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BackgroundThere is currently no undisputed, validated, clinically meaningful measure for deficits in the broad spectrum of PSP phenotypes.ObjectiveTo develop a scale to monitor clinical deficits in patients with PSP across its broad phenotypes.MethodsThe Progressive Supranuclear Palsy Clinical Deficits Scale was conceptualized to cover seven clinical domains (Akinesia-rigidity, Bradyphrenia, Communication, Dysphagia, Eye movements, Finger dexterity, and Gait & balance), each scored from 0 to 3 (no, mild, moderate, or severe deficits). User guidelines were developed to standardize its application. Progressive Supranuclear Palsy Clinical Deficits Scale scores were collected in patients fulfilling the MDS-PSP diagnostic criteria in two independent, multicenter, observational studies, both cross-sectionally (exploratory DescribePSP cohort; confirmatory ProPSP cohort) and longitudinally (12-months' follow-up, both cohorts).ResultsCognitive pretesting demonstrated easy scale utility. In total, 164 patients were scored (70.4 ± 7.6 years; 62% males, 35% variant phenotypes). Mean Progressive Supranuclear Palsy Clinical Deficits Scale completion time was 4 minutes. The Progressive Supranuclear Palsy Clinical Deficits Scale total score correlated with existing scales (e.g., Progressive Supranuclear Palsy Rating Scale: R = 0.88; P

BackgroundThe Movement Disorder Society criteria for progressive supranuclear palsy define diagnostic allocations, stratified by certainty levels and clinical predominance types. We aimed to study the frequency of ambiguous multiple allocations and to develop rules to eliminate them.MethodsWe retrospectively collected standardized clinical data by chart review in a multicenter cohort of autopsy-confirmed patients with progressive supranuclear palsy, to classify them by diagnostic certainty level and predominance type and to identify multiple allocations.ResultsComprehensive data were available from 195 patients. More than one diagnostic allocation occurred in 157 patients (80.5%). On average, 5.4 allocations were possible per patient. We developed four rules for Multiple Allocations eXtinction (MAX). They reduced the number of patients with multiple allocations to 22 (11.3%), and the allocations per patient to 1.1.ConclusionsThe proposed MAX rules help to standardize the application of the Movement Disorder Society criteria for progressive supranuclear palsy. © 2019 International Parkinson and Movement Disorder Society.

BackgroundProgressive supranuclear palsy (PSP) -Richardson's Syndrome and Corticobasal Syndrome (CBS) are the two classic clinical syndromes associated with underlying four repeat (4R) tau pathology. The PSP Rating Scale is a commonly used assessment in PSP clinical trials; there is an increasing interest in designing combined 4R tauopathy clinical trials involving both CBS and PSP.ObjectivesTo determine contributions of each domain of the PSP Rating Scale to overall severity and characterize the probable sequence of clinical progression of PSP as compared to CBS.MethodsMulticenter clinical trial and natural history study data were analyzed from 545 patients with PSP and 49 with CBS. Proportional odds models were applied to model normalized cross-sectional PSP Rating Scale, estimating the probability that a patient would experience impairment in each domain using the PSP Rating Scale total score as the index of overall disease severity.ResultsThe earliest symptom domain to demonstrate impairment in PSP patients was most likely to be Ocular Motor, followed jointly by Gait/Midline and Daily Activities, then Limb Motor and Mentation, and finally Bulbar. For CBS, Limb Motor manifested first and ocular showed less probability of impairment throughout the disease spectrum. An online tool to visualize predicted disease progression was developed to predict relative disability on each subscale per overall disease severity.ConclusionThe PSP Rating Scale captures disease severity in both PSP and CBS. Modelling how domains change in relation to one other at varying disease severities may facilitate detection of therapeutic effects in future clinical trials.

Background: Several magnetic resonance imaging (MRI) measures have been suggested as progression biomarkers in progressive supranuclear palsy (PSP), and some PSP staging systems have been recently proposed. Objective: Comparing structural MRI measures and staging systems in tracking atrophy progression in PSP and estimating the sample size to use them as endpoints in clinical trials. Methods: Progressive supranuclear palsy‐Richardson's syndrome (PSP‐RS) patients with one‐year‐follow‐up longitudinal brain MRI were selected from the placebo arms of international trials (NCT03068468, NCT01110720, NCT01049399) and the DescribePSP cohort. The discovery cohort included patients from the NCT03068468 trial; the validation cohort included patients from other sources. Multisite age‐matched healthy controls (HC) were included for comparison. Several MRI measures were compared: automated atlas‐based volumetry (44 regions), automated planimetric measures of brainstem regions, and four previously described staging systems, applied to volumetric data. Results: Of 508 participants, 226 PSP patients including discovery (n = 121) and validation (n = 105) cohorts, and 251 HC were included. In PSP patients, the annualized percentage change of brainstem and midbrain volume, and a combined index including midbrain, frontal lobe, and third ventricle volume change, were the progression biomarkers with the highest effect size in both cohorts (discovery: >1.6; validation cohort: >1.3). These measures required the lowest sample sizes (n < 100) to detect 30% atrophy progression, compared with other volumetric/planimetric measures and staging systems. Conclusions: This evidence may inform the selection of imaging endpoints to assess the treatment efficacy in reducing brain atrophy rate in PSP clinical trials, with automated atlas‐based volumetry requiring smaller sample size than staging systems and planimetry to observe significant treatment effects. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

BackgroundProgressive supranuclear palsy (PSP) is a neuropathologically defined disease presenting with a broad spectrum of clinical phenotypes.ObjectiveTo identify clinical features and investigations that predict or exclude PSP pathology during life, aiming at an optimization of the clinical diagnostic criteria for PSP.MethodsWe performed a systematic review of the literature published since 1996 to identify clinical features and investigations that may predict or exclude PSP pathology. We then extracted standardized data from clinical charts of patients with pathologically diagnosed PSP and relevant disease controls and calculated the sensitivity, specificity, and positive predictive value of key clinical features for PSP in this cohort.ResultsOf 4166 articles identified by the database inquiry, 269 met predefined standards. The literature review identified clinical features predictive of PSP, including features of the following 4 functional domains: ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction. No biomarker or genetic feature was found reliably validated to predict definite PSP. High-quality original natural history data were available from 206 patients with pathologically diagnosed PSP and from 231 pathologically diagnosed disease controls (54 corticobasal degeneration, 51 multiple system atrophy with predominant parkinsonism, 53 Parkinson's disease, 73 behavioral variant frontotemporal dementia). We identified clinical features that predicted PSP pathology, including phenotypes other than Richardson's syndrome, with varying sensitivity and specificity.ConclusionsOur results highlight the clinical variability of PSP and the high prevalence of phenotypes other than Richardson's syndrome. The features of variant phenotypes with high specificity and sensitivity should serve to optimize clinical diagnosis of PSP. © 2017 International Parkinson and Movement Disorder Society.

BackgroundPSP is a neuropathologically defined disease entity. Clinical diagnostic criteria, published in 1996 by the National Institute of Neurological Disorders and Stroke/Society for PSP, have excellent specificity, but their sensitivity is limited for variant PSP syndromes with presentations other than Richardson's syndrome.ObjectiveWe aimed to provide an evidence- and consensus-based revision of the clinical diagnostic criteria for PSP.MethodsWe searched the PubMed, Cochrane, Medline, and PSYCInfo databases for articles published in English since 1996, using postmortem diagnosis or highly specific clinical criteria as the diagnostic standard. Second, we generated retrospective standardized clinical data from patients with autopsy-confirmed PSP and control diseases. On this basis, diagnostic criteria were drafted, optimized in two modified Delphi evaluations, submitted to structured discussions with consensus procedures during a 2-day meeting, and refined in three further Delphi rounds.ResultsDefined clinical, imaging, laboratory, and genetic findings serve as mandatory basic features, mandatory exclusion criteria, or context-dependent exclusion criteria. We identified four functional domains (ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction) as clinical predictors of PSP. Within each of these domains, we propose three clinical features that contribute different levels of diagnostic certainty. Specific combinations of these features define the diagnostic criteria, stratified by three degrees of diagnostic certainty (probable PSP, possible PSP, and suggestive of PSP). Clinical clues and imaging findings represent supportive features.ConclusionsHere, we present new criteria aimed to optimize early, sensitive, and specific clinical diagnosis of PSP on the basis of currently available evidence. © 2017 International Parkinson and Movement Disorder Society.

Background: International clinical criteria are the reference for the diagnosis of degenerative parkinsonism in clinical research, but they may lack sensitivity and specificity in the early stages. Objectives: To determine whether magnetic resonance imaging (MRI) analysis, through visual reading or machine‐learning approaches, improves diagnostic accuracy compared with clinical diagnosis at an early stage in patients referred for suspected degenerative parkinsonism. Materials: Patients with initial diagnostic uncertainty between Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multisystem atrophy (MSA), with brain MRI performed at the initial visit (V1) and available 2‐year follow‐up (V2), were included. We evaluated the accuracy of the diagnosis established based on: (1) the international clinical diagnostic criteria for PD, PSP, and MSA at V1 ("Clin1"); (2) MRI visual reading blinded to the clinical diagnosis ("MRI"); (3) both MRI visual reading and clinical criteria at V1 ("MRI and Clin1"), and (4) a machine‐learning algorithm ("Algorithm"). The gold standard diagnosis was established by expert consensus after a 2‐year follow‐up. Results: We recruited 113 patients (53 with PD, 31 with PSP, and 29 with MSA). Considering the whole population, compared with clinical criteria at the initial visit ("Clin1": balanced accuracy, 66.2%), MRI visual reading showed a diagnostic gain of 14.3% ("MRI": 80.5%; P = 0.01), increasing to 19.2% when combined with the clinical diagnosis at the initial visit ("MRI and Clin1": 85.4%; P < 0.0001). The algorithm achieved a diagnostic gain of 9.9% ("Algorithm": 76.1%; P = 0.08). Conclusion: Our study shows the use of MRI analysis, whether by visual reading or machine‐learning methods, for early differentiation of parkinsonism. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: The locus coeruleus/subcoeruleus complex (LC/LsC) is a structure comprising melanized noradrenergic neurons. Objective: To study the LC/LsC damage across Parkinson's disease (PD) and atypical parkinsonism in a large group of subjects. Methods: We studied 98 healthy control subjects, 47 patients with isolated rapid eye movement sleep behavior disorder (RBD), 75 patients with PD plus RBD, 142 patients with PD without RBD, 19 patients with progressive supranuclear palsy (PSP), and 19 patients with multiple system atrophy (MSA). Twelve patients with MSA had proven RBD. LC/LsC signal intensity was derived from neuromelanin magnetic resonance imaging using automated software. Results: The signal intensity was reduced in all parkinsonian syndromes compared with healthy control subjects, except in PD without RBD. The signal intensity decreased as age increased. Moreover, the signal intensity was lower in MSA than in isolated RBD and PD without RBD groups. In PD, the signal intensity correlated negatively with the percentage of REM sleep without atonia. There were no differences in signal intensity between PD plus RBD, PSP, and MSA. Conclusions: Neuromelanin signal intensity was reduced in all parkinsonian disorders, except in PD without RBD. The presence of RBD in parkinsonian disorders appears to be associated with lower neuromelanin signal intensity. Furthermore, lower LC/LsC signal changes in PSP could be partly caused by the effect of age. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Neurodegeneration in the substantia nigra pars compacta (SNc) in parkinsonian syndromes may affect the nigral territories differently. Objective: The objective of this study was to investigate the regional selectivity of neurodegenerative changes in the SNc in patients with Parkinson's disease (PD) and atypical parkinsonism using neuromelanin‐sensitive magnetic resonance imaging (MRI). Methods: A total of 22 healthy controls (HC), 38 patients with PD, 22 patients with progressive supranuclear palsy (PSP), 20 patients with multiple system atrophy (MSA, 13 with the parkinsonian variant, 7 with the cerebellar variant), 7 patients with dementia with Lewy body (DLB), and 4 patients with corticobasal syndrome were analyzed. volume and signal‐to‐noise ratio (SNR) values of the SNc were derived from neuromelanin‐sensitive MRI in the whole SNc. Analysis of signal changes was performed in the sensorimotor, associative, and limbic territories of the SNc. Results: SNc volume and corrected volume were significantly reduced in PD, PSP, and MSA versus HC. Patients with PSP had lower volume, corrected volume, SNR, and contrast‐to‐noise ratio than HC and patients with PD and MSA. Patients with PSP had greater SNR reduction in the associative region than HC and patients with PD and MSA. Patients with PD had reduced SNR in the sensorimotor territory, unlike patients with PSP. Patients with MSA did not differ from patients with PD. Conclusions: This study provides the first MRI comparison of the topography of neuromelanin changes in parkinsonism. The spatial pattern of changes differed between PSP and synucleinopathies. These nigral topographical differences are consistent with the topography of the extranigral involvement in parkinsonian syndromes. © 2022 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: The Progressive Supranuclear Palsy Rating Scale is a prospectively validated physician‐rated measure of disease severity for progressive supranuclear palsy. We hypothesized that, according to experts' opinion, individual scores of items would differ in relevance for patients' quality of life, functionality in daily living, and mortality. Thus, changes in the score may not equate to clinically meaningful changes in the patient's status. Objective: The aim of this work was to establish a condensed modified version of the scale focusing on meaningful disease milestones. Methods: Sixteen movement disorders experts evaluated each scale item for its capacity to capture disease milestones (0 = no, 1 = moderate, 2 = severe milestone). Items not capturing severe milestones were eliminated. Remaining items were recalibrated in proportion to milestone severity by collapsing across response categories that yielded identical milestone severity grades. Items with low sensitivity to change were eliminated, based on power calculations using longitudinal 12‐month follow‐up data from 86 patients with possible or probable progressive supranuclear palsy. Results: The modified scale retained 14 items (yielding 0–2 points each). The items were rated as functionally relevant to disease milestones with comparable severity. The modified scale was sensitive to change over 6 and 12 months and of similar power for clinical trials of disease‐modifying therapy as the original scale (achieving 80% power for two‐sample t test to detect a 50% slowing with n = 41 and 25% slowing with n = 159 at 12 months). Conclusions: The modified Progressive Supranuclear Palsy Rating Scale may serve as a clinimetrically sound scale to monitor disease progression in clinical trials and routine. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Autosomal recessive early-onset parkinsonism is clinically and genetically heterogeneous. Mutations of three genes, PRKN, PINK1 , and DJ-1 cause pure phenotypes usually characterized by levodopa-responsive Parkinson's disease. By contrast, mutations of other genes, including ATP13A2, PLA2G6, FBXO7, DNAJC6, SYNJ1, VPS13C , and PTRHD1 , cause rarer, more severe diseases with a poor response to levodopa, generally with additional atypical features. We performed data mining on a gene panel or whole-exome sequencing in 460 index cases with early-onset (≤ 40 years) Parkinson's disease, including 57 with autosomal recessive disease and 403 isolated cases. We identified two isolated cases carrying biallelic mutations of SYNJ1 (double-heterozygous p.D791fs/p.Y232H and homozygous p. Y832C mutations) and two siblings with the recurrent homozygous p.R258Q mutation. All four variants were absent or rare in the Genome Aggregation Database, were predicted to be deleterious on in silico analysis and were found to be highly conserved between species. The patient with both the previously unknown p.D791fs and p.Y232H mutations presented with dystonia-parkinsonism accompanied by a frontal syndrome and oculomotor disturbances at the age of 39. In addition, two siblings from an Algerian consanguineous family carried the homozygous p.R258Q mutation and presented generalized tonic-clonic seizures during childhood, with severe intellectual disability, followed by progressive parkinsonism during their teens. By contrast, the isolated patient with the homozygous p. Y832C mutation, diagnosed at the age of 20, had typical parkinsonism, with no atypical symptoms and slow disease progression. Our findings expand the mutational spectrum and phenotypic profile of SYNJ1 -related parkinsonism. [ABSTRACT FROM AUTHOR]

Background: Machine learning algorithms using magnetic resonance imaging (MRI) data can accurately discriminate parkinsonian syndromes. Validation in patients recruited in routine clinical practice is missing. Objective: The aim of this study was to assess the accuracy of a machine learning algorithm trained on a research cohort and tested on an independent clinical replication cohort for the categorization of parkinsonian syndromes. Methods: Three hundred twenty‐two subjects, including 94 healthy control subjects, 119 patients with Parkinson's disease (PD), 51 patients with progressive supranuclear palsy (PSP) with Richardson's syndrome, 35 with multiple system atrophy (MSA) of the parkinsonian variant (MSA‐P), and 23 with MSA of the cerebellar variant (MSA‐C), were recruited. They were divided into a training cohort (n = 179) scanned in a research environment and a replication cohort (n = 143) examined in clinical practice on different MRI systems. Volumes and diffusion tensor imaging (DTI) metrics in 13 brain regions were used as input for a supervised machine learning algorithm. To harmonize data across scanners and reduce scanner‐dependent effects, we tested two types of normalizations using patient data or healthy control data. Results: In the replication cohort, high accuracies were achieved using volumetry in the classification of PD–PSP, PD–MSA‐C, PSP–MSA‐C, and PD‐atypical parkinsonism (balanced accuracies: 0.840–0.983, area under the receiver operating characteristic curves: 0.907–0.995). Performances were lower for the classification of PD–MSA‐P, MSA‐C–MSA‐P (balanced accuracies: 0.765–0.784, area under the receiver operating characteristic curve: 0.839–0.871) and PD–PSP–MSA (balanced accuracies: 0.773). Performance using DTI was improved when normalizing by controls, but remained lower than that using volumetry alone or combined with DTI. Conclusions: A machine learning approach based on volumetry enabled accurate classification of subjects with early‐stage parkinsonism, examined on different MRI systems, as part of their clinical assessment. © 2020 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration (FTD) are two clinicohistological entities that share a severe prefrontal syndrome. To what extent do the cognitive syndrome and the location of the underlying brain atrophy unify or segregate these entities? Here, we examined the clinical and radiological patterns of frontal involvement and the neural bases of the cognitive dysfunctions observed in the Richardson form of PSP and the behavioral variant of FTD (bvFTD). The cognitive profile and grey and white matter volume of PSP (n = 19) and bvFTD (n = 16) patients and control participants (n = 18) were compared using a standard battery of neuropsychological tests and voxel-based morphometry (VBM), respectively. Analyses of correlations between neuropsychological and morphometric data were additionally performed. The severity and qualitative pattern of cognitive dysfunction was globally similar between the two patient groups. Grey matter volume was decreased in widespread frontal areas and in the temporal uncus in bvFTD, while it was decreased in the frontal and temporal lobes as well as in the thalamus in PSP. We also found an unexpected involvement of the frontal rectal gyrus in PSP patients compared to controls. Correlation analyses yielded different results in the two groups, with no area showing significant correlations in PSP patients, while several frontal and some temporal areas did so in bvFTD patients. In spite of minor neuropsychological and morphological differences, this study shows that the patterns of cognitive dysfunction and atrophy are very similar in PSP and bvFTD. However, executive dysfunction in these diseases may stem from partially divergent cortical and subcortical neural circuits. [ABSTRACT FROM AUTHOR]

Background: Progressive supranuclear palsy (PSP) is a rare parkinsonian syndrome with a wide spectrum of clinical presentations. Recently, the MDS published revised diagnosis criteria to provide early and reliable diagnosis of PSP and its variants. Two large randomized clinical trials were initiated in 2017, but the question remains regarding the extrapolation of their results to the general PSP population.Objective: To determine if PSP patients included in clinical trials are representative of the general PSP population.Methods: We conducted a single center retrospective study of PSP patients referred to a tertiary department of Neurology (Pitié-Salpêtrière Hospital, Paris) for clinical diagnosis and clinical trial inclusion, over a 12-month period. We collected and analyzed gender, age at examination, age at disease onset, disease duration, and core clinical features regarding oculo-motor dysfunction, postural instability, akinesia and cognitive dysfunction, and inclusion/exclusion criteria of clinical trials to assess eligibility for inclusion. We assessed the relative proportions of different PSP subtypes, as defined by the MDS-PSP criteria, in the whole population compared to patients eligible in trials.Results: 206 PSP patients were included, among which 175 (85%) were diagnosed with probable PSP-Richardson's syndrome (RS) subtype, with a mean age of 73 and mean disease duration of 5 years. Among those patients, 29 (21%) were eligible (age 71 ± 10.7, disease duration 3.1 ± 1.2 years) and 19 were included in trials, all with a diagnosis of probable PSP-RS. As compared to the whole population, patients included in clinical trials tended to be younger, and showed more PSP-RS subtypes (p < 0.05).Conclusion: The PSP population included in trials is very similar to the general PSP population, but younger, with shorter disease duration. By definition, only probable PSP subtypes are included in clinical trials. The time window for inclusion is short because of diagnosis delay, fast disease progression and old age of the population. [ABSTRACT FROM AUTHOR]

Quantitative biomarkers for clinical differentiation of parkinsonian syndromes are still lacking. Our aim was to evaluate the value of combining clinically feasible manual measurements of R2* relaxation rates and mean diffusivity (MD) in subcortical regions and brainstem morphometric measurements to improve the discrimination of parkinsonian syndromes. Twenty-two healthy controls (HC), 25 patients with Parkinson's disease (PD), 19 with progressive supranuclear palsy (PSP) and 27 with multiple system atrophy (MSA, 21 with the parkinsonian variant -MSAp, 6 with the cerebellar variant -MSAc) were recruited. R2*, MD measurements and morphometric biomarkers including the midbrain to pons area ratio and the Magnetic Resonance Parkinsonism Index (MRPI) were compared between groups and their diagnostic performances were assessed. Morphometric biomarkers discriminated better patients with PSP (ratio: AUC 0.89, MRPI: AUC 0.89) and MSAc (ratio: AUC 0.82, MRPI: AUC 0.75) from other groups. R2* and MD measurements in the posterior putamen performed better in separating patients with MSAp from PD (R2*: AUC 0.89; MD: AUC 0.89). For the three-class classification "MSA vs PD vs PSP", the combination of MD and R2* measurements in the posterior putamen with morphometric biomarkers (AUC: 0.841) outperformed each marker separately. At the individual-level, there were seven discordances between imaging-based prediction and clinical diagnosis involving MSA. Using the new Movement Disorder Society criteria for the diagnosis of MSA, three of these seven patients were clinically reclassified as predicted by quantitative imaging. Combining R2* and MD measurements in the posterior putamen with morphometric biomarkers improves the discrimination of parkinsonism. • R2* and MD measurements in the posterior putamen are robust clinically usable biomarkers for the discrimination of MSAp. • Their combination with brainstem morphometric biomarkers increases the performance of the multiclass classification "MSA versus PD versus PSP". • Concordance between MRI-based diagnostic prediction and clinical diagnosis was improved using the new diagnostic criteria for MSA. [ABSTRACT FROM AUTHOR]