identify any known pathogenic variant in the studied genes in our cSVD cohort (\u003cb\u003eTable S7\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eNone of the detected variants in heterozygosity has been reported as pathogenic or likely pathogenic in ClinVar database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/clinvar\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/clinvar\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSix variants (\u003cem\u003eATP13A2\u003c/em\u003e p.Q377R and p.G372R, \u003cem\u003ePINK1\u003c/em\u003e p.R326C, \u003cem\u003eLRRK2\u003c/em\u003e p.D41Y, p.M167L and p.P1661T) are not present in the ClinVar database.\u003c/p\u003e \u003cp\u003e \u003cem\u003ePRKN\u003c/em\u003e p.G430D was found in heterozygosity in a male patient with very early-onset (41y) familial cSVD with a positive familial history (grand-mother affected) and hypertension treated with medications. Importantly, \u003cem\u003ePRKN\u003c/em\u003e p.G430D in homozygosity causes autosomal recessive juvenile Parkinson whereas in heterozygosity it has not been associated to increased risk for PD \u003csup\u003e29\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOverall elderly controls displayed an higher relative frequency of variants in the studied genes (\u003cb\u003eFigure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e). The only exception was in \u003cem\u003eSNCA\u003c/em\u003e, presenting a relative frequency of 1% (1/96) and 0.4% (1/243) in cSVD patients and elderly controls, respectively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eMoreover, 10/96 (10%) early-onset cSVD cases and 82/243 (34%) elderly controls carried at least 1 rare coding variant in the studied genes. All the variants detected in the cSVD cohort were singletons. None of the cSVD patients carried any variant in homozygosity or compound heterozygosity. Moreover, in this cSVD cases we have not identified any rare coding variants in \u003cem\u003eGBA\u003c/em\u003e, \u003cem\u003eLAMP3\u003c/em\u003e, \u003cem\u003eMAPT\u003c/em\u003e, \u003cem\u003eDJ1\u003c/em\u003e, \u003cem\u003eSTK39\u003c/em\u003e and \u003cem\u003eVPS35\u003c/em\u003e and we detected a total of 9 rare coding variants in \u003cem\u003eATP13A2\u003c/em\u003e, \u003cem\u003ePINK1, SNCA\u003c/em\u003e, \u003cem\u003ePRKN\u003c/em\u003e and \u003cem\u003eLRRK2\u003c/em\u003e, absent in controls (\u003cb\u003eTable S7\u003c/b\u003e and \u003cb\u003eTable S8\u003c/b\u003e)\u003c/p\u003e \u003cp\u003e \u003cem\u003eATP13A2\u003c/em\u003e and \u003cem\u003ePRKN\u003c/em\u003e, \u003cem\u003ePINK1\u003c/em\u003e and \u003cem\u003eSNCA\u003c/em\u003e harbor the lowest and highest relative frequency of low-frequency and rare coding variants (mean 0.5 and 0.3 low-frequency-rare variants per kb of coding sequence) respectively. 90% of the variants were described as probably-damaging or possibly-damaging by \u003cem\u003ein-silico\u003c/em\u003e prediction software (PolyPhen2).\u003c/p\u003e \u003cp\u003eAdditionally, \u003cem\u003eLRRK2\u003c/em\u003e p.G2019S, the most common cause of familial PD (5\u0026ndash;6%) and a risk factor for sporadic PD (1%) was detected with a frequency of 4e-4 in the elderly controls and none of the cSVD familial cases \u003csup\u003e30\u003c/sup\u003e (\u003cb\u003eTable S8\u003c/b\u003e and \u003cb\u003eTable S7\u003c/b\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eUsing neuroradiology and genetics, we explored the hypothesis that familial PD, VP, and its hallmark, cSVD, which exhibit varying degrees of overlapping phenotype, may have been linked by a shared pathophysiology. To this end, we selected a cohort of 104 familial PD and familial PD prodromal patients from the PPMI database and used a modified Scheltens Scale to screen MRI T2 Flair sequences for the main cSVD neuroradiological biomarkers (ie, periventricular hyperintensities, lobar superficial white matter hyperintensities, lobar deep white matter hyperintensities, status cribrosus, lobar cortical small-microinfarcts, lacunar Infarcts) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFamilial PD and prodromal PD patients presented a statistically significant enrichment for superficial white matter hyperintensities particularly in the frontal superior and inferior gyrus and to a lesser extent in the parietal lobe, mainly corresponding to the Brodmann area 8 and to the premotor cortex (Brodmann area 6) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e3\u003c/span\u003eA-C).\u003c/p\u003e \u003cp\u003eImportantly, superficial white matter represents a very vulnerable area, located beneath the infragranular layer of the cerebral cortex, containing the last fibers to myelinate and extensive cortico-cortical connections \u003csup\u003e15\u003c/sup\u003e and has been already associated to ischemic and hemorragic damage during Covid-19 infection and cititoxic lesions that are due deposition of Aẞ plaques, and may trigger epileptic seizures in patients with small vessel disease \u003csup\u003e11,31\u003cb\u003e\u0026ndash;\u003c/b\u003e32\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAlthough statistically significant, this white matter hyperintensity burden did not present a clinical correlate and was not associated with a parallel statistically significant worsening of the cognitive or motoric function and may likely be interpreted as a global neurodegenerative process. In line with this hypothesis and in concert with our findings, a growing body of evidence described microstructural damages in the frontal cortex patients involving Broadmann area 6 and 8 (premotor cortex, supplementary motor area, the presupplementary motor area) in the early stages of PD \u003csup\u003e33,34\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAccordingly, a burden of superficial white matter hyperintensity has been associated to different neurodegenerative disorders such as AD \u003csup\u003e35\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn addition, we report an enrichment for lacunar infarcts in the basal ganglia and especially in thalamus in the elderly familial PD patients, corresponding to a mild although not statistically significant increase of the UPDRS scores.\u003c/p\u003e \u003cp\u003eImportantly, white matter hyperintensities in the frontal and parietal lobe and lacunar infarcts in the basal ganglia and particularly in the thalamus have been linked to an increased risk for mild parkinsonism, likely driven by the interruption of the basal ganglia\u0026ndash;thalamofrontal cortical circuits leading to a reduction in the thalamocortical drive \u003csup\u003e3\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThus suggesting that the statistically significant enrichment for superficial white matter hyperintensities particularly clustering in the frontal lobe and lacunar infarcts in the thalamus may shape familial PD endophenotypes mostly influencing the progression of classical basal ganglia symptoms such as akinesia and rigidity.\u003c/p\u003e \u003cp\u003eBy contrast, mutations in PD genes were associated to a severe and rapidly progressive dementia and moderate worsening of the motoric function.\u003c/p\u003e \u003cp\u003eWe next tested the hypothesis that the main PD genetic causative and risk factors may have explained the enrichment for cSVD neuroradiological biomarkers such as superficial white matter hyperintensities and lacunar infarcts in familial PD and prodromal patients, screening protein coding variability in \u003cem\u003eVPS35\u003c/em\u003e, \u003cem\u003eDJ1\u003c/em\u003e, \u003cem\u003ePINK1\u003c/em\u003e, \u003cem\u003eATP13A2\u003c/em\u003e, \u003cem\u003ePRKN\u003c/em\u003e, \u003cem\u003eSNCA\u003c/em\u003e, \u003cem\u003eGBA\u003c/em\u003e, \u003cem\u003eMAPT\u003c/em\u003e, \u003cem\u003eLAMP3\u003c/em\u003e, \u003cem\u003eSTK39\u003c/em\u003e in a cohort of familial 96 small vessel disease patients. We did not report any pathogenic variant in the studied genes in this cohort, arguing for a non-critical role of the main PD genes for the development and progression of cSVD.\u003c/p\u003e \u003cp\u003eThe burden of superficial white matter as well as white matter cumulative score were not associated to a parallel clinical motoric and cognitive worsening and, on the contrary, Mendelian mutations corresponded to a severe dementia and to a lesser extent motoric impairment, suggesting that white matter degeneration may shape the familial PD phenotype and likely influence the variant penetrance but do not play a critical role for the progression of PD. Moreover, PD Mendelian mutations were associated to modest increase of white matter hyperintensity cumulative scores implying that these genes are not likely to influence white matter burden.\u003c/p\u003e \u003cp\u003eOn the other hand, cSVD may facilitate the penetrance of some pathogenic mutations such as \u003cem\u003eLRRK2\u003c/em\u003e p.G2019S \u003csup\u003e30\u003c/sup\u003e and prime the α-synuclein protein misfolding and lead to Lewy body formation, as already described for other neurodegenerative disorders such Alzheimer\u0026rsquo;s disease \u003csup\u003e36\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWe conclude that small vessel disease may not crucially influence familial PD severity and progression and are not critically linked to PD genetic main causative and risk factors.\u003c/p\u003e \u003cp\u003eOur findings should foster a validation in a bigger cohort of familial PD and cSVD patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eProf. Ulrich Dirnagl from the Center for Stroke Research Berlin (CSB), Charit\u0026eacute; , Universit\u0026auml;tsmedizin Berlin, Corporate Member of Freie Universit\u0026auml;t Berlin, Humboldt-Universit\u0026auml;t and Berlin Institute of Health, for the supervision, Dr. Zocholl Dario from Institute of Biometry and Clinical Epidemiology, Berlin, who provided the statistical advice.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData used in the preparation of this article were obtained [22\u003csup\u003end\u003c/sup\u003e December 2021] from the Parkinson\u0026rsquo;s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/access-data-specimens/download-data), RRID:SCR_006431. For up-to-date information on the study, visit www.ppmi-info.org. Funding: PPMI \u0026ndash; a public-private partnership \u0026ndash; is funded by the Michael J. Fox Foundation for Parkinson\u0026rsquo;s Research and funding partners, including 4D Pharma, Abbvie, AcureX, Allergan, Amathus Therapeutics, Aligning Science Across Parkinson\u0026apos;s, AskBio, Avid Radiopharmaceuticals, BIAL, Biogen, Biohaven, BioLegend, BlueRock Therapeutics, Bristol-Myers Squibb, Calico Labs, Celgene, Cerevel Therapeutics, Coave Therapeutics, DaCapo Brainscience, Denali, Edmond J. Safra Foundation, Eli Lilly, Gain Therapeutics, GE HealthCare, Genentech, GSK, Golub Capital, Handl Therapeutics, Insitro, Janssen Neuroscience, Lundbeck, Merck, Meso Scale Discovery, Mission Therapeutics, Neurocrine Biosciences, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi, Servier, Sun Pharma Advanced Research Company, Takeda, Teva, UCB, Vanqua Bio, Verily, Voyager Therapeutics, the Weston Family Foundation and Yumanity Therapeutics.\u0026rdquo;\u003c/p\u003e\n\u003cp\u003eDNA panels from the NINDS Repository were used in this study, as well as clinical data. Data used in the preparation of this article were obtained from the Parkinson\u0026rsquo;s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data). For up-to-date information on the study, visit www.ppmi-info.org. PPMI, a public private partnership, was funded by the Michael J. Fox Foundation (MJFF) for Parkinson\u0026rsquo;s Research and funding partners, including Abbvie, Avid Radiopharmaceuticals, Biogen, Britsol-Myers Squibb, Covance, GE Healthcare, Genetech, GlaxoSmithKline, Lilly, Lundbeck, Merck, Meso Scale Discovery,Pfizer, Piramal, Roche, Servier, and UCB. Neither the funding agency nor any of the sponsors of the PPMI were involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDISCLOSURES\u003c/strong\u003e\u003cbr\u003e \u003cstrong\u003eFUNDING SOURCES AND CONFLICT OF INTEREST\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by NeuroCure,\u0026nbsp;Deutsches Zentrum f\u0026uuml;r Neurodegenerative Erkrankungen (DZNE), Alexander von Humboldt Fellowship (to Celeste Sassi).\u003c/p\u003e\n\u003cp\u003eAll the authors declare that there are no conflicts of interest relevant to this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article (and its Supplementary Information files).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKalra, S., Grosset, D. G. \u0026amp; Benamer, H. T. S. Differentiating vascular parkinsonism from idiopathic Parkinson\u0026rsquo;s disease: a systematic review. Mov Disord 25, 149\u0026ndash;156 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeralta, C. \u003cem\u003eet al.\u003c/em\u003e Parkinsonism following striatal infarcts: incidence in a prospective stroke unit cohort. J Neural Transm (Vienna) 111, 1473\u0026ndash;1483 (2004).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede Laat, K. F. \u003cem\u003eet al.\u003c/em\u003e Cerebral white matter lesions and lacunar infarcts contribute to the presence of mild parkinsonian signs. Stroke 43, 2574\u0026ndash;2579 (2012).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBohnen, N. I. \u0026amp; Albin, R. L. White matter lesions in Parkinson disease. Nat Rev Neurol 7, 229\u0026ndash;236 (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGattellaro, G. \u003cem\u003eet al.\u003c/em\u003e White matter involvement in idiopathic Parkinson disease: a diffusion tensor imaging study. AJNR Am J Neuroradiol 30, 1222\u0026ndash;1226 (2009).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFazekas, F., Chawluk, J. B., Alavi, A., Hurtig, H. I. \u0026amp; Zimmerman, R. A. MR signal abnormalities at 1.5 T in Alzheimer\u0026rsquo;s dementia and normal aging. AJR Am J Roentgenol 149, 351\u0026ndash;356 (1987).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWardlaw, J. M., Smith, C. \u0026amp; Dichgans, M. Small vessel disease: mechanisms and clinical implications. The Lancet Neurology 18, 684\u0026ndash;696 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eParkinson Progression Marker Initiative. The Parkinson Progression Marker Initiative (PPMI). Prog Neurobiol 95, 629\u0026ndash;635 (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePais\u0026aacute;n-Ruiz, C., Lewis, P. A. \u0026amp; Singleton, A. B. LRRK2: Cause, Risk, and Mechanism. J Parkinsons Dis 3, 85\u0026ndash;103 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScheltens, P. \u003cem\u003eet al.\u003c/em\u003e A semiquantative rating scale for the assessment of signal hyperintensities on magnetic resonance imaging. J Neurol Sci 114, 7\u0026ndash;12 (1993).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang, S. \u003cem\u003eet al.\u003c/em\u003e Superficial white matter microstructure affects processing speed in cerebral small vessel disease. 2021.12.30.474604 Preprint at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1101/2021.12.30.474604\u003c/span\u003e\u003cspan address=\"10.1101/2021.12.30.474604\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerrer, I., Bella, R., Serrano, M. T., Mart\u0026iacute;, E. \u0026amp; Guionnet, N. Arteriolosclerotic leucoencephalopathy in the elderly and its relation to white matter lesions in Binswanger\u0026rsquo;s disease, multi-infarct encephalopathy and Alzheimer\u0026rsquo;s disease. J Neurol Sci 98, 37\u0026ndash;50 (1990).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXiong, L. \u003cem\u003eet al.\u003c/em\u003e Cerebral Cortical Microinfarcts on Magnetic Resonance Imaging and Their Association With Cognition in Cerebral Amyloid Angiopathy. Stroke 49, 2330\u0026ndash;2336 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReijmer, Y. D., van Veluw, S. J. \u0026amp; Greenberg, S. M. Ischemic brain injury in cerebral amyloid angiopathy. J Cereb Blood Flow Metab 36, 40\u0026ndash;54 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReginold, W. \u003cem\u003eet al.\u003c/em\u003e Altered Superficial White Matter on Tractography MRI in Alzheimer\u0026rsquo;s Disease. Dement Geriatr Cogn Dis Extra 6, 233\u0026ndash;241 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede Reuck, J., Sieben, G., de Coster, W. \u0026amp; vander Ecken, H. Parkinsonism in patients with cerebral infarcts. Clin Neurol Neurosurg 82, 177\u0026ndash;185 (1980).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePoirier, J. \u0026amp; Derouesn\u0026eacute;, C. [The concept of cerebral lacunae from 1838 to the present]. Rev Neurol (Paris) 141, 3\u0026ndash;17 (1985).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRiba-Llena, I. \u003cem\u003eet al.\u003c/em\u003e Small cortical infarcts: prevalence, determinants, and cognitive correlates in the general population. Int J Stroke 10 Suppl A100, 18\u0026ndash;24 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbraham, H. M. A. \u003cem\u003eet al.\u003c/em\u003e Cardiovascular risk factors and small vessel disease of the brain: Blood pressure, white matter lesions, and functional decline in older persons. J. Cereb. Blood Flow Metab. 36, 132\u0026ndash;142 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede Leeuw, F. E. \u003cem\u003eet al.\u003c/em\u003e Atrial fibrillation and the risk of cerebral white matter lesions. Neurology 54, 1795\u0026ndash;1801 (2000).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuerreiro, R. \u003cem\u003eet al.\u003c/em\u003e A comprehensive assessment of benign genetic variability for neurodegenerative disorders. bioRxiv 270686 (2018) doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1101/270686\u003c/span\u003e\u003cspan address=\"10.1101/270686\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJeong, S. H. \u003cem\u003eet al.\u003c/em\u003e White Matter Hyperintensities, Dopamine Loss, and Motor Deficits in De Novo Parkinson\u0026rsquo;s Disease. Mov Disord 36, 1411\u0026ndash;1419 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShulman, L. M. \u003cem\u003eet al.\u003c/em\u003e The clinically important difference on the unified Parkinson\u0026rsquo;s disease rating scale. Arch Neurol 67, 64\u0026ndash;70 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLalvay, L. \u003cem\u003eet al.\u003c/em\u003e Quantitative Measurement of Akinesia in Parkinson\u0026rsquo;s Disease. Mov Disord Clin Pract 4, 316\u0026ndash;322 (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBlauwendraat, C. \u003cem\u003eet al.\u003c/em\u003e Genetic modifiers of risk and age at onset in GBA associated Parkinson\u0026rsquo;s disease and Lewy body dementia. Brain 143, 234\u0026ndash;248 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee, A. J. \u003cem\u003eet al.\u003c/em\u003e Penetrance estimate of LRRK2 p.G2019S mutation in individuals of non-Ashkenazi Jewish ancestry. Mov Disord 32, 1432\u0026ndash;1438 (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGroot, C. \u003cem\u003eet al.\u003c/em\u003e Clinical phenotype, atrophy, and small vessel disease in APOEε2 carriers with Alzheimer disease. Neurology 91, e1851\u0026ndash;e1859 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGesierich, B. \u003cem\u003eet al.\u003c/em\u003e APOE ɛ2 is associated with white matter hyperintensity volume in CADASIL. J. Cereb. Blood Flow Metab. 36, 199\u0026ndash;203 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKay, D. M. \u003cem\u003eet al.\u003c/em\u003e Heterozygous parkin point mutations are as common in control subjects as in Parkinson\u0026rsquo;s patients. Ann Neurol 61, 47\u0026ndash;54 (2007).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTan, M. M. X. \u003cem\u003eet al.\u003c/em\u003e Genetic analysis of Mendelian mutations in a large UK population-based Parkinson\u0026rsquo;s disease study. Brain 142, 2828\u0026ndash;2844 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKirschenbaum, D. \u003cem\u003eet al.\u003c/em\u003e Intracerebral endotheliitis and microbleeds are neuropathological features of COVID-19. Neuropathol Appl Neurobiol 47, 454\u0026ndash;459 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSt\u0026ouml;sser, S., B\u0026ouml;ckler, S., Ludolph, A. C., Kassubek, J. \u0026amp; Neugebauer, H. Juxtacortical lesions are associated with seizures in cerebral small vessel disease. J Neurol 266, 1230\u0026ndash;1235 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaragulle Kendi, A. T., Lehericy, S., Luciana, M., Ugurbil, K. \u0026amp; Tuite, P. Altered diffusion in the frontal lobe in Parkinson disease. AJNR Am J Neuroradiol 29, 501\u0026ndash;505 (2008).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoshikawa, K., Nakata, Y., Yamada, K. \u0026amp; Nakagawa, M. Early pathological changes in the parkinsonian brain demonstrated by diffusion tensor MRI. J Neurol Neurosurg Psychiatry 75, 481\u0026ndash;484 (2004).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVeale, T. \u003cem\u003eet al.\u003c/em\u003e Loss and dispersion of superficial white matter in Alzheimer\u0026rsquo;s disease: a diffusion MRI study. Brain Commun 3, fcab272 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaz, L., Knoefel, J. \u0026amp; Bhaskar, K. The neuropathology and cerebrovascular mechanisms of dementia. J Cereb Blood Flow Metab 36, 172\u0026ndash;186 (2016).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Parkinson’s disease (PD), vascular parkinsonism (VP), Parkinson Mendelian genes, cerebral small vessel disease (cSVD), white matter hyperintensities (WMH)","lastPublishedDoi":"10.21203/rs.3.rs-4518069/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4518069/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eFamilial Parkinson\u0026rsquo;s disease (PD) and vascular parkinsonism (VP) overlap in their clinical, neuroradiologic and neuropathologic features. To investigate whether PD and VP may share a pathogenic link, we used the modified Scheltens scale and assessed the classic neuroradiological features of cerebral small vessel disease in the axial T2 MRI flair sequences in a cohort of 58 familial PD patients, 46 familial PD prodromal patients and 48 age-matched controls from the PPMI publicly available database. We next examined the protein coding variability in the main PD-causing genes and genetic risk factors in a cohort of 96 patients with familial cerebral small vessel disease (cSVD) and 243 elderly healthy individuals from the HEX database. Patients with familial and prodromal PD have a moderate but still significant burden of superficial white matter hyperintensities compared to age-matched controls (Wilcox Test p-value\u0026thinsp;=\u0026thinsp;4.335e-07, OR\u0026thinsp;=\u0026thinsp;4.1, 95% CI\u0026thinsp;=\u0026thinsp;1.8\u0026ndash;9.23), with moderate motor impairment and minimal and non-pathological cognitive decline (UPDRS and MoCa up to 25 and 26,respectively). In contrast, 100% of patients carrying \u003cem\u003eSNCA\u003c/em\u003e p.A53T and 25% of patients carrying \u003cem\u003eLRRK2\u003c/em\u003e p.G2019S, p.R1441C or \u003cem\u003eGBA\u003c/em\u003e p.N409S, p.E365K and p.L483P had moderate to very severe dementia (average MoCa Score\u0026thinsp;=\u0026thinsp;21) and mild motor impairment (mean UPDRS III score\u0026thinsp;=\u0026thinsp;20) and only very modest white matter lesions. Finally, we report no known pathogenic coding variant in the PD genes studied in cSVD patients. Our study shows that familial PD and small vessel disease likely have distinct not necessarily mutually exclusive, pathogenic mechanisms.\u003c/p\u003e","manuscriptTitle":"Cerebral small vessel disease may not critically influence familial Parkinson’s disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-26 14:36:41","doi":"10.21203/rs.3.rs-4518069/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"424846bf-53d2-4204-a2fe-e609eb1d9475","owner":[],"postedDate":"June 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":33319671,"name":"Biological sciences/Genetics"},{"id":33319672,"name":"Biological sciences/Neuroscience"},{"id":33319673,"name":"Health sciences/Neurology"},{"id":33319674,"name":"Health sciences/Pathogenesis"}],"tags":[],"updatedAt":"2024-08-08T08:47:02+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-26 14:36:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4518069","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4518069","identity":"rs-4518069","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}