Dual Biomarker Potential of 18F-PR04.MZ-PET: Assessing Dopaminergic Function and Cerebral Blood Flow in Degenerative Parkinsonian Syndromes

Dual Biomarker Potential of 18F-PR04.MZ-PET: Assessing Dopaminergic Function and Cerebral Blood Flow in Degenerative Parkinsonian Syndromes | 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 Research Article Dual Biomarker Potential of 18F-PR04.MZ-PET: Assessing Dopaminergic Function and Cerebral Blood Flow in Degenerative Parkinsonian Syndromes Andres Damian, Vasko Kramer, Ignacio Amorin, Luis Gutierrez, Germán Falasco, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6711157/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 Objective 18 F-PR04.MZ is a new PET radiopharmaceutical for the dopamine transporter (DAT), characterized by enhanced affinity and selectivity for this membrane protein. Previous investigations employing various radiotracers in dementia and movement disorders have suggested that R1 images, derived from compartmental analysis of dynamic studies, can serve as a proxy for cerebral blood flow (CBF). This study aims to evaluate the relationship between R1 values from dynamic 18 F-PR04.MZ studies as a proxy of CBF and brain glucose metabolism in patients with degenerative parkinsonisms (DP). Methods: Fifteen patients with DP (10 with Parkinson's disease, 4 with multiple system atrophy, and 1 with progressive supranuclear palsy) underwent PET/CT imaging with both, 18 F-FDG and 18 F-PR04.MZ. Additionally, 15 healthy controls (HC) who underwent PET/CT scans with 18 F-PR04.MZ were included in the study. Parametric R1 images were generated using compartmental analysis of dynamic 18 F-PR04.MZ studies via the Simplified Reference Tissue Model (SRTM). Specific Uptake Index (SUI) were calculated to assess dopaminergic integrity in both patients and HC. Comparisons of SUI values between the two groups were performed, and the correlation between R1 and brain glucose metabolism was analyzed across cortical and subcortical regions. Results: DP patients exhibited significantly lower SUI values for the caudate (11.5 ± 3.2), putamen (8.6 ± 3.9), and substantia nigra (1.5 ± 0.9) compared to HC (17.9 ± 2.9, 22.3 ± 3.1, and 4.7 ± 1.4, respectively; p < 0.001 for all regions). A strong correlation was identified between R1 values derived from 18 F-PR04.MZ studies and brain metabolism in various regions, including the putamen (correlation coefficient [CC] 0.82), caudate nuclei (CC 0.73), parietal (CC 0.68), occipital (CC 0.63), frontal (CC 0.69), and temporal cortex (CC 0.82, p<0.001 for all comparisons). Conclusion: R1 images derived from dynamic 18 F-PR04.MZ studies offer promising insights into CBF changes in cortical and subcortical regions affected by DP. This strategy holds potential as a tool in the differential diagnosis of DP. DAT parkinsonism dopamine metabolism Figures Figure 1 Figure 2 Figure 3 Introduction Degenerative parkinsonisms (DP) are characterized by the progressive degeneration of the nigrostriatal dopaminergic system. DP includes Parkinson's disease (PD) and the so-called atypical parkinsonisms (AP, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration)( 1 ). Each of these clinical entities presents distinct differences regarding patient diagnosis, prognosis, and clinical management( 1 ). Although all DP exhibit presynaptic dopaminergic system degeneration, the patterns of cerebral blood flow (CBF) and glucose metabolism alterations differ among clinical entities( 2 ). Parkinsonian multisystem atrophy (MSAp) typically presents with hypometabolism in the striatum, whereas cerebellar multisystem atrophy (MSAc) shows more pronounced hypometabolism in the cerebellum. Progressive supranuclear palsy (PSP) usually exhibits hypometabolism in the basal ganglia, as well as in the mesial and orbitofrontal cortex. Corticobasal degeneration (CBD), on the other hand, commonly displays markedly asymmetric hypometabolism, involving the frontal and parietal cortices and the striatum contralateral to the symptoms( 2 ). These patterns can aid in the differential diagnosis of AP versus PD, which typically demonstrates preserved metabolism in the basal ganglia and various cortical structures(3–5). Given that cerebral glucose metabolism and CBF are coupled in many neurodegenerative pathologies( 6 , 7 ), both 18 F-FDG-PET and cerebral perfusion SPECT have been used to identify these patterns and establish differential diagnoses among clinical entities( 2 , 3 , 8 – 10 ). Radiopharmaceuticals for diagnostic PET/CT imaging of the dopamine transporter (DAT) have proven useful in detecting the dopaminergic depletion characteristic of DP, facilitating their differentiation from other parkinsonian syndromes, such as drug-induced parkinsonism and essential tremor( 11 – 14 ). Among these tracers, 18 F-PR04.MZ is a newly developed PET radiopharmaceutical that exhibits exceptional affinity and selectivity for the dopamine transporter( 15 – 20 ). This radiotracer has demonstrated outstanding efficacy in identifying dopaminergic depletion in patients with parkinsonian syndromes, specifically in the striatum and substantia nigra( 16 ). Previous studies using various radiotracers in dementia and movement disorders have indicated that early phase images, derived from the dynamic and compartmental analysis of PET/CT acquisitions, may serve as a proxy for CBF and, consequently, as potential biomarkers of neurodegeneration ( 21 – 26 ). This approach enables the simultaneous assessment of neurodegeneration and dopaminergic depletion in a single study, with the potential to aid in the differential diagnosis between PD and AP. 18 F-PR04.MZ is a lipophilic radiotracer capable of crossing the blood-brain barrier. While kinetic models have been validated to study the behavior of this radiotracer in the brain, the association between R1 images of 18 F-PR04.MZ and cerebral glucose metabolism in patients with DP has yet to be investigated. This study aimed to explore the association between R1 values from dynamic 18 F-PR04.MZ studies, as a proxy of CBF, and brain glucose metabolism in patients diagnosed with DP. Materials and methods Subjects This prospective clinical study was approved by the respective ethical committees (approval CEHC-UDELAR-20160615 and CEC-SSM-Oriente approval 20140520), and all subjects read and signed the informed consent form before their participation. In total, fifteen patients with DP (six females, 60 ± 9.9 years, range 40–77 years) were enrolled at the Uruguayan Center of Molecular Imaging (CUDIM) and examined with dual PET/CT imaging with 18 F-PR04.MZ and 18 F-FDG. Among the patients with DP, 10 patients had Parkinson's disease [Unified Parkinson Disease Rating Scale III (UPDRS III) 30 ± 6.8, Hoehn and Yahr Scale (HYS) 2.2 ± 0.4], four had multiple system atrophy [2 MSAp, 2 MSAc, HYS 3], and one had PSP [UPDRS III 29, HYS 3]). The patients were eligible for inclusion if they were 20 years of age or older and had a clinical diagnosis of a DP confirmed by a neurologist specializing in movement disorders. Exclusion criteria included pregnancy, current breastfeeding, claustrophobia or conditions that prevented them from remaining comfortably on the scanner bed. Patients with both PD and AP were intentionally included, as this sample would represent the spectrum of DP in which this approach may be useful as differential diagnosis. The diagnosis of PD was based on the UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria( 27 ). Patients with a diagnosis of MSA met the criteria of Gilman et al. ( 28 ), and patients with PSP met the criteria of Gunter et al( 29 ). All patients underwent a structural magnetic resonance imaging (MRI), that included a volumetric T1, axial FLAIR, axial T2, T2star, and DWI to exclude any significant vascular lesions. Table 1 provides a summary of clinical and demographic data of the patients. Table 1 Summary of clinical, demographic, and dopaminergic imaging data in patients and HC. *UPDRS III only for PD and PSP patients. HC: Healthy Controls. DP: Degenerative Parkinsonisms. HYS: Hoehn and Yahr Scale. UPDRSIII: Unified Parkinson Disease Rating Scale III. SUI: Specific Uptake Index. MSA: Multisystemic atrophy. PD: Parkinson´s disease. Patient N° HC (n = 15) DP (n = 15) P value 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Sex F F F M M M F F M M M M F M M 3 females 6 females 0.427 Age 52 47 59 59 57 58 77 62 64 40 68 72 67 68 50 53.1 (22–80) 60 (40–77) 0.575 HYS 3 2 3 2 2 2 2 2 3 2 3 3 3 2 3 - 2 ( 2 – 3 ) - UPRDS III - 33 38 29 30 30 19 31 - 35 - 37 - 18 29 - 30 (18–38) - Diagnosis MSA PD PD PD PD PD PD PD MSA PD MSA PD MSA PD PSP - 10 PD, 4 MSA, 1 PSP - Caudate SUI 9.9 12.55 14.12 11.17 11.16 9.46 12.41 6.15 9.79 17.68 9.8 5.44 13.2 13.87 15.07 17.9 ± 2.9 11.45 ± 3.23 < 0.001 Putamen SUI 7.73 8.74 12.52 8.57 9.58 5.36 11.15 3.04 4.36 12.66 6.2 2.96 10.98 16.66 8.3 22.3 ± 3.1 8.59 ± 3.85 < 0.001 Substantia nigra SUI 0.94 1.18 1.56 2.15 1.31 0.99 3.57 0.63 0.85 2.22 0.88 0.57 0.32 3.26 1.85 4.7 ± 1.4 1.49 ± 0.96 < 0.001 In addition, 15 HC (3 females, 53.1 ± 20-year, range 23–80 years) were recruited at the Nuclear Medicine and PET/CT Center Positronmed, Santiago, Chile. All HCs were 20 years of age or older and showed no signs of neurological or psychiatric disorders as confirmed by standard neurological examination. PET/CT acquisition All patients with DP underwent a PET/CT scan with 18 F-FDG and a dynamic PET/CT scan with 18 F-PR04.MZ within a three-month interval (42.4 ± 20.9 days apart, range 15 to 94 days). Both studies were conducted under resting conditions, with the patients’ eyes open, ambient sound, and dim lighting. 18 F-PR04.MZ was produced under GMP-compliant conditions as previously described ( 20 ), and provided with a global radiochemical purity determined by HPLC and TLC of 97.3 \(\:\pm\:\) 1.6% and a specific activity of 234 \(\:\pm\:\) 183 (range 34 to 753) GBq/µmol. All the batches were released in agreement with quality control specifications. For the 18 F-PR04.MZ study, patients were positioned in a GE Discovery 690 or STE PET/CT scanner (GE Healthcare, USA) and the head was secured with a strap. A low-dose CT scan was performed for attenuation correction (140 kV manual; 120 mA; rotation time 0,8 sec; slice thickness 3,75 mm; pitch 0,984:1; speed 39,37). Subsequently, an intravenous injection of 18 PR04.MZ at 3 MBq/kg body weight (bw) was administered, followed by a 30-minute dynamic acquisition of 3D PET images in LIST-mode (reconstructed as 4x30sec, 9x60sec, 3x180sec, 2x300sec frames). Patients were retired from the scanner and allowed to rest for 30 min. At 65 minutes post-injection patients were repositioned in the scanner, a low-dose CT scan was conducted, and delayed images were acquired from 70 to 90 minutes post-injection (reconstructed as 4x300sec frames). Images were reconstructed using OSEM VUEPOINT, 2/24 (iterations/subsets). For 18 F-FDG studies, patients were requested to fast for at least 6 hours and blood glucose levels were measured to ensure that all patients had less than 150 mg/dL before the injection. The patients were injected with 18 F-FDG at 3 MBq/kg bw and allowed to rest for 40 min before being positioned in the PET/CT scanner with the head secured. A low-dose CT scan was acquired for attenuation correction, followed by the acquisition of a static 3D PET scan for 20 min (reconstructed as 4x300sec frames). Images were reconstructed with OSEM VUEPOINT, 2/24 (iterations/subsets) and summed images were used for further analysis. All HCs were positioned in a PET/CT scanner (Siemens mCT Flow, Erlangen, Germany) and a low-dose CT scan was performed for attenuation correction. Subsequently, 3 MBq/kg bw of 18 F-PR04.MZ were administered intravenously, and a dynamic 3D PET scan was acquired over 90 minutes (reconstructed in 6x10sec, 6x20sec, 5x60sec, 6x120sec, 14x300sec frames). Attenuation correction and scatter correction were applied, and the images were reconstructed using an iterative algorithm (2 iterations and 21 subsets). Image analysis The images were visually inspected and, if required, corrected for motion or misalignment using the Pmod software (Version 3.9; PMOD Technologies Ltd). Subsequently, 18 F-PR04.MZ images were coregistered to 18 F-FDG images, which were used as an input for spatial normalization to the Montreal Neurological Institute (MNI) space. Spatial normalization to the 18 F-FDG template implemented in PMOD (mutual information algorithm) was calculated, and the transformations were applied to the 18 F-PR04.MZ studies (PNeuro V3.9, PMOD Technologies). Parametric R1 images were then obtained (PxMOD V3.9, PMOD Technologies) using the Simplified Reference Tissue Model (SRTM) with the cerebellum (CER) as reference region. The SRTM allows parametric quantification of the local delivery rate of the radioligand (R1: [mL / (cm 3 * min)]), the effective tissue efflux constant (k2: 1/min) and the binding potential without the need to measure the arterial input function. It further provides a good fit for time-activity-curves of 18 F-PR04.MZ and stable and reproducible values when using the CER as a reference( 20 ). R1 values were calculated as indicated below and the parametric image, obtained from R1 in each subject, represents the regional CBF, normalized to the CER considered as a reference signal. $$\:R1VOI=\frac{K1VOI}{K1CER}$$ In HC, two sets of R1 images were obtained: one calculated from 90-minute dynamic studies and the other from 30-minute studies. The correlation between these two sets of images was analysed in the 15 subjects, using composite cortical and basal ganglia VOIs, to determine whether R1 data could be derived from shorter studies (30 minutes) that would be better tolerated by patients with DP. Given the excellent correlation observed between both sets of images (see Results section), R1 images in patients with DP were obtained from 30-minute dynamic studies. For the analysis of dopaminergic integrity, the 70–90-minute post-injection images from 18 F-PR04.MZ studies were visually inspected to assess movement artifacts. The 18 F-PR04.MZ images were coregistered with the 18 F-FDG images of each patient. Subsequently, the 18 F-FDG images were used as a reference for spatial normalization to the MNI space, using mutual information algorithms and an 18 F-FDG template available in PMOD. The transformations calculated from the 18 F-FDG images were applied to the previously coregistered 18 F-PR04.MZ studies. Predefined volumes of interest (VOIs) in MNI space were used in regions such as the caudate nuclei, putamen, substantia nigra, and cerebellum. The Specific Uptake Index (SUI) for each region was calculated as follows: $$\:SUI\:=\:\frac{mean\:uptake\:VOI-cerebellum}{cerebellum}$$ For the correlation analysis between R1 and 18 F-FDG, a set of VOIs predefined for MNI (Hammers atlas) was used, grouping VOIs of the frontal, temporal, occipital, and parietal cortices, as well as the caudate nuclei, putamen, and cerebellum. For the analysis of the 18 F-FDG images, motion correction and spatial normalization to the MNI space were performed using the same procedure mentioned earlier, applying the same set of VOIs. The intensity of all images was normalized to the CER uptake (reference region for kinetic analysis). Statistics The comparison between the SUIs of patients and controls was performed using a two-tailed t-test, considering an alpha of 0.05. Age and gender in both groups were compared by a non-parametric test (Mann–Whitney U and Fisher exact tests). A correlation analyses between R1 and 18 F-FDG of the cortical and basal ganglia VOIs was performed using a two-tailed Pearson's test. A p-value < 0.05 was considered significant. To account for the factor of multiple VOI comparisons (six in total), a Bonferroni correction was applied, setting a p-value threshold of 0.008. Statistical analyses were conducted in SigmaPlot. Additionally, correlations obtained based on VOIs were compared with voxel-based correlation analysis. For this, the Statistical Parametric Mapping software version 12 (SPM12) was used as previously described by Rodriguez-Vieitez et al.( 26 ) Briefly, parametric R1 images and 18 F-FDG images were normalized to MNI space and smoothed by applying an 8 mm FWHM Gaussian filter. A Pearson correlation analysis was performed on MatLab (corr function, MATLAB VERSION: 8.3.0, R2014a), applying a threshold of correlation coefficient > 0.7 and p < 0.05. Cerebellar uptake was used as a covariate in the analysis. Results were projected onto a cortical surface template using BrainNet Viewer (Xia et al., 2013, http://www.nitrc.org/projects/bnv/ ). Results Patients Patients with DP did not show significant differences compared to HCs in age (53.1 ± 20 years and 60 ± 9.9 years for HC and patients, respectively) and in sex (3 and 6 females in the HC and DP group, respectively). None of the PD patients did present significant alterations in structural MRI (e.g., cortical or subcortical infarcts and other significant vascular lesions or other lesions) that would have required their exclusion from the analyses. Table 1 summarizes the demographic and clinical data of the patients. All DP patients showed lower SUIs in all of the measured subcortical regions (11.5 ± 3.2, 8.6 ± 3.9, and 1.5 ± 0.9 for caudate, putamen, and substantia nigra, respectively) in comparison with HC (17.9 ± 2.9, 22.3 ± 3.1, and 4.7 ± 1.4 for caudate, putamen, and substantia nigra, respectively, p < 0.001, Fig. 1 ). Relationship between F-FDG and R1 Values for F-PR04.MZ First, the correlation between the R1 values obtained at 30 and 90 minutes in HCs was studied, with the aim of determining the validity of the dynamic analysis of the 30-minute studies. A significant correlation was found between the R1 values derived from the 90-minute and 30-minute scan (Fig. 2 -A) in both, in the cortex (Correlation coefficient [CC] 0.99, p < 0.001) and in the basal ganglia (CC 0.97, p < 0.001). Therefore, the R1 values obtained from the 30-minute acquisition were used for the subsequent evaluation of DP patients. The correlation coefficients between the R1 and 18 F-FDG values of DP patients are shown in Fig. 2 -B. In general, a significant correlation was found in all cortical and subcortical regions (p < 0.001), with correlation coefficients ranging from 0.63 to 0.82, with the highest being observed in the putamen and in the temporal cortex. Voxel based analysis confirmed the significant correlation in several structures, with the highest cortical correlation coefficients in the temporal, occipital and parietal cortex (Fig. 2 -C). Figure 3 shows representative patients diagnosed with PD, PSP and MSAp. The dopaminergic depletion is shown in each case. Metabolic 18 F-FDG images showed preserved metabolism in the basal ganglia of the PD patient, severe hypometabolism in both striatum in the MSAp patient, and moderate frontal hypometabolism in the PSP patient. In all cases R1 images showed similar CBF findings. Discussion This prospective study evaluated the relationship between R1 values derived from the 18 F-PR04.MZ examinations as a proxy of CBF, and cerebral glucose metabolism in patients with DP. By analysing the correlations across various cortical and subcortical regions, our study revealed a robust association between the two variables. These findings suggest that R1 images could provide valuable, additional information for the differential diagnosis of parkinsonian syndromes. Within various neurodegenerative pathologies, there is a coupling between CBF and glucose metabolism( 6 ). In dementias, it has been shown that metabolic alterations are generally slightly more pronounced than CBF changes, although both tend to follow the same pattern( 7 ). Importantly, both methodologies demonstrate strong diagnostic performance in identifying the underlying causes of cognitive decline. This is why PET with 18 F-FDG and cerebral perfusion SPECT are both employed for the differential diagnosis of diverse neurodegenerative diseases, yielding reliable results in distinguishing between clinical entities( 30 , 31 ). Furthermore, both are valuable tools for assessing parkinsonian syndromes, helping to identify the characteristic patterns of PD and AP( 2 , 8 , 10 ). The association between R1 and cerebral metabolism was observed in both cortical and subcortical regions. Notably, this association was particularly significant in the striatum. This finding is highly relevant, as the striatum is a region frequently affected in AP but typically spared in early PD( 2 , 32 ). Detecting reduced CBF in the striatum through R1 alterations could represent a valuable strategy for the differential diagnosis between these clinical entities. Previous studies using other radiotracers in dementias and parkinsonian syndromes (such as 11 C-PIB or others) have demonstrated that early images derived from compartmental analysis of dynamic studies can serve as a rough index of CBF( 21 – 23 , 25 , 26 ). This approach has been utilized in previous studies to assess neurodegeneration in dementias ( 7 , 33 ). Other authors have also shown significant correlations for proxies of CBF of other dopaminergic radiotracers in cortical and subcortical regions, with similar correlation coefficient values in comparison to our results. Appel et al. showed a strong correlation of R1 obtained from the compartmental analysis of 11 C-PE2I studies and 18 F-FDG images, both in the cortex and the striatum( 25 ). Jin et al. analysed the correlation of a proxy of CBF in 18 F-FP-CIT studies and 18 F-FDG with good correlation results( 24 ). As expected, PD patients exhibited significant dopaminergic depletion compared to HC. Although numerous studies have demonstrated that the pattern of dopaminergic depletion differs between PD and AP, utilizing these differences for the differential diagnosis of these clinical entities is not recommended due to limited diagnostic reliability( 4 , 5 , 9 , 34 ). Recent diagnostic algorithms advocate the use of 18 F-FDG PET to distinguish PD from various forms of AP( 2 – 4 ). The approach proposed in this study could complement these recommendations by enhancing diagnostic strategies through the simultaneous identification of altered CBF and dopaminergic depletion, thereby guiding the differential diagnosis between PD and AP syndromes. The potential use of R1 images derived from 18 F-PR04.MZ studies for the differential diagnosis of parkinsonian syndromes offers significant advantages compared to performing two separate studies (DAT and 18 F-FDG). These benefits include reduced costs, optimized evaluation times, and lower radiation exposure for patients. One significant technical consideration arising from this work is the feasibility of acquiring a reliable R1 parametric image using an initial 30minute scan with this radiopharmaceutical. This is particularly relevant for scaling the approach to a larger patient population, as patients with DP may struggle to tolerate 90-minute acquisition protocols. Shorter acquisition times could improve the practicality and feasibility of generating R1 images. Furthermore, in high-demand clinical settings, optimizing scanner utilization is critical to meet patient care demands effectively. The limitations of the study include the limited number of patients and the small sample of AP. Nevertheless, previous studies applying similar approaches have relied on a comparable number of cases ( 24 – 26 ). It would be necessary to compare the diagnostic performance of R1 and 18 F-FDG in larger scale studies to determine whether the similarities in uptake patterns may impact into diagnostic decisions. Conclusions This study assessed the relationship between a proxy of CBF obtained from dynamic studies with the DAT-targeting radiopharmaceutical 18 F-PR04.MZ and brain metabolism, revealing a strong correlation that supports the use of these images to highlight the characteristic alterations of DP. This approach has the potential to assist in the differential diagnosis of degenerative parkinsonian syndromes, with a potential impact on patient management. Declarations Acknowledgments The authors would like to express their sincere gratitude to Dr. Henry Engler for his valuable contributions to this work. We are also deeply thankful to the patients and their families for their participation and trust, which made this study possible. This research was financially supported by the Uruguayan Centre of Molecular Imaging (CUDIM), Montevideo, Uruguay. We dedicate this work to the memory of Dr. Ricardo Buzo, whose contributions were essential to both the conception and development of this study. Conflicts of Interest The authors declare no conflicts of interest related to this study. References Bruno MK, Dhall R, Duquette A, Haq IU, Honig LS, Lamotte G, et al. A General Neurologist’s Practical Diagnostic Algorithm for Atypical Parkinsonian Disorders A Consensus Statement. 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Höglinger GU, Respondek G, Stamelou M, Kurz C, Josephs KA, Lang AE, et al. Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria. Movement Disorders. 2017 Jun;32(6):853–64. Ferrando R, Damian A. Brain SPECT as a Biomarker of Neurodegeneration in Dementia in the Era of Molecular Imaging: Still a Valid Option? Vol. 12, Frontiers in Neurology. 2021. Damian A, Portugal F, Niell N, Quagliata A, Bayardo K, Alonso O, et al. Clinical Impact of PET With 18F-FDG and 11C-PIB in Patients With Dementia in a Developing Country. Front Neurol. 2021;12. Kapitan M, Ferrando R, Dieguez E, de Medina O, Aljanati R, Ventura R, et al. [Regional cerebral blood flow changes in Parkinson’s disease: correlation with disease duration]. Rev Esp Med Nucl [Internet]. 2009/06/30. 2009;28(3):114–20. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19558951 Gietl A, Warnock G, Riese F, Kälin A, Saake A, Gruber E, et al. Regional cerebral blood flow estimated by early PiB uptake is reduced in mild cognitive impairment and associated with age in an amyloid-dependent manner. Neurobiol Aging. 2015;36(4):1619–28. S. H, F. A, A. K, R. B, O.H. W, W. V, et al. [18F]FDG-PET is superior to [123I]IBZM-SPECT for the differential diagnosis of parkinsonism. Neurology. 2012;79(13):1314–22. 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6711157","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":462173625,"identity":"c6812e9f-17e4-452d-acbf-53ed239a1ce5","order_by":0,"name":"Andres Damian","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8ElEQVRIiWNgGAWjYHACAxDB2ABCDBVA5mHStJwhTQuIbAMSBwio55/dvO3Dhz8Msv3TDjd+Lpxnl9h3nDuB4eOeWpxaJO4cK545s43BeMbtxGbpmduSE2ce5t3AOOPZcdzW3MgxZuZtYEhsuJ3YIM277UDiBqAWZp4Dx3DqkAdp+fOHIXE+0JbfvHOI0GIA0sLAxpC44XZimzRvA1xLDU4thjfSihl72ySMNwK1WPMcSzYG+eXgjAMHcGqRu5G8meHHHxvZebfTH9/mqbGT7Tt/duODDwfqcHsfAiRQuQeIilB0QNCWUTAKRsEoGDkAAFN6YCGJj4epAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-5275-6067","institution":"Centro Uruguayo de Imagenología Molecular (CUDIM)","correspondingAuthor":true,"prefix":"","firstName":"Andres","middleName":"","lastName":"Damian","suffix":""},{"id":462173626,"identity":"3f2ba9ca-7874-41ea-ae67-712bd2928857","order_by":1,"name":"Vasko Kramer","email":"","orcid":"","institution":"Nuclear Medicine and PET/CT Center PositronMed. Julio Prado 714, Providencia, Santiago, Chile. PositronPharma SA. Julio Prado 738, Santiago, Chile","correspondingAuthor":false,"prefix":"","firstName":"Vasko","middleName":"","lastName":"Kramer","suffix":""},{"id":462173627,"identity":"bf1e9b6f-6777-4bba-ab11-f95aeea2b5a4","order_by":2,"name":"Ignacio Amorin","email":"","orcid":"","institution":"5-\tInstituto de Neurología, Hospital de Clínicas, Universidad de la República (UdelaR). Hospital de Clínicas, Av. Italia s/n. Montevideo, Uruguay.","correspondingAuthor":false,"prefix":"","firstName":"Ignacio","middleName":"","lastName":"Amorin","suffix":""},{"id":462173628,"identity":"fc54f11b-1f1d-46f0-8391-c520f02b4858","order_by":3,"name":"Luis Gutierrez","email":"","orcid":"","institution":"2-\tUnidad Académica de Medicina Nuclear e Imagenología Molecular, Hospital de Clínicas, Universidad de la República (UdelaR), Hospital de Clínicas. Av. Italia s/n. Montevideo, Uruguay","correspondingAuthor":false,"prefix":"","firstName":"Luis","middleName":"","lastName":"Gutierrez","suffix":""},{"id":462173629,"identity":"506231f4-c2f5-4e6f-9599-9038d49c1255","order_by":4,"name":"Germán Falasco","email":"","orcid":"","institution":"Uruguayan Centre of Molecular Imaging (CUDIM). Av. Ricaldoni 2010, Montevideo, Uruguay.","correspondingAuthor":false,"prefix":"","firstName":"Germán","middleName":"","lastName":"Falasco","suffix":""},{"id":462173630,"identity":"4eccad66-1872-4834-9b59-77253c106dfa","order_by":5,"name":"Leandro Urrutia","email":"","orcid":"","institution":"Uruguayan Centre of Molecular Imaging (CUDIM). Av. Ricaldoni 2010, Montevideo, Uruguay.","correspondingAuthor":false,"prefix":"","firstName":"Leandro","middleName":"","lastName":"Urrutia","suffix":""},{"id":462173631,"identity":"ad702bfd-3b95-4164-95d2-5b7ed1078fce","order_by":6,"name":"Ismael Cordero","email":"","orcid":"","institution":"Uruguayan Centre of Molecular Imaging (CUDIM). Av. Ricaldoni 2010, Montevideo, Uruguay.","correspondingAuthor":false,"prefix":"","firstName":"Ismael","middleName":"","lastName":"Cordero","suffix":""},{"id":462173632,"identity":"45eaf539-1541-4c5f-947a-5b17fd6c18de","order_by":7,"name":"Eduardo Savio","email":"","orcid":"","institution":"Uruguayan Centre of Molecular Imaging (CUDIM). Av. Ricaldoni 2010, Montevideo, Uruguay.","correspondingAuthor":false,"prefix":"","firstName":"Eduardo","middleName":"","lastName":"Savio","suffix":""},{"id":462173633,"identity":"a0ceafb3-e51b-4e7f-b3d9-23bc2280071c","order_by":8,"name":"Enrique Cuña","email":"","orcid":"","institution":"1-\tUruguayan Centre of Molecular Imaging (CUDIM). Av. Ricaldoni 2010, Montevideo, Uruguay.","correspondingAuthor":false,"prefix":"","firstName":"Enrique","middleName":"","lastName":"Cuña","suffix":""},{"id":462173634,"identity":"3887476b-aea5-408b-828f-f19f755adcb9","order_by":9,"name":"Cristian Soza-Ried","email":"","orcid":"","institution":"Nuclear Medicine and PET/CT Center PositronMed. Julio Prado 714, Providencia, Santiago, Chile. PositronPharma SA. Julio Prado 738, Santiago, Chile","correspondingAuthor":false,"prefix":"","firstName":"Cristian","middleName":"","lastName":"Soza-Ried","suffix":""},{"id":462173635,"identity":"f0a10b71-308d-4e98-a82f-ca88f8f1863b","order_by":10,"name":"Pedro Chana Cuevas","email":"","orcid":"","institution":"Department of Neurology, Facultad de Medicina, Universidad de Santiago. Av. Independencia 1027. Chile Centro de Estudio de Trastornos del Movimiento. Av. José Joaquín Prieto 7271. Santiago, Chile","correspondingAuthor":false,"prefix":"","firstName":"Pedro","middleName":"Chana","lastName":"Cuevas","suffix":""},{"id":462173636,"identity":"07d21dcc-7a31-4709-abf3-a1885a3fb641","order_by":11,"name":"Juan R. Higgie","email":"","orcid":"","institution":"5-\tInstituto de Neurología, Hospital de Clínicas, Universidad de la República (UdelaR). Hospital de Clínicas, Av. Italia s/n. Montevideo, Uruguay.","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"R.","lastName":"Higgie","suffix":""},{"id":462173637,"identity":"8c2bcf9d-815f-4455-a445-4bad050adb87","order_by":12,"name":"Andrés Lescano","email":"","orcid":"","institution":"Instituto de Neurología, Hospital de Clínicas, Universidad de la República (UdelaR). Hospital de Clínicas, Av. Italia s/n. Montevideo, Uruguay.","correspondingAuthor":false,"prefix":"","firstName":"Andrés","middleName":"","lastName":"Lescano","suffix":""},{"id":462173638,"identity":"dca3990e-077f-4f51-a3f6-7f0feec0ddb8","order_by":13,"name":"Thalia Arias","email":"","orcid":"","institution":"Unidad Académica de Medicina Nuclear e Imagenología Molecular, Hospital de Clínicas, Universidad de la República (UdelaR), Hospital de Clínicas. Av. Italia s/n. Montevideo, Uruguay","correspondingAuthor":false,"prefix":"","firstName":"Thalia","middleName":"","lastName":"Arias","suffix":""},{"id":462173639,"identity":"b1801578-c175-4256-a9f3-010ed3a33e08","order_by":14,"name":"Pablo Duarte","email":"","orcid":"","institution":"Uruguayan Centre of Molecular Imaging (CUDIM). Av. Ricaldoni 2010, Montevideo, Uruguay.","correspondingAuthor":false,"prefix":"","firstName":"Pablo","middleName":"","lastName":"Duarte","suffix":""},{"id":462173640,"identity":"663bcfae-d778-40cf-98e5-6d153334f481","order_by":15,"name":"Omar Alonso","email":"","orcid":"","institution":"Uruguayan Centre of Molecular Imaging (CUDIM). Av. Ricaldoni 2010, Montevideo, Uruguay. Unidad Académica de Medicina Nuclear e Imagenología Molecular, Hospital de Clínicas, Universidad de la República (UdelaR), Hospital de Clínicas. Av. Italia s/n. Montevideo, Uruguay.","correspondingAuthor":false,"prefix":"","firstName":"Omar","middleName":"","lastName":"Alonso","suffix":""},{"id":462173641,"identity":"edc799fb-aa56-4d8c-9c01-5ca939599a88","order_by":16,"name":"Rodolfo Ferrando","email":"","orcid":"","institution":"Uruguayan Centre of Molecular Imaging (CUDIM). Av. Ricaldoni 2010, Montevideo, Uruguay. Unidad Académica de Medicina Nuclear e Imagenología Molecular, Hospital de Clínicas, Universidad de la República (UdelaR), Hospital de Clínicas. Av. Italia s/n. Montevideo, Uruguay.","correspondingAuthor":false,"prefix":"","firstName":"Rodolfo","middleName":"","lastName":"Ferrando","suffix":""}],"badges":[],"createdAt":"2025-05-20 23:21:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6711157/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6711157/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83681076,"identity":"f7fa342f-5c49-4df9-9e51-2d6d3f7905c7","added_by":"auto","created_at":"2025-05-30 16:08:53","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":34537,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSUI comparison between patients and HC.\u003c/strong\u003e SUI comparison between HC and DP for the Caudate nuclei (a), Putamen (b) and Sustantia Nigra (c). A significant decrease in SUI is observed in DP patients in all regions (p\u0026lt;0.001). SUI: Specific Uptake Index. HC: Healthy Controls. DP: Degenerative parkinsonisms.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6711157/v1/b32991fa69732acca31a37ed.png"},{"id":83681078,"identity":"d62fe71d-175a-49c3-88c1-4c93e65f4843","added_by":"auto","created_at":"2025-05-30 16:08:53","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":250366,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation analysis.\u003c/strong\u003e Correlation between R1 obtained from 30 min and 90 min acquisitions (Correlation coefficient [CC] 0.99, p\u0026lt;0.001 for the cortex, CC 0.97 p\u0026lt;0.001 for the basal ganglia) (a). Correlation between R1 and \u003csup\u003e18\u003c/sup\u003eF-FDG images in cortical and subcortical regions (b). The correlation analysis was significant in all comparison (p\u0026lt;0.001), accounting for multiple comparison correction (Bonferroni adjusted p 0.008). Correlation coefficients vary from 0.63 to 0.82. Voxel wise correlation analysis (c) Pearson correlation p\u0026lt;0.05. Correlation coef. \u0026gt; 0.7\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6711157/v1/a66969b85baa3d61120ca60e.png"},{"id":83681546,"identity":"9ee65264-48f6-4030-b163-ae7a7d531061","added_by":"auto","created_at":"2025-05-30 16:16:54","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":348957,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRepresentative cases.\u003c/strong\u003e Representative cases with PD, MSAp and PSP. The first column shows dopaminergic depletion in all cases (SUI). The column on the right column shows metabolic parametric images, that revealed preserved metabolism in the basal ganglia in PD (white arrow), severe hypometabolism in the striatum of the patient with MSAp (red arrow) and mesial frontal hypometabolism of the PSP patient (blue arrow). In all cases the R1 parametric images shows similar CBF alterations (middle column). R1 and metabolic normalized to cerebellum.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6711157/v1/a5a8ed2df180c7e0129e497d.png"},{"id":85630030,"identity":"746391c9-e692-4a75-9472-5c5c8c0c3d6b","added_by":"auto","created_at":"2025-06-30 03:03:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1410313,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6711157/v1/f47f43c6-0fc5-4ee9-a452-3baf083535f5.pdf"}],"financialInterests":"","formattedTitle":"Dual Biomarker Potential of 18F-PR04.MZ-PET: Assessing Dopaminergic Function and Cerebral Blood Flow in Degenerative Parkinsonian Syndromes","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDegenerative parkinsonisms (DP) are characterized by the progressive degeneration of the nigrostriatal dopaminergic system. DP includes Parkinson's disease (PD) and the so-called atypical parkinsonisms (AP, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration)(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Each of these clinical entities presents distinct differences regarding patient diagnosis, prognosis, and clinical management(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlthough all DP exhibit presynaptic dopaminergic system degeneration, the patterns of cerebral blood flow (CBF) and glucose metabolism alterations differ among clinical entities(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Parkinsonian multisystem atrophy (MSAp) typically presents with hypometabolism in the striatum, whereas cerebellar multisystem atrophy (MSAc) shows more pronounced hypometabolism in the cerebellum. Progressive supranuclear palsy (PSP) usually exhibits hypometabolism in the basal ganglia, as well as in the mesial and orbitofrontal cortex. Corticobasal degeneration (CBD), on the other hand, commonly displays markedly asymmetric hypometabolism, involving the frontal and parietal cortices and the striatum contralateral to the symptoms(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). These patterns can aid in the differential diagnosis of AP versus PD, which typically demonstrates preserved metabolism in the basal ganglia and various cortical structures(3\u0026ndash;5). Given that cerebral glucose metabolism and CBF are coupled in many neurodegenerative pathologies(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), both \u003csup\u003e18\u003c/sup\u003eF-FDG-PET and cerebral perfusion SPECT have been used to identify these patterns and establish differential diagnoses among clinical entities(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRadiopharmaceuticals for diagnostic PET/CT imaging of the dopamine transporter (DAT) have proven useful in detecting the dopaminergic depletion characteristic of DP, facilitating their differentiation from other parkinsonian syndromes, such as drug-induced parkinsonism and essential tremor(\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Among these tracers, \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ is a newly developed PET radiopharmaceutical that exhibits exceptional affinity and selectivity for the dopamine transporter(\u003cspan additionalcitationids=\"CR16 CR17 CR18 CR19\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). This radiotracer has demonstrated outstanding efficacy in identifying dopaminergic depletion in patients with parkinsonian syndromes, specifically in the striatum and substantia nigra(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePrevious studies using various radiotracers in dementia and movement disorders have indicated that early phase images, derived from the dynamic and compartmental analysis of PET/CT acquisitions, may serve as a proxy for CBF and, consequently, as potential biomarkers of neurodegeneration (\u003cspan additionalcitationids=\"CR22 CR23 CR24 CR25\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). This approach enables the simultaneous assessment of neurodegeneration and dopaminergic depletion in a single study, with the potential to aid in the differential diagnosis between PD and AP. \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ is a lipophilic radiotracer capable of crossing the blood-brain barrier. While kinetic models have been validated to study the behavior of this radiotracer in the brain, the association between R1 images of \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ and cerebral glucose metabolism in patients with DP has yet to be investigated.\u003c/p\u003e \u003cp\u003eThis study aimed to explore the association between R1 values from dynamic \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ studies, as a proxy of CBF, and brain glucose metabolism in patients diagnosed with DP.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSubjects\u003c/h2\u003e \u003cp\u003e This prospective clinical study was approved by the respective ethical committees (approval CEHC-UDELAR-20160615 and CEC-SSM-Oriente approval 20140520), and all subjects read and signed the informed consent form before their participation. In total, fifteen patients with DP (six females, 60\u0026thinsp;\u0026plusmn;\u0026thinsp;9.9 years, range 40\u0026ndash;77 years) were enrolled at the Uruguayan Center of Molecular Imaging (CUDIM) and examined with dual PET/CT imaging with \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ and \u003csup\u003e18\u003c/sup\u003eF-FDG. Among the patients with DP, 10 patients had Parkinson's disease [Unified Parkinson Disease Rating Scale III (UPDRS III) 30\u0026thinsp;\u0026plusmn;\u0026thinsp;6.8, Hoehn and Yahr Scale (HYS) 2.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4], four had multiple system atrophy [2 MSAp, 2 MSAc, HYS 3], and one had PSP [UPDRS III 29, HYS 3]). The patients were eligible for inclusion if they were 20 years of age or older and had a clinical diagnosis of a DP confirmed by a neurologist specializing in movement disorders. Exclusion criteria included pregnancy, current breastfeeding, claustrophobia or conditions that prevented them from remaining comfortably on the scanner bed. Patients with both PD and AP were intentionally included, as this sample would represent the spectrum of DP in which this approach may be useful as differential diagnosis. The diagnosis of PD was based on the UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Patients with a diagnosis of MSA met the criteria of Gilman et al. (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e), and patients with PSP met the criteria of Gunter et al(\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). All patients underwent a structural magnetic resonance imaging (MRI), that included a volumetric T1, axial FLAIR, axial T2, T2star, and DWI to exclude any significant vascular lesions. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e provides a summary of clinical and demographic data of the patients.\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\u003eSummary of clinical, demographic, and dopaminergic imaging data in patients and HC.\u003c/b\u003e *UPDRS III only for PD and PSP patients. HC: Healthy Controls. DP: Degenerative Parkinsonisms. HYS: Hoehn and Yahr Scale. UPDRSIII: Unified Parkinson Disease Rating Scale III. SUI: Specific Uptake Index. MSA: Multisystemic atrophy. PD: Parkinson\u0026acute;s disease.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"19\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c19\" colnum=\"19\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"15\" nameend=\"c16\" namest=\"c2\"\u003e \u003cp\u003ePatient N\u0026deg;\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c17\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eHC (n\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c18\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eDP (n\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c19\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c13\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c14\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c15\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c16\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003e3 females\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cp\u003e6 females\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cp\u003e0.427\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e 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colname=\"c12\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003e53.1 (22\u0026ndash;80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cp\u003e60 (40\u0026ndash;77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cp\u003e0.575\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHYS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUPRDS III\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cp\u003e30 (18\u0026ndash;38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eMSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eMSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eMSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003ePSP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cp\u003e10 PD, 4 MSA, 1 PSP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCaudate SUI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e9.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e17.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e9.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e5.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e13.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e13.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e15.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003e17.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cp\u003e11.45\u0026thinsp;\u0026plusmn;\u0026thinsp;3.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePutamen SUI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e11.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e12.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e6.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e10.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e16.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e8.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003e22.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cp\u003e8.59\u0026thinsp;\u0026plusmn;\u0026thinsp;3.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubstantia nigra SUI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e3.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e1.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c17\"\u003e \u003cp\u003e4.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c18\"\u003e \u003cp\u003e1.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c19\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn addition, 15 HC (3 females, 53.1\u0026thinsp;\u0026plusmn;\u0026thinsp;20-year, range 23\u0026ndash;80 years) were recruited at the Nuclear Medicine and PET/CT Center Positronmed, Santiago, Chile. All HCs were 20 years of age or older and showed no signs of neurological or psychiatric disorders as confirmed by standard neurological examination.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePET/CT acquisition\u003c/h3\u003e\n\u003cp\u003eAll patients with DP underwent a PET/CT scan with \u003csup\u003e18\u003c/sup\u003eF-FDG and a dynamic PET/CT scan with \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ within a three-month interval (42.4\u0026thinsp;\u0026plusmn;\u0026thinsp;20.9 days apart, range 15 to 94 days). Both studies were conducted under resting conditions, with the patients\u0026rsquo; eyes open, ambient sound, and dim lighting.\u003c/p\u003e \u003cp\u003e \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ was produced under GMP-compliant conditions as previously described (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e), and provided with a global radiochemical purity determined by HPLC and TLC of 97.3 \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\pm\\:\\)\u003c/span\u003e\u003c/span\u003e 1.6% and a specific activity of 234 \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\pm\\:\\)\u003c/span\u003e\u003c/span\u003e 183 (range 34 to 753) GBq/\u0026micro;mol. All the batches were released in agreement with quality control specifications.\u003c/p\u003e \u003cp\u003eFor the \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ study, patients were positioned in a GE Discovery 690 or STE PET/CT scanner (GE Healthcare, USA) and the head was secured with a strap. A low-dose CT scan was performed for attenuation correction (140 kV manual; 120 mA; rotation time 0,8 sec; slice thickness 3,75 mm; pitch 0,984:1; speed 39,37). Subsequently, an intravenous injection of \u003csup\u003e18\u003c/sup\u003ePR04.MZ at 3 MBq/kg body weight (bw) was administered, followed by a 30-minute dynamic acquisition of 3D PET images in LIST-mode (reconstructed as 4x30sec, 9x60sec, 3x180sec, 2x300sec frames). Patients were retired from the scanner and allowed to rest for 30 min. At 65 minutes post-injection patients were repositioned in the scanner, a low-dose CT scan was conducted, and delayed images were acquired from 70 to 90 minutes post-injection (reconstructed as 4x300sec frames). Images were reconstructed using OSEM VUEPOINT, 2/24 (iterations/subsets).\u003c/p\u003e \u003cp\u003eFor \u003csup\u003e18\u003c/sup\u003eF-FDG studies, patients were requested to fast for at least 6 hours and blood glucose levels were measured to ensure that all patients had less than 150 mg/dL before the injection. The patients were injected with \u003csup\u003e18\u003c/sup\u003eF-FDG at 3 MBq/kg bw and allowed to rest for 40 min before being positioned in the PET/CT scanner with the head secured. A low-dose CT scan was acquired for attenuation correction, followed by the acquisition of a static 3D PET scan for 20 min (reconstructed as 4x300sec frames). Images were reconstructed with OSEM VUEPOINT, 2/24 (iterations/subsets) and summed images were used for further analysis.\u003c/p\u003e \u003cp\u003eAll HCs were positioned in a PET/CT scanner (Siemens mCT Flow, Erlangen, Germany) and a low-dose CT scan was performed for attenuation correction. Subsequently, 3 MBq/kg bw of \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ were administered intravenously, and a dynamic 3D PET scan was acquired over 90 minutes (reconstructed in 6x10sec, 6x20sec, 5x60sec, 6x120sec, 14x300sec frames). Attenuation correction and scatter correction were applied, and the images were reconstructed using an iterative algorithm (2 iterations and 21 subsets).\u003c/p\u003e\n\u003ch3\u003eImage analysis\u003c/h3\u003e\n\u003cp\u003eThe images were visually inspected and, if required, corrected for motion or misalignment using the Pmod software (Version 3.9; PMOD Technologies Ltd). Subsequently, \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ images were coregistered to \u003csup\u003e18\u003c/sup\u003eF-FDG images, which were used as an input for spatial normalization to the Montreal Neurological Institute (MNI) space. Spatial normalization to the \u003csup\u003e18\u003c/sup\u003eF-FDG template implemented in PMOD (mutual information algorithm) was calculated, and the transformations were applied to the \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ studies (PNeuro V3.9, PMOD Technologies). Parametric R1 images were then obtained (PxMOD V3.9, PMOD Technologies) using the Simplified Reference Tissue Model (SRTM) with the cerebellum (CER) as reference region. The SRTM allows parametric quantification of the local delivery rate of the radioligand (R1: [mL / (cm\u003csup\u003e3\u003c/sup\u003e * min)]), the effective tissue efflux constant (k2: 1/min) and the binding potential without the need to measure the arterial input function. It further provides a good fit for time-activity-curves of \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ and stable and reproducible values when using the CER as a reference(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). R1 values were calculated as indicated below and the parametric image, obtained from R1 in each subject, represents the regional CBF, normalized to the CER considered as a reference signal.\u003cdiv id=\"Equa\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e\n$$\\:R1VOI=\\frac{K1VOI}{K1CER}$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eIn HC, two sets of R1 images were obtained: one calculated from 90-minute dynamic studies and the other from 30-minute studies. The correlation between these two sets of images was analysed in the 15 subjects, using composite cortical and basal ganglia VOIs, to determine whether R1 data could be derived from shorter studies (30 minutes) that would be better tolerated by patients with DP. Given the excellent correlation observed between both sets of images (see Results section), R1 images in patients with DP were obtained from 30-minute dynamic studies.\u003c/p\u003e \u003cp\u003eFor the analysis of dopaminergic integrity, the 70\u0026ndash;90-minute post-injection images from \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ studies were visually inspected to assess movement artifacts. The \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ images were coregistered with the \u003csup\u003e18\u003c/sup\u003eF-FDG images of each patient. Subsequently, the \u003csup\u003e18\u003c/sup\u003eF-FDG images were used as a reference for spatial normalization to the MNI space, using mutual information algorithms and an \u003csup\u003e18\u003c/sup\u003eF-FDG template available in PMOD. The transformations calculated from the \u003csup\u003e18\u003c/sup\u003eF-FDG images were applied to the previously coregistered \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ studies. Predefined volumes of interest (VOIs) in MNI space were used in regions such as the caudate nuclei, putamen, substantia nigra, and cerebellum. The Specific Uptake Index (SUI) for each region was calculated as follows:\u003cdiv id=\"Equb\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equb\" name=\"EquationSource\"\u003e\n$$\\:SUI\\:=\\:\\frac{mean\\:uptake\\:VOI-cerebellum}{cerebellum}$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eFor the correlation analysis between R1 and \u003csup\u003e18\u003c/sup\u003eF-FDG, a set of VOIs predefined for MNI (Hammers atlas) was used, grouping VOIs of the frontal, temporal, occipital, and parietal cortices, as well as the caudate nuclei, putamen, and cerebellum. For the analysis of the \u003csup\u003e18\u003c/sup\u003eF-FDG images, motion correction and spatial normalization to the MNI space were performed using the same procedure mentioned earlier, applying the same set of VOIs. The intensity of all images was normalized to the CER uptake (reference region for kinetic analysis).\u003c/p\u003e\n\u003ch3\u003eStatistics\u003c/h3\u003e\n\u003cp\u003eThe comparison between the SUIs of patients and controls was performed using a two-tailed t-test, considering an alpha of 0.05. Age and gender in both groups were compared by a non-parametric test (Mann\u0026ndash;Whitney U and Fisher exact tests). A correlation analyses between R1 and \u003csup\u003e18\u003c/sup\u003eF-FDG of the cortical and basal ganglia VOIs was performed using a two-tailed Pearson's test. A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant. To account for the factor of multiple VOI comparisons (six in total), a Bonferroni correction was applied, setting a p-value threshold of 0.008. Statistical analyses were conducted in SigmaPlot. Additionally, correlations obtained based on VOIs were compared with voxel-based correlation analysis. For this, the Statistical Parametric Mapping software version 12 (SPM12) was used as previously described by Rodriguez-Vieitez et al.(\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) Briefly, parametric R1 images and \u003csup\u003e18\u003c/sup\u003eF-FDG images were normalized to MNI space and smoothed by applying an 8 mm FWHM Gaussian filter. A Pearson correlation analysis was performed on MatLab (corr function, MATLAB VERSION: 8.3.0, R2014a), applying a threshold of correlation coefficient\u0026thinsp;\u0026gt;\u0026thinsp;0.7 and p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Cerebellar uptake was used as a covariate in the analysis. Results were projected onto a cortical surface template using BrainNet Viewer (Xia et al., 2013, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.nitrc.org/projects/bnv/\u003c/span\u003e\u003cspan address=\"http://www.nitrc.org/projects/bnv/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003ePatients with DP did not show significant differences compared to HCs in age (53.1\u0026thinsp;\u0026plusmn;\u0026thinsp;20 years and 60\u0026thinsp;\u0026plusmn;\u0026thinsp;9.9 years for HC and patients, respectively) and in sex (3 and 6 females in the HC and DP group, respectively). None of the PD patients did present significant alterations in structural MRI (e.g., cortical or subcortical infarcts and other significant vascular lesions or other lesions) that would have required their exclusion from the analyses. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the demographic and clinical data of the patients.\u003c/p\u003e \u003cp\u003eAll DP patients showed lower SUIs in all of the measured subcortical regions (11.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2, 8.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9, and 1.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9 for caudate, putamen, and substantia nigra, respectively) in comparison with HC (17.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9, 22.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1, and 4.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4 for caudate, putamen, and substantia nigra, respectively, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRelationship between F-FDG and R1 Values for F-PR04.MZ\u003c/h3\u003e\n\u003cp\u003eFirst, the correlation between the R1 values obtained at 30 and 90 minutes in HCs was studied, with the aim of determining the validity of the dynamic analysis of the 30-minute studies. A significant correlation was found between the R1 values derived from the 90-minute and 30-minute scan (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e-A) in both, in the cortex (Correlation coefficient [CC] 0.99, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and in the basal ganglia (CC 0.97, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Therefore, the R1 values obtained from the 30-minute acquisition were used for the subsequent evaluation of DP patients.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe correlation coefficients between the R1 and \u003csup\u003e18\u003c/sup\u003eF-FDG values of DP patients are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e-B. In general, a significant correlation was found in all cortical and subcortical regions (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), with correlation coefficients ranging from 0.63 to 0.82, with the highest being observed in the putamen and in the temporal cortex. Voxel based analysis confirmed the significant correlation in several structures, with the highest cortical correlation coefficients in the temporal, occipital and parietal cortex (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e-C).\u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows representative patients diagnosed with PD, PSP and MSAp. The dopaminergic depletion is shown in each case. Metabolic \u003csup\u003e18\u003c/sup\u003eF-FDG images showed preserved metabolism in the basal ganglia of the PD patient, severe hypometabolism in both striatum in the MSAp patient, and moderate frontal hypometabolism in the PSP patient. In all cases R1 images showed similar CBF findings.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis prospective study evaluated the relationship between R1 values derived from the \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ examinations as a proxy of CBF, and cerebral glucose metabolism in patients with DP. By analysing the correlations across various cortical and subcortical regions, our study revealed a robust association between the two variables. These findings suggest that R1 images could provide valuable, additional information for the differential diagnosis of parkinsonian syndromes.\u003c/p\u003e \u003cp\u003eWithin various neurodegenerative pathologies, there is a coupling between CBF and glucose metabolism(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). In dementias, it has been shown that metabolic alterations are generally slightly more pronounced than CBF changes, although both tend to follow the same pattern(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Importantly, both methodologies demonstrate strong diagnostic performance in identifying the underlying causes of cognitive decline. This is why PET with \u003csup\u003e18\u003c/sup\u003eF-FDG and cerebral perfusion SPECT are both employed for the differential diagnosis of diverse neurodegenerative diseases, yielding reliable results in distinguishing between clinical entities(\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Furthermore, both are valuable tools for assessing parkinsonian syndromes, helping to identify the characteristic patterns of PD and AP(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe association between R1 and cerebral metabolism was observed in both cortical and subcortical regions. Notably, this association was particularly significant in the striatum. This finding is highly relevant, as the striatum is a region frequently affected in AP but typically spared in early PD(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Detecting reduced CBF in the striatum through R1 alterations could represent a valuable strategy for the differential diagnosis between these clinical entities.\u003c/p\u003e \u003cp\u003ePrevious studies using other radiotracers in dementias and parkinsonian syndromes (such as \u003csup\u003e11\u003c/sup\u003eC-PIB or others) have demonstrated that early images derived from compartmental analysis of dynamic studies can serve as a rough index of CBF(\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). This approach has been utilized in previous studies to assess neurodegeneration in dementias (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). Other authors have also shown significant correlations for proxies of CBF of other dopaminergic radiotracers in cortical and subcortical regions, with similar correlation coefficient values in comparison to our results. Appel et al. showed a strong correlation of R1 obtained from the compartmental analysis of \u003csup\u003e11\u003c/sup\u003eC-PE2I studies and \u003csup\u003e18\u003c/sup\u003eF-FDG images, both in the cortex and the striatum(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Jin et al. analysed the correlation of a proxy of CBF in \u003csup\u003e18\u003c/sup\u003eF-FP-CIT studies and \u003csup\u003e18\u003c/sup\u003eF-FDG with good correlation results(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAs expected, PD patients exhibited significant dopaminergic depletion compared to HC. Although numerous studies have demonstrated that the pattern of dopaminergic depletion differs between PD and AP, utilizing these differences for the differential diagnosis of these clinical entities is not recommended due to limited diagnostic reliability(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). Recent diagnostic algorithms advocate the use of \u003csup\u003e18\u003c/sup\u003eF-FDG PET to distinguish PD from various forms of AP(\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). The approach proposed in this study could complement these recommendations by enhancing diagnostic strategies through the simultaneous identification of altered CBF and dopaminergic depletion, thereby guiding the differential diagnosis between PD and AP syndromes.\u003c/p\u003e \u003cp\u003eThe potential use of R1 images derived from \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ studies for the differential diagnosis of parkinsonian syndromes offers significant advantages compared to performing two separate studies (DAT and \u003csup\u003e18\u003c/sup\u003eF-FDG). These benefits include reduced costs, optimized evaluation times, and lower radiation exposure for patients. One significant technical consideration arising from this work is the feasibility of acquiring a reliable R1 parametric image using an initial 30minute scan with this radiopharmaceutical. This is particularly relevant for scaling the approach to a larger patient population, as patients with DP may struggle to tolerate 90-minute acquisition protocols. Shorter acquisition times could improve the practicality and feasibility of generating R1 images. Furthermore, in high-demand clinical settings, optimizing scanner utilization is critical to meet patient care demands effectively.\u003c/p\u003e \u003cp\u003eThe limitations of the study include the limited number of patients and the small sample of AP. Nevertheless, previous studies applying similar approaches have relied on a comparable number of cases (\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). It would be necessary to compare the diagnostic performance of R1 and \u003csup\u003e18\u003c/sup\u003eF-FDG in larger scale studies to determine whether the similarities in uptake patterns may impact into diagnostic decisions.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis study assessed the relationship between a proxy of CBF obtained from dynamic studies with the DAT-targeting radiopharmaceutical \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ and brain metabolism, revealing a strong correlation that supports the use of these images to highlight the characteristic alterations of DP. This approach has the potential to assist in the differential diagnosis of degenerative parkinsonian syndromes, with a potential impact on patient management.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to express their sincere gratitude to Dr. Henry Engler for his valuable contributions to this work. We are also deeply thankful to the patients and their families for their participation and trust, which made this study possible. This research was financially supported by the Uruguayan Centre of Molecular Imaging (CUDIM), Montevideo, Uruguay.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe dedicate this work to the memory of Dr. Ricardo Buzo, whose contributions were essential to both the conception and development of this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest related to this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBruno MK, Dhall R, Duquette A, Haq IU, Honig LS, Lamotte G, et al. A General Neurologist\u0026rsquo;s Practical Diagnostic Algorithm for Atypical Parkinsonian Disorders A Consensus Statement. Vol. 14, Neurology: Clinical Practice. Lippincott Williams and Wilkins; 2024. \u003c/li\u003e\n\u003cli\u003eMeles SK, Teune LK, de Jong BM, Dierckx RA, Leenders KL. Metabolic Imaging in Parkinson Disease. Journal of Nuclear Medicine. 2017 Jan;58(1):23\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eWalker Z, Gandolfo F, Orini S, Garibotto V, Agosta F, Arbizu J, et al. Clinical utility of FDG PET in Parkinson\u0026rsquo;s disease and atypical parkinsonism associated with dementia. Vol. 45, European Journal of Nuclear Medicine and Molecular Imaging. 2018. p. 1534\u0026ndash;45. \u003c/li\u003e\n\u003cli\u003eArbizu J, Luquin MR, Abella J, de la Fuente-Fern\u0026aacute;ndez R, Fernandez-Torr\u0026oacute;n R, Garc\u0026iacute;a-Sol\u0026iacute;s D, et al. Neuroimagen funcional en el diagn\u0026oacute;stico de pacientes con s\u0026iacute;ndrome parkinsoniano: actualizaci\u0026oacute;n y recomendaciones para el uso cl\u0026iacute;nico. Rev Esp Med Nucl Imagen Mol [Internet]. 2015;34(03):215\u0026ndash;26. Available from: http://www.elsevier.es/es-revista-revista-espanola-medicina-nuclear-e-125-articulo-neuroimagen-funcional-el-diagnostico-pacientes-90333663\u003c/li\u003e\n\u003cli\u003eMorbelli S, Esposito G, Arbizu J, Barthel H, Boellaard R, Bohnen NI, et al. EANM practice guideline/SNMMI procedure standard for dopaminergic imaging in Parkinsonian syndromes 1.0. Eur J Nucl Med Mol Imaging. 2020;47(8):1885\u0026ndash;912. \u003c/li\u003e\n\u003cli\u003ePaulson OB, Hasselbalch SG, Rostrup E, Knudsen GM, Pelligrino D. Cerebral Blood Flow Response to Functional Activation. Journal of Cerebral Blood Flow \u0026amp; Metabolism. 2010 Jan 9;30(1):2\u0026ndash;14. \u003c/li\u003e\n\u003cli\u003eGerm\u0026aacute;n F, Andres D, Leandro U, Nicol\u0026aacute;s N, Graciela L, Yanina B, et al. Connectivity and Patterns of Regional Cerebral Blood Flow, Cerebral Glucose Uptake, and A\u0026beta;-Amyloid Deposition in Alzheimer\u0026rsquo;s Disease (Early and Late-Onset) Compared to Normal Ageing. Curr Alzheimer Res. 2021 Jul;18(8):646\u0026ndash;55. \u003c/li\u003e\n\u003cli\u003eWang L, Zhang Q, Li H, Zhang H. SPECT Molecular Imaging in Parkinson\u0026rsquo;s Disease. J Biomed Biotechnol. 2012;2012:1\u0026ndash;11. \u003c/li\u003e\n\u003cli\u003eLiu ZY, Liu FT, Zuo CT, Koprich JB, Wang J. Update on Molecular Imaging in Parkinson\u0026rsquo;s Disease. Neuroscience Bulletin. 2018. \u003c/li\u003e\n\u003cli\u003eMeyer PT, Hellwig S. Update on SPECT and PET in parkinsonism - Part 1: Imaging for differential diagnosis. Curr Opin Neurol. 2014;27(4):390\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003ePagano G, Niccolini F, Politis M. Imaging in Parkinson\u0026rsquo;s disease. Clin Med (Lond). 2016 Aug;16(4):371\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eBrooks DJ, Pavese N. Imaging biomarkers in Parkinson\u0026rsquo;s disease. Progress in Neurobiology. 2011. \u003c/li\u003e\n\u003cli\u003eStoessl AJ, Martin WRW, McKeown MJ, Sossi V. Advances in imaging in Parkinson\u0026rsquo;s disease. The Lancet Neurology. 2011. \u003c/li\u003e\n\u003cli\u003eAbbasi Gharibkandi N, Hosseinimehr SJ. Radiotracers for imaging of Parkinson\u0026rsquo;s disease. Eur J Med Chem. 2019 Mar;166:75\u0026ndash;89. \u003c/li\u003e\n\u003cli\u003eJuri C, Kramer V, Riss PJ, Soza-Ried C, Haeger A, Pruzzo R, et al. PR04.MZ PET/CT Imaging for Evaluation of Nigrostriatal Neuron Integrity in Patients with Parkinson Disease. Clin Nucl Med. 2021; \u003c/li\u003e\n\u003cli\u003eJuri C, Kramer V, Riss PJ, Soza-Ried C, Haeger A, Pruzzo R, et al. [18F]PR04.MZ PET/CT Imaging for Evaluation of Nigrostriatal Neuron Integrity in Patients With Parkinson Disease. Clin Nucl Med. 2021 Feb;46(2):119\u0026ndash;24. \u003c/li\u003e\n\u003cli\u003eLehnert W, Riss PJ, Hurtado de Mendoza A, Lopez S, Fernandez G, Ilheu M, et al. Whole-body biodistribution and radiation dosimetry of [18F]PR04.MZ: a new PET radiotracer for clinical management of patients with movement disorders. EJNMMI Res. 2022 Dec 10;12(1):1. \u003c/li\u003e\n\u003cli\u003eKramer V, Pruzzo R, Rioseco C, Hernandez E, Chana P, Juri C, et al. Evaluation and Dosimetry of [18F]PR04.MZ - Dopamine Transporter Quantification in Healthy Volunteers. In: XXV Congreso de ALASBIMN. 2015. \u003c/li\u003e\n\u003cli\u003eRiss PJ, Debus F, Hummerich R, Schmidt U, Schloss P, Lueddens H, et al. Ex vivo and in vivo evaluation of [18F]PR04.MZ in rodents: a selective dopamine transporter imaging agent. ChemMedChem [Internet]. 2009;4(9):1480\u0026ndash;7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19588472\u003c/li\u003e\n\u003cli\u003eKramer V, Juri C, Riss PJ, Pruzzo R, Soza-Ried C, Flores J, et al. Pharmacokinetic evaluation of [18F]PR04.MZ for PET/CT imaging and quantification of dopamine transporters in the human brain. Eur J Nucl Med Mol Imaging. 2020 Jul 1;47(8):1927\u0026ndash;37. \u003c/li\u003e\n\u003cli\u003eForsberg A, Engler H, Blomquist G, L\u0026aring;ngstr\u0026ouml;m B, Nordberg A. The use of PIB-PET as a dual pathological and functional biomarker in AD. Biochim Biophys Acta [Internet]. 2012 Mar [cited 2015 Sep 11];1822(3):380\u0026ndash;5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22115832\u003c/li\u003e\n\u003cli\u003eMeyer PT, Hellwig S, Amtage F, Rottenburger C, Sahm U, Reuland P, et al. Dual-biomarker imaging of regional cerebral amyloid load and neuronal activity in dementia with PET and 11C-labeled Pittsburgh compound B. J Nucl Med. 2011;52(3):393\u0026ndash;400. \u003c/li\u003e\n\u003cli\u003eHong CM, Ryu HS, Ahn BC. Early perfusion and dopamine transporter imaging using (18)F-FP-CIT PET/CT in patients with parkinsonism. Am J Nucl Med Mol Imaging. 2018;8(6):360\u0026ndash;72. \u003c/li\u003e\n\u003cli\u003eJin S, Oh M, Oh SJ, Oh JS, Lee SJ, Chung SJ, et al. Additional Value of Early-Phase 18F-FP-CIT PET Image for Differential Diagnosis of Atypical Parkinsonism. Clin Nucl Med. 2017 Feb;42(2):e80\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eAppel L, Jonasson M, Danfors T, Nyholm D, Askmark H, Lubberink M, et al. Use of \u003csup\u003e11\u003c/sup\u003e C-PE2I PET in Differential Diagnosis of Parkinsonian Disorders. Journal of Nuclear Medicine. 2015 Feb;56(2):234\u0026ndash;42. \u003c/li\u003e\n\u003cli\u003eRodriguez-Vieitez E, Carter SF, Chiotis K, Saint-Aubert L, Leuzy A, Scholl M, et al. Comparison of Early-Phase 11C-Deuterium-L-Deprenyl and 11C-Pittsburgh Compound B PET for Assessing Brain Perfusion in Alzheimer Disease. Journal of Nuclear Medicine. 2016;57(7):1071\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eDaniel SE, Lees AJ. Parkinson\u0026rsquo;s Disease Society Brain Bank, London: Overview and research. In: Journal of Neural Transmission, Supplement. 1993. \u003c/li\u003e\n\u003cli\u003eGilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008;71(9). \u003c/li\u003e\n\u003cli\u003eH\u0026ouml;glinger GU, Respondek G, Stamelou M, Kurz C, Josephs KA, Lang AE, et al. Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria. Movement Disorders. 2017 Jun;32(6):853\u0026ndash;64. \u003c/li\u003e\n\u003cli\u003eFerrando R, Damian A. Brain SPECT as a Biomarker of Neurodegeneration in Dementia in the Era of Molecular Imaging: Still a Valid Option? Vol. 12, Frontiers in Neurology. 2021. \u003c/li\u003e\n\u003cli\u003eDamian A, Portugal F, Niell N, Quagliata A, Bayardo K, Alonso O, et al. Clinical Impact of PET With 18F-FDG and 11C-PIB in Patients With Dementia in a Developing Country. Front Neurol. 2021;12. \u003c/li\u003e\n\u003cli\u003eKapitan M, Ferrando R, Dieguez E, de Medina O, Aljanati R, Ventura R, et al. [Regional cerebral blood flow changes in Parkinson\u0026rsquo;s disease: correlation with disease duration]. Rev Esp Med Nucl [Internet]. 2009/06/30. 2009;28(3):114\u0026ndash;20. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\u0026amp;db=PubMed\u0026amp;dopt=Citation\u0026amp;list_uids=19558951\u003c/li\u003e\n\u003cli\u003eGietl A, Warnock G, Riese F, K\u0026auml;lin A, Saake A, Gruber E, et al. Regional cerebral blood flow estimated by early PiB uptake is reduced in mild cognitive impairment and associated with age in an amyloid-dependent manner. Neurobiol Aging. 2015;36(4):1619\u0026ndash;28. \u003c/li\u003e\n\u003cli\u003eS. H, F. A, A. K, R. B, O.H. W, W. V, et al. [18F]FDG-PET is superior to [123I]IBZM-SPECT for the differential diagnosis of parkinsonism. Neurology. 2012;79(13):1314\u0026ndash;22. \u003c/li\u003e\n\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":"DAT, parkinsonism, dopamine, metabolism","lastPublishedDoi":"10.21203/rs.3.rs-6711157/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6711157/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003eObjective\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e18\u003c/sup\u003eF-PR04.MZ is a new PET radiopharmaceutical for the dopamine transporter (DAT), characterized by enhanced affinity and selectivity for this membrane protein. Previous investigations employing various radiotracers in dementia and movement disorders have suggested that R1 images, derived from compartmental analysis of dynamic studies, can serve as a proxy for cerebral blood flow (CBF). This study aims to evaluate the relationship between R1 values from dynamic \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ studies as a proxy of CBF and brain glucose metabolism in patients with degenerative parkinsonisms (DP).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMethods:\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFifteen patients with DP (10 with Parkinson's disease, 4 with multiple system atrophy, and 1 with progressive supranuclear palsy) underwent PET/CT imaging with both, \u003csup\u003e18\u003c/sup\u003eF-FDG and \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ. Additionally, 15 healthy controls (HC) who underwent PET/CT scans with \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ were included in the study. Parametric R1 images were generated using compartmental analysis of dynamic \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ studies via the Simplified Reference Tissue Model (SRTM). Specific Uptake Index (SUI) were calculated to assess dopaminergic integrity in both patients and HC. Comparisons of SUI values between the two groups were performed, and the correlation between R1 and brain glucose metabolism was analyzed across cortical and subcortical regions.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eResults:\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eDP patients exhibited significantly lower SUI values for the caudate (11.5 ± 3.2), putamen (8.6 ± 3.9), and substantia nigra (1.5 ± 0.9) compared to HC (17.9 ± 2.9, 22.3 ± 3.1, and 4.7 ± 1.4, respectively; p \u0026lt; 0.001 for all regions). A strong correlation was identified between R1 values derived from \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ studies and brain metabolism in various regions, including the putamen (correlation coefficient [CC] 0.82), caudate nuclei (CC 0.73), parietal (CC 0.68), occipital (CC 0.63), frontal (CC 0.69), and temporal cortex (CC 0.82, p\u0026lt;0.001 for all comparisons).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConclusion:\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eR1 images derived from dynamic \u003csup\u003e18\u003c/sup\u003eF-PR04.MZ studies offer promising insights into CBF changes in cortical and subcortical regions affected by DP. This strategy holds potential as a tool in the differential diagnosis of DP.\u003c/p\u003e","manuscriptTitle":"Dual Biomarker Potential of 18F-PR04.MZ-PET: Assessing Dopaminergic Function and Cerebral Blood Flow in Degenerative Parkinsonian Syndromes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-30 16:08:49","doi":"10.21203/rs.3.rs-6711157/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":"6836ea04-3398-472f-a317-6faabda77a8d","owner":[],"postedDate":"May 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-06-30T02:55:38+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-30 16:08:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6711157","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6711157","identity":"rs-6711157","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}