Search

3R/4R-tau species are found in Alzheimer disease (AD) and ∼50% of Lewy body dementias at autopsy (LBD+tau); 4R-tau accumulations are found in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Digital image analysis techniques can elucidate patterns of tau pathology more precisely than traditional methods but repeatability across centers is unclear. We calculated regional percentage areas occupied by tau pathological inclusions from the middle frontal cortex (MFC), superior temporal cortex (STC), and angular gyrus (ANG) from cases from the University of Pennsylvania and the University of California San Diego with AD, LBD+tau, PSP, or CBD (n = 150) using QuPath. In both cohorts, AD and LBD+tau had the highest grey and white matter tau burden in the STC (p ≤ 0.04). White matter tau burden was relatively higher in 4R-tauopathies than 3R/4R-tauopathies (p

BACKGROUND: Prior studies indicate more severe brainstem cholinergic deficits in Progressive Supranuclear Palsy (PSP) compared to Parkinson’s disease (PD), but the extent and topography of subcortical deficits remains poorly understood. OBJECTIVE: To investigate differential cholinergic systems changes in progressive supranuclear palsy (PSP, n=8) versus Parkinson’s disease (PD, n=107) and older controls (n=19) using vesicular acetylcholine transporter [(18)F]-fluoroethoxybenzovesamicol (FEOBV) positron emission tomography (PET). METHODS: A whole-brain voxel-based PET analysis using Statistical Parametric Mapping (SPM) software (SPM12) for inter-group comparisons using parametric [(18)F]-FEOBV DVR images. RESULTS: Voxel-based analyses showed lower FEOBV binding in the tectum, metathalamus, epithalamus, pulvinar, bilateral frontal opercula, anterior insulae, superior temporal pole, anterior cingulum, some striatal subregions, lower brainstem, and cerebellum in PSP versus PD (p

Progressive supranuclear palsy (PSP) and idiopathic normal pressure hydrocephalus (iNPH) share several clinical and radiological features, making the differential diagnosis challenging. In this study, we aimed to differentiate between these two diseases using a machine learning approach based on cortical thickness and volumetric data.Twenty-three iNPH patients, 50 PSP patients and 55 control subjects were enrolled. All participants underwent a brain 3T-MRI, and cortical thickness and volumes were extracted using Freesurfer 6 on T1-weighted images and compared among groups. Finally, the performance of a machine learning approach with random forest using the extracted cortical features was investigated to differentiate between iNPH and PSP patients.iNPH patients showed cortical thinning and volume loss in the frontal lobe, temporal lobe and cingulate cortex, and thickening in the superior parietal gyrus in comparison with controls and PSP patients. PSP patients only showed mild thickness and volume reduction in the frontal lobe, compared to control subjects. Random Forest algorithm distinguished iNPH patients from controls with AUC of 0.96 and from PSP patients with AUC of 0.95, while a lower performance (AUC 0.76) was reached in distinguishing PSP from controls.This study demonstrated a more severe and widespread cortical involvement in iNPH than in PSP, possibly due to the marked lateral ventricular enlargement which characterizes iNPH. A machine learning model using thickness and volumetric data led to accurate differentiation between iNPH and PSP patients, which may help clinicians in the differential diagnosis and in the selection of patients for shunt procedures.

Movement disorders have been carefully clinically defined, based on clinico-pathological series; however there is often diagnostic and prognostic uncertainty, especially in early stage disease. Blood-based biomarkers for Alzheimer's disease (AD), particularly p-tau181 and p-tau217, may be useful in the movement disorder clinic, especially in identifying corticobasal syndrome due to AD pathology and in identifying Parkinson's disease (PD) patients at high risk for the future development of dementia. Serum or plasma neurofilament light (NfL) may be useful in separating Parkinson's plus syndromes (progressive supranuclear palsy-PSP, multiple system atrophy - MSA, and corticobasal syndrome-CBS) from PD. NfL is also a prognostic biomarker, in that the level of baseline or cross-sectional plasma/serum NfL is associated with a worse prognosis in PD and PSP. The development of protein aggregation assays in cerebrospinal fluid and multiplex assays which can measure 100 s-1000s of proteins in blood will provide new tools and insights for movement disorders for clinicians and researchers. The challenge is in efficiently integrating these tools into clinical practice and multi-modal approaches, where biomarkers are combined with clinical, genetic, and imaging data may guide the future use of these technologies.

We recently developed a positron emission tomography (PET) probe, [sup18/supF]PM-PBB3, to detect tau lesions in diverse tauopathies, including mixed three-repeat and four-repeat (3R + 4R) tau fibrils in Alzheimer's disease (AD) and 4R tau aggregates in progressive supranuclear palsy (PSP). For wider availability of this technology for clinical settings, bias-free quantitative evaluation of tau images without a priori disease information is needed.We aimed to establish tau PET pathology indices to characterize PSP and AD using a machine learning approach and test their validity and tracer capabilities.Data were obtained from 50 healthy control subjects, 46 patients with PSP Richardson syndrome, and 37 patients on the AD continuum. Tau PET data from 114 regions of interest were subjected to Elastic Net cross-validation linear classification analysis with a one-versus-the-rest multiclass strategy to obtain a linear function that discriminates diseases by maximizing the area under the receiver operating characteristic curve. We defined PSP- and AD-tau scores for each participant as values of the functions optimized for differentiating PSP (4R) and AD (3R + 4R), respectively, from others.The discriminatory ability of PSP- and AD-tau scores assessed as the area under the receiver operating characteristic curve was 0.98 and 1.00, respectively. PSP-tau scores correlated with the PSP rating scale in patients with PSP, and AD-tau scores correlated with Mini-Mental State Examination scores in healthy control-AD continuum patients. The globus pallidus and amygdala were highlighted as regions with high weight coefficients for determining PSP- and AD-tau scores, respectively.These findings highlight our technology's unbiased capability to identify topologies of 3R + 4R versus 4R tau deposits. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

INTRODUCTION: Multiple system atrophy (MSA) typically presents with parkinsonism, ataxia and/or autonomic dysfunction. Occasionally, clinically atypical (ca-MSA) cases masquerade as progressive supranuclear palsy (PSP). We aimed to investigate whether different neuroimaging modalities could facilitate differentiation and whether histopathologic characteristics could explain the atypical presentation. METHODS: We identified 3 neuropathologically-defined ca-MSA patients with clinically diagnosed PSP who underwent various antemortem brain imaging: MRI and PET imaging using (11)C-Pittsburgh compound B, (18)F-flortaucipir, and (18)F-fluorodeoxyglucose. We compared clinical features, brainstem planimetry, and radiotracer standardized uptake value ratios in ca-MSA to 10 autopsy-confirmed PSP patients and 10 healthy controls (imaging only). We also compared histologic count of neuronal loss, iron deposition and α-synuclein-immunoreactive glial cytoplasmic inclusion burden to 10 autopsy-confirmed MSA-parkinsonism (MSA-P) cases. RESULTS: Ca-MSA had better PSP Saccadic Impairment Scale scores (p=0.003) and more frequent good levodopa response (p=0.061) than PSP. Ca-MSA showed higher midbrain-to-pons ratio and lower Magnetic Resonance Parkinsonism Index than PSP (each, p=0.036) and exhibited lower glucose metabolism in the putamen and globus pallidus versus PSP (p=0.017) and controls (p=0.007). These same regions showed higher flortaucipir uptake in ca-MSA than PSP (p=0.007 for putamen, p=0.049 for pallidum) and controls (p=0.012). Lower flortaucipir retention was observed in the subthalamic nucleus versus PSP (p=0.007). The putamen-to-subthalamic ratio distinguished ca-MSA from PSP. No histopathological differences were observed for ca-MSA versus typical MSA-P. CONCLUSION: Severity of saccadic impairment, levodopa responsiveness, MRI planimetric measurements, and different patterns of fluorodeoxyglucose and flortaucipir uptake can help improve antemortem differentiation of MSA masquerading as PSP from true PSP.

To date, the diagnoses of Parkinson syndromes are based on clinical examination. Therefore, these specific diagnoses are made, when the neuropathological process is already advanced. However, disease modification or neuroprotection, is considered to be most effective before marked neurodegeneration has occurred. In recent years, early clinical or prodromal stages of Parkinson syndromes came into focus. Moreover, subtypes of distinct diseases will allow predictions of the individual course of the diseases more precisely. Thereby, patients will be enrolled into clinical trials with more specific disease entities and endpoints. Furthermore, novel fluid and imaging biomarkers that allow biochemical diagnoses are under development. These will lead to earlier diagnoses and earlier therapy in the future as consequence. Furthermore, therapeutic approaches will take the underlying neuropathological process of neurodegenerative Parkinson syndromes more specific into account. Specifically, future therapies will target the aggregation of aggregation-prone proteins such as alpha-synuclein and tau, the degradation of pathological aggregates, and the spreading of pathological protein aggregates throughout the brain. Many of these approaches are already in (pre)clinical development. In addition, anti-inflammatory approaches are in development. Furthermore, drug-repurposing is a feasible approach to shorten the developmental process of new drugs.

Small ubiquitin-like modifiers (SUMO) have been implicated in several neurodegenerative diseases. SUMO1 conjugation has been shown to promote aggregation and regulate phosphorylation of the tau protein linked to Alzheimer’s disease and related tauopathies. The current study has demonstrated that SUMO1 co-localizes with intraneuronal tau inclusions in progressive supranuclear palsy (PSP). Immunoprecipitation of isolated and solubilized tau fibrils from PSP tissues revealed SUMO1 conjugation to a cleaved and N-terminally truncated tau. The effects of SUMOylation were examined using tau-SUMO fusion proteins which showed a higher propensity for tau oligomerization of PSP-truncated tau and accumulation on microtubules as compared to the full-length protein. This was found to be specific for SUMO1 as the corresponding SUMO2 fusion protein did not display a significantly altered cytoplasmic distribution or aggregation of tau. Blocking proteasome-mediated degradation promoted the aggregation of the tau fusion proteins with the greatest effect observed for truncated tau-SUMO1. The SUMO1 modification of the truncated tau in PSP may represent a detrimental event that promotes aggregation and impedes the ability of cells to remove the resulting protein deposits. This combination of tau truncation and SUMO1 modification may be a contributing factor in PSP pathogenesis.

Parkinsonian diseases and cerebellar ataxia among movement disorders, are representative diseases which present with distinct pathological gaits. We proposed a machine learning system that can differentiate Parkinson's disease (PD), cerebellar ataxia and progressive supranuclear palsy Richardson syndrome (PSP-RS) based on postural instability and gait analysis.We screened 1467 gait (GAITRite) and postural instability (Pedoscan) analyses performed in Samsung Medical Center from January 2019 to December 2020. PD, probable PSP-RS, and cerebellar ataxia (i.e., probable MSA-C, hereditary ataxia, and sporadic adult-onset ataxia) were included in the study. The gated recurrent units for GaitRite and the deep neural network for Pedoscan were applied. The enhanced weight voting ensemble (EWVE) method was applied to incorporate the two modalities.We included 551 PD, 38 PSP-RS, 113 cerebellar ataxia and among them, 71 were MSA-C. Pedoscan-based and Gait-based model showed high sensitivity but low specificity in differentiating atypical parkinsonism from PD. The EWVE showed significantly improved specificity and reliable performance in differentiation between PD vs. ataxia patients (AUC 0.974 ± 0.036, sensitivity 0.829 ± 0.217, specificity 0.969 ± 0.038), PD vs. MSA-C (AUC 0.975 ± 0.020, sensitivity 0.823 ± 0.162, specificity 0.932 ± 0.030) and PD vs. PSP-RS (AUC 0.963 ± 0.028, sensitivity 0.555 ± 0.157, specificity 0.936 ± 0.031).We proposed reliable Pedoscan-based, Gait-based and EWVE model in differentiating gait disorders by integrating information from gait and postural instability. This model can provide diagnosis guidelines to primary caregivers and assist in differential diagnosis of PD from atypical parkinsonism for neurologists.

BACKGROUND AND PURPOSE: Progressive supranuclear palsy (PSP) encompasses a broader range of disease courses than previously appreciated. The most frequent clinical presentations of PSP are Richardson syndrome (RS) and PSP with a predominant Parkinsonism phenotype (PSP-P). Time to reach gait dependence and cognitive impairment have been proposed as prognostic disease milestones. Genetic polymorphisms in TRIM11 and SLC2A13 genes have been associated with longer disease duration (DD). METHODS: Methods used include retrospective chart review, genetic single nucleotide polymorphism analyses (in three cases), and neuropathology. RESULTS: We identified four cases with long (>10–15 years) or very long (>15 years) DD. Stage 1 PSP tau pathology was present in two cases (one PSP-P and one undifferentiated phenotype), whereas pallidonigroluysian atrophy (PSP-RS) and Stage 4/6 (PSP-P) PSP pathology were found in the other two cases. Three cases were homozygous for the rs564309-C allele of the TRIM11 gene and the H1 MAPT haplotype. Two were heterozygous for rs2242367 (G/A) in SLC2A13, whereas the third was homozygous for the G-allele. CONCLUSIONS: We propose a protracted course subtype of PSP (PC-PSP) based on clinical or neuropathological criteria in two cases with anatomically restricted PSP pathology, and very long DD and slower clinical progression in the other two cases. The presence of the rs564309-C allele may influence the protracted disease course. Crystallizing the concept of PC-PSP is important to further understand the pathobiology of tauopathies in line with current hypotheses of protein misfolding, seeding activity, and propagation.

Background: Differentiating progressive supranuclear palsy-parkinsonism (PSP-P) from Parkinson's disease (PD) is clinically challenging. Objective: This study aimed to develop an automated Magnetic Resonance Parkinsonism Index 2.0 (MRPI 2.0) algorithm to distinguish PSP-P from PD and to validate its diagnostic performance in two large independent cohorts. Methods: We enrolled 676 participants: a training cohort (n=346; 43 PSP-P, 194 PD, and 109 control subjects) from our center and an independent testing cohort (n=330; 62 PSP-P, 171 PD, and 97 control subjects) from an international research group. We developed a new in-house algorithm for MRPI 2.0 calculation and assessed its performance in distinguishing PSP-P from PD and control subjects in both cohorts using receiver operating characteristic curves. Results: The automated MRPI 2.0 showed excellent performance in differentiating patients with PSP-P from patients with PD and control subjects both in the training cohort (area under the receiver operating characteristic curve [AUC]=0.93 [95% confidence interval, 0.89–0.98] and AUC=0.97 [0.93–1.00], respectively) and in the international testing cohort (PSP-P versus PD, AUC=0.92 [0.87–0.97]; PSP-P versus controls, AUC=0.94 [0.90–0.98]), suggesting the generalizability of the results. The automated MRPI 2.0 also accurately distinguished between PSP-P and PD in the early stage of the diseases (AUC=0.91 [0.84–0.97]). A strong correlation (r=0.91, P < 0.001) was found between automated and manual MRPI 2.0 values. Conclusions: Our study provides an automated, validated, and generalizable magnetic resonance biomarker to distinguish PSP-P from PD. The use of the automated MRPI 2.0 algorithm rather than manual measurements could be important to standardize measures in patients with PSP-P across centers, with a positive impact on multicenter studies and clinical trials involving patients from different geographic regions. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The reliability of the Progressive Supranuclear Palsy Rating Scale (PSPRS) using teleneurology has not been assessed.To test whether removing items inadequately assessed by video would impact measurement of PSP severity and progression.We performed secondary analyses of two data sets: the phase 2/3 trial of Davunetide in PSP and a large single-center cohort. We examined two modifications of the PSPRS: (1) removing neck rigidity, limb rigidity, and postural stability (25 items; mPSPRS-25) and (2) also removing three ocular motor items and limb dystonia (21 items; mPSPRS-21). Proportional agreement relative to the possible total scores was measured using the intraclass correlation coefficient, compared to the original PSPRS baseline values and change over 6 and 12 months. We examined the ability of both scales to predict survival in the single-center cohort using proportional hazards models.The mPSPRS-25 showed excellent agreement (0.99; P 0.001) with the original PSPRS at baseline, 0.98 (P 0.001) agreement in measuring change over 6 months, and 0.98 (P 0.001) over 12 months. The mPSPRS-21 showed agreement of 0.94 (P 0.001) with the original PSPRS at baseline, 0.92 (P 0.001) at 6 months, and 0.95 (P 0.001) at 12 months. Baseline and 6-month change in both modified scales were highly predictive of survival in the single-center cohort.Modified versions of the PSPRS which can be administered remotely show excellent agreement with the original scale and predict survival in PSP. The mPSPRS-21 should facilitate clinical care and research in PSP via teleneurology. © 2022 International Parkinson and Movement Disorder Society.

The occurrence of neurodegenerative disease in patients with normal pressure hydrocephalus (NPH) is emphasized in recent reports. Based on this common co-occurrence, some of the hydrocephalic disorders appearing in late adulthood have been hypothesized to result from initially unapparent parenchymal abnormalities of neurodegenerative origin. Among these diseases, progressive supranuclear palsy (PSP) has been specifically remarked on. We aimed to comparatively investigate the neuroimaging clues of iNPH in our PSP subjects.Eighteen patients with a clinical diagnosis of PSP, 44 with Parkinson's disease (PD), and 44 healthy control (HC) individuals were enrolled. The disproportionately enlarged subarachnoid space hydrocephalus (DESH) score, the Evans' index (EI), and the callosal angle (CA) were measured on the conventional magnetic resonance imaging (MRI). The comparative analyses were performed using IBM SPSS Statistics 26.We found that dilated Sylvian fissures score (p = 0.016) and focal sulcal dilatation score (p = 0.037) were higher in the PSP group in comparison to HC whereas the CA score was higher in PSP subjects in comparison to both PD patients and HC (p = 0.000). Remarkably, the DESH score was also found to be higher in the PSP group in comparison to the age-matched HC group (p = 0.024).We found that the NPH-like MRI features were more common in PSP subjects in comparison to PD subjects and age-matched HC. These results may provide critical contributions to the literature regarding the overlap between PSP and NPH.

Background Progressive supranuclear palsy (PSP) may present as a speech/language disorder (PSP-SL). Objective We assessed pathological correlates of patients with PSP-SL who retained the suggestive of PSP-SL (s.o. PSP-SL) diagnosis versus those who progressed to possible/probable (poss./prob.) PSP. Methods Thirty-four prospectively recruited patient with s.o. PSP-SL completed comprehensive speech/language and neurological assessments longitudinally, died, and underwent autopsy. Results Twelve patients (35%) evolved to poss./prob PSP, while 22 (65%) remained as s.o. PSP-SL. Pathological diagnoses differed across the groups (P = 0.025). Patients with s.o. PSP-SL had four different neuropathologies (corticobasal degeneration [59%], PSP [13%], Pick's disease [14%], and frontotemporal lobar degeneration with TDP-43 [14%]), while all patients with poss./prob. PSP had a 4R-tauopathy (PSP [67%] and corticobasal degeneration [33%]). Development of poss./prob. PSP increased the chance of having PSP pathology by 2.38 times. Conclusions PSP-SL is associated with heterogenous pathologies. Evolution of PSP-SL into poss./prob. PSP is more predictive of underlying PSP pathology than s.o. PSP-SL. © 2021 International Parkinson and Movement Disorder Society.

Introduction Little is known about metabolic changes in progressive supranuclear palsy. Goals of the present study are to: (1) investigate whether early progressive supranuclear palsy is associated with changes in energy expenditure, body composition and dietary intake compared with Parkinson’s disease and healthy controls; (2) assess the accuracy of the Harris–Benedict equation to predict measured rest energy expenditure in progressive supranuclear palsy; (3) verify differences according to sex, phenotypes, disease severity and presence of dysphagia in progressive supranuclear palsy. Methods Twenty-one progressive supranuclear palsy, 41 Parkinson’s disease and nine healthy controls were included. Rest energy expenditure was assessed with indirect calorimeter, body composition with bio-impedance analysis and physical activity and dietary intake were estimated with a validated frequency questionnaire. Parametric testing was used to analyze differences between groups. Results Progressive supranuclear palsy showed reduced total daily energy expenditure and physical activity compared to both other cohorts (p 0.05). Limited accuracy was shown for the Harris–Benedict equation (accurate prediction frequency

Introduction Progressive supranuclear palsy (PSP) variants other than PSP-Richardson Syndrome (PSP-RS) have been recognized, including PSP with speech and language problems (PSP-SL). Given the reported sleep disruptions in PSP-RS, we investigated sleep abnormalities in PSP-SL. Methods Four sleep-related screening questions were given to the caregivers of 90 patients with PSP-SL (59 suggestive of PSP-SL and 31 possible PSP-SL) and 71 probable PSP-RS (prob. PSP-RS) patients. Results At least one sleep-related disturbance was observed in 35.6% of suggestive of PSP-SL, 38.7% of possible PSP-SL, and 67.6% of prob. PSP-RS, the most common being “unable to fall or stay asleep”. Prob. PSP-RS showed higher frequency of “screaming or talking in sleep”, “acting out dreams”, and “unable to fall or stay asleep” compared to both PSP-SL groups, but did not differ from possible PSP-SL in “excessive daytime sleepiness”. Conclusion Sleep abnormalities are common in PSP-SL, but less frequent than prob.PSP-RS.

Background Frontotemporal lobar degeneration (FTLD) is a neuropathological construct with multiple clinical presentations, including the behavioural variant of frontotemporal dementia (bvFTD), primary progressive aphasia—both non-fluent variant (nfvPPA) and semantic variant (svPPA)—progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), characterised by the deposition of abnormal tau protein in the brain. A major challenge for treating FTLD is early diagnosis and accurate discrimination among different syndromes. The main goal here was to investigate the cortical architecture of FTLD syndromes using cortical diffusion tensor imaging (DTI) analysis and to test its power to discriminate between different clinical presentations. Methods A total of 271 individuals were included in the study: 87 healthy subjects (HS), 31 semantic variant primary progressive aphasia (svPPA), 37 behavioural variant (bvFTD), 30 non-fluent/agrammatic variant primary progressive aphasia (nfvPPA), 47 PSP Richardson’s syndrome (PSP-RS) and 39 CBS cases. 3T MRI T1-weighted images and DTI scans were analysed to extract three cortical DTI derived measures (AngleR, PerpPD and ParlPD) and mean diffusivity (MD), as well as standard volumetric measurements. Whole brain and regional data were extracted. Linear discriminant analysis was used to assess the group discrimination capability of volumetric and DTI measures to differentiate the FTLD syndromes. In addition, in order to further investigate differential diagnosis in CBS and PSP-RS, a subgroup of subjects with autopsy confirmation in the training cohort was used to select features which were then tested in the test cohort. Three different challenges were explored: a binary classification (controls vs all patients), a multiclass classification (HS vs bvFTD vs svPPA vs nfvPPA vs CBS vs PSP-RS) and an additional binary classification to differentiate CBS and PSP-RS using features selected in an autopsy confirmed subcohort. Results Linear discriminant analysis revealed that PerpPD was the best feature to distinguish between controls and all patients (ACC 86%). PerpPD regional values were able to classify correctly the different FTLD syndromes with an accuracy of 85.6%. The PerpPD and volumetric values selected to differentiate CBS and PSP-RS patients showed a classification accuracy of 85.2%. Conclusions (I) PerpPD achieved the highest classification power for differentiating healthy controls and FTLD syndromes and FTLD syndromes among themselves. (II) PerpPD regional values could provide an additional marker to differentiate FTD, PSP-RS and CBS.

Background Tauopathies are a group of neurodegenerative diseases where there is pathologic accumulation of hyperphosphorylated tau protein (ptau). The most common tauopathy is Alzheimer’s disease (AD), but chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and argyrophilic grain disease (AGD) are significant health risks as well. Currently, it is unclear what specific molecular factors might drive each distinct disease and represent therapeutic targets. Additionally, there is a lack of biomarkers that can differentiate each disease in life. Recent work has suggested that neuroinflammatory changes might be specific among distinct diseases and offers a novel resource for mechanistic targets and biomarker candidates. Methods To better examine each tauopathy, a 71 immune-related protein multiplex ELISA panel was utilized to analyze anterior cingulate grey matter from 127 individuals neuropathologically diagnosed with AD, CTE, PSP, CBD, and AGD. A partial least square regression analysis was carried out to perform unbiased clustering and identify proteins that are distinctly correlated with each tauopathy correcting for age and gender. Receiver operator characteristic and binary logistic regression analyses were then used to examine the ability of each candidate protein to distinguish diseases. Validation in postmortem cerebrospinal fluid (CSF) from 15 AD and 14 CTE cases was performed to determine if candidate proteins could act as possible novel biomarkers. Results Five clusters of immune proteins were identified and compared to each tauopathy to determine if clusters were specific to distinct disease. Each cluster was found to correlate with either CTE, AD, PSP, CBD, or AGD. When examining which proteins were the strongest driver of each cluster, it was observed the most distinctive protein for CTE was CCL21, AD was FLT3L, and PSP was IL13. Individual proteins that were specific to CBD and AGD were not observed. CCL21 was observed to be elevated in CTE CSF compared to AD cases (p = 0.02), further validating the use as possible biomarkers. Sub-analyses for male only cases confirmed the results were not skewed by gender differences. Conclusions Overall, these results highlight that different neuroinflammatory responses might underlie unique mechanisms in related neurodegenerative pathologies. Additionally, the use of distinct neuroinflammatory signatures could help differentiate between tauopathies and act as novel biomarker candidate to increase specificity for in-life diagnoses.

BACKGROUND: Globular glial tauopathy (GGT) has been associated with frontotemporal dementia syndromes; little is known about the clinical and imaging characteristics of GGT and how they differ from other non-globular glial 4-repeat tauopathies (N4GT) such as progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). METHODS: For this case-control study the Mayo Clinic brain banks were queried for all cases with an autopsy-confirmed diagnosis of GGT between 01/01/2011 and 31/10/2021. Fifty patients with N4GT (30 PSP, 20 CBD) were prospectively recruited and followed at Mayo Clinic, Minnesota. MR imaging was used to characterize patterns of gray/white matter atrophy, MR-parkinsonism index, midbrain volume, and white matter hyperintensities.(18)F-Fluorodeoxyglucose-, (11)C Pittsburg compound-, and (18)F-flortaucipir-PET scans were reviewed. RESULTS: Twelve patients with GGT were identified: 83% were women compared to 42% in NG4T (P=0.02) with median age at death 76.5 years (range: 55–87). The most frequent clinical features were eye movement abnormalities, parkinsonism, behavioral changes, cognitive impairment followed by pyramidal tract signs and speech abnormalities. Lower motor neuron involvement was present in 17% and distinguished GGT from NG4T, P=0.035. Primary progressive apraxia of speech was the most frequent initial diagnosis (25%); 50% had a Parkinson-plus syndrome before death. Most GGT patients had asymmetric frontotemporal atrophy with matching hypometabolism. GGT patients had more gray matter atrophy in temporal lobes, normal MR-parkinsonism index, and larger midbrain volumes. CONCLUSIONS: Female sex, lower motor neuron involvement in the context of a frontotemporal dementia syndrome and asymmetric brain atrophy with preserved midbrain might be suggestive of underlying GGT.

The early differential diagnosis of Parkinson's disease (PD) and atypical Parkinsonian syndromes (APS), including corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), is challenging because of an overlap of clinical features and the lack of reliable biomarkers. Neural-derived extracellular vesicles (NDEVs) isolated from blood provide a window into the brain's biochemistry and may assist in distinguishing between PD and APS. We verified in a case-control study whether oligomeric α-Synuclein and Tau aggregates isolated from NDEVs could allow the differential diagnosis of these conditions. Blood sampling and clinical data, including disease duration, motor severity, global cognition, and levodopa equivalent daily dose (LEDD), were collected from patients with a diagnosis of either PD (n = 70), PSP (n = 21), or CBD (n = 19). NDEVs were isolated from serum by immunocapture using an antibody against the neuronal surface marker L1CAM; oligomeric α-Synuclein and aggregated Tau were measured by ELISA. NDEVs analyses showed that oligomeric α-Synuclein is significantly augmented in PD compared to APS, whereas Tau aggregates are significantly increased in APS compared to PD (p 0.0001). ROC analyses showed that these two biomarkers have a "good" power of classification (p 0.0001 for both proteins), with high sensitivity and specificity, with NDEVs concentration of Tau aggregates and oligomeric α-Synuclein being respectively the best biomarker for PD/PSP and PD/CBD diagnostic differentiation. Logistic and multiple regression analysis confirmed that NDEVs-derived oligomeric α-Synuclein and Tau aggregates differentiate PD from CBD and PSP (p 0.001). Notably, a positive correlation between NDEVs oligomeric α-Synuclein and disease severity (disease duration, p = 0.023; Modified HY, p = 0.015; UPDRS motor scores, p = 0.004) was found in PD patients and, in these same patients, NDEVs Tau aggregates concentration inversely correlated with global cognitive scores (p = 0.043). A minimally invasive blood test measuring the concentration of α-synuclein and Tau aggregates in NDEVs can represent a promising tool to distinguish with high sensitivity and specificity PD from CBD or PSP patients. Optimization and validation of these data will be needed to confirm the diagnostic value of these biomarkers in distinguishing synucleinopathies from taupathies.

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) progress relentlessly and lead to a need for care. Caregiving is often burdensome. Little is known about the course of caregiver burden (CB) in PSP and CBS patients. Longitudinal analysis of CB in family members caring for PSP and CBS patients. Single-center longitudinal pilot study in 68 newly diagnosed patients with probable PSP and CBS (52 Richardson’s syndrome; 1 progressive gait freezing of PSP; 15 CBS). Demographic, educational, occupational parameters, family status, motor functions (UPDRSIII, Hoehn and Yahr Score, Tinetti) and neuropsychological performance (CERAD Plus, Frontal Assessment Battery) were assessed, as well as behavioral and neuropsychiatric impairments (Frontal Behavioral Inventory, Neuropsychiatric Inventory), activities of daily living (ADL) and caregiver burden using the Caregiver Strain Index (CSI), in most patients also the Zarit Burden Interview (ZBI). Patients were followed up every 6 months for up to 2 years. Caregivers reported mild to moderate CB at baseline, which increased by 25–30% in 2 years and was significantly greater in PSP than in CBS. Risk for mental health problems increased over time, especially in female caregivers (depression). Important patient-related factors were apathy, aspontaneity, depression, irritability, disorganization, poor judgment, impairment of language, impairments in ADL, a high educational level of the patient and close family relationship. Behavioral symptoms and impaired ADL are the main patient-related factors of CB in PSP and CBS. CB can be severe and needs to be assessed repeatedly from the time of diagnosis to provide comprehensive support.

Delayed phase 18F-FP-CIT PET (dCIT) can assess the striatal dopamine transporter binding to detect degenerative parkinsonism (DP). Early phase 18F-FP-CIT (eCIT) can assess the regional brain activity for differential diagnosis among parkinsonism similar with 18F-FDG PET. We evaluated the diagnostic performance of dual phase 18F-FP-CIT PET (dual CIT) and 18F-FDG PET compared with clinical diagnosis in 141 subjects [36 with idiopathic Parkinson’s disease (IPD), 77 with multiple system atrophy (MSA), 18 with progressive supranuclear palsy (PSP), and 10 with non-DP)]. Visual assessment of eCIT, dCIT, dual CIT, 18F-FDG and 18F-FDG PET with dCIT was in agreement with the clinical diagnosis in 61.7%, 69.5%, 95.7%, 81.6%, and 97.2% of cases, respectively. ECIT showed about 90% concordance with non-DP and MSA, and 8.3% and 27.8% with IPD and PSP, respectively. DCIT showed ≥ 88% concordance with non-DP, IPD, and PSP, and 49.4% concordance with MSA. Dual CIT showed ≥ 90% concordance in all groups. 18F-FDG PET showed ≥ 90% concordance with non-DP, MSA, and PSP, but only 33.3% concordance with IPD. The combination of 18F-FDG and dCIT yielded ≥ 90% concordance in all groups. Dual CIT may represent a powerful alternative to the combination of 18F-FDG PET and dCIT for differential diagnosis of parkinsonian disorders.

Introduction Several reports have shown that neuromelanin-sensitive magnetic resonance imaging (NMI) using 3T magnetic resonance imaging is useful for the differential diagnosis of Parkinson's disease (PD), progressive supranuclear palsy (PSP), and other neurological diseases. However, the number of cases in previous studies has been insufficient. We aimed to determine the relationship between NMI and severity of PD and related disorders, and thereby establish the diagnostic utility of NMI for diagnosing neurological diseases. Methods We enrolled 591 patients (531 subjects after removal of duplicates) with parkinsonism who underwent NMI. The contrast ratio of the locus coeruleus (LC-CR) and the area of the substantia nigra pars compacta (SNc) were analyzed in each patient. Results The patients’ clinical diagnoses were as follows: 11 patients in the disease control group (DCG), 244 patients with PD, 49 patients with PSP, and 19 patients with multiple system atrophy with predominant parkinsonism. Additionally, some patients were diagnosed with dementia with Lewy bodies, vascular parkinsonism, and drug-induced parkinsonism. SNc in the patients with PD and PSP was significantly smaller than that in DCG. LC-CR in the patients with PD was lower than that in DCG; furthermore, LC-CR in the patients with PD was significantly lower than that in the patients with PSP. We found that an area under the receiver-operating characteristic curve, indicating diagnostic efficacy, of 0.85 for LC-CR is a promising biomarker for differentiating PD from PSP. Conclusion NMI effectively contributes to differentiating neurodegenerative diseases, such as PD and PSP.

Purpose of review Differential diagnosis of Parkinsonism may be difficult. The objective of this review is to present the work of the last three years in the field of imaging for diagnostic categorization of parkinsonian syndromes focusing on progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). Recent findings Two main complementary approaches are being pursued. The first seeks to develop and validate manual qualitative or semi-quantitative imaging markers that can be easily used in clinical practice. The second is based on quantitative measurements of magnetic resonance imaging abnormalities integrated in a multimodal approach and in automatic categorization machine learning tools. Summary These two complementary approaches obtained high diagnostic around 90% and above in the classical Richardson form of PSP and probable MSA. Future work will determine if these techniques can improve diagnosis in other PSP variants and early forms of the diseases when all clinical criteria are not fully met.

Background Hyposmia is characteristic of idiopathic Parkinson's disease (PD) and dementia with Lewy bodies (DLBs), whereas progressive supranuclear palsy (PSP) typically has normal sense of smell. However, there is a lack of pathologically confirmed data. Objective The objective is to study hyposmia in pathologically confirmed PSP patients and compare to PD patients and nondegenerative controls. Methods We studied autopsied subjects in the Arizona Study of Aging and Neurodegenerative Disorders who had antemortem olfactory testing and a neuropathological diagnosis of either PD, PSP, or control. Results This study included 281 cases. Those with neuropathologically confirmed PSP (N = 24) and controls (N = 174) had significantly better sense of smell than those with PD (N = 76). Although most PSP patients had normal olfaction, there were some with hyposmia, resulting in an overall reduced sense of smell in PSP compared to controls. The sensitivity of having PSP pathologically in those presenting with parkinsonism and normosmia was 93.4% with a specificity of 64.7%. Cases with both PSP and PD pathologically had reduced sense of smell similar to PD alone (N = 7). Hyposmic PSP patients had significantly higher Lewy body burden not meeting criteria for additional PD/DLB diagnosis. Conclusions Pathologically confirmed PD had reduced olfaction compared with PSP or controls. In the setting of parkinsonism in this sample, the presence of normosmia had high sensitivity for PSP. Hyposmia in PSP suggests the presence of additional Lewy body pathology. © 2021 International Parkinson and Movement Disorder Society.

Introduction The MDS-PSP criteria expand the phenotypic spectrum of PSP by adding to Richardson's syndrome (PSP-RS) other presentations such as PSP-parkinsonism (PSP–P), PSP-pure-gait-freezing (PSP-PGF), PSP-speech-language (PSP-SL), PSP-frontal (PSP–F), PSP-postural-instability (PSP-PI) and PSP-corticobasal-syndrome (PSP-CBS). Evidence about the prognostic differences between PSP phenotypes is scarce and focused on PSP-RS vs. non-PSP-RS. Using a brain-bank cohort we assessed PSP survival not only in PSP-RS vs. non-PSP-RS, but also in PSP-RS + cortical vs. subcortical phenotypes. Besides, we assessed sensitivity and specificity of the MDS-PSP criteria in of PSP and other degenerative parkinsonisms. Methods We retrospectively applied the MDS-PSP diagnostic criteria to 32 definite PSP cases and 30 cases with other degenerative parkinsonian syndromes (Parkinson's disease [PD; n = 11], multiple system atrophy [MSA; n = 11], corticobasal degeneration [CBD; n = 8]). We conducted survival statistics in neuropathologically confirmed PSP cases considering PSP-RS vs. non-PSP-RS and PSP-RS + PSP-cortical (PSP–F + PSP-SL + PSP-CBS) vs. PSP-subcortical (PSP–P + PSP-PGF) phenotypes. We also adjusted survival analyses for PSP tau scores. Results Diagnostic sensitivity was 100% and specificity ranged from 47% to 87% when excluding cases that met the “suggestive of PSP” definition early in their disease course but with other clinical features better matching with a non-PSP pathological diagnosis. Survival was significantly shorter in PSP-RS vs. non-PSP-RS cases, but it was more markedly shorter in PSP-RS + PSP-cortical vs. PSP-subcortical, independently of PSP tau scores, which were not associated with survival. Conclusions PSP-subcortical phenotypes appear to have longer survival than PSP-RS and cortical phenotypes. This might be of prognostic relevance when informing patients upon clinical diagnosis.

Background: Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are sporadic adult-onset primary tauopathies clinically classified among the atypical parkinsonian syndromes. They are intrinsically related with regard to their clinical features, pathology, biochemistry, and genetic risk factors. Objectives: This review highlights the current knowledge on PSP and CBD, focusing on evolving clinical concepts, new diagnostic criteria, and advances in biomarkers. Methods: We performed a non-systematic literature review through the PubMed database. The search was restricted to articles written in English, published from 1964 to date. Results: Clinicopathologic and in vivo biomarkers studies have broadened PSP and CBD clinical phenotypes. They are now recognized as a range of motor and behavioral syndromes associated with underlying 4R-tauopathy neuropathology. The Movement Disorders Society PSP diagnostic criteria included clinical variants apart from the classical description, increasing diagnostic sensitivity. Meanwhile, imaging biomarkers have explored the complexity of symptoms and pathological processes related to corticobasal syndrome and CBD. Conclusions: In recent years, several prospective or clinicopathologic studies have assessed clinical, radiological, and fluid biomarkers that have helped us gain a better understanding of the complexity of the 4R-tauopathies, mainly PSP and CBD. RESUMO Antecedentes: A paralisia supranuclear progressiva (PSP) e a degeneração corticobasal (DCB) são taupatias esporádicas primárias clinicamente classificadas no grupo das síndromes parkinsonianas atípicas. Ambas estão intrinsecamente relacionadas no que concerne aos aspectos clínicos, patológicos, bioquímicos e genéticos. Objetivos: Abordar os avanços recentes no conhecimento da PSP e DCB, focando na evolução dos conceitos clínicos, critérios diagnósticos, e avanços em biomarcadores. Métodos: Trata-se de uma revisão não-sistemática através da base de dados PubMed. Foram revisados artigos escritos em língua inglesa, publicados desde 1964 até a presente data. Resultados: Estudos com biomarcadores e análises postmortem ampliaram os fenótipos conhecidos da PSP e DCB. Tais doenças englobam um espectro amplo de síndromes motoras e cognitivas, associadas a neuropatologia tau com isoforma predominante 4R. O atual critério para PSP estabeleceu novas variantes clínicas para além da descrição clássica, aumentando a sensibilidade diagnóstica. Concomitantemente, biomarcadores in vivo exploraram a complexidade dos sintomas e processos patológicos relacionados à síndrome e degeneração corticobasal. Conclusões: Recentemente, alguns estudos prospectivos e clinicopatológicos investigaram aspectos clínicos, radiológicos e de biofluidos, que ajudaram a melhor compreender a heterogeneidade e complexidade clínica das taupatias 4R, sobretudo PSP e DCB.

Background We have previously shown that wearable technology and machine learning techniques can accurately discriminate between progressive supranuclear palsy (PSP), Parkinson's disease, and healthy controls. To date these techniques have not been applied in longitudinal studies of disease progression in PSP. Objectives We aimed to establish whether data collected by a body-worn inertial measurement unit (IMU) network could predict clinical rating scale scores in PSP and whether it could be used to track disease progression. Methods We studied gait and postural stability in 17 participants with PSP over five visits at 3-month intervals. Participants performed a 2-minute walk and an assessment of postural stability by standing for 30 seconds with their eyes closed, while wearing an array of six IMUs. Results Thirty-two gait and posture features were identified, which progressed significantly with time. A simple linear regression model incorporating the three features with the clearest progression pattern was able to detect statistically significant progression 3 months in advance of the clinical scores. A more complex linear regression and a random forest approach did not improve on this. Conclusions The reduced variability of the models, in comparison to clinical rating scales, allows a significant change in disease status from baseline to be observed at an earlier stage. The current study sheds light on the individual features that are important in tracking disease progression. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Background The degree of involvement of the autonomic nervous system in progressive supranuclear palsy (PSP) has been investigated in several studies, often providing conflicting results. There is a need for a better characterization of autonomic dysfunction in PSP, to enhance our understanding of this highly disabling neurodegenerative disease including patients’ needs and possibly be of value for clinicians in the differential diagnosis among Parkinsonian syndromes. Methods We applied a systematic methodology to review existing literature on Pubmed regarding autonomic nervous system involvement in PSP. Results PSP reported quite frequently symptoms suggestive of autonomic dysfunction in all domains. Cardiovascular autonomic testing showed in some cases a certain degree of impairment (never severe). There was some evidence suggesting bladder dysfunction particularly in the storage phase. Dysphagia and constipation were the most common gastrointestinal symptoms. Instrumental tests seemed to confirm sudomotor and pupillomotor disturbances. Conclusions PSP patients frequently reported visceral symptoms, however objective testing showed that not always these reflected actual autonomic impairment. Further studies are needed to better delineate autonomic profile and its prognostic role in PSP.

Saccades, rapid movements of the eyes towards a visual or remembered target, are useful in understanding the healthy brain and the pathology of neurological conditions such as progressive supranuclear palsy (PSP). We set out to investigate the parameters of horizontal reflexive and volitional saccades, both visually guided and memory-guided, over a 1 min epoch in healthy individuals and PSP patients.An experimental paradigm tested reflexive, volitional visually guided, and volitional memory-guided saccades in young healthy controls (n = 14; 20-31 years), PSP patients (n = 11; 46-75 years) and older age-matched healthy controls (n = 6; 56-71 years). The accuracy and velocity of saccades was recorded using an EyeBrain T2® video eye tracker and analyses performed using the MyEyeAnalysis® software. Two-way analysis of variance (ANOVA) was used to identify significant effects (p 0.01) between young and older controls to investigate the effects of ageing upon saccades, and between PSP patients and age-matched controls to study the effects of PSP upon saccades.In both healthy individuals and PSP patients, volitional saccades are slower and less accurate than reflexive saccades. In PSP patients, accuracy is lower across all saccade types compared to age-matched controls, but velocity is lower only for reflexive saccades. Crucially, there is no change in accuracy or velocity of consecutive saccades over short (one-minute) timescales in controls or PSP patients.Velocity and accuracy of saccades in PSP does not decrease over one-minute timescales, contrary to that previously observed in Parkinson's Disease (PD), suggesting a potential clinical biomarker for the distinction of PSP from PD.

In the quest for in vivo diagnostic biomarkers to discriminate Parkinson's disease (PD) from progressive supranuclear palsy (PSP) and multiple system atrophy (MSA, mainly p phenotype), many advanced magnetic resonance imaging (MRI) techniques have been studied. Morphometric indices, such as the Magnetic Resonance Parkinsonism Index (MRPI), demonstrated high diagnostic value in the comparison between PD and PSP. The potential of quantitative susceptibility mapping (QSM) was hypothesized, as increased magnetic susceptibility (Δχ) was reported in the red nucleus (RN) and medial part of the substantia nigra (SNImed) of PSP patients and in the putamen of MSA patients. However, disease-specific susceptibility values for relevant regions of interest are yet to be identified. The aims of the study were to evaluate the diagnostic potential of a multimodal MRI protocol combining morphometric and QSM imaging in patients with determined parkinsonisms and to explore its value in a population of undetermined cases.Patients with suspected degenerative parkinsonism underwent clinical evaluation, 3 T brain MRI and clinical follow-up. The MRPI was manually calculated on T1-weighted images. QSM maps were generated from 3D multi-echo T2*-weighted sequences.In determined cases the morphometric evaluation confirmed optimal diagnostic accuracy in the comparison between PD and PSP but failed to discriminate PD from MSA-p. Significant nigral and extranigral differences were found with QSM. RN Δχ showed excellent diagnostic accuracy in the comparison between PD and PSP and good accuracy in the comparison of PD and MSA-p. Optimal susceptibility cut-off values of RN and SNImed were tested in undetermined cases in addition to MRPI.A combined use of morphometric imaging and QSM could improve the diagnostic phase of degenerative parkinsonisms.

Abnormal iron accumulation around the substantia nigra (SN) is a diagnostic indicator of Parkinsonism. This study aimed to identify iron-related microarchitectural changes around the SN of brains with progressive supranuclear palsy (PSP) via postmortem validations and in vivo magnetic resonance imaging (MRI). 7 T high-resolution MRI was applied to two postmortem brain tissues, from one normal brain and one PSP brain. Histopathological examinations were performed to demonstrate the molecular origin of the high-resolution postmortem MRI findings, by using ferric iron staining, myelin staining, and two-dimensional laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging. In vivo iron-related MRI was performed on five healthy controls, five patients with Parkinson’s disease (PD), and five patients with PSP. In the postmortem examination, excessive iron deposition along the myelinated fiber at the anterior SN and third cranial nerve (oculomotor nerve) fascicles of the PSP brain was verified by LA-ICP-MS. This region corresponded to those with high R2* values and positive susceptibility from quantitative susceptibility mapping (QSM), but was less sensitive in Perls’ Prussian blue staining. In in vivo susceptibility-weighted imaging, hypointense pixels were observed in the region between the SN and red nucleus (RN) in patients with PSP, but not in healthy controls and patients with PD. R2* and QSM values of such region were significantly higher in patients with PSP compared to those in healthy controls and patients with PD as well (vs. healthy control: p = 0.008; vs. PD: p = 0.008). Thus, excessive iron accumulation along the myelinated fibers at the anterior SN and oculomotor nerve fascicles may be a pathological characteristic and crucial MR biomarker in a brain with PSP.

Background: Various cerebrospinal fluid (CSF) biomarkers are studied in Parkinson’s disease (PD) and atypical parkinsonian syndromes (APS). Several studies found reduced 5-hydroxyindoleacetic acid (5-HIAA), the main serotonin metabolite, in PD. There is little evidence regarding its levels in APS. Methods: We measured 5-HIAA in the CSF of 90 PD patients, 16 MSA patients, 26 progressive supranuclear palsy (PSP) patients, 11 corticobasal syndrome (CBS) patients, and 31 controls. We also compared the values in depressed and nondepressed patients. Results: There was a statistically significant difference in CSF 5-HIAA in PD and MSA compared to the control group (median in PD 15.8 μg/L, in MSA 13.6 μg/L vs. 24.3 μg/L in controls; p = 0.0008 in PD, p = 0.006 in MSA). There was no statistically significant difference in CSF 5-HIAA in PSP and CBS compared to the control group (median in PSP 22.7 μg/L, in CBS 18.7 μg/L vs. 24.3 μg/L in controls; p = 1 in both PSP and CBS). CSF 5-HIAA levels were lower in PD patients with depression compared to PD patients without depression (median 8.34 vs. 18.48, p < 0.0001). Conclusions: CSF 5-HIAA is decreased in PD and MSA. The CSF 5-HIAA levels in PSP and CBS did not differ from those of the control group. There was a tendency toward lower CSF 5-HIAA in MSA than in PD; however, the results did not reach statistical significance. These results may be explained by more severe damage of the serotonergic system in synucleinopathies (PD and MSA) than in tauopathies (PSP and CBS).

Introduction Quantitative MR planimetric measurements were reported to discriminate between progressive supranuclear palsy (PSP) and non-PSP parkinsonism, yet few data exist on the usefulness of these markers in early disease stages. Methods The pons-to-midbrain area ratio (P/M) and the Magnetic Resonance Parkinsonism Index (MRPI) as well as new indices, termed P/M2.0 and MRPI2.0, multiplying the former by a ratio of the third ventricle (3rdV) width/frontal horns (FH) width, were calculated on T1-weighted images in 84 patients with clinically unclassifiable neurodegenerative parkinsonism (CUP) at the time of imaging. Areas under the curve (AUCs) of these markers for predicting future PSP was determined. The final clinical diagnosis was made after at least 24 months of follow-up. Results Final diagnosis was Parkinson's disease in 55 patients, multiple system atrophy in 12 cases, and PSP in 17. At baseline imaging, patients with a final PSP diagnosis had significantly higher MRPI, P/M, MRPI2.0 and P/M2.0 values compared to the other groups. AUCs in discriminating between future PSP and non-PSP parkinsonism were 0.91 for both the P/M and the MRPI and 0.98 for the P/M2.0 and the MRPI2.0. Conclusions Brainstem-derived MR planimetric measures yield high diagnostic accuracy for separating PSP from non-PSP parkinsonism in early disease stages when clinical criteria are not yet fully met. Consistent with the underlying pathology in PSP, our study suggests that inclusion of 3rdV width makes P/M2.0 and MRPI2.0 more accurate in diagnosing early stage PSP patients than the P/M and MRPI.

Background A reliable measure of PSP-specific midbrain atrophy, the midbrain-to-pons ratio (MTPR) has been reported to support the differential diagnosis of progressive supranuclear palsy (PSP) from idiopathic Parkinson’s disease (IPD). Since longitudinal analyses are lacking so far, the present study aimed to evaluate the diagnostic value of the relative change of MTPR (relΔt_MTPR) over a 1-year period in patients with PSP, IPD, and healthy controls (HC). Methods Midsagittal individual MRIs of patients with PSP (n = 15), IPD (n = 15), and healthy controls (HC; n = 15) were assessed and the MTPR at baseline and after 1 year were defined. The diagnostic accuracy of the MTPR and its relative change were evaluated using ROC curve analyses. Results PSP-patients had a significantly lower MTPR at baseline (M = 0.45 ± 0.06), compared to both non-PSP groups (F (2, 41) = 62.82, p p t_MTPR for PSP (M = − 4.74% ± 4.48) from IPD (M = + 1.29 ± 3.77) was good (76.6%), ROC analysis did not reveal a significant improvement of diagnostic accuracy by combining the MTPR and relΔt_MTPR (p = 0.670). Still, specificity for PSP increased, though not significantly (p = 0.500). Conclusion The present results indicate that the relΔt_MTPR is a potentially useful tool to support the differential diagnosis of PSP from IPD. For its relative 1-year change, still, more evaluation is needed.

Introduction Primary progressive apraxia of speech (PPAOS) is a neurodegenerative syndrome in which patients present with an isolated motor speech disorder. Some PPAOS patients develop parkinsonism and other features of progressive supranuclear palsy (PSP) and/or corticobasal syndrome (CBS) over time. We aimed to assess the evolution of parkinsonian characteristics in PPAOS patients who had been followed yearly for at least six years. Methods From a large cohort of 46 PPAOS patients, eight were followed yearly for > 6-years in multiple NIH-funded grants. Parkinsonian and other features, including bradykinesia, tremor, rigidity, postural instability, apraxia, ocular motor function and cognition were assessed at each visit, and research criteria applied for PSP and CBS diagnosis. Neurological, speech-language test scores, and [18F]fluorodeoxyglucose PET (FDG-PET) and MRI midbrain volumes were assessed. Results A Parkinson's plus syndrome developed in all eight patients (100%). Bradykinesia was the earliest feature, followed by rigidity and postural instability. Tremor was not a significant feature. Parkinsonism, limb apraxia and ocular motor impairment tended to develop four-to-five years after onset with some patients having slight asymmetric parkinsonism. Six patients (75%) met research criteria for probable PSP, although only one for PSP-Richardson's syndrome; three patients met criteria for possible CBS. Slightly asymmetric, left-sided, hypometabolism was observed on FDG-PET, not matching asymmetry of Parkinsonism. Midbrain hypometabolism was absent-minimal. Three patients had progressive midbrain volumes in the PSP-Richardson's syndrome range. Conclusions A Parkinson's plus syndrome may inevitably develop in PPAOS supporting PPAOS as an early presentation of a Parkinson's plus disorder.

ObjectiveTo investigate whether tau phosphorylated at Thr217 (p-tau T217) assay in CSF can distinguish patients with Alzheimer disease (AD) from patients with other dementias and healthy controls.MethodsWe developed and validated a novel Simoa immunoassay to detect p-tau T217 in CSF. There was a total of 190 participants from 3 cohorts with AD (n = 77) and other neurodegenerative diseases (n = 69) as well as healthy participants (n = 44).ResultsThe p-tau T217 assay (cutoff 242 pg/mL) identified patients with AD with accuracy of 90%, with 78% positive predictive value (PPV), 97% negative predictive value (NPV), 93% sensitivity, and 88% specificity, compared favorably with p-tau T181 ELISA (52 pg/mL), showing 78% accuracy, 58% PPV, 98% NPV, 71% specificity, and 97% sensitivity. The assay distinguished patients with AD from age-matched healthy controls (cutoff 163 pg/mL, 98% sensitivity, 93% specificity), similarly to p-tau T181 ELISA (cutoff 60 pg/mL, 96% sensitivity, 86% specificity). In patients with AD, we found a strong correlation between p-tau T217 and p-tau T181, total tau and β-amyloid 40, but not β-amyloid 42.ConclusionsThis study demonstrates that p-tau T217 displayed better diagnostic accuracy than p-tau T181. The data suggest that the new p-tau T217 assay has potential as an AD diagnostic test in clinical evaluation.Classification of evidenceThis study provides Class III evidence that a CSF immunoassay for p-tau T217 distinguishes patients with AD from patients with other dementias and healthy controls.

Background The clinical diagnosis of Parkinson's disease (PD) requires the presence of parkinsonism and supportive criteria that include a clear and dramatic beneficial response to dopaminergic therapy. Our aim was to test the diagnostic criterion of dopaminergic response by evaluating its association with pathologically confirmed diagnoses in a large population of parkinsonian patients. Methods We reviewed clinical data maintained in an electronic medical record from all patients with autopsy data who had been seen in the Movement Disorders Center at Washington University, St. Louis, between 1996 and 2018. All patients with parkinsonism who underwent postmortem neuropathologic examination were included in this analysis. Results There were 257 unique parkinsonian patients with autopsy-based diagnoses who had received dopaminergic therapy. Marked or moderate response to dopaminergic therapy occurred in 91.2% (166/182) of those with autopsy-confirmed PD, 52.0% (13/25) of those with autopsy-confirmed multiple systems atrophy, 44.4% (8/18) of those with autopsy-confirmed progressive supranuclear palsy, and 1 (1/8) with autopsy-confirmed corticobasal degeneration. Other diagnoses were responsible for the remaining 24 individuals, 9 of whom had a moderate response to dopaminergic therapy. Conclusion A substantial response to dopaminergic therapy is frequent but not universal in PD. An absent response does not exclude PD. In other neurodegenerative disorders associated with parkinsonism, a prominent response may also be evident, but this occurs less frequently than in PD. © 2020 International Parkinson and Movement Disorder Society.

Sleep complaints are the most prevalent syndromes in older adults, particularly in women. Moreover, they are frequently accompanied with a high level of depression and stress. Although several diffusion tensor imaging (DTI) studies reported associations between sleep quality and brain white matter (WM) microstructure, it is still unclear whether gender impacts the effect of sleep quality on structural alterations, and whether these alterations mediate the effects of sleep quality on emotional regulation. We included 389 older participants (176 females, age = 65.5 ± 5.5 years) from the 1000BRAINS project. Neuropsychological examinations covered the assessments of sleep quality, depressive symptomatology, current stress level, visual working memory, and selective attention ability. Based on the DTI dataset, the diffusion parameter maps, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), were calculated and normalized to a population-specific FA template. According to the global Pittsburgh Sleep Quality Index (PSQI), 119 poor sleepers (PSQI: 10∼17) and 120 good sleepers (PSQI: 3∼6) were identified. We conducted a two by two (good sleepers/poor sleepers) × (males/females) analysis of variance by using tract-based spatial statistics (TBSS) and JHU-ICBM WM atlas-based comparisons. Moreover, we performed a voxel-wise correlation analysis of brain WM microstructure with the neuropsychological tests. Finally, we applied a mediation analysis to explore if the brain WM microstructure mediates the relationship between sleep quality and emotional regulation. No significant differences in brain WM microstructure were detected on the main effect of sleep quality. However, the MD, AD, and RD of pontine crossing tract and bilateral inferior cerebellar peduncle were significant lower in the males than females. Voxel-wise correlation analysis revealed that FA and RD values in the corpus callosum were positively related with depressive symptomatology and negatively related with current stress levels. Additionally, we found a significantly positive association between higher FA values in visual-related WM tracts and better outcomes in a visual pattern recognition test. Furthermore, a mediation analysis suggested that diffusion metrics within the corpus callosum partially mediated the associations between poor sleep quality/high stress and depressive symptomatology.

Objectives Progressive supranuclear palsy-Richardson syndrome (PSP-RS) is characterized by symmetrical parkinsonism with postural instability and frontal dysfunction. This study aims to use the whole brain structural connectome (SC) to gain insights into the underlying disconnectivity which may be implicated in the clinical features of PSP-RS. Methods Sixteen patients of PSP-RS and 12 healthy controls were recruited. Disease severity was quantified using PSP rating scale (PSPRS), and mini-mental scale was applied to evaluate cognition. Thirty-two direction diffusion MRIs were acquired and used to compute the structural connectome of the whole brain using deterministic fiber tracking. Group analyses were performed at the edge-wise, nodal, and global levels. Age and gender were used as nuisance covariates for all the subsequent analyses, and FDR correction was applied. Results Network-based statistics revealed a 34-edge network with significantly abnormal edge-wise connectivity in the patient group. Of these, 25 edges were cortical connections, of which 68% were frontal connections. Abnormal deep gray matter connections were predominantly comprised of connections between structures of the basal ganglia. The characteristic path length of the SC was lower in PSP-RS, and nodal analysis revealed abnormal degree, strength, local efficiency, betweenness centrality, and participation coefficient in several nodes. Conclusions Significant alterations in the structural connectivity of the whole brain connectome were observed in PSP-RS. The higher degree of abnormality observed in nodes belonging to the frontal lobe and basal ganglia substantiates the predominant frontal dysfunction and parkinsonism observed in PSP-RS. The findings of this study support the concept that PSP-RS may be a network-based disorder.

It remains unclear whether the supportive imaging features described in the diagnostic criteria for progressive supranuclear palsy (PSP) are suitable for the full clinical spectrum. The aim of the current study was to define and cross-validate the pattern of glucose metabolism in the brain associated with a diagnosis of different PSP variants. A retrospective multicenter cohort study performed on 73 PSP patients who were referred for a fluorodeoxyglucose positron emission tomography PET scan: PSP-Richardson's syndrome, n = 47; PSP-parkinsonian variant, n = 18; and progressive gait freezing, n = 8. In addition, we included 55 healthy controls and 58 Parkinson's disease (PD) patients. Scans were normalized by global mean activity. We analyzed the regional differences in metabolism between the groups. Moreover, we applied a multivariate analysis to obtain a PSP-related pattern that was cross-validated in independent populations at the individual level. Group analysis showed relative hypometabolism in the midbrain, basal ganglia, thalamus, and frontoinsular cortices and hypermetabolism in the cerebellum and sensorimotor cortices in PSP patients compared with healthy controls and PD patients, the latter with more severe involvement in the basal ganglia and occipital cortices. The PSP-related pattern obtained confirmed the regions described above. At the individual level, the PSP-related pattern showed optimal diagnostic accuracy to distinguish between PSP and healthy controls (sensitivity, 80.4%; specificity, 96.9%)s and between PSP and PD (sensitivity, 80.4%; specificity, 90.7%). Moreover, PSP-Richardson's syndrome and PSP-parkinsonian variant patients showed significantly more PSP-related pattern expression than PD patients and healthy controls. The glucose metabolism assessed by fluorodeoxyglucose PET is a useful and reproducible supportive diagnostic tool for PSP-Richardson's syndrome and PSP-parkinsonian variant. © 2020 International Parkinson and Movement Disorder Society.

Missense variants ABI3_rs616338-T and PLCG2_rs72824905-G were previously associated with elevated or reduced risk of Alzheimer’s disease (AD), respectively. Despite reports of associations with other neurodegenerative diseases, there are few studies of these variants in purely neuropathologically diagnosed cohorts. Further, the effect of these mutations on neurodegenerative disease pathologies is unknown. In this study, we tested the effects of ABI3_rs616338-T and PLCG2_rs72824905-G on disease risk in autopsy cohorts comprised of 973 patients diagnosed neuropathologically with Lewy body disease (LBD-NP) and 1040 with progressive supranuclear palsy (PSP), compared to 3351 controls. LBD-NP patients were further categorized as high, intermediate and low likelihood of clinical dementia with Lewy bodies (DLB-CL) based on DLB Consortium criteria. We also tested for association with both Braak neurofibrillary tau tangle (nTotal = 2008, nPSP = 1037, nLBD-NP = 971) and Thal phase amyloid plaque scores (nTotal = 1786, nPSP = 1018, nLBD-NP = 768). Additionally, 841 PSP patients had quantitative tau neuropathology measures that were assessed for genetic associations. There was no statistically significant association with disease risk for either LBD-NP or PSP in our study. LBD intermediate category disease risk was significantly associated with ABI3_rs616338-T (OR = 2.65, 95% CI 1.46–4.83, p = 0.001). PLCG2_rs72824905-G was associated with lower Braak stage (ß = − 0.822, 95% CI − 1.439 to − 0.204, p = 0.009). This effect was more pronounced in the PSP (ß = − 0.995, 95% CI − 1.773 to − 0.218, p = 0.012) than LBD-NP patients (ß = − 0.292, 95% CI − 1.283 to 0.698, p = 0.563). PLCG2_rs72824905-G also showed association with reduced quantitative tau pathology for each lesion type and overall tau burden in PSP (ß = − 0.638, 95% CI − 1.139 to − 0.136, p = 0.013). These findings support a role for PLCG2_rs72824905-G in suppressing tau neuropathology. ABI3_rs616338-T may influence disease risk specifically in the LBD-NP intermediate category comprised of patients with diffuse neocortical or limbic LB, concurrently with moderate or high AD neuropathology, respectively. Our study provides a potential mechanism of action for the missense PLCG2 variant and suggests a differential disease risk effect for ABI3 in a distinct LBD-NP neuropathologic category.

Introduction Separating progressive supranuclear palsy (PSP) from Parkinson's disease (PD) and multiple system atrophy (MSA) is often challenging in early disease but is important for appropriate management. Magnetic resonance imaging (MRI) can aid the diagnostics and manual 2D measurements are often used. However, new fully automatic brainstem volumetry could potentially be more accurate and increase availability of brainstem metrics. Methods Clinical 3D T1-weighted MRI were obtained from 196 consecutive patients; 29 PSP, 27 MSA, 140 PD. Midbrain-pons ratio and magnetic resonance parkinsonism index (MRPI) 1.0 and 2.0 were manually calculated, and intra-rater and inter-rater reliability was assessed. FreeSurfer was used to automatically segment brainstem substructures, normalized to the intracranial volume. The robustness of the automated analysis was evaluated in 3 healthy controls. The diagnostic accuracy of the brainstem biomarkers was assessed using receiver operating characteristic curves. Results Automatic brainstem volumetry had good repeatability/reproducibility with intra-scanner coefficient of variation 0.3–5.5% and inter-scanner coefficient of variation 0.9–8.4% in the different brainstem regions. Midbrain volume performs better than planimetric measurements in separating PSP from PD (Area under the curve (AUC) 0.90 compared with 0.81 for midbrain-pons ratio (p = 0.019), 0.77 for MRPI 1.0 (p = 0.007) and 0.81 for MRPI 2.0 (p = 0.021)). Midbrain volume performed on par with planimetry for separation between PSP and MSA. Conclusion Automatic brainstem segmentation is robust and shows promising diagnostic performance in separating PSP from PD and MSA. If further developed, it could play a role in diagnosing PSP and could potentially be used as an outcome in clinical trials.

Background The International Parkinson and Movement Disorder Society-endorsed Progressive Supranuclear Palsy Study Group published clinical diagnostic criteria for progressive supranuclear palsy in 2017, aiming to optimize early, sensitive and specific diagnosis. Objective To assist physicians in the application of these criteria, we developed a video-based tutorial in which all core clinical features and clinical clues are depicted and explained. Methods Patients provided written informed consent to the publication of their videos. High-quality videos along with essential descriptions were collected by the study group members. Most educational videos were selected in a structured consensus process. Results We provide 68 videos of all core clinical features and clinical clues defined by the diagnostic criteria, along with instructive descriptions of the depicted patients, examination techniques and clinical findings. Conclusions This comprehensive video-based tutorial will support physicians in the application of the diagnostic criteria of progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is an atypical Parkinsonism characterized by motor and neuropsycological disorders. Language could be impaired in PSP patients, also in Richardson variant (PSP-RS). The analysis of connected speech is used in neurodegenerative disorder to investigate different levels of language organization, including phonetic, phonological, lexico-semantic, morpho-syntactic, and pragmatic processing. In our study, we aimed to investigate the language profile, especially connected speech, in early-stage PSP-RS and Parkinson’s disease (PD) patients without predominant speech or language disorders. Language was assessed using the Screening for Aphasia in NeuroDegeneration (SAND); connected speech analysis was conducted from the picture description subtest. We enrolled 48 patients, 22 PD and 26 PSP (18 PSP-RS and 8 non-RS). PSP-RS patients presented an impairment in language domain, particularly regarding connected speech. PSP-RS patients presented worse performances than PD in different scores. The output of PSP-RS patients was characterized by a reduction in number of sentences and subordinates with respect to PD; PSP presented also more repaired sequences and phonological and lexico-semantic errors than PD. Number of sentences and number of subordinates of the picture description task were identified as predictors of PSP diagnosis. In summary, the SAND scale is able to identify language impairment in PSP patients. The analysis of connected speech could highlight some important aspects of language impairment in PSP-RS patients, and it could be helpful in the differential diagnosis with PD.

Parkinsonism has heterogeneous nature, showing distinctive patterns of disease progression and prognosis. We aimed to find clusters of parkinsonism based on 18F‐fluoropropyl‐carbomethoxyiodophenylnortropane (FP‐CIT) PET as a data‐driven approach to evaluate heterogenous dopaminergic neurodegeneration patterns. Two different cohorts of patients who received FP‐CIT PET were collected. A labeled cohort (n = 94) included patients with parkinsonism who underwent a clinical follow‐up of at least 3 years (mean 59.0 ± 14.6 months). An unlabeled cohort (n = 813) included all FP‐CIT PET data of a single‐center. All PET data were clustered by a dimension reduction method followed by hierarchical clustering. Four distinct clusters were defined according to the imaging patterns. When the diagnosis of the labeled cohort of 94 patients was compared with the corresponding cluster, parkinsonism patients were mostly included in two clusters, cluster “0” and “2.” Specifically, patients with progressive supranuclear palsy were significantly more included in cluster 0. The two distinct clusters showed significantly different clinical features. Furthermore, even in PD patients, two clusters showed a trend of different clinical features. We found distinctive clusters of parkinsonism based on FP‐CIT PET‐derived heterogeneous neurodegeneration patterns, which were associated with different clinical features. Our results support a biological underpinning for the heterogeneity of neurodegeneration in parkinsonism.

BACKGROUND: Synaptic loss is a prominent and early feature of many neurodegenerative diseases. OBJECTIVES: We tested the hypothesis that synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) (Richardson's syndrome) and amyloid-negative corticobasal syndrome (CBS). METHODS: Forty-four participants (15 CBS, 14 PSP, and 15 age-/sex-/education-matched controls) underwent PET with the radioligand [11 C]UCB-J, which binds to synaptic vesicle glycoprotein 2A, a marker of synaptic density; participants also had 3 Tesla MRI and clinical and neuropsychological assessment. RESULTS: Nine CBS patients had negative amyloid biomarkers determined by [11 C]PiB PET and hence were deemed likely to have corticobasal degeneration (CBD). Patients with PSP-Richardson's syndrome and amyloid-negative CBS were impaired in executive, memory, and visuospatial tasks. [11 C]UCB-J binding was reduced across frontal, temporal, parietal, and occipital lobes, cingulate, hippocampus, insula, amygdala, and subcortical structures in both PSP and CBD patients compared to controls (P < 0.01), with median reductions up to 50%, consistent with postmortem data. Reductions of 20% to 30% were widespread even in areas of the brain with minimal atrophy. There was a negative correlation between global [11 C]UCB-J binding and the PSP and CBD rating scales (R = -0.61, P < 0.002; R = -0.72, P < 0.001, respectively) and a positive correlation with the revised Addenbrooke's Cognitive Examination (R = 0.52; P = 0.01). CONCLUSIONS: We confirm severe synaptic loss in PSP and CBD in proportion to disease severity, providing critical insight into the pathophysiology of primary degenerative tauopathies. [11 C]UCB-J may facilitate treatment strategies for disease-modification, synaptic maintenance, or restoration. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background Idiopathic normal pressure hydrocephalus and PSP share several clinical and radiological features, making differential diagnosis, at times, challenging. Objectives To differentiate idiopathic normal pressure hydrocephalus from PSP using MR volumetric and linear measurements. Methods Twenty-seven idiopathic normal pressure hydrocephalus patients, 103 probable PSP patients, and 43 control subjects were consecutively enrolled. Automated ventricular volumetry was performed using Freesurfer 6 on MR T1 -weighted images. Linear measurements, such as callosal angle and a new measure, termed MR Hydrocephalic Index, were calculated on MR T1 -weighted images. Receiver operating characteristic analyses were used for differentiating between patient groups. Generalizability and reproducibility of the results were validated, dividing each participant group in two cohorts used as training and testing subsets. Results Ventricular volumes and linear measurements (callosal angle and Magnetic Resonance Hydrocephalic Index) revealed greater ventricular enlargement in patients with idiopathic normal pressure hydrocephalus than in PSP patients and controls. PSP patients had ventricular volume larger than controls. Automated ventricular volumetry and Magnetic Resonance Hydrocephalic Index were the most accurate measures (98.5%) in differentiating patients with idiopathic normal pressure hydrocephalus from PSP patients, whereas callosal angle misclassified several PSP patients and showed low positive predictive value (70.0%) in differentiating between these two diseases. All measurements accurately differentiated idiopathic normal pressure hydrocephalus patients from controls. Accuracy values obtained in the training set (automated ventricular volumetry, 98.4%; Magnetic Resonance Hydrocephalic Index, 98.4%; callosal angle, 87.5%) were confirmed in the testing set. Conclusions Our study demonstrates that AVV and Magnetic Resonance Hydrocephalic Index were the most accurate measures for differentiation between idiopathic normal pressure hydrocephalus and PSP patients. Magnetic Resonance Hydrocephalic Index is easy to measure and can be used in clinical practice to prevent misdiagnosis and ineffective shunt procedures in idiopathic normal pressure hydrocephalus mimics. © 2020 International Parkinson and Movement Disorder Society.

OBJECTIVE Accurate diagnosis is particularly challenging in Parkinson's disease (PD), multiple system atrophy (MSAp), and progressive supranuclear palsy (PSP). We compare the utility of 3 promising biomarkers to differentiate disease state and explain disease severity in parkinsonism: the Automated Imaging Differentiation in Parkinsonism (AID-P), the Magnetic Resonance Parkinsonism Index (MRPI), and plasma-based neurofilament light chain protein (NfL). METHODS For each biomarker, the area under the curve (AUC) of receiver operating characteristic curves were quantified for PD versus MSAp/PSP and MSAp versus PSP and statistically compared. Unique combinations of variables were also assessed. Furthermore, each measures association with disease severity was determined using stepwise multiple regression. RESULTS For PD versus MSAp/PSP, AID-P (AUC, 0.900) measures had higher AUC compared with NfL (AUC, 0.747) and MRPI (AUC, 0.669), P

Clear speech refers to intentionally modifying conversational speech to maximise intelligibility. This study aimed to compare the speech behaviour of patients with progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and Parkinson's disease (PD) under conversational and clear speech conditions to gain greater pathophysiological insight. A total of 68 participants including 17 PD, 17 MSA, 17 PSP and 17 healthy controls (HC) performed two readings of the same standardized passage. During the first reading, participants were instructed to read the text in an ordinary way, while during the second reading to read the text as clearly as possible. Acoustic analyses were based upon measurements of mean loudness, loudness variability, pitch variability, vowel articulation, articulation rate and speech severity. During clear speech production, PD patients were able to achieve improvements mainly in loudness (p