Cholinergic substrates of gait and postural impairments in Progressive Supranuclear Palsy

Cholinergic substrates of gait and postural impairments in Progressive Supranuclear Palsy | 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 Cholinergic substrates of gait and postural impairments in Progressive Supranuclear Palsy Prabesh Kanel, Giulia Carli, Stiven Roytman, Sygrid van der Zee, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8778777/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 Purpose Progressive Supranuclear Palsy (PSP) is an atypical parkinsonian syndrome characterized by significant postural instability and gait difficulties (PIGD). While brain cholinergic deficits are documented in PSP, their role in the pathophysiology of PIGD is an area of active research. This cross-sectional study aimed to elucidate relationships between regional cholinergic denervation, assessed by [ 18 F]FEOBV PET, and PIGD severity in PSP patients. Methods Nineteen subjects characterized clinically as PSP (twelve males, seven females; mean age of 69.47 ± 6.46 years [range 55–79]). Based on the Movement Disorders Society-PSP diagnostic criteria, sixteen patients had probable PSP (eleven males; five females) and three had suggestive PSP (one male; two females). Clinical assessments showed significant motor impairments, a mean MDS-UPDRS Part III “off state” score of 42.36 ± 13.52 and a mean modified Hoehn and Yahr stage of 3.36 ± 1.22. Results Statistical parametric mapping (SPM) based voxel-wise analysis of [ 18 F]FEOBV PET data revealed a significant inverse correlation between lower regional [ 18 F]FEOBV binding and more severe PIGD motor rating scores. This association was observed across brain regions, including orbitofrontal cortices, gyrus rectus, septal nuclei, medial temporal lobe, insula, metathalamus, dorsomedial thalamus, pericentral cortices, caudate nuclei, anterior greater than mid and posterior and retrosplenial cingulate cortices, frontal lobe, and cerebellum. Conclusions These findings highlight the potential roles of cholinergic systems degenerations in mediating PIGD in PSP. This suggests that cholinergic systems degeneration plays a substantial role in the pathophysiology of PIGD in PSP, offering a potential avenue for targeted therapeutic interventions to improve mobility and quality of life for these patients. Progressive Supranuclear Palsy cholinergic deficits PET imaging PIGD Figures Figure 1 Figure 2 Introduction Progressive supranuclear palsy (PSP) is a debilitating neurodegenerative disorder characterized by early-onset and severe postural instability and gait difficulties (PIGD), often leading to frequent falls [ 1 , 2 ]. While PSP shares some clinical features with Parkinson disease (PD), particularly the presence of balance and gait impairments, PSP’s underlying neuropathology and neurochemical changes are significantly different. Unlike the α-synucleinopathy of PD, PSP is primarily associated with the accumulation of 4-repeat (4R) tau protein deposits in neurons and glial cells, particularly in subcortical regions, along with characteristic atrophy of the subthalamic nuclei, midbrain, and superior cerebellar peduncles [ 3 – 6 ]. In contrast to PD, where falls tend to occur later in disease progression, PSP patients experience falls in early disease, often falling backwards due to postural rigidity [ 7 ]. Early onset and severity of PIGD in PSP poses a significant clinical challenge, as falls are a leading cause of morbidity and mortality in this population [ 8 , 9 ]. While loss of nigrostriatal dopaminergic function is a major contributor to motor impairments in PD [ 10 , 11 ], its role in PSP features is less clear. Studies show dopaminergic losses in PSP [ 12 , 13 ], but responses to dopamine replacement therapies are generally limited. Poor responses to dopaminergic replacement suggest that apart from post-synaptic dopaminergic system pathologies, other neurotransmitter systems are involved in the pathophysiology of PIGD in PSP. In PD, cholinergic deficits involving the (meta-) thalamus, striatum, hippocampus, amygdala, and some cortical regions were shown to be associated with episodic PIGD motor features (falls and freezing of gait) [ 10 , 14 ]. These results suggested a cholinergic deficits-based systems-level model of PIGD pathophysiology in PD, which might generalize to PSP. Although the regional distribution of PIGD-related cholinergic system deficits is characterized in PD, there is lack of data regarding cholinergic changes associated with PIGD in PSP. Our previous research, using vesicular acetylcholine transporter (VAChT) [ 18 F]Fluoroethoxybenzovesamicol ([ 18 F]FEOBV) PET imaging, revealed widespread cholinergic deficits in PSP, more severe and extensive than those observed in PD patients [ 15 ]. The affected areas included the tectum, metathalamus, epithalamus, pulvinar, bilateral frontal opercula, anterior insulae, superior temporal pole, anterior cingulate, several striatal subregions, the lower brainstem, and the cerebellum. This result suggests that cholinergic systems are involved more extensively as the substrates of PIGD in PSP. This study aims to investigate in vivo regional cortical and subcortical cholinergic denervation in PSP patients as related to PIGD using VAChT [ 18 F]FEOBV PET imaging. We hypothesize that cholinergic system changes play a role in the PIGD motor features in PSP and may be due to extensive subcortical (striatal, brainstem, thalamic and cerebellar) losses. By elucidating the regionally specific cholinergic deficits associated with PIGD in PSP, this study aims to inform the development of novel therapeutic strategies targeting cholinergic dysfunction in PSP. Material and Methods Study design and participants Sixteen PSP subjects were recruited from the Atypical Parkinsonism Clinic at Michigan Medicine. Three subjects were part of the Dutch Parkinson Cohort (DUPARC) study at the University of Groningen Medical Center in the Netherlands [ 16 ]. Participant recruitment and assessment protocols varied between sites. In Groningen, individuals later identified with PSP were initially enrolled as having de novo PD, and their motor function at the time of imaging was assessed with the Movement Disorder Society Revised Unified PD Rating Scale (MDS-UPDRS). The Michigan study, primarily focused on PD, also incorporated sub-studies designed for PSP. All Michigan participants, including those with PSP, were evaluated with the MDS-UPDRS, with a limited number of PSP patients receiving the PSP rating scale (see Table 1 for available PSP rating scale scores). Subjects with evidence of large vessel strokes or other intracranial lesions on MRI were excluded from the study. The Institutional Review Board of the University of Michigan School of Medicine, and Medical Ethical Committees of the University of Groningen and Veterans Affairs Ann Arbor Healthcare System approved this study (ClinicalTrials.gov Identifier: NCT02458430 & NCT01754168) in compliance with Declaration of Helsinki guidelines. Written informed consent was obtained from all participants (or legal representatives) prior to any study procedures. A subset of subjects from the Michigan site were previously included in an investigation of distinct topographies of cholinergic deficits in PSP compared to PD and neurologically healthy older individuals [ 15 ]. Subject classification utilized the 2017 Movement Disorder Society clinical diagnosis criteria for PSP (MDS-PSP) [ 17 ]. This framework allows subtyping of PSP based on predominant clinical features and levels of diagnostic certainty. In Michigan, two movement disorder specialists, with expertise in atypical parkinsonian syndromes, retrospectively applied the MDS-PSP criteria. In Groningen, a single movement disorder specialist applied the MDS-PSP criteria along with [ 18 F]Fluorodeoxyglucose-PET ([ 18 F]FDG PET) imaging to validate the PSP diagnosis at subsequent visits. These assessments focused on clinical features present at the time of imaging. To calculate MDS-UPDRS PIGD sub-scores, we used the sum of items 2.12 (Walking and balance), 2.13 (Freezing), 3.10 (Gait), 3.11 (Freezing of Gait), 3.12 (Postural Stability), 3.13 (Body stooping) from the MDS-UPDRS (Part II and Part III) and self-reported history of falls within the last year (yes or no) [ 10 ]. Imaging acquisition and pre-processing MRI was performed on a 3 Tesla Philips Achieva system (Philips, Best, The Netherlands) at Michigan Medicine and a 3 Tesla Philips Intera system (Philips, The Netherlands) at the University Medical Center Groningen (UMCG) as previously described [ 10 , 18 ]. PET imaging was performed using a Biograph 6 TruPoint PET/CT scanner (Siemens Molecular Imaging, Inc., Knoxville, TN) at the university of Michigan and Biograph 40-mCT or 64-mCT TruPoint PET/CT scanner (Siemens Molecular Imaging, Inc., Knoxville, TN) at the UMCG as previously described [ 18 , 19 ]. [ 18 F]FEOBV delayed dynamic imaging was performed over 30 minutes (in six 5-minute frames) starting at 3 hours in Michigan and 3.5 hours in Groningen after intravenous bolus dose injections of 8 mCi [ 18 F]FEOBV [ 18 ]. To ensure consistent data across PET images from both centers, we implemented a thorough harmonization process for the NC and PD populations to validate our method. This process was later applied to our PSP population. Even though both sites used the same scanner model, we calculated SUVs for the reference region, which reflect actual biological differences rather than site-specific technical variations. We addressed potential discrepancies arising from different acquisition protocols by using the same reconstruction algorithms and standardizing these parameters via post-reconstruction filtering. This approach minimized inter-center bias and established a unified dataset that is suitable for robust statistical analysis. A detail description of data harmonization process across centers available in the reference paper [ 18 ]. Equilibrium distribution volume ratio (DVR) parametric PET images were obtained using a reference region normalization approach, with eroded supraventricular cerebral white matter as the reference region. Frames 2–6 of the delayed dynamic [ 18 F]FEOBV PET image were rigidly co-registered to frame 1 to correct for motion artifacts. The dynamic PET images were subsequently averaged across frames. To obtain the reference region mask, structural MR images were AC-PC-aligned and segmented using the standard FreeSurfer software suite ( https://surfer.nmr.mgh.harvard.edu/ ). Cerebral white matter labels were truncated below the lateral ventricle and eroded with a 3mm radius sphere in MRI space. A rigid-body transformation from MR to PET space was computed and applied to the reference region labels, which were then resampled to PET resolution using nearest neighbor interpolation. Finally, parametric images were generated in PET space by dividing voxel values in each frame-averaged dynamic PET image by the mean activity of all the voxels belonging to the reference region. Structural MR images went through high-dimensional DARTEL registration and spatial normalization into Montreal Neurological Institute (MNI) space template. Using the information from MR, the registered parametric PET images were transformed to MNI space as previously described [ 15 ]. Correction for partial volume effects before standardizing into MNI space was done using Müller-Gartner method [ 20 ]. A smoothing of 8 mm full width at half maximum (FWHM = 8mm) was applied to remove random noise. [ 18 F]FEOBV Imaging analyses Voxel-wise approach : To explore regional cholinergic deficit correlates of PIGD features in PSP without any predefined restrictions (no a priori hypotheses), we conducted a whole-brain voxel-wise regression analysis using SPM12. PIGD scores were used as the independent variable and [ 18 F]FEOBV images as the dependent variable, with sex, disease duration and levodopa equivalent dose (LEDD) as nuisance covariates. Resulting statistical parametric maps were voxel-wise thresholded at an uncorrected p-value cutoff of less than 0.001, and then cluster-level false discovery rate (FDR) multiple comparison correction applied. Clusters with an FDR-corrected q-value of less than 0.01 were considered statistically significant. Primary analysis was performed on images corrected for partial volume effect, but an additional supplementary analysis was also done on images without partial volume correction (PVC; Supplementary Materials Section 1). An additional analysis was conducted using total MDS-UPDRS Part III scores to see the effects of motor symptom severity associated with cholinergic deficits (Supplementary Materials Section 2). Univariate correlation post-hoc : To obtain the proportion of variance in PIGD scores explained by [ 18 F]FEOBV uptake in relevant regions, a post-hoc univariate correlation analysis was performed, using mean [ 18 F]FEOBV uptake of the clusters which survived FDR-correction in the voxel-wise analysis as the independent variable and the MDS-PIGD score as the dependent variable. The relationship between the two variables was visualized as a scatterplot with the regression line of best fit. An additional post-hoc sensitivity analysis was performed, examining whether individual subregions contained within the cluster of statistically significant voxels (separated based on the sources of cholinergic innervation) exhibited differential strengths of association with PIGD scores (Supplementary Materials Section 3). An additional supplementary analysis was performed, examining the association between age, center (University of Michigan vs. University of Groningen), and PIGD scores and standardized uptake value (SUV) of the reference region, to support that our findings were not driven by reference region related bias (see Supplementary Materials Section 4 for detailed methods). Results This cross-sectional study included nineteen subjects with PSP, twelve males and seven females, with a mean age of 69.47 ± 6.46 years (range 55–79). Based on the 2017 MDS-PSP diagnostic criteria, sixteen subjects had probable PSP (eleven males; five females) and three had suspected PSP (one males; two females). Subtype analysis revealed thirteen with probable Richardson Syndrome (PSP-RS), one probable PSP with predominant Parkinsonian criteria (PSP-P), and three suggestive PSP with the PSP-P phenotype. Two subjects diagnosed with probable PSP were missing information required for subtyping based on the MDS-PSP criteria and were therefore classified as uncertain subtypes. The mean MDS-UPDRS Part III score in the medication ‘off’ state was 42.36 ± 13.52 and the mean modified Hoehn and Yahr stage was 3.36 ± 1.22. Phenotypic details of study subjects are provided in Table 1 . Detailed clinical and demographic characteristics are provided in Table 2 . Table 1 Clinical descriptions of study subjects based on the Movement Disorder Society clinical diagnosis criteria for PSP (MDS-PSP). Patient number Sites Ocular Motor Dysfunction Postural Instability Akinesia Cognitive Dysfunction PSP Rating Scale Total Subtype PSP01 Michigan O1 P1 -- -- -- Probable PSP-RS PSP02 Michigan O2 P1 A3 C1 -- Probable PSP-RS PSP03 Michigan O1 P1 -- C1 -- Probable PSP-RS PSP04 Michigan O1 unavailable A2 -- -- Probable PSP* PSP05 Michigan O2 P1 A2 -- -- Probable PSP-RS PSP06 Michigan O1 unavailable A2 -- -- Probable PSP* PSP07 Michigan O1 P2 A1 -- 34 Probable PSP-RS PSP08 Michigan O1 P1 -- C3 53 Probable PSP-RS PSP09 Michigan O1 P1 A1 -- 30 Probable PSP-RS PSP10 Michigan O1 P1 A1 -- 24 Probable PSP-RS PSP11 Michigan O1 -- A2 -- 24 Probable PSP-P PSP12 Michigan O1 P1 A1 C2 47 Probable PSP-RS PSP13 Michigan O1 P1 -- C2 45 Probable PSP-RS PSP14 Michigan O2 P1 A1 -- 25 Probable PSP-RS PSP15 Michigan O1 P1 A2 C2 -- Probable PSP-RS PSP16 Michigan O2 P1 A3 - 35 Probable PSP-RS PSP17 Groningen -- -- A3 C2 -- Suggestive PSP-P PSP18 Groningen -- P1 A2 -- -- Suggestive PSP-P PSP19 Groningen -- -- A3 C2 -- Suggestive PSP-P *Denotes those patients in whom details regarding the timing of postural instability relative to their disease onset was unavailable. In those cases, formal subtyping was not pursued to avoid misclassification. Table 2 Demographic, clinical, motor and cognitive details for PSP Participants Demographics Mean (SD) Age 69.47 (6.46) Gender Females: 7 Males: 12 Disease Duration (years from first symptom) 5.2 (3.70) LED (mg) 255.26 (304.09) Motor Assessments Hoehn & Yahr stage 3.36 (1.22) MDS-UPDRS Part III 42.37 (13.52) Neuropsychological Assessments MoCA 22.58 (5.49) Voxel-wise results - Voxel-based analysis revealed that lower [ 18 F]FEOBV binding in several brain regions (Fig. 1 ) correlated with more severe PIGD motor rating scores. These associations were observed in the orbitofrontal cortices, gyrus rectus, septal nuclei, medial temporal lobe, insulae, metathalamus, dorsomedial thalamus, pericentral cortices, caudate nuclei, anterior more than the mid and posterior and retrosplenial cingulate cortices, frontal lobe, and cerebellum. Table 3 details the main significant clusters, peak MNI coordinates, and associated regions. Results of analysis on images without PVC applied are presented in Supplementary Materials Section 1. Non-PVC analysis recapitulates the topography of correlated deficits found with PVC corrected images but with more extensive statistically significant voxels observed in the brainstem, pons, and midbrain (Supplementary Figure S1 ). We supplemented our primary analysis with MDS-UPDRS Part III total scores (Supplementary Materials Section 2) to observe cholinergic system deficits associated with overall motor severity. Although both models showed comparable cortical clusters, the PIGD-associated findings uniquely highlighted both cortical (insulae) and subcortical regions (striatum, thalamus, and cerebellum). This suggests that these subcortical associations are specific to PIGD rather than a reflection of global motor impairment (Supplementary Figure S2). Table 3 Significant PIGD-associated reduced [¹⁸F]FEOBV binding clusters (minimum 50 voxels) using SPM voxel-based morphometry analysis corrected for multiple comparisons using cluster-level method corrected at FDR (p < 0.001, q < 0.05) showing the peak voxel location, t-values, and associated brain regions for each cluster. Cluster (voxels) Peak MNI Coordinates BA Peak t-value Peak Voxel location Predominant Network Hub X Y Z 6080 32 10 -30 13,18 19,20 21,22 27,28 30,34 35,36 37,38 44,45 47 8.053 Right superior temporal pole Right Amygdala Right Calcarine Right lobule IV, V, VI, VIIb, VIII of cerebellar hemisphere Right Crus I and II of cerebellar hemisphere Right Posterior cingulate gyrus Right Inferior frontal gyrus Right Fusiform Right Heschl Right Hippocampus Right Insula Right Lingual Right Inferior occipital gyrus Right Posterior orbital gyrus Right ParaHippocampal gyrus Right Precuneus Right Rolandic operculum Right Inferior temporal gyrus Right Middle temporal gyrus Right Superior temporal pole Right Lateral geniculate nuclei Right Pulvinar 3567 -14 -42 4 18,19 20,21 23,27 28,29 30,34 35 8.579 Left Precuneus Left Amygdala Left Calcarine Left lobule IV, V, VI, VIIb, VIII of cerebellar hemisphere Left Crus I and II of cerebellar hemisphere Left Posterior cingulate gyrus Left Fusiform Left Hippocampus Left Lingual Left Inferior occipital gyrus Left ParaHippocampal gyrus Left Precuneus Left Inferior temporal gyrus Left Middle temporal gyrus Left Superior temporal gyrus Left Lateral geniculate nuclei Left Pulvinar Lobule IV, V and V of vermis 3022 14 32 -24 9,10 11,24 25,32 47 8.14 Right medial orbital frontal cortex Left Anterior cingulate cortex Right Anterior cingulate cortex Left Caudate Right Caudate Right Inferior frontal gyrus Right Middle frontal gyrus Left Superior frontal gyrus Right Superior frontal gyrus Left Nucleus accumbens Right Nucleus accumbens Right Anterior orbital gyrus Right Lateral orbital gyrus Left Medial orbital gyrus Right Medial orbital gyrus Left Olfactory cortex Right Olfactory cortex Left Putamen Left Rectus Right Rectus 1553 -54 -24 6 6,13 21,22 38,40 41,42 43,45 47 5.85 Left superior temporal gyrus Left Inferior frontal gyrus Left Heschl Left Insula Left Postcentral Left Rolandic operculum Left supramarginal gyrus Left Superior temporal gyrus Left superior temporal gyrus 938 -8 -6 6 5.89 Left VA thalamus Right Caudate Left Anterior nucleus Right Anterior nucleus Left Intralaminar nucleus Right Intralaminar nucleus Left Lateral posterior nucleus Right Lateral posterior nucleus Left Mediodorsal nucleus Right Mediodorsal nucleus Left Pulvinar Right Pulvinar Left Ventral anterior nucleus Right Ventral anterior nucleus Left Ventral lateral nucleus Right Ventral lateral nucleus Left Ventral posterolateral Right Ventral posterolateral 560 50 -20 12 13,22 40,41 42,43 5.26 Right opercular Rolandic cortex Right Heschl Right Insula Right Rolandic operculum Right Supramarginal gyrus Right superior temporal gyrus 282 -2 -38 24 23,31 6.58 Left posterior cingulate Left Middle cingulate gyrus Right Middle cingulate gyrus Left Posterior cingulate gyrus Right Posterior cingulate gyrus 278 16 18 36 6,9 24,32 6.43 Right middle cingulate Right anterior cingulate cortex Right Middle cingulate gyrus Right Superior frontal gyrus Right Supplementary motor area Univariate post-hoc results – Univariate post-hoc correlation analysis demonstrated that the [ 18 F]FEOBV topography from the primary voxel-wise analysis accounts for just over half of the variance in MDS-UPDRS PIGD sub-scores among PSP participants ( F = 22.94, R 2 = 0.574, p = 0.00017), with lower [ 18 F]FEOBV uptake in the discovered topography correlating with higher MDS-UPDRS PIGD sub-scores (R=-0.758 [-1.092, -0.424]). A scatterplot of the univariate relationship is presented in Fig. 2 . The sensitivity analysis demonstrated that the greatest amount of variance in PIGD scores was accounted for by voxels in the hippocampus innervated by medial septum and vertical limb of the diagonal band ( R 2 = 0.459) and voxels in the thalamus innervated by the pedunculopontine nucleus ( R 2 = 0.451). In either instance, however, variance accounted for did not exceed that obtained from the mean [ 18 F]FEOBV uptake of the entire cluster’s assemblage. Supplementary analysis demonstrated that neither age, site, nor PIGD scores associated significantly with reference region [ 18 F]FEOBV SUV (Supplementary Materials Section 4). These findings were in agreement with a previously published analysis of inter-site harmonization performed in a larger sample of normal controls and Parkinson’s disease patients [ 18 ]. Discussion This study employed [ 18 F]FEOBV VAChT brain PET imaging to quantify the extent of regional cholinergic denervation in relationship to MDS-UPDRS PIGD sub-scores in subjects with PSP. The results revealed significantly associated regional cholinergic deficits across an assemblage of brain regions. These regions include the anterior cingulate, (meta-)thalamus, striatum, limbic and paralimbic structures (hippocampus, parahippocampal gyrus and the insulae), peri-central cortices and the cerebellum. These results are highly consistent with the topography of cholinergic deficits we previously described in PSP patients compared to controls [ 15 ]. The association of cholinergic deficits in these regions with PIGD aligns with previous research describing cortical and subcortical dysfunctions in PSP motor deficits [ 21 – 24 ]. The affected regions are associated with a diverse range of functions, including oculomotor control, sensory integration, and cognitive processing, all of which are likely to contribute to maintenance of posture and gait control [ 7 , 21 , 25 , 26 ]. This result suggests that the pathophysiology of PIGD features is likely multifactorial in PSP, potentially arising from multilayered failures in sensory processing, balance, cognition, and motor control. Our results also align with the hypothesis that PSP and its clinical manifestations should be conceptualized as an assemblage of network-based disorders [ 27 ]. Our post-hoc sensitivity analysis findings supports this conclusion, given that none of the individual cholinergic innervation target subregions (separated by source of innervation) were as predictive of PIGD severity as the composite of all relevant targets. Our results implicate degeneration of all major brain cholinergic projections in the pathophysiology of PIGD in PSP. In this PSP cohort, cholinergic deficits in subcortical structures, including the bilateral metathalamus and left more than right caudate nucleus, demonstrated strong associations with PIGD features severity, substantially overlapping with our previous findings in a PD cohort [ 10 ], but with additional greater involvement of the cerebellar hemispheres. These regional cholinergic terminal deficits align with the known anatomy of cholinergic nuclei and their projections. The brainstem pedunculopontine tegmental nucleus (PPN) and the laterodorsal pontine tegmentum (LDT) complex are the primary sources of cholinergic projections to the thalamus [ 28 , 29 ]. The PPN and LDT are implicated in the coordination of gait [ 30 ]. Thalamic dysfunction is closely associated with the characteristic gait disturbances and early falls observed in PSP, with dysfunction in the mesencephalic brainstem-thalamic loop playing a crucial role in multisensory postural control [ 21 ]. The striatum is characterized by the presence of cholinergic interneurons [ 28 ], which play a central role in the basal ganglia circuitry, influencing both the control of voluntary movements and the pathophysiology of movement disorders [ 31 – 33 ]. Cerebellar cholinergic deficits likely reflect degeneration of projections from the medial vestibular complex, another structure with a critical role in postural and gait control. We also found novel evidence that PIGD motor features in PSP associated with losses of cholinergic forebrain limbocortical and paralimbic projections. These structures significantly influence cognition and behavior, particularly through the frontal-subcortical circuits [ 34 – 36 ]. Such cholinergic deficits suggest a disruption in the complex interplay of these regions and the disruption of broader neural networks subserving mobility. [ 37 – 41 ]. Entorhinal cortex, parahippocampal gyrus and retrosplenial cortex are crucial brain regions for spatial navigation [ 42 – 45 ]. Entorhinal cortex receives vestibular inputs, relayed via thalamic nuclei, providing information about balance and spatial orientation. Entorhinal dysfunction would plausibly lead to problems with spatial memory and navigation [ 42 – 44 ]. Cholinergic forebrain limbic and paralimbic projections and related deficits in attentional function and spatial navigation may be critical contributors to the multifactorial PIGD symptoms in PSP. Similarly, Anterior Cingulate Cortex (ACC), which connects the supplementary eye field, frontal eye field, and midbrain regions, plays a role in cognitive control and action valuation, including indirect role to those related to saccadic eye movement [ 25 ]. Cholinergic deficits in regions suggest a potential link between oculomotor dysfunction and overall motor impairment in PSP. The images without partial volume correction did show correlations with upper brainstem regions that are directly involved with vertical gaze functions. It is possible that the small size of the structures was the reason that findings did not survive partial volume correction. Further research with more detailed brainstem atlases and more sensitive PET images is needed. It is clear that oculomotor impairments with vertical movement difficulty and convergence as well as reduced blinking and involuntary eyelid closure, can influence gait instability, altered step length, and an increase frequency of falls in PSP [ 46 – 48 ]. The ACC participates in both medial frontal-subcortical and dorsolateral prefrontal-subcortical circuits and cholinergic ACC deficits might contribute to apathy and executive dysfunction in PSP [ 34 , 49 ]. Cognitive problems, such as executive dysfunction, slowed processing speed, attention deficits, and diminished working memory, likely also contribute to the gait instability in PSP [ 50 ]. This study has several limitations. The relatively small sample size of 19 PSP subjects, with varying subtypes, may limit the generalizability of the findings. Specifically, the observed patterns of cholinergic denervation may be primarily driven by the PSP-RS subtype, which comprised the majority of the participants. Consequently, we may have overlooked subtle topographic patterns of cholinergic loss that could explain the characteristic features of other PSP subtypes, such as PSP-P. Future studies with larger cohorts, specifically designed to include a balanced representation of different PSP subtypes, are needed to validate these findings and explore potential subtype-specific patterns of cholinergic dysfunction. However, this study provides insights into the association between regional cholinergic deficits and PIGD motor dysfunction in PSP, offering potential avenues for improving diagnosis, prognostication, and treatment of these challenging neurodegenerative disorders. The observed widespread reductions of regional cholinergic terminal density across various brain regions emphasizes the complex interplay between neurotransmitter systems and clinical manifestations of the disease. Further research is warranted to elucidate the specific mechanisms underlying these cholinergic deficits in PSP. In conclusion, our study suggests that PIGD symptoms in PSP are associated with cholinergic degeneration across an assemblage of brain regions, indicating the involvement of multifactorial deficits, including cognitive, multi-sensory, oculomotor, and emotional components. These regions significantly overlap with those found to be associated with PIGD motor features in PD, suggesting that the cholinergic system may have inherent vulnerabilities to neurodegeneration, independent of specific proteinopathies. Our study suggests that the degeneration of cholinergic innervation in thalamic, striatal, limbic, and frontal brain structures may underlie the debilitating symptoms in PSP and could serve as a target for future interventions. A novel finding is that cholinergic forebrain losses are also associated with PIGD motor features in PSP. Future cholinergic enhancement strategies, such as subtype specific cholinergic receptor agents, may offer avenues for mitigating motor dysfunction in individuals with PSP. Declarations Acknowledgements The authors thank Christine Minderovic, Cyrus Sarosh, Olivia Dickinson, Fotini Michalakis, Austin Luker, the PET technologists, cyclotron operators, and chemists, for their assistance. We are indebted to the subjects who participated in this study. Funding The work was supported by the National Institutes of Health (P01 NS015655, R01 NS070856, P50 NS091856, P50 NS123067), Department of Veterans Affairs grant (I01 RX001631), the Michael J. Fox Foundation, and the Parkinson’s Foundation. None of the funding agencies had a role in the design and conduct of the study, in the collection, management, analysis and interpretation of the data, in the preparation, review or approval of the manuscript, nor in the decision to submit the manuscript for publication. Competing Interests The authors have no relevant financial or non-financial interests to disclose. Author Contributions Prabesh Kanel, Roger L. Albin, and Nicolaas I. Bohnen contributed to the conception and design of the study. Giulia Carli, Stiven Roytman, Sygrid van der Zee, Taylor Brown, Jaimie Barr, Robert Vangel, C Chauncey Spears, Amanda Narkis, Sofie Slingerland, Sanne Meles, Teus van Laar, and Peter J.H. Scott contributed to the acquisition and analysis of data. Prabesh Kanel, Giulia Carli, Robert Vangel, and Stiven Roytman contributed to drafting the text and preparing the figures. Data Availability The data that support the findings of this study are available from the corresponding author, upon reasonable request and legal status compliance of international data. Ethics Approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board of the University of Michigan School of Medicine, Medical Ethical Committees of the University of Groningen, and Veterans Affairs Ann Arbor Healthcare System (ClinicalTrials.gov Identifier: NCT02458430 & NCT01754168). Consent to Participate Informed consent was obtained from all individual participants included in the study. References Xie T, Kang UJ, Kuo SH, Poulopoulos M, Greene P, Fahn S (2015) Comparison of clinical features in pathologically confirmed PSP and MSA patients followed at a tertiary center. NPJ Parkinsons Dis [Internet]. ;1:15007. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28725681 Hirsch EC, Graybiel AM, Duyckaerts C, Javoy-Agid F (1987) Neuronal loss in the pedunculopontine tegmental nucleus in Parkinson disease and in progressive supranuclear palsy. Proc Natl Acad Sci U S A [Internet]. ;84:5976–80. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=3475716 Kovacs GG, Lukic MJ, Irwin DJ, Arzberger T, Respondek G, Lee EB et al (2020) Distribution patterns of tau pathology in progressive supranuclear palsy. Acta Neuropathol [Internet]. ;140:99–119. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32383020 Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC et al (1996) Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology [Internet]. ;47:1–9. Available from: http://dx.doi.org/10.1212/wnl.47.1.1 Dickson DW (1999) Neuropathologic differentiation of progressive supranuclear palsy and corticobasal degeneration. J Neurol [Internet]. ;246 Suppl 2:II6-15. Available from: https://www.ncbi.nlm.nih.gov/pubmed/10525997 Dickson DW, Rademakers R, Hutton ML (2007) Progressive supranuclear palsy: pathology and genetics. Brain Pathol [Internet]. ;17:74–82. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17493041 Brown FS, Rowe JB, Passamonti L, Rittman T (2020) Falls in Progressive Supranuclear Palsy. Mov Disord Clin Pract [Internet]. ;7:16–24. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31970205 Stevens JA, Corso PS, Finkelstein EA, Miller TR (2006) The costs of fatal and non-fatal falls among older adults. Inj Prev [Internet]. ;12:290–5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17018668 Bluett B, Litvan I, Cheng S, Juncos J, Riley DE, Standaert DG et al (2017) Understanding falls in progressive supranuclear palsy. Parkinsonism Relat Disord [Internet]. ;35:75–81. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28007518 Bohnen NI, Kanel P, Koeppe RA, Sanchez-Catasus CA, Frey KA, Scott P et al (2021) Regional cerebral cholinergic nerve terminal integrity and cardinal motor features in Parkinson’s disease. Brain Communications [Internet]. ;3. Available from: http://dx.doi.org/10.1093/braincomms/fcab109 Wallert ED, van de Giessen E, Knol RJJ, Beudel M, de Bie RMA, Booij J (2022) Imaging Dopaminergic Neurotransmission in Neurodegenerative Disorders. J Nucl Med [Internet]. ;63:27S-32S. Available from: https://www.ncbi.nlm.nih.gov/pubmed/35649651 Pascual J, Berciano J, Grijalba B, del Olmo E, Gonzalez AM, Figols J et al (1992) Dopamine D1 and D2 receptors in progressive supranuclear palsy: an autoradiographic study. Ann Neurol [Internet]. ;32:703–7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/1449252 Gonzalez AM, Berciano J, Figols J, Pazos A, Pascual J (2000) Loss of dopamine uptake sites and dopamine D2 receptors in striatonigral degeneration. Brain Res [Internet]. ;852:228–32. Available from: https://www.ncbi.nlm.nih.gov/pubmed/10661519 Bohnen NI, Kanel P, Zhou Z, Koeppe RA, Frey KA, Dauer WT et al (2019) Cholinergic system changes of falls and freezing of gait in Parkinson’s disease. Ann Neurol [Internet]. ;85:538–49. Available from: http://dx.doi.org/10.1002/ana.25430 Kanel P, Spears CC, Roytman S, Koeppe RA, Frey KA, Scott PJH et al (2022) Differential cholinergic systems’ changes in progressive supranuclear palsy versus Parkinson’s disease: an exploratory analysis. J Neural Transm (Vienna) [Internet]. ;129:1469–79. Available from: https://www.ncbi.nlm.nih.gov/pubmed/36222971 Boertien JM, van der Zee S, Chrysou A, Gerritsen MJJ, Jansonius NM, Spikman JM et al (2020) Study protocol of the DUtch PARkinson Cohort (DUPARC): a prospective, observational study of de novo Parkinson’s disease patients for the identification and validation of biomarkers for Parkinson’s disease subtypes, progression and pathophysiology. BMC Neurol [Internet]. ;20:245. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32534583 Hoglinger GU, Respondek G, Stamelou M, Kurz C, Josephs KA, Lang AE et al (2017) Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria. Mov Disord [Internet]. ;32:853–64. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28467028 Bohnen NI, Roytman S, van der Zee S, Carli G, Michalakis F, Luker A et al (2025) A multicenter longitudinal study of cholinergic subgroups in Parkinson disease. Nat Commun [Internet]. ; Available from: http://dx.doi.org/10.1038/s41467-025-60815-0 Kanel P, Müller M, van der Zee S, Sanchez-Catasus CA, Koeppe RA, Frey KA et al (2020) Topography of Cholinergic Changes in Dementia With Lewy Bodies and Key Neural Network Hubs. J Neuropsychiatry Clin Neurosci [Internet]. ;32:370–5. Available from: http://dx.doi.org/10.1176/appi.neuropsych.19070165 Muller-Gartner HW, Links JM, Prince JL, Bryan RN, McVeigh E, Leal JP et al (1992) Measurement of radiotracer concentration in brain gray matter using positron emission tomography: MRI-based correction for partial volume effects. J Cereb Blood Flow Metab [Internet]. ;12:571–83. Available from: http://dx.doi.org/10.1038/jcbfm.1992.81 Zwergal A, la Fougère C, Lorenzl S, Rominger A, Xiong G, Deutschenbaur L et al (2011) Postural imbalance and falls in PSP correlate with functional pathology of the thalamus. Neurology [Internet]. ;77:101–9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21613601 Schofield EC, Hodges JR, Macdonald V, Cordato NJ, Kril JJ, Halliday GM (2011) Cortical atrophy differentiates Richardson’s syndrome from the parkinsonian form of progressive supranuclear palsy. Mov Disord [Internet]. ;26:256–63. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21412832 Nelson AB, Kreitzer AC (2014) Reassessing models of basal ganglia function and dysfunction. Annu Rev Neurosci [Internet]. ;37:117–35. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25032493 Stoodley CJ, Schmahmann JD (2010) Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing. Cortex [Internet]. ;46:831–44. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20152963 Pouget P (2015) The cortex is in overall control of voluntary eye movement. EYE [Internet]. ;29:241–5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25475239 Rittman T, Coyle-Gilchrist IT, Rowe JB (2016) Managing cognition in progressive supranuclear palsy. Neurodegener Dis Manag [Internet]. ;6:499–508. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27879155 Prasad S, Rajan A, Pasha SA, Mangalore S, Saini J, Ingalhalikar M et al (2021) Abnormal structural connectivity in progressive supranuclear palsy-Richardson syndrome. Acta Neurol Scand [Internet]. ;143:430–40. Available from: http://dx.doi.org/10.1111/ane.13372 Mesulam MM, Mash D, Hersh L, Bothwell M, Geula C (1992) Cholinergic innervation of the human striatum, globus pallidus, subthalamic nucleus, substantia nigra, and red nucleus. J Comp Neurol [Internet]. ;323:252–68. Available from: http://dx.doi.org/10.1002/cne.903230209 Mesulam MM, Mufson EJ, Wainer BH, Levey AI (1983) Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1-Ch6). Neuroscience [Internet]. ;10:1185–201. Available from: http://dx.doi.org/10.1016/0306-4522(83)90108-2 Jenkinson N, Nandi D, Muthusamy K, Ray NJ, Gregory R, Stein JF et al (2009) Anatomy, physiology, and pathophysiology of the pedunculopontine nucleus. Mov Disord [Internet]. ;24:319–28. Available from: http://dx.doi.org/10.1002/mds.22189 Aosaki T, Miura M, Suzuki T, Nishimura K, Masuda M (2010) Acetylcholine-dopamine balance hypothesis in the striatum: an update. Geriatr Gerontol Int [Internet]. ;10 Suppl 1:S148-57. Available from: http://dx.doi.org/10.1111/j.1447-0594.2010.00588.x Pisani A, Bernardi G, Ding J, Surmeier DJ (2007) Re-emergence of striatal cholinergic interneurons in movement disorders. Trends Neurosci [Internet]. ;30:545–53. Available from: http://dx.doi.org/10.1016/j.tins.2007.07.008 Pisani A, Bonsi P, Centonze D, Calabresi P, Bernardi G (2000) Activation of D2-like dopamine receptors reduces synaptic inputs to striatal cholinergic interneurons. J Neurosci [Internet]. ;20:RC69. Available from: http://dx.doi.org/10.1523/jneurosci.20-07-j0003.2000 Litvan I, Mega MS, Cummings JL, Fairbanks L (1996) Neuropsychiatric aspects of progressive supranuclear palsy. Neurology [Internet]. ;47:1184–9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/8909427 Alexander GE, DeLong MR, Strick PL (1986) Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci [Internet]. ;9:357–81. Available from: https://www.ncbi.nlm.nih.gov/pubmed/3085570 O’Callaghan C, Bertoux M, Hornberger M (2014) Beyond and below the cortex: the contribution of striatal dysfunction to cognition and behaviour in neurodegeneration. J Neurol Neurosurg Psychiatry [Internet]. ;85:371–8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23833269 Warren NM, Piggott MA, Perry EK, Burn DJ (2005) Cholinergic systems in progressive supranuclear palsy. Brain [Internet]. ;128:239–49. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15649952 Ray NJ, Kanel P, Bohnen NI (2023) Atrophy of the Cholinergic Basal Forebrain can Detect Presynaptic Cholinergic Loss in Parkinson’s Disease. Ann Neurol [Internet]. ;93:991–8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/36597786 Kasashima S, Oda Y (2003) Cholinergic neuronal loss in the basal forebrain and mesopontine tegmentum of progressive supranuclear palsy and corticobasal degeneration. Acta Neuropathol [Internet]. ;105:117–24. Available from: https://www.ncbi.nlm.nih.gov/pubmed/12536222 Peter J, Mayer I, Kammer T, Minkova L, Lahr J, Kloppel S et al (2021) The relationship between cholinergic system brain structure and function in healthy adults and patients with mild cognitive impairment. Sci Rep [Internet]. ;11:16080. Available from: https://www.ncbi.nlm.nih.gov/pubmed/34373525 Chakraborty S, Haast RAM, Onuska KM, Kanel P, Prado MAM, Prado VF et al (2024) Multimodal gradients of basal forebrain connectivity across the neocortex. bioRxiv [Internet]. ; Available from: https://www.ncbi.nlm.nih.gov/pubmed/37292595 Hafting T, Fyhn M, Molden S, Moser MB, Moser EI (2005) Microstructure of a spatial map in the entorhinal cortex. Nature [Internet]. ;436:801–6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15965463 Best C, Lange E, Buchholz HG, Schreckenberger M, Reuss S, Dieterich M (2014) Left hemispheric dominance of vestibular processing indicates lateralization of cortical functions in rats. Brain Struct Funct [Internet]. ;219:2141–58. Available from: http://dx.doi.org/10.1007/s00429-013-0628-1 Reuss S, Siebrecht E, Stier U, Buchholz HG, Bausbacher N, Schabbach N et al (2020) Modeling Vestibular Compensation: Neural Plasticity Upon Thalamic Lesion. Front Neurol [Internet]. ;11:441. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32528401 Epstein RA (2008) Parahippocampal and retrosplenial contributions to human spatial navigation. Trends Cogn Sci [Internet]. ;12:388–96. Available from: http://dx.doi.org/10.1016/j.tics.2008.07.004 Lubarsky M, Juncos JL (2008) Progressive supranuclear palsy: a current review. Neurologist [Internet]. ;14:79–88. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18332837 Di Fabio RP, Zampieri C, Tuite P (2008) Gaze control and foot kinematics during stair climbing: characteristics leading to fall risk in progressive supranuclear palsy. Phys Ther [Internet]. ;88:240–50. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18073265 Quattrone A, Caligiuri ME, Morelli M, Nigro S, Vescio B, Arabia G et al (2019) Imaging counterpart of postural instability and vertical ocular dysfunction in patients with PSP: A multimodal MRI study. Parkinsonism Relat Disord [Internet]. ;63:124–30. Available from: https://www.ncbi.nlm.nih.gov/pubmed/30803901 Gerstenecker A, Duff K, Mast B, Litvan I, ENGENE-PSP Study Group (2013). Behavioral abnormalities in progressive supranuclear palsy. Psychiatry Res [Internet]. ;210:1205–10. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24035530 Egerton T, Williams DR, Iansek R (2012) Comparison of gait in progressive supranuclear palsy, Parkinson’s disease and healthy older adults. BMC Neurol [Internet]. ;12:116. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23031506 Additional Declarations The authors declare no competing interests. Supplementary Files SupplementaryMaterials.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8778777","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":585209619,"identity":"4cf81da5-8dd5-4e58-b8a9-ae76a7527d8e","order_by":0,"name":"Prabesh Kanel","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxklEQVRIiWNgGAWjYHACNiA+YMAPIhkbQCSxWiQbSNZiAFJJlBZz6cPPHnz4c8fY+EZ24oGfOxjk+G4k4Ndi2Zdmbjiz7ZmZ2Y3cDQd7zzAYSxLSYnCGwUyat+GwDUjLYcY2hsQNhLWwf5P+8+ewjfEMiJZ6IrTwmEkzsB02M5CAaEkwIOiXHp5yw962w8YSZ94C/dImYTjzzAP8Wsx52Lc9+PHnsGF/e+7mDz/bbOT5jhNyGBpfAr9ybFpGwSgYBaNgFGACACfLTr0o1AsMAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-1418-2960","institution":"University of Michigan","correspondingAuthor":true,"prefix":"","firstName":"Prabesh","middleName":"","lastName":"Kanel","suffix":""},{"id":585209620,"identity":"cd5b2fc8-bf04-4f0c-849c-bed255427325","order_by":1,"name":"Giulia Carli","email":"","orcid":"","institution":"University of Michigan","correspondingAuthor":false,"prefix":"","firstName":"Giulia","middleName":"","lastName":"Carli","suffix":""},{"id":585209621,"identity":"574ae84a-3e77-43d5-a401-f38039819bbe","order_by":2,"name":"Stiven Roytman","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Stiven","middleName":"","lastName":"Roytman","suffix":""},{"id":585213667,"identity":"e92524fc-8c62-4a27-a651-442f56fae3e4","order_by":3,"name":"Sygrid van der Zee","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Sygrid","middleName":"van der","lastName":"Zee","suffix":""},{"id":585213668,"identity":"e11386a1-632c-416d-8dc7-e3e2e078a7b7","order_by":4,"name":"Robert Vangel","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Robert","middleName":"","lastName":"Vangel","suffix":""},{"id":585213669,"identity":"0c4e3967-6572-4f3d-85c5-6229b71f62f4","order_by":5,"name":"Jaimie Barr","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Jaimie","middleName":"","lastName":"Barr","suffix":""},{"id":585213670,"identity":"b5dd0375-2fec-41ad-ad89-0ade874a5520","order_by":6,"name":"Taylor Brown","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Taylor","middleName":"","lastName":"Brown","suffix":""},{"id":585213671,"identity":"0a697163-e1de-4e1e-987b-d528b76db4cb","order_by":7,"name":"C Chauncey Spears","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"C","middleName":"Chauncey","lastName":"Spears","suffix":""},{"id":585213672,"identity":"2cf87eaf-dd12-4316-bae7-d65eb0f371d1","order_by":8,"name":"Amanda Narkis","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Amanda","middleName":"","lastName":"Narkis","suffix":""},{"id":585213673,"identity":"3cffd0b5-2f55-4dc4-88d9-d6e19bcd1451","order_by":9,"name":"Sofie Slingerland","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Sofie","middleName":"","lastName":"Slingerland","suffix":""},{"id":585213674,"identity":"f83c55a3-4135-46b6-b0bd-0a8270cdebbf","order_by":10,"name":"Sanne Meles","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Sanne","middleName":"","lastName":"Meles","suffix":""},{"id":585213675,"identity":"0f0522e4-aae2-4c9c-a6d0-1e6fc8710674","order_by":11,"name":"Teus van Laar","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Teus","middleName":"van","lastName":"Laar","suffix":""},{"id":585213676,"identity":"9fef1468-7b6b-4254-8ee7-ea5ad8f69e14","order_by":12,"name":"Peter J.H. Scott","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Peter","middleName":"J.H.","lastName":"Scott","suffix":""},{"id":585213677,"identity":"1de123b0-5a76-4b17-be48-4ef93fbcfee3","order_by":13,"name":"Roger L. Albin","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Roger","middleName":"L.","lastName":"Albin","suffix":""},{"id":585213678,"identity":"f5185fff-e787-4d0d-9412-bf4fb6d8d72b","order_by":14,"name":"Nicolaas I. Bohnen","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Nicolaas","middleName":"I.","lastName":"Bohnen","suffix":""}],"badges":[],"createdAt":"2026-02-03 17:18:39","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-8778777/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8778777/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101833860,"identity":"af0669d6-172c-45c8-80ca-db2b8b930257","added_by":"auto","created_at":"2026-02-04 07:06:32","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":808318,"visible":true,"origin":"","legend":"\u003cp\u003eVoxels where [\u003csup\u003e18\u003c/sup\u003eF]FEOBV uptake exhibited statistically significant negative correlation with MDS-PIGD scores in PSP subjects. Color indicates SPM voxel-based regression analysis strength of correlation between lower cholinergic binding and MDS-PIGD scores in PSP subjects with yellower color indicating more robust significant correlations (voxel-level uncorrected p\u0026lt;0.001, cluster-level FDR-corrected at P\u0026lt;0.01; adjusted for sex, disease duration and Levodopa Equivalent Dose).\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8778777/v1/b20d58193b4ece1be3707ea9.png"},{"id":101833858,"identity":"3cc21ba0-390a-41b4-8597-d6073c4a3658","added_by":"auto","created_at":"2026-02-04 07:06:31","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":185907,"visible":true,"origin":"","legend":"\u003cp\u003eScatterplot of the univariate correlation between MDS-PIGD scores and mean [\u003csup\u003e18\u003c/sup\u003eF]FEOBV uptake in SPM clusters which survived correction for multiple comparisons. Individual observations are colored based on PSP subtype.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8778777/v1/b1723da7250fc4fe7b98e3ba.png"},{"id":101833864,"identity":"a93a3016-299d-4cb1-9051-4ae736b4f755","added_by":"auto","created_at":"2026-02-04 07:06:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2126575,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8778777/v1/7e68e9b7-6515-4982-b7f2-77b5a9cce762.pdf"},{"id":101833859,"identity":"2a8881c8-24b9-4aef-8a14-d86d91d01c0a","added_by":"auto","created_at":"2026-02-04 07:06:31","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1227005,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-8778777/v1/e74a223809cf6bc76bbcd0d8.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eCholinergic substrates of gait and postural impairments in Progressive Supranuclear Palsy\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eProgressive supranuclear palsy (PSP) is a debilitating neurodegenerative disorder characterized by early-onset and severe postural instability and gait difficulties (PIGD), often leading to frequent falls [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. While PSP shares some clinical features with Parkinson disease (PD), particularly the presence of balance and gait impairments, PSP\u0026rsquo;s underlying neuropathology and neurochemical changes are significantly different. Unlike the α-synucleinopathy of PD, PSP is primarily associated with the accumulation of 4-repeat (4R) tau protein deposits in neurons and glial cells, particularly in subcortical regions, along with characteristic atrophy of the subthalamic nuclei, midbrain, and superior cerebellar peduncles [\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn contrast to PD, where falls tend to occur later in disease progression, PSP patients experience falls in early disease, often falling backwards due to postural rigidity [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Early onset and severity of PIGD in PSP poses a significant clinical challenge, as falls are a leading cause of morbidity and mortality in this population [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. While loss of nigrostriatal dopaminergic function is a major contributor to motor impairments in PD [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], its role in PSP features is less clear. Studies show dopaminergic losses in PSP [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], but responses to dopamine replacement therapies are generally limited. Poor responses to dopaminergic replacement suggest that apart from post-synaptic dopaminergic system pathologies, other neurotransmitter systems are involved in the pathophysiology of PIGD in PSP. In PD, cholinergic deficits involving the (meta-) thalamus, striatum, hippocampus, amygdala, and some cortical regions were shown to be associated with episodic PIGD motor features (falls and freezing of gait) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. These results suggested a cholinergic deficits-based systems-level model of PIGD pathophysiology in PD, which might generalize to PSP. Although the regional distribution of PIGD-related cholinergic system deficits is characterized in PD, there is lack of data regarding cholinergic changes associated with PIGD in PSP.\u003c/p\u003e \u003cp\u003eOur previous research, using vesicular acetylcholine transporter (VAChT) [\u003csup\u003e18\u003c/sup\u003eF]Fluoroethoxybenzovesamicol ([\u003csup\u003e18\u003c/sup\u003eF]FEOBV) PET imaging, revealed widespread cholinergic deficits in PSP, more severe and extensive than those observed in PD patients [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The affected areas included the tectum, metathalamus, epithalamus, pulvinar, bilateral frontal opercula, anterior insulae, superior temporal pole, anterior cingulate, several striatal subregions, the lower brainstem, and the cerebellum. This result suggests that cholinergic systems are involved more extensively as the substrates of PIGD in PSP.\u003c/p\u003e \u003cp\u003eThis study aims to investigate \u003cem\u003ein vivo\u003c/em\u003e regional cortical and subcortical cholinergic denervation in PSP patients as related to PIGD using VAChT [\u003csup\u003e18\u003c/sup\u003eF]FEOBV PET imaging. We hypothesize that cholinergic system changes play a role in the PIGD motor features in PSP and may be due to extensive subcortical (striatal, brainstem, thalamic and cerebellar) losses. By elucidating the regionally specific cholinergic deficits associated with PIGD in PSP, this study aims to inform the development of novel therapeutic strategies targeting cholinergic dysfunction in PSP.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and participants\u003c/h2\u003e \u003cp\u003eSixteen PSP subjects were recruited from the Atypical Parkinsonism Clinic at Michigan Medicine. Three subjects were part of the Dutch Parkinson Cohort (DUPARC) study at the University of Groningen Medical Center in the Netherlands [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Participant recruitment and assessment protocols varied between sites. In Groningen, individuals later identified with PSP were initially enrolled as having \u003cem\u003ede novo\u003c/em\u003e PD, and their motor function at the time of imaging was assessed with the Movement Disorder Society Revised Unified PD Rating Scale (MDS-UPDRS). The Michigan study, primarily focused on PD, also incorporated sub-studies designed for PSP. All Michigan participants, including those with PSP, were evaluated with the MDS-UPDRS, with a limited number of PSP patients receiving the PSP rating scale (see Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e for available PSP rating scale scores). Subjects with evidence of large vessel strokes or other intracranial lesions on MRI were excluded from the study. The Institutional Review Board of the University of Michigan School of Medicine, and Medical Ethical Committees of the University of Groningen and Veterans Affairs Ann Arbor Healthcare System approved this study (ClinicalTrials.gov Identifier: NCT02458430 \u0026amp; NCT01754168) in compliance with Declaration of Helsinki guidelines. Written informed consent was obtained from all participants (or legal representatives) prior to any study procedures. A subset of subjects from the Michigan site were previously included in an investigation of distinct topographies of cholinergic deficits in PSP compared to PD and neurologically healthy older individuals [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSubject classification utilized the 2017 Movement Disorder Society clinical diagnosis criteria for PSP (MDS-PSP) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This framework allows subtyping of PSP based on predominant clinical features and levels of diagnostic certainty. In Michigan, two movement disorder specialists, with expertise in atypical parkinsonian syndromes, retrospectively applied the MDS-PSP criteria. In Groningen, a single movement disorder specialist applied the MDS-PSP criteria along with [\u003csup\u003e18\u003c/sup\u003eF]Fluorodeoxyglucose-PET ([\u003csup\u003e18\u003c/sup\u003eF]FDG PET) imaging to validate the PSP diagnosis at subsequent visits. These assessments focused on clinical features present at the time of imaging. To calculate MDS-UPDRS PIGD sub-scores, we used the sum of items 2.12 (Walking and balance), 2.13 (Freezing), 3.10 (Gait), 3.11 (Freezing of Gait), 3.12 (Postural Stability), 3.13 (Body stooping) from the MDS-UPDRS (Part II and Part III) and self-reported history of falls within the last year (yes or no) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eImaging acquisition and pre-processing\u003c/h3\u003e\n\u003cp\u003eMRI was performed on a 3 Tesla Philips Achieva system (Philips, Best, The Netherlands) at Michigan Medicine and a 3 Tesla Philips Intera system (Philips, The Netherlands) at the University Medical Center Groningen (UMCG) as previously described [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. PET imaging was performed using a Biograph 6 TruPoint PET/CT scanner (Siemens Molecular Imaging, Inc., Knoxville, TN) at the university of Michigan and Biograph 40-mCT or 64-mCT TruPoint PET/CT scanner (Siemens Molecular Imaging, Inc., Knoxville, TN) at the UMCG as previously described [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. [\u003csup\u003e18\u003c/sup\u003eF]FEOBV delayed dynamic imaging was performed over 30 minutes (in six 5-minute frames) starting at 3 hours in Michigan and 3.5 hours in Groningen after intravenous bolus dose injections of 8 mCi [\u003csup\u003e18\u003c/sup\u003eF]FEOBV [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. To ensure consistent data across PET images from both centers, we implemented a thorough harmonization process for the NC and PD populations to validate our method. This process was later applied to our PSP population. Even though both sites used the same scanner model, we calculated SUVs for the reference region, which reflect actual biological differences rather than site-specific technical variations. We addressed potential discrepancies arising from different acquisition protocols by using the same reconstruction algorithms and standardizing these parameters via post-reconstruction filtering. This approach minimized inter-center bias and established a unified dataset that is suitable for robust statistical analysis. A detail description of data harmonization process across centers available in the reference paper [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEquilibrium distribution volume ratio (DVR) parametric PET images were obtained using a reference region normalization approach, with eroded supraventricular cerebral white matter as the reference region. Frames 2\u0026ndash;6 of the delayed dynamic [\u003csup\u003e18\u003c/sup\u003eF]FEOBV PET image were rigidly co-registered to frame 1 to correct for motion artifacts. The dynamic PET images were subsequently averaged across frames. To obtain the reference region mask, structural MR images were AC-PC-aligned and segmented using the standard \u003cem\u003eFreeSurfer\u003c/em\u003e software suite (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://surfer.nmr.mgh.harvard.edu/\u003c/span\u003e\u003cspan address=\"https://surfer.nmr.mgh.harvard.edu/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Cerebral white matter labels were truncated below the lateral ventricle and eroded with a 3mm radius sphere in MRI space. A rigid-body transformation from MR to PET space was computed and applied to the reference region labels, which were then resampled to PET resolution using nearest neighbor interpolation. Finally, parametric images were generated in PET space by dividing voxel values in each frame-averaged dynamic PET image by the mean activity of all the voxels belonging to the reference region.\u003c/p\u003e \u003cp\u003eStructural MR images went through high-dimensional DARTEL registration and spatial normalization into Montreal Neurological Institute (MNI) space template. Using the information from MR, the registered parametric PET images were transformed to MNI space as previously described [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Correction for partial volume effects before standardizing into MNI space was done using M\u0026uuml;ller-Gartner method [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. A smoothing of 8 mm full width at half maximum (FWHM\u0026thinsp;=\u0026thinsp;8mm) was applied to remove random noise.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e[\u003csup\u003e18\u003c/sup\u003eF]FEOBV Imaging analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e \u003cem\u003eVoxel-wise approach\u003c/em\u003e: To explore regional cholinergic deficit correlates of PIGD features in PSP without any predefined restrictions (no a priori hypotheses), we conducted a whole-brain voxel-wise regression analysis using SPM12. PIGD scores were used as the independent variable and [\u003csup\u003e18\u003c/sup\u003eF]FEOBV images as the dependent variable, with sex, disease duration and levodopa equivalent dose (LEDD) as nuisance covariates. Resulting statistical parametric maps were voxel-wise thresholded at an uncorrected p-value cutoff of less than 0.001, and then cluster-level false discovery rate (FDR) multiple comparison correction applied. Clusters with an FDR-corrected q-value of less than 0.01 were considered statistically significant. Primary analysis was performed on images corrected for partial volume effect, but an additional supplementary analysis was also done on images without partial volume correction (PVC; Supplementary Materials Section 1). An additional analysis was conducted using total MDS-UPDRS Part III scores to see the effects of motor symptom severity associated with cholinergic deficits (Supplementary Materials Section 2).\u003c/p\u003e \u003cp\u003e \u003cem\u003eUnivariate correlation post-hoc\u003c/em\u003e: To obtain the proportion of variance in PIGD scores explained by [\u003csup\u003e18\u003c/sup\u003eF]FEOBV uptake in relevant regions, a post-hoc univariate correlation analysis was performed, using mean [\u003csup\u003e18\u003c/sup\u003eF]FEOBV uptake of the clusters which survived FDR-correction in the voxel-wise analysis as the independent variable and the MDS-PIGD score as the dependent variable. The relationship between the two variables was visualized as a scatterplot with the regression line of best fit. An additional post-hoc sensitivity analysis was performed, examining whether individual subregions contained within the cluster of statistically significant voxels (separated based on the sources of cholinergic innervation) exhibited differential strengths of association with PIGD scores (Supplementary Materials Section 3). An additional supplementary analysis was performed, examining the association between age, center (University of Michigan vs. University of Groningen), and PIGD scores and standardized uptake value (SUV) of the reference region, to support that our findings were not driven by reference region related bias (see Supplementary Materials Section 4 for detailed methods).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThis cross-sectional study included nineteen subjects with PSP, twelve males and seven females, with a mean age of 69.47\u0026thinsp;\u0026plusmn;\u0026thinsp;6.46 years (range 55\u0026ndash;79). Based on the 2017 MDS-PSP diagnostic criteria, sixteen subjects had probable PSP (eleven males; five females) and three had suspected PSP (one males; two females). Subtype analysis revealed thirteen with probable Richardson Syndrome (PSP-RS), one probable PSP with predominant Parkinsonian criteria (PSP-P), and three suggestive PSP with the PSP-P phenotype. Two subjects diagnosed with probable PSP were missing information required for subtyping based on the MDS-PSP criteria and were therefore classified as uncertain subtypes. The mean MDS-UPDRS Part III score in the medication \u0026lsquo;off\u0026rsquo; state was 42.36\u0026thinsp;\u0026plusmn;\u0026thinsp;13.52 and the mean modified Hoehn and Yahr stage was 3.36\u0026thinsp;\u0026plusmn;\u0026thinsp;1.22. Phenotypic details of study subjects are provided in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Detailed clinical and demographic characteristics are provided in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical descriptions of study subjects based on the Movement Disorder Society clinical diagnosis criteria for PSP (MDS-PSP).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient number\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSites\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOcular Motor Dysfunction\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePostural Instability\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAkinesia\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCognitive Dysfunction\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePSP Rating Scale Total\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eSubtype\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSP01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMichigan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eO1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eProbable PSP-RS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSP02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMichigan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eO2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eProbable PSP-RS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSP03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMichigan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eO1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eProbable PSP-RS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSP04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMichigan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eO1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eunavailable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eProbable PSP*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSP05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMichigan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eO2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eProbable PSP-RS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSP06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMichigan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eO1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eunavailable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eProbable PSP*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSP07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMichigan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eO1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eProbable PSP-RS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSP08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMichigan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eO1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eProbable PSP-RS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSP09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMichigan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eO1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e--\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\u003eProbable PSP-RS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSP10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMichigan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eO1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eProbable PSP-RS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSP11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMichigan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eO1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eProbable PSP-P\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSP12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMichigan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eO1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eProbable PSP-RS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSP13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMichigan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eO1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eProbable PSP-RS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSP14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMichigan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eO2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eProbable PSP-RS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSP15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMichigan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eO1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eProbable PSP-RS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSP16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMichigan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eO2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eProbable PSP-RS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSP17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroningen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eSuggestive PSP-P\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSP18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroningen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eSuggestive PSP-P\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSP19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroningen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eSuggestive PSP-P\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003e*Denotes those patients in whom details regarding the timing of postural instability relative to their disease onset was unavailable. In those cases, formal subtyping was not pursued to avoid misclassification.\u003c/em\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic, clinical, motor and cognitive details for PSP Participants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDemographics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean (SD)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69.47 (6.46)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemales: 7\u003c/p\u003e \u003cp\u003eMales: 12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease Duration (years from first symptom)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.2 (3.70)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLED (mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e255.26 (304.09)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMotor Assessments\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHoehn \u0026amp; Yahr stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.36 (1.22)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMDS-UPDRS Part III\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42.37 (13.52)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNeuropsychological Assessments\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMoCA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22.58 (5.49)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e\u003cem\u003eVoxel-wise results\u003c/em\u003e - Voxel-based analysis revealed that lower [\u003csup\u003e18\u003c/sup\u003eF]FEOBV binding in several brain regions (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) correlated with more severe PIGD motor rating scores. These associations were observed in the orbitofrontal cortices, gyrus rectus, septal nuclei, medial temporal lobe, insulae, metathalamus, dorsomedial thalamus, pericentral cortices, caudate nuclei, anterior more than the mid and posterior and retrosplenial cingulate cortices, frontal lobe, and cerebellum. Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e details the main significant clusters, peak MNI coordinates, and associated regions. Results of analysis on images without PVC applied are presented in Supplementary Materials Section 1. Non-PVC analysis recapitulates the topography of correlated deficits found with PVC corrected images but with more extensive statistically significant voxels observed in the brainstem, pons, and midbrain (Supplementary \u003cb\u003eFigure S1\u003c/b\u003e). We supplemented our primary analysis with MDS-UPDRS Part III total scores (Supplementary Materials Section 2) to observe cholinergic system deficits associated with overall motor severity. Although both models showed comparable cortical clusters, the PIGD-associated findings uniquely highlighted both cortical (insulae) and subcortical regions (striatum, thalamus, and cerebellum). This suggests that these subcortical associations are specific to PIGD rather than a reflection of global motor impairment (Supplementary Figure S2).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSignificant PIGD-associated reduced [\u0026sup1;⁸F]FEOBV binding clusters (minimum 50 voxels) using SPM voxel-based morphometry analysis corrected for multiple comparisons using cluster-level method corrected at FDR (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, q\u0026thinsp;\u0026lt;\u0026thinsp;0.05) showing the peak voxel location, t-values, and associated brain regions for each cluster.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCluster (voxels)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003ePeak MNI Coordinates\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePeak\u003c/p\u003e \u003cp\u003et-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePeak Voxel location\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePredominant Network Hub\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eZ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6080\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e13,18\u003c/p\u003e \u003cp\u003e19,20\u003c/p\u003e \u003cp\u003e21,22\u003c/p\u003e \u003cp\u003e27,28\u003c/p\u003e \u003cp\u003e30,34\u003c/p\u003e \u003cp\u003e35,36\u003c/p\u003e \u003cp\u003e37,38\u003c/p\u003e \u003cp\u003e44,45\u003c/p\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e8.053\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRight superior temporal pole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eRight Amygdala\u003c/p\u003e \u003cp\u003eRight Calcarine\u003c/p\u003e \u003cp\u003eRight lobule IV, V, VI, VIIb, VIII of cerebellar hemisphere\u003c/p\u003e \u003cp\u003eRight Crus I and II of cerebellar hemisphere\u003c/p\u003e \u003cp\u003eRight Posterior cingulate gyrus\u003c/p\u003e \u003cp\u003eRight Inferior frontal gyrus\u003c/p\u003e \u003cp\u003eRight Fusiform\u003c/p\u003e \u003cp\u003eRight Heschl\u003c/p\u003e \u003cp\u003eRight Hippocampus\u003c/p\u003e \u003cp\u003eRight Insula\u003c/p\u003e \u003cp\u003eRight Lingual\u003c/p\u003e \u003cp\u003eRight Inferior occipital gyrus\u003c/p\u003e \u003cp\u003eRight Posterior orbital gyrus\u003c/p\u003e \u003cp\u003eRight ParaHippocampal gyrus\u003c/p\u003e \u003cp\u003eRight Precuneus\u003c/p\u003e \u003cp\u003eRight Rolandic operculum\u003c/p\u003e \u003cp\u003eRight Inferior temporal gyrus\u003c/p\u003e \u003cp\u003eRight Middle temporal gyrus\u003c/p\u003e \u003cp\u003eRight Superior temporal pole\u003c/p\u003e \u003cp\u003eRight Lateral geniculate nuclei\u003c/p\u003e \u003cp\u003eRight Pulvinar\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3567\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e18,19\u003c/p\u003e \u003cp\u003e20,21\u003c/p\u003e \u003cp\u003e23,27\u003c/p\u003e \u003cp\u003e28,29\u003c/p\u003e \u003cp\u003e30,34\u003c/p\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e8.579\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLeft Precuneus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLeft Amygdala\u003c/p\u003e \u003cp\u003eLeft Calcarine\u003c/p\u003e \u003cp\u003eLeft lobule IV, V, VI, VIIb, VIII of cerebellar hemisphere\u003c/p\u003e \u003cp\u003eLeft Crus I and II of cerebellar hemisphere\u003c/p\u003e \u003cp\u003eLeft Posterior cingulate gyrus\u003c/p\u003e \u003cp\u003eLeft Fusiform\u003c/p\u003e \u003cp\u003eLeft Hippocampus\u003c/p\u003e \u003cp\u003eLeft Lingual\u003c/p\u003e \u003cp\u003eLeft Inferior occipital gyrus\u003c/p\u003e \u003cp\u003eLeft ParaHippocampal gyrus\u003c/p\u003e \u003cp\u003eLeft Precuneus\u003c/p\u003e \u003cp\u003eLeft Inferior temporal gyrus\u003c/p\u003e \u003cp\u003eLeft Middle temporal gyrus\u003c/p\u003e \u003cp\u003eLeft Superior temporal gyrus\u003c/p\u003e \u003cp\u003eLeft Lateral geniculate nuclei\u003c/p\u003e \u003cp\u003eLeft Pulvinar\u003c/p\u003e \u003cp\u003eLobule IV, V and V of vermis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9,10\u003c/p\u003e \u003cp\u003e11,24\u003c/p\u003e \u003cp\u003e25,32\u003c/p\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e8.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRight medial orbital frontal cortex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLeft Anterior cingulate cortex\u003c/p\u003e \u003cp\u003eRight Anterior cingulate cortex\u003c/p\u003e \u003cp\u003eLeft Caudate\u003c/p\u003e \u003cp\u003eRight Caudate\u003c/p\u003e \u003cp\u003eRight Inferior frontal gyrus\u003c/p\u003e \u003cp\u003eRight Middle frontal gyrus\u003c/p\u003e \u003cp\u003eLeft Superior frontal gyrus\u003c/p\u003e \u003cp\u003eRight Superior frontal gyrus\u003c/p\u003e \u003cp\u003eLeft Nucleus accumbens\u003c/p\u003e \u003cp\u003eRight Nucleus accumbens\u003c/p\u003e \u003cp\u003eRight Anterior orbital gyrus\u003c/p\u003e \u003cp\u003eRight Lateral orbital gyrus\u003c/p\u003e \u003cp\u003eLeft Medial orbital gyrus\u003c/p\u003e \u003cp\u003eRight Medial orbital gyrus\u003c/p\u003e \u003cp\u003eLeft Olfactory cortex\u003c/p\u003e \u003cp\u003eRight Olfactory cortex\u003c/p\u003e \u003cp\u003eLeft Putamen\u003c/p\u003e \u003cp\u003eLeft Rectus\u003c/p\u003e \u003cp\u003eRight Rectus\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1553\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6,13\u003c/p\u003e \u003cp\u003e21,22\u003c/p\u003e \u003cp\u003e38,40\u003c/p\u003e \u003cp\u003e41,42\u003c/p\u003e \u003cp\u003e43,45\u003c/p\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLeft superior temporal gyrus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLeft Inferior frontal gyrus\u003c/p\u003e \u003cp\u003eLeft Heschl\u003c/p\u003e \u003cp\u003eLeft Insula\u003c/p\u003e \u003cp\u003eLeft Postcentral\u003c/p\u003e \u003cp\u003eLeft Rolandic operculum\u003c/p\u003e \u003cp\u003eLeft supramarginal gyrus\u003c/p\u003e \u003cp\u003eLeft Superior temporal gyrus\u003c/p\u003e \u003cp\u003eLeft superior temporal gyrus\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e938\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLeft VA thalamus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eRight Caudate\u003c/p\u003e \u003cp\u003eLeft Anterior nucleus\u003c/p\u003e \u003cp\u003eRight Anterior nucleus\u003c/p\u003e \u003cp\u003eLeft Intralaminar nucleus\u003c/p\u003e \u003cp\u003eRight Intralaminar nucleus\u003c/p\u003e \u003cp\u003eLeft Lateral posterior nucleus\u003c/p\u003e \u003cp\u003eRight Lateral posterior nucleus\u003c/p\u003e \u003cp\u003eLeft Mediodorsal nucleus\u003c/p\u003e \u003cp\u003eRight Mediodorsal nucleus\u003c/p\u003e \u003cp\u003eLeft Pulvinar\u003c/p\u003e \u003cp\u003eRight Pulvinar\u003c/p\u003e \u003cp\u003eLeft Ventral anterior nucleus\u003c/p\u003e \u003cp\u003eRight Ventral anterior nucleus\u003c/p\u003e \u003cp\u003eLeft Ventral lateral nucleus\u003c/p\u003e \u003cp\u003eRight Ventral lateral nucleus\u003c/p\u003e \u003cp\u003eLeft Ventral posterolateral\u003c/p\u003e \u003cp\u003eRight Ventral posterolateral\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e560\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e13,22\u003c/p\u003e \u003cp\u003e40,41\u003c/p\u003e \u003cp\u003e42,43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRight opercular Rolandic cortex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eRight Heschl\u003c/p\u003e \u003cp\u003eRight Insula\u003c/p\u003e \u003cp\u003eRight Rolandic operculum\u003c/p\u003e \u003cp\u003eRight Supramarginal gyrus\u003c/p\u003e \u003cp\u003eRight superior temporal gyrus\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e282\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e23,31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e6.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLeft posterior cingulate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLeft Middle cingulate gyrus\u003c/p\u003e \u003cp\u003eRight Middle cingulate gyrus\u003c/p\u003e \u003cp\u003eLeft Posterior cingulate gyrus\u003c/p\u003e \u003cp\u003eRight Posterior cingulate gyrus\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e278\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6,9\u003c/p\u003e \u003cp\u003e24,32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e6.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRight middle cingulate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eRight anterior cingulate cortex\u003c/p\u003e \u003cp\u003eRight Middle cingulate gyrus\u003c/p\u003e \u003cp\u003eRight Superior frontal gyrus\u003c/p\u003e \u003cp\u003eRight Supplementary motor area\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eUnivariate post-hoc results\u003c/em\u003e \u0026ndash; Univariate post-hoc correlation analysis demonstrated that the [\u003csup\u003e18\u003c/sup\u003eF]FEOBV topography from the primary voxel-wise analysis accounts for just over half of the variance in MDS-UPDRS PIGD sub-scores among PSP participants (\u003cem\u003eF\u003c/em\u003e\u0026thinsp;=\u0026thinsp;22.94, \u003cem\u003eR\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.574, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.00017), with lower [\u003csup\u003e18\u003c/sup\u003eF]FEOBV uptake in the discovered topography correlating with higher MDS-UPDRS PIGD sub-scores (R=-0.758 [-1.092, -0.424]). A scatterplot of the univariate relationship is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The sensitivity analysis demonstrated that the greatest amount of variance in PIGD scores was accounted for by voxels in the hippocampus innervated by medial septum and vertical limb of the diagonal band (\u003cem\u003eR\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.459) and voxels in the thalamus innervated by the pedunculopontine nucleus (\u003cem\u003eR\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.451). In either instance, however, variance accounted for did not exceed that obtained from the mean [\u003csup\u003e18\u003c/sup\u003eF]FEOBV uptake of the entire cluster\u0026rsquo;s assemblage. Supplementary analysis demonstrated that neither age, site, nor PIGD scores associated significantly with reference region [\u003csup\u003e18\u003c/sup\u003eF]FEOBV SUV (Supplementary Materials Section 4). These findings were in agreement with a previously published analysis of inter-site harmonization performed in a larger sample of normal controls and Parkinson\u0026rsquo;s disease patients [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study employed [\u003csup\u003e18\u003c/sup\u003eF]FEOBV VAChT brain PET imaging to quantify the extent of regional cholinergic denervation in relationship to MDS-UPDRS PIGD sub-scores in subjects with PSP. The results revealed significantly associated regional cholinergic deficits across an assemblage of brain regions. These regions include the anterior cingulate, (meta-)thalamus, striatum, limbic and paralimbic structures (hippocampus, parahippocampal gyrus and the insulae), peri-central cortices and the cerebellum. These results are highly consistent with the topography of cholinergic deficits we previously described in PSP patients compared to controls [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The association of cholinergic deficits in these regions with PIGD aligns with previous research describing cortical and subcortical dysfunctions in PSP motor deficits [\u003cspan additionalcitationids=\"CR22 CR23\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The affected regions are associated with a diverse range of functions, including oculomotor control, sensory integration, and cognitive processing, all of which are likely to contribute to maintenance of posture and gait control [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. This result suggests that the pathophysiology of PIGD features is likely multifactorial in PSP, potentially arising from multilayered failures in sensory processing, balance, cognition, and motor control. Our results also align with the hypothesis that PSP and its clinical manifestations should be conceptualized as an assemblage of network-based disorders [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Our post-hoc sensitivity analysis findings supports this conclusion, given that none of the individual cholinergic innervation target subregions (separated by source of innervation) were as predictive of PIGD severity as the composite of all relevant targets.\u003c/p\u003e \u003cp\u003eOur results implicate degeneration of all major brain cholinergic projections in the pathophysiology of PIGD in PSP. In this PSP cohort, cholinergic deficits in subcortical structures, including the bilateral metathalamus and left more than right caudate nucleus, demonstrated strong associations with PIGD features severity, substantially overlapping with our previous findings in a PD cohort [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], but with additional greater involvement of the cerebellar hemispheres. These regional cholinergic terminal deficits align with the known anatomy of cholinergic nuclei and their projections. The brainstem pedunculopontine tegmental nucleus (PPN) and the laterodorsal pontine tegmentum (LDT) complex are the primary sources of cholinergic projections to the thalamus [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The PPN and LDT are implicated in the coordination of gait [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Thalamic dysfunction is closely associated with the characteristic gait disturbances and early falls observed in PSP, with dysfunction in the mesencephalic brainstem-thalamic loop playing a crucial role in multisensory postural control [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The striatum is characterized by the presence of cholinergic interneurons [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], which play a central role in the basal ganglia circuitry, influencing both the control of voluntary movements and the pathophysiology of movement disorders [\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Cerebellar cholinergic deficits likely reflect degeneration of projections from the medial vestibular complex, another structure with a critical role in postural and gait control.\u003c/p\u003e \u003cp\u003eWe also found novel evidence that PIGD motor features in PSP associated with losses of cholinergic forebrain limbocortical and paralimbic projections. These structures significantly influence cognition and behavior, particularly through the frontal-subcortical circuits [\u003cspan additionalcitationids=\"CR35\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Such cholinergic deficits suggest a disruption in the complex interplay of these regions and the disruption of broader neural networks subserving mobility. [\u003cspan additionalcitationids=\"CR38 CR39 CR40\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Entorhinal cortex, parahippocampal gyrus and retrosplenial cortex are crucial brain regions for spatial navigation [\u003cspan additionalcitationids=\"CR43 CR44\" citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Entorhinal cortex receives vestibular inputs, relayed via thalamic nuclei, providing information about balance and spatial orientation. Entorhinal dysfunction would plausibly lead to problems with spatial memory and navigation [\u003cspan additionalcitationids=\"CR43\" citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Cholinergic forebrain limbic and paralimbic projections and related deficits in attentional function and spatial navigation may be critical contributors to the multifactorial PIGD symptoms in PSP.\u003c/p\u003e \u003cp\u003eSimilarly, Anterior Cingulate Cortex (ACC), which connects the supplementary eye field, frontal eye field, and midbrain regions, plays a role in cognitive control and action valuation, including indirect role to those related to saccadic eye movement [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Cholinergic deficits in regions suggest a potential link between oculomotor dysfunction and overall motor impairment in PSP. The images without partial volume correction did show correlations with upper brainstem regions that are directly involved with vertical gaze functions. It is possible that the small size of the structures was the reason that findings did not survive partial volume correction. Further research with more detailed brainstem atlases and more sensitive PET images is needed. It is clear that oculomotor impairments with vertical movement difficulty and convergence as well as reduced blinking and involuntary eyelid closure, can influence gait instability, altered step length, and an increase frequency of falls in PSP [\u003cspan additionalcitationids=\"CR47\" citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. The ACC participates in both medial frontal-subcortical and dorsolateral prefrontal-subcortical circuits and cholinergic ACC deficits might contribute to apathy and executive dysfunction in PSP [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. Cognitive problems, such as executive dysfunction, slowed processing speed, attention deficits, and diminished working memory, likely also contribute to the gait instability in PSP [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study has several limitations. The relatively small sample size of 19 PSP subjects, with varying subtypes, may limit the generalizability of the findings. Specifically, the observed patterns of cholinergic denervation may be primarily driven by the PSP-RS subtype, which comprised the majority of the participants. Consequently, we may have overlooked subtle topographic patterns of cholinergic loss that could explain the characteristic features of other PSP subtypes, such as PSP-P. Future studies with larger cohorts, specifically designed to include a balanced representation of different PSP subtypes, are needed to validate these findings and explore potential subtype-specific patterns of cholinergic dysfunction. However, this study provides insights into the association between regional cholinergic deficits and PIGD motor dysfunction in PSP, offering potential avenues for improving diagnosis, prognostication, and treatment of these challenging neurodegenerative disorders. The observed widespread reductions of regional cholinergic terminal density across various brain regions emphasizes the complex interplay between neurotransmitter systems and clinical manifestations of the disease. Further research is warranted to elucidate the specific mechanisms underlying these cholinergic deficits in PSP.\u003c/p\u003e \u003cp\u003eIn conclusion, our study suggests that PIGD symptoms in PSP are associated with cholinergic degeneration across an assemblage of brain regions, indicating the involvement of multifactorial deficits, including cognitive, multi-sensory, oculomotor, and emotional components. These regions significantly overlap with those found to be associated with PIGD motor features in PD, suggesting that the cholinergic system may have inherent vulnerabilities to neurodegeneration, independent of specific proteinopathies. Our study suggests that the degeneration of cholinergic innervation in thalamic, striatal, limbic, and frontal brain structures may underlie the debilitating symptoms in PSP and could serve as a target for future interventions. A novel finding is that cholinergic forebrain losses are also associated with PIGD motor features in PSP. Future cholinergic enhancement strategies, such as subtype specific cholinergic receptor agents, may offer avenues for mitigating motor dysfunction in individuals with PSP.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank Christine Minderovic, Cyrus Sarosh, Olivia Dickinson, Fotini Michalakis, Austin Luker, the PET technologists, cyclotron operators, and chemists, for their assistance. We are indebted to the subjects who participated in this study.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe work was supported by the National Institutes of Health (P01 NS015655, R01 NS070856, P50 NS091856, P50 NS123067), Department of Veterans Affairs grant (I01 RX001631), the Michael J. Fox Foundation, and the Parkinson\u0026rsquo;s Foundation. None of the funding agencies had a role in the design and conduct of the study, in the collection, management, analysis and interpretation of the data, in the preparation, review or approval of the manuscript, nor in the decision to submit the manuscript for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrabesh Kanel, Roger L. Albin, and Nicolaas I. Bohnen contributed to the conception and design of the study. Giulia Carli, Stiven Roytman, Sygrid van der Zee, Taylor Brown, Jaimie Barr, Robert Vangel, C Chauncey Spears, Amanda Narkis, Sofie Slingerland, Sanne Meles, Teus van Laar, and Peter J.H. Scott contributed to the acquisition and analysis of data. Prabesh Kanel, Giulia Carli, Robert Vangel, and Stiven Roytman contributed to drafting the text and preparing the figures. \u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author, upon reasonable request and legal status compliance of international data.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eEthics Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board of the University of Michigan School of Medicine, Medical Ethical Committees of the University of Groningen, and Veterans Affairs Ann Arbor Healthcare System (ClinicalTrials.gov Identifier: NCT02458430 \u0026amp; NCT01754168).\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eConsent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all individual participants included in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eXie T, Kang UJ, Kuo SH, Poulopoulos M, Greene P, Fahn S (2015) Comparison of clinical features in pathologically confirmed PSP and MSA patients followed at a tertiary center. NPJ Parkinsons Dis [Internet]. ;1:15007. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/28725681\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/28725681\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHirsch EC, Graybiel AM, Duyckaerts C, Javoy-Agid F (1987) Neuronal loss in the pedunculopontine tegmental nucleus in Parkinson disease and in progressive supranuclear palsy. Proc Natl Acad Sci U S A [Internet]. ;84:5976\u0026ndash;80. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\u0026amp;db=PubMed\u0026amp;dopt=Citation\u0026amp;list_uids=3475716\u003c/span\u003e\u003cspan address=\"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\u0026amp;db=PubMed\u0026amp;dopt=Citation\u0026amp;list_uids=3475716\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKovacs GG, Lukic MJ, Irwin DJ, Arzberger T, Respondek G, Lee EB et al (2020) Distribution patterns of tau pathology in progressive supranuclear palsy. Acta Neuropathol [Internet]. ;140:99\u0026ndash;119. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/32383020\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/32383020\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLitvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC et al (1996) Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology [Internet]. ;47:1\u0026ndash;9. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1212/wnl.47.1.1\u003c/span\u003e\u003cspan address=\"10.1212/wnl.47.1.1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDickson DW (1999) Neuropathologic differentiation of progressive supranuclear palsy and corticobasal degeneration. J Neurol [Internet]. ;246 Suppl 2:II6-15. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/10525997\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/10525997\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDickson DW, Rademakers R, Hutton ML (2007) Progressive supranuclear palsy: pathology and genetics. Brain Pathol [Internet]. ;17:74\u0026ndash;82. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/17493041\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/17493041\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrown FS, Rowe JB, Passamonti L, Rittman T (2020) Falls in Progressive Supranuclear Palsy. Mov Disord Clin Pract [Internet]. ;7:16\u0026ndash;24. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/31970205\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/31970205\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStevens JA, Corso PS, Finkelstein EA, Miller TR (2006) The costs of fatal and non-fatal falls among older adults. Inj Prev [Internet]. ;12:290\u0026ndash;5. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/17018668\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/17018668\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBluett B, Litvan I, Cheng S, Juncos J, Riley DE, Standaert DG et al (2017) Understanding falls in progressive supranuclear palsy. Parkinsonism Relat Disord [Internet]. ;35:75\u0026ndash;81. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/28007518\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/28007518\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBohnen NI, Kanel P, Koeppe RA, Sanchez-Catasus CA, Frey KA, Scott P et al (2021) Regional cerebral cholinergic nerve terminal integrity and cardinal motor features in Parkinson\u0026rsquo;s disease. Brain Communications [Internet]. ;3. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1093/braincomms/fcab109\u003c/span\u003e\u003cspan address=\"10.1093/braincomms/fcab109\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWallert ED, van de Giessen E, Knol RJJ, Beudel M, de Bie RMA, Booij J (2022) Imaging Dopaminergic Neurotransmission in Neurodegenerative Disorders. J Nucl Med [Internet]. ;63:27S-32S. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/35649651\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/35649651\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePascual J, Berciano J, Grijalba B, del Olmo E, Gonzalez AM, Figols J et al (1992) Dopamine D1 and D2 receptors in progressive supranuclear palsy: an autoradiographic study. Ann Neurol [Internet]. ;32:703\u0026ndash;7. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/1449252\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/1449252\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGonzalez AM, Berciano J, Figols J, Pazos A, Pascual J (2000) Loss of dopamine uptake sites and dopamine D2 receptors in striatonigral degeneration. Brain Res [Internet]. ;852:228\u0026ndash;32. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/10661519\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/10661519\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBohnen NI, Kanel P, Zhou Z, Koeppe RA, Frey KA, Dauer WT et al (2019) Cholinergic system changes of falls and freezing of gait in Parkinson\u0026rsquo;s disease. Ann Neurol [Internet]. ;85:538\u0026ndash;49. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1002/ana.25430\u003c/span\u003e\u003cspan address=\"10.1002/ana.25430\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKanel P, Spears CC, Roytman S, Koeppe RA, Frey KA, Scott PJH et al (2022) Differential cholinergic systems\u0026rsquo; changes in progressive supranuclear palsy versus Parkinson\u0026rsquo;s disease: an exploratory analysis. J Neural Transm (Vienna) [Internet]. ;129:1469\u0026ndash;79. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/36222971\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/36222971\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoertien JM, van der Zee S, Chrysou A, Gerritsen MJJ, Jansonius NM, Spikman JM et al (2020) Study protocol of the DUtch PARkinson Cohort (DUPARC): a prospective, observational study of de novo Parkinson\u0026rsquo;s disease patients for the identification and validation of biomarkers for Parkinson\u0026rsquo;s disease subtypes, progression and pathophysiology. BMC Neurol [Internet]. ;20:245. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/32534583\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/32534583\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoglinger GU, Respondek G, Stamelou M, Kurz C, Josephs KA, Lang AE et al (2017) Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria. Mov Disord [Internet]. ;32:853\u0026ndash;64. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/28467028\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/28467028\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBohnen NI, Roytman S, van der Zee S, Carli G, Michalakis F, Luker A et al (2025) A multicenter longitudinal study of cholinergic subgroups in Parkinson disease. Nat Commun [Internet]. ; Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1038/s41467-025-60815-0\u003c/span\u003e\u003cspan address=\"10.1038/s41467-025-60815-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKanel P, M\u0026uuml;ller M, van der Zee S, Sanchez-Catasus CA, Koeppe RA, Frey KA et al (2020) Topography of Cholinergic Changes in Dementia With Lewy Bodies and Key Neural Network Hubs. J Neuropsychiatry Clin Neurosci [Internet]. ;32:370\u0026ndash;5. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1176/appi.neuropsych.19070165\u003c/span\u003e\u003cspan address=\"10.1176/appi.neuropsych.19070165\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMuller-Gartner HW, Links JM, Prince JL, Bryan RN, McVeigh E, Leal JP et al (1992) Measurement of radiotracer concentration in brain gray matter using positron emission tomography: MRI-based correction for partial volume effects. J Cereb Blood Flow Metab [Internet]. ;12:571\u0026ndash;83. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1038/jcbfm.1992.81\u003c/span\u003e\u003cspan address=\"10.1038/jcbfm.1992.81\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZwergal A, la Foug\u0026egrave;re C, Lorenzl S, Rominger A, Xiong G, Deutschenbaur L et al (2011) Postural imbalance and falls in PSP correlate with functional pathology of the thalamus. Neurology [Internet]. ;77:101\u0026ndash;9. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/21613601\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/21613601\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchofield EC, Hodges JR, Macdonald V, Cordato NJ, Kril JJ, Halliday GM (2011) Cortical atrophy differentiates Richardson\u0026rsquo;s syndrome from the parkinsonian form of progressive supranuclear palsy. Mov Disord [Internet]. ;26:256\u0026ndash;63. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/21412832\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/21412832\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNelson AB, Kreitzer AC (2014) Reassessing models of basal ganglia function and dysfunction. Annu Rev Neurosci [Internet]. ;37:117\u0026ndash;35. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/25032493\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/25032493\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStoodley CJ, Schmahmann JD (2010) Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing. Cortex [Internet]. ;46:831\u0026ndash;44. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/20152963\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/20152963\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePouget P (2015) The cortex is in overall control of voluntary eye movement. EYE [Internet]. ;29:241\u0026ndash;5. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/25475239\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/25475239\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRittman T, Coyle-Gilchrist IT, Rowe JB (2016) Managing cognition in progressive supranuclear palsy. Neurodegener Dis Manag [Internet]. ;6:499\u0026ndash;508. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/27879155\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/27879155\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePrasad S, Rajan A, Pasha SA, Mangalore S, Saini J, Ingalhalikar M et al (2021) Abnormal structural connectivity in progressive supranuclear palsy-Richardson syndrome. Acta Neurol Scand [Internet]. ;143:430\u0026ndash;40. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1111/ane.13372\u003c/span\u003e\u003cspan address=\"10.1111/ane.13372\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMesulam MM, Mash D, Hersh L, Bothwell M, Geula C (1992) Cholinergic innervation of the human striatum, globus pallidus, subthalamic nucleus, substantia nigra, and red nucleus. J Comp Neurol [Internet]. ;323:252\u0026ndash;68. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1002/cne.903230209\u003c/span\u003e\u003cspan address=\"10.1002/cne.903230209\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMesulam MM, Mufson EJ, Wainer BH, Levey AI (1983) Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1-Ch6). Neuroscience [Internet]. ;10:1185\u0026ndash;201. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1016/0306-4522(83)90108-2\u003c/span\u003e\u003cspan address=\"10.1016/0306-4522(83)90108-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJenkinson N, Nandi D, Muthusamy K, Ray NJ, Gregory R, Stein JF et al (2009) Anatomy, physiology, and pathophysiology of the pedunculopontine nucleus. Mov Disord [Internet]. ;24:319\u0026ndash;28. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1002/mds.22189\u003c/span\u003e\u003cspan address=\"10.1002/mds.22189\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAosaki T, Miura M, Suzuki T, Nishimura K, Masuda M (2010) Acetylcholine-dopamine balance hypothesis in the striatum: an update. Geriatr Gerontol Int [Internet]. ;10 Suppl 1:S148-57. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1111/j.1447-0594.2010.00588.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1447-0594.2010.00588.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePisani A, Bernardi G, Ding J, Surmeier DJ (2007) Re-emergence of striatal cholinergic interneurons in movement disorders. Trends Neurosci [Internet]. ;30:545\u0026ndash;53. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1016/j.tins.2007.07.008\u003c/span\u003e\u003cspan address=\"10.1016/j.tins.2007.07.008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePisani A, Bonsi P, Centonze D, Calabresi P, Bernardi G (2000) Activation of D2-like dopamine receptors reduces synaptic inputs to striatal cholinergic interneurons. J Neurosci [Internet]. ;20:RC69. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1523/jneurosci.20-07-j0003.2000\u003c/span\u003e\u003cspan address=\"10.1523/jneurosci.20-07-j0003.2000\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLitvan I, Mega MS, Cummings JL, Fairbanks L (1996) Neuropsychiatric aspects of progressive supranuclear palsy. Neurology [Internet]. ;47:1184\u0026ndash;9. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/8909427\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/8909427\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlexander GE, DeLong MR, Strick PL (1986) Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci [Internet]. ;9:357\u0026ndash;81. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/3085570\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/3085570\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eO\u0026rsquo;Callaghan C, Bertoux M, Hornberger M (2014) Beyond and below the cortex: the contribution of striatal dysfunction to cognition and behaviour in neurodegeneration. J Neurol Neurosurg Psychiatry [Internet]. ;85:371\u0026ndash;8. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/23833269\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/23833269\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWarren NM, Piggott MA, Perry EK, Burn DJ (2005) Cholinergic systems in progressive supranuclear palsy. Brain [Internet]. ;128:239\u0026ndash;49. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/15649952\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/15649952\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRay NJ, Kanel P, Bohnen NI (2023) Atrophy of the Cholinergic Basal Forebrain can Detect Presynaptic Cholinergic Loss in Parkinson\u0026rsquo;s Disease. Ann Neurol [Internet]. ;93:991\u0026ndash;8. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/36597786\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/36597786\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKasashima S, Oda Y (2003) Cholinergic neuronal loss in the basal forebrain and mesopontine tegmentum of progressive supranuclear palsy and corticobasal degeneration. Acta Neuropathol [Internet]. ;105:117\u0026ndash;24. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/12536222\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/12536222\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeter J, Mayer I, Kammer T, Minkova L, Lahr J, Kloppel S et al (2021) The relationship between cholinergic system brain structure and function in healthy adults and patients with mild cognitive impairment. Sci Rep [Internet]. ;11:16080. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/34373525\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/34373525\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChakraborty S, Haast RAM, Onuska KM, Kanel P, Prado MAM, Prado VF et al (2024) Multimodal gradients of basal forebrain connectivity across the neocortex. bioRxiv [Internet]. ; Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/37292595\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/37292595\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHafting T, Fyhn M, Molden S, Moser MB, Moser EI (2005) Microstructure of a spatial map in the entorhinal cortex. Nature [Internet]. ;436:801\u0026ndash;6. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/15965463\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/15965463\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBest C, Lange E, Buchholz HG, Schreckenberger M, Reuss S, Dieterich M (2014) Left hemispheric dominance of vestibular processing indicates lateralization of cortical functions in rats. Brain Struct Funct [Internet]. ;219:2141\u0026ndash;58. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1007/s00429-013-0628-1\u003c/span\u003e\u003cspan address=\"10.1007/s00429-013-0628-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReuss S, Siebrecht E, Stier U, Buchholz HG, Bausbacher N, Schabbach N et al (2020) Modeling Vestibular Compensation: Neural Plasticity Upon Thalamic Lesion. Front Neurol [Internet]. ;11:441. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/32528401\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/32528401\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEpstein RA (2008) Parahippocampal and retrosplenial contributions to human spatial navigation. Trends Cogn Sci [Internet]. ;12:388\u0026ndash;96. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1016/j.tics.2008.07.004\u003c/span\u003e\u003cspan address=\"10.1016/j.tics.2008.07.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLubarsky M, Juncos JL (2008) Progressive supranuclear palsy: a current review. Neurologist [Internet]. ;14:79\u0026ndash;88. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/18332837\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/18332837\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDi Fabio RP, Zampieri C, Tuite P (2008) Gaze control and foot kinematics during stair climbing: characteristics leading to fall risk in progressive supranuclear palsy. Phys Ther [Internet]. ;88:240\u0026ndash;50. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/18073265\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/18073265\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQuattrone A, Caligiuri ME, Morelli M, Nigro S, Vescio B, Arabia G et al (2019) Imaging counterpart of postural instability and vertical ocular dysfunction in patients with PSP: A multimodal MRI study. Parkinsonism Relat Disord [Internet]. ;63:124\u0026ndash;30. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/30803901\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/30803901\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGerstenecker A, Duff K, Mast B, Litvan I, ENGENE-PSP Study Group (2013). Behavioral abnormalities in progressive supranuclear palsy. Psychiatry Res [Internet]. ;210:1205\u0026ndash;10. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/24035530\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/24035530\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEgerton T, Williams DR, Iansek R (2012) Comparison of gait in progressive supranuclear palsy, Parkinson\u0026rsquo;s disease and healthy older adults. BMC Neurol [Internet]. ;12:116. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pubmed/23031506\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pubmed/23031506\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[{"identity":"870181c4-62e5-4657-8bea-811999ca8457","identifier":"10.13039/100000002","name":"National Institutes of Health","awardNumber":"P01NS015655, R01NS070856, P50NS091856, P50NS123067","order_by":0},{"identity":"49a73c3b-8853-46d6-9b6a-bb4341c1ea1c","identifier":"10.13039/100000738","name":"U.S. Department of Veterans Affairs","awardNumber":"I01RX001631","order_by":1},{"identity":"24fa1540-1624-4fc4-99ca-5a0eec138f24","identifier":"10.13039/100000864","name":"Michael J. Fox Foundation for Parkinson's Research","awardNumber":".","order_by":2},{"identity":"8093658b-a37e-4c7e-a942-65368c45dc60","identifier":"10.13039/100013301","name":"Parkinson's Foundation","awardNumber":".","order_by":3}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"University of Michigan–Ann Arbor","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":"Progressive Supranuclear Palsy, cholinergic deficits, PET imaging, PIGD","lastPublishedDoi":"10.21203/rs.3.rs-8778777/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8778777/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eProgressive Supranuclear Palsy (PSP) is an atypical parkinsonian syndrome characterized by significant postural instability and gait difficulties (PIGD). While brain cholinergic deficits are documented in PSP, their role in the pathophysiology of PIGD is an area of active research. This cross-sectional study aimed to elucidate relationships between regional cholinergic denervation, assessed by [\u003csup\u003e18\u003c/sup\u003eF]FEOBV PET, and PIGD severity in PSP patients.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eNineteen subjects characterized clinically as PSP (twelve males, seven females; mean age of 69.47\u0026thinsp;\u0026plusmn;\u0026thinsp;6.46 years [range 55\u0026ndash;79]). Based on the Movement Disorders Society-PSP diagnostic criteria, sixteen patients had probable PSP (eleven males; five females) and three had suggestive PSP (one male; two females). Clinical assessments showed significant motor impairments, a mean MDS-UPDRS Part III \u0026ldquo;off state\u0026rdquo; score of 42.36\u0026thinsp;\u0026plusmn;\u0026thinsp;13.52 and a mean modified Hoehn and Yahr stage of 3.36\u0026thinsp;\u0026plusmn;\u0026thinsp;1.22.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eStatistical parametric mapping (SPM) based voxel-wise analysis of [\u003csup\u003e18\u003c/sup\u003eF]FEOBV PET data revealed a significant inverse correlation between lower regional [\u003csup\u003e18\u003c/sup\u003eF]FEOBV binding and more severe PIGD motor rating scores. This association was observed across brain regions, including orbitofrontal cortices, gyrus rectus, septal nuclei, medial temporal lobe, insula, metathalamus, dorsomedial thalamus, pericentral cortices, caudate nuclei, anterior greater than mid and posterior and retrosplenial cingulate cortices, frontal lobe, and cerebellum.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThese findings highlight the potential roles of cholinergic systems degenerations in mediating PIGD in PSP. This suggests that cholinergic systems degeneration plays a substantial role in the pathophysiology of PIGD in PSP, offering a potential avenue for targeted therapeutic interventions to improve mobility and quality of life for these patients.\u003c/p\u003e","manuscriptTitle":"Cholinergic substrates of gait and postural impairments in Progressive Supranuclear Palsy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-04 07:06:26","doi":"10.21203/rs.3.rs-8778777/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":"e04b62f2-5df3-4750-a82d-e18a9554679d","owner":[],"postedDate":"February 4th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-04T07:06:26+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-04 07:06:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8778777","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8778777","identity":"rs-8778777","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}