Trial of Cinpanemab in Early Parkinson's Disease.

BACKGROUND: Aggregated α-synuclein plays an important role in Parkinson's disease pathogenesis. Cinpanemab, a human-derived monoclonal antibody that binds to α-synuclein, is being evaluated as a disease-modifying treatment for Parkinson's disease. METHODS: In a 52-week, multicenter, double-blind, phase 2 trial, we randomly assigned, in a 2:1:2:2 ratio, participants with early Parkinson's disease to receive intravenous infusions of placebo (control) or cinpanemab at a dose of 250 mg, 1250 mg, or 3500 mg every 4 weeks, followed by an active-treatment dose-blinded extension period for up to 112 weeks. The primary end points were the changes from baseline in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score (range, 0 to 236, with higher scores indicating worse performance) at weeks 52 and 72. Secondary end points included MDS-UPDRS subscale scores and striatal binding as assessed on dopamine transporter single-photon-emission computed tomography (DaT-SPECT). RESULTS: Of the 357 enrolled participants, 100 were assigned to the control group, 55 to the 250-mg cinpanemab group, 102 to the 1250-mg group, and 100 to the 3500-mg group. The trial was stopped after the week 72 interim analysis owing to lack of efficacy. The change to week 52 in the MDS-UPDRS score was 10.8 points in the control group, 10.5 points in the 250-mg group, 11.3 points in the 1250-mg group, and 10.9 points in the 3500-mg group (adjusted mean difference vs. control, -0.3 points [95% confidence interval {CI}, -4.9 to 4.3], P = 0.90; 0.5 points [95% CI, -3.3 to 4.3], P = 0.80; and 0.1 point [95% CI, -3.8 to 4.0], P = 0.97, respectively). The adjusted mean difference at 72 weeks between participants who received cinpanemab through 72 weeks and the pooled group of those who started cinpanemab at 52 weeks was -0.9 points (95% CI, -5.6 to 3.8) for the 250-mg dose, 0.6 points (95% CI, -3.3 to 4.4) for the 1250-mg dose, and -0.8 points (95% CI, -4.6 to 3.0) for the 3500-mg dose. Results for secondary end points were similar to those for the primary end points. DaT-SPECT imaging at week 52 showed no differences between the control group and any cinpanemab group. The most common adverse events with cinpanemab were headache, nasopharyngitis, and falls. CONCLUSIONS: In participants with early Parkinson's disease, the effects of cinpanemab on clinical measures of disease progression and changes in DaT-SPECT imaging did not differ from those of placebo over a 52-week period. (Funded by Biogen; SPARK ClinicalTrials.gov number, NCT03318523.).

Trial of Prasinezumab in Early-Stage Parkinson's Disease.

BACKGROUND: Aggregated α-synuclein plays an important role in the pathogenesis of Parkinson's disease. The monoclonal antibody prasinezumab, directed at aggregated α-synuclein, is being studied for its effect on Parkinson's disease. METHODS: In this phase 2 trial, we randomly assigned participants with early-stage Parkinson's disease in a 1:1:1 ratio to receive intravenous placebo or prasinezumab at a dose of 1500 mg or 4500 mg every 4 weeks for 52 weeks. The primary end point was the change from baseline to week 52 in the sum of scores on parts I, II, and III of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 236, with higher scores indicating greater impairment). Secondary end points included the dopamine transporter levels in the putamen of the hemisphere ipsilateral to the clinically more affected side of the body, as measured by 123I-ioflupane single-photon-emission computed tomography (SPECT). RESULTS: A total of 316 participants were enrolled; 105 were assigned to receive placebo, 105 to receive 1500 mg of prasinezumab, and 106 to receive 4500 mg of prasinezumab. The baseline mean MDS-UPDRS scores were 32.0 in the placebo group, 31.5 in the 1500-mg group, and 30.8 in the 4500-mg group, and mean (±SE) changes from baseline to 52 weeks were 9.4±1.2 in the placebo group, 7.4±1.2 in the 1500-mg group (difference vs. placebo, -2.0; 80% confidence interval [CI], -4.2 to 0.2; P = 0.24), and 8.8±1.2 in the 4500-mg group (difference vs. placebo, -0.6; 80% CI, -2.8 to 1.6; P = 0.72). There was no substantial difference between the active-treatment groups and the placebo group in dopamine transporter levels on SPECT. The results for most clinical secondary end points were similar in the active-treatment groups and the placebo group. Serious adverse events occurred in 6.7% of the participants in the 1500-mg group and in 7.5% of those in the 4500-mg group; infusion reactions occurred in 19.0% and 34.0%, respectively. CONCLUSIONS: Prasinezumab therapy had no meaningful effect on global or imaging measures of Parkinson's disease progression as compared with placebo and was associated with infusion reactions. (Funded by F. Hoffmann-La Roche and Prothena Biosciences; PASADENA ClinicalTrials.gov number, NCT03100149.).

Spoken Language Alterations can Predict Phenoconversion in Isolated Rapid Eye Movement Sleep Behavior Disorder: A Multicenter Study.

OBJECTIVE: This study assessed the relationship between speech and language impairment and outcome in a multicenter cohort of isolated/idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD). METHODS: Patients with iRBD from 7 centers speaking Czech, English, German, French, and Italian languages underwent a detailed speech assessment at baseline. Story-tale narratives were transcribed and linguistically annotated using fully automated methods based on automatic speech recognition and natural language processing algorithms, leading to the 3 distinctive linguistic and 2 acoustic patterns of language deterioration and associated composite indexes of their overall severity. Patients were then prospectively followed and received assessments for parkinsonism or dementia during follow-up. The Cox proportional hazard was performed to evaluate the predictive value of language patterns for phenoconversion over a follow-up period of 5 years. RESULTS: Of 180 patients free of parkinsonism or dementia, 156 provided follow-up information. After a mean follow-up of 2.7 years, 42 (26.9%) patients developed neurodegenerative disease. Patients with higher severity of linguistic abnormalities (hazard ratio [HR = 2.35]) and acoustic abnormalities (HR = 1.92) were more likely to develop a defined neurodegenerative disease, with converters having lower content richness (HR = 1.74), slower articulation rate (HR = 1.58), and prolonged pauses (HR = 1.46). Dementia-first (n = 16) and parkinsonism-first with mild cognitive impairment (n = 9) converters had higher severity of linguistic abnormalities than parkinsonism-first with normal cognition converters (n = 17). INTERPRETATION: Automated language analysis might provide a predictor of phenoconversion from iRBD into synucleinopathy subtypes with cognitive impairment, and thus can be used to stratify patients for neuroprotective trials. ANN NEUROL 2024;95:530-543.

DNA Methylation Age Acceleration as a Potential Biomarker for Early Onset of Rapid Eye Movement Sleep Behavior Disorder.

Rapid eye movement sleep behavior disorder (RBD) is the strongest prodromal marker for α-synucleinopathies. The Horvath DNA methylation age (DNAm-age) is an epigenetic clock reflecting biological aging. We found an association of DNAm-age acceleration with RBD age at onset at baseline (N = 162, B = -0.68, standard error [SE] = 0.12, p = 2.59e-08) and follow-up (n = 45, B = -1.07, SE = 0.21, p = 9.73e-06). The result remained similar after accounting for genetic risk factors (eg, RBD polygenic risk score). On average, RBD patients with faster versus slow/normal epigenetic aging had a 5.2-year earlier phenoconversion, and the Cox regression analysis revealed a trend toward significance (n = 53, hazard ratio = 1.05, 95% confidence interval = 0.99-1.11, p = 0.06). Our findings suggest that DNAm-age acceleration is a potential biomarker for earlier RBD onset. ANN NEUROL 2023.

Advantages and Challenges of Platform Trials for Disease Modifying Therapies in Parkinson's Disease.

Traditional drug development in Parkinson's disease (PD) faces significant challenges because of its protracted timeline and high costs. In response, innovative master protocols are emerging and designed to address multiple research questions within a single overarching protocol. These trials may offer advantages such as increased efficiency, agility in adding new treatment arms, and potential cost savings. However, they also present organizational, methodological, funding, regulatory, and sponsorship challenges. We review the potential of master protocols, focusing on platform trials, for disease modifying therapies in PD. These trials share a common control group and allow for the termination or addition of treatment arms during a trial with non-predetermined end. Specific issues exist for a platform trial in the PD field considering the heterogeneity of patients in terms of phenotype, genotype and staging, the confounding effects of symptomatic treatments, and the choice of outcome measures with no consensus on a non-clinical biomarker to serve as a surrogate and the slowness of PD progression. We illustrate these aspects using the examples of the main PD platform trials currently in development with each one targeting distinct goals, populations, and outcomes. Overall, platform trials hold promise in expediting the evaluation of potential therapies for PD. However, it remains to be proven whether these theoretical benefits will translate into increased production of high-quality trial data. Success also depends on the willingness of pharmaceutical companies to engage in such trials and whether this approach will ultimately hasten the identification and licensing of effective disease-modifying drugs. © 2024 International Parkinson and Movement Disorder Society.

Transitioning from Subtyping to Precision Medicine in Parkinson's Disease: A Purpose-Driven Approach.

The International Parkinson and Movement Disorder Society (MDS) created a task force (TF) to provide a critical overview of the Parkinson's disease (PD) subtyping field and develop a guidance on future research in PD subtypes. Based on a literature review, we previously concluded that PD subtyping requires an ultimate alignment with principles of precision medicine, and consequently novel approaches were needed to describe heterogeneity at the individual patient level. In this manuscript, we present a novel purpose-driven framework for subtype research as a guidance to clinicians and researchers when proposing to develop, evaluate, or use PD subtypes. Using a formal consensus methodology, we determined that the key purposes of PD subtyping are: (1) to predict disease progression, for both the development of therapies (use in clinical trials) and prognosis counseling, (2) to predict response to treatments, and (3) to identify therapeutic targets for disease modification. For each purpose, we describe the desired product and the research required for its development. Given the current state of knowledge and data resources, we see purpose-driven subtyping as a pragmatic and necessary step on the way to precision medicine. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Technical challenges in REM sleep microstructure classification: A study of patients with REM sleep behaviour disorder.

While commonly treated as a uniform state in practice, rapid eye movement sleep contains two distinct microstructures-phasic (presence of rapid eye movement) and tonic (no rapid eye movement). This study aims to identify technical challenges during rapid eye movement sleep microstructure visual classification in patients with rapid eye movement sleep behaviour disorder, and to propose solutions to enhance reliability between scorers. Fifty-seven sleep recordings were randomly allocated into three subsequent batches (n = 10, 13 and 34) for scoring. To reduce single-centre bias, we recruited three raters/scorers, with each trained from a different institution. Two raters independently scored each 30-s rapid eye movement sleep into 10â€…× fSEM3-s phasic/tonic microstructures based on the AASM guidelines. The third rater acted as an "arbitrator" to resolve opposite opinions persisting during the revision between batches. Besides interrater differences in artefact rejection rate, interrater variance frequently occurred due to transitioning between microstructures and moderate-to-severe muscular/electrode artefact interference. To enhance interrater agreement, a rapid eye movement scoring schematic graph was developed, incorporating proxy electrode use, filters and cut-offs for microstructure transitioning. To assess potential effectiveness of the schematic graph proposed, raters were instructed to systematically apply it in scoring for the third batch. Of the 34 recordings, 27 reached a Cohen's kappa score above 0.8 (i.e. almost perfect agreement between raters), significantly improved from the prior batches (p = 0.0003, Kruskal-Wallis test). Our study illustrated potential solutions and guidance for challenges that may be encountered during rapid eye movement sleep microstructure classification.

Mitochondrial function-associated genes underlie cortical atrophy in prodromal synucleinopathies.

Isolated rapid eye movement sleep behaviour disorder (iRBD) is a sleep disorder characterized by the loss of rapid eye movement sleep muscle atonia and the appearance of abnormal movements and vocalizations during rapid eye movement sleep. It is a strong marker of incipient synucleinopathy such as dementia with Lewy bodies and Parkinson's disease. Patients with iRBD already show brain changes that are reminiscent of manifest synucleinopathies including brain atrophy. However, the mechanisms underlying the development of this atrophy remain poorly understood. In this study, we performed cutting-edge imaging transcriptomics and comprehensive spatial mapping analyses in a multicentric cohort of 171 polysomnography-confirmed iRBD patients [67.7 ± 6.6 (49-87) years; 83% men] and 238 healthy controls [66.6 ± 7.9 (41-88) years; 77% men] with T1-weighted MRI to investigate the gene expression and connectivity patterns associated with changes in cortical thickness and surface area in iRBD. Partial least squares regression was performed to identify the gene expression patterns underlying cortical changes in iRBD. Gene set enrichment analysis and virtual histology were then done to assess the biological processes, cellular components, human disease gene terms, and cell types enriched in these gene expression patterns. We then used structural and functional neighbourhood analyses to assess whether the atrophy patterns in iRBD were constrained by the brain's structural and functional connectome. Moreover, we used comprehensive spatial mapping analyses to assess the specific neurotransmitter systems, functional networks, cytoarchitectonic classes, and cognitive brain systems associated with cortical changes in iRBD. All comparisons were tested against null models that preserved spatial autocorrelation between brain regions and compared to Alzheimer's disease to assess the specificity of findings to synucleinopathies. We found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to the cortical thinning occurring in iRBD. Moreover, we demonstrated that cortical thinning was constrained by the brain's structural and functional connectome and that it mapped onto specific networks involved in motor and planning functions. In contrast with cortical thickness, changes in cortical surface area were related to distinct genes, namely genes involved in the inflammatory response, and to different spatial mapping patterns. The gene expression and connectivity patterns associated with iRBD were all distinct from those observed in Alzheimer's disease. In summary, this study demonstrates that the development of brain atrophy in synucleinopathies is constrained by specific genes and networks.

Prodromal dementia with Lewy bodies in REM sleep behavior disorder: A multicenter study.

INTRODUCTION: Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a powerful early predictor of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). This provides an opportunity to directly observe the evolution of prodromal DLB and to identify which cognitive variables are the strongest predictors of evolving dementia. METHODS: IRBD participants (n = 754) from 10 centers of the International RBD Study Group underwent annual neuropsychological assessment. Competing risk regression analysis determined optimal predictors of dementia. Linear mixed-effect models determined the annual progression of neuropsychological testing. RESULTS: Reduced attention and executive function, particularly performance on the Trail Making Test Part B, were the strongest identifiers of early DLB. In phenoconverters, the onset of cognitive decline began up to 10 years prior to phenoconversion. Changes in verbal memory best differentiated between DLB and PD subtypes. DISCUSSION: In iRBD, attention and executive dysfunction strongly predict dementia and begin declining several years prior to phenoconversion. HIGHLIGHTS: Cognitive decline in iRBD begins up to 10 years prior to phenoconversion. Attention and executive dysfunction are the strongest predictors of dementia in iRBD. Decline in episodic memory best distinguished dementia-first from parkinsonism-first phenoconversion.

Risk Factors for Phenoconversion in Rapid Eye Movement Sleep Behavior Disorder.

OBJECTIVE: This study was undertaken to follow up predictive factors for α-synuclein-related neurodegenerative diseases in a multicenter cohort of idiopathic/isolated rapid eye movement sleep behavior disorder (iRBD). METHODS: Patients with iRBD from 12 centers underwent a detailed assessment for potential environmental and lifestyle risk factors via a standardized questionnaire at baseline. Patients were then prospectively followed and received assessments for parkinsonism or dementia during follow-up. The cumulative incidence of parkinsonism or dementia was estimated with competing risk analysis. Cox regression analyses were used to evaluate the predictive value of environmental/lifestyle factors over a follow-up period of 11 years, adjusting for age, sex, and center. RESULTS: Of 319 patients who were free of parkinsonism or dementia, 281 provided follow-up information. After a mean follow-up of 5.8 years, 130 (46.3%) patients developed neurodegenerative disease. The overall phenoconversion rate was 24.2% after 3 years, 44.8% after 6 years, and 67.5% after 10 years. Patients with older age (adjusted hazard ratio [aHR] = 1.05) and nitrate derivative use (aHR = 2.18) were more likely to phenoconvert, whereas prior pesticide exposure (aHR = 0.21-0.64), rural living (aHR = 0.53), lipid-lowering medication use (aHR = 0.59), and respiratory medication use (aHR = 0.36) were associated with lower phenoconversion risk. Risk factors for those converting to primary dementia and parkinsonism were generally similar, with dementia-first converters having lower coffee intake and beta-blocker intake, and higher occurrence of family history of dementia. INTERPRETATION: Our findings elucidate the predictive values of environmental factors and comorbid conditions in identifying RBD patients at higher risk of phenoconversion. ANN NEUROL 2022;91:404-416.

Diagnostic value of cerebrospinal fluid alpha-synuclein seed quantification in synucleinopathies.

Several studies have confirmed the α-synuclein real-time quaking-induced conversion (RT-QuIC) assay to have high sensitivity and specificity for Parkinson's disease. However, whether the assay can be used as a robust, quantitative measure to monitor disease progression, stratify different synucleinopathies and predict disease conversion in patients with idiopathic REM sleep behaviour disorder remains undetermined. The aim of this study was to assess the diagnostic value of CSF α-synuclein RT-QuIC quantitative parameters in regard to disease progression, stratification and conversion in synucleinopathies. We performed α-synuclein RT-QuIC in the CSF samples from 74 Parkinson's disease, 24 multiple system atrophy and 45 idiopathic REM sleep behaviour disorder patients alongside 55 healthy controls, analysing quantitative assay parameters in relation to clinical data. α-Synuclein RT-QuIC showed 89% sensitivity and 96% specificity for Parkinson's disease. There was no correlation between RT-QuIC quantitative parameters and Parkinson's disease clinical scores (e.g. Unified Parkinson's Disease Rating Scale motor), but RT-QuIC positivity and some quantitative parameters (e.g. Vmax) differed across the different phenotype clusters. RT-QuIC parameters also added value alongside standard clinical data in diagnosing Parkinson's disease. The sensitivity in multiple system atrophy was 75%, and CSF samples showed longer T50 and lower Vmax compared to Parkinson's disease. All RT-QuIC parameters correlated with worse clinical progression of multiple system atrophy (e.g. change in Unified Multiple System Atrophy Rating Scale). The overall sensitivity in idiopathic REM sleep behaviour disorder was 64%. In three of the four longitudinally followed idiopathic REM sleep behaviour disorder cohorts, we found around 90% sensitivity, but in one sample (DeNoPa) diagnosing idiopathic REM sleep behaviour disorder earlier from the community cases, this was much lower at 39%. During follow-up, 14 of 45 (31%) idiopathic REM sleep behaviour disorder patients converted to synucleinopathy with 9/14 (64%) of convertors showing baseline RT-QuIC positivity. In summary, our results showed that α-synuclein RT-QuIC adds value in diagnosing Parkinson's disease and may provide a way to distinguish variations within Parkinson's disease phenotype. However, the quantitative parameters did not correlate with disease severity in Parkinson's disease. The assay distinguished multiple system atrophy patients from Parkinson's disease patients and in contrast to Parkinson's disease, the quantitative parameters correlated with disease progression of multiple system atrophy. Our results also provided further evidence for α-synuclein RT-QuIC having potential as an early biomarker detecting synucleinopathy in idiopathic REM sleep behaviour disorder patients prior to conversion. Further analysis of longitudinally followed idiopathic REM sleep behaviour disorder patients is needed to better understand the relationship between α-synuclein RT-QuIC signature and the progression from prodromal to different synucleinopathies.

Brain atrophy in prodromal synucleinopathy is shaped by structural connectivity and gene expression.

Isolated REM sleep behaviour disorder (iRBD) is a synucleinopathy characterized by abnormal behaviours and vocalizations during REM sleep. Most iRBD patients develop dementia with Lewy bodies, Parkinson's disease or multiple system atrophy over time. Patients with iRBD exhibit brain atrophy patterns that are reminiscent of those observed in overt synucleinopathies. However, the mechanisms linking brain atrophy to the underlying alpha-synuclein pathophysiology are poorly understood. Our objective was to investigate how the prion-like and regional vulnerability hypotheses of alpha-synuclein might explain brain atrophy in iRBD. Using a multicentric cohort of 182 polysomnography-confirmed iRBD patients who underwent T1-weighted MRI, we performed vertex-based cortical surface and deformation-based morphometry analyses to quantify brain atrophy in patients (67.8 years, 84% male) and 261 healthy controls (66.2 years, 75%) and investigated the morphological correlates of motor and cognitive functioning in iRBD. Next, we applied the agent-based Susceptible-Infected-Removed model (i.e. a computational model that simulates in silico the spread of pathologic alpha-synuclein based on structural connectivity and gene expression) and tested if it recreated atrophy in iRBD by statistically comparing simulated regional brain atrophy to the atrophy observed in patients. The impact of SNCA and GBA gene expression and brain connectivity was then evaluated by comparing the model fit to the one obtained in null models where either gene expression or connectivity was randomized. The results showed that iRBD patients present with cortical thinning and tissue deformation, which correlated with motor and cognitive functioning. Next, we found that the computational model recreated cortical thinning (r = 0.51, P = 0.0007) and tissue deformation (r = 0.52, P = 0.0005) in patients, and that the connectome's architecture along with SNCA and GBA gene expression contributed to shaping atrophy in iRBD. We further demonstrated that the full agent-based model performed better than network measures or gene expression alone in recreating the atrophy pattern in iRBD. In summary, atrophy in iRBD is extensive, correlates with motor and cognitive function and can be recreated using the dynamics of agent-based modelling, structural connectivity and gene expression. These findings support the concepts that both prion-like spread and regional susceptibility account for the atrophy observed in prodromal synucleinopathies. Therefore, the agent-based Susceptible-Infected-Removed model may be a useful tool for testing hypotheses underlying neurodegenerative diseases and new therapies aimed at slowing or stopping the spread of alpha-synuclein pathology.

Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases.

Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer's disease based on inferred underlying histopathology. Parkinson's disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM sleep behaviour disorder. Huntington's disease benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. Spinal muscular atrophy clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in frontotemporal dementia illustrate the differential role of biomarkers based on genotype. Similar advances in amyotrophic lateral sclerosis would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic amyotrophic lateral sclerosis relies on a clear conceptual framework for defining the earliest stages of disease. Clinically manifest amyotrophic lateral sclerosis may emerge abruptly, especially among those who harbour genetic mutations associated with rapidly progressive amyotrophic lateral sclerosis. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioural impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioural impairment before progression to amyotrophic lateral sclerosis. Biomarkers are critically important to studying pre-symptomatic amyotrophic lateral sclerosis and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counselling, informed consent, communication of results and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counselling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building on what we have learned-more broadly from other pre-symptomatic neurodegenerative diseases and specifically from amyotrophic lateral sclerosis gene mutation carriers-we present a road map to early intervention, and perhaps even disease prevention, for all forms of amyotrophic lateral sclerosis.

A Prodromal Brain-Clinical Pattern of Cognition in Synucleinopathies.

OBJECTIVE: Isolated (or idiopathic) rapid eye movement sleep behavior disorder (iRBD) is associated with dementia with Lewy bodies (DLB) and Parkinson's disease (PD). Biomarkers are lacking to predict conversion to a dementia or a motor-first phenotype. Here, we aimed at identifying a brain-clinical signature that predicts dementia in iRBD. METHODS: A brain-clinical signature was identified in 48 patients with polysomnography-confirmed iRBD using partial least squares between brain deformation and 27 clinical variables. The resulting variable was applied to 78 patients with iRBD followed longitudinally to predict conversion to a synucleinopathy, specifically DLB. The deformation scores from patients with iRBD were compared with 207 patients with PD, DLB, or prodromal DLB to assess if scores were higher in DLB compared to PD. RESULTS: One latent variable explained 31% of the brain-clinical covariance in iRBD, combining cortical and subcortical deformation and subarachnoid/ventricular expansion to cognitive and motor variables. The deformation score of this signature predicted conversion to a synucleinopathy in iRBD (p = 0.036, odds ratio [OR] = 2.249; 95% confidence interval [CI] = 1.053-4.803), specifically to DLB (OR = 4.754; 95% CI = 1.283-17.618, p = 0.020) and not PD (p = 0.286). Patients with iRBD who developed dementia had scores similar to clinical and prodromal patients with DLB but higher scores compared with patients with PD. The deformation score also predicted cognitive performance over 1, 2, and 4 years in patients with PD. INTERPRETATION: We identified a brain-clinical signature that predicts conversion in iRBD to more severe/dementing forms of synucleinopathy. This pattern may serve as a new biomarker to optimize patient care, target risk reduction strategies, and administer neuroprotective trials. ANN NEUROL 2021;89:341-357.

Speech Biomarkers in Rapid Eye Movement Sleep Behavior Disorder and Parkinson Disease.

OBJECTIVE: This multilanguage study used simple speech recording and high-end pattern analysis to provide sensitive and reliable noninvasive biomarkers of prodromal versus manifest α-synucleinopathy in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) and early-stage Parkinson disease (PD). METHODS: We performed a multicenter study across the Czech, English, German, French, and Italian languages at 7 centers in Europe and North America. A total of 448 participants (337 males), including 150 with iRBD (mean duration of iRBD across language groups 0.5-3.4 years), 149 with PD (mean duration of disease across language groups 1.7-2.5 years), and 149 healthy controls were recorded; 350 of the participants completed the 12-month follow-up. We developed a fully automated acoustic quantitative assessment approach for the 7 distinctive patterns of hypokinetic dysarthria. RESULTS: No differences in language that impacted clinical parkinsonian phenotypes were found. Compared with the controls, we found significant abnormalities of an overall acoustic speech severity measure via composite dysarthria index for both iRBD (p = 0.002) and PD (p < 0.001). However, only PD (p < 0.001) was perceptually distinct in a blinded subjective analysis. We found significant group differences between PD and controls for monopitch (p < 0.001), prolonged pauses (p < 0.001), and imprecise consonants (p = 0.03); only monopitch was able to differentiate iRBD patients from controls (p = 0.004). At the 12-month follow-up, a slight progression of overall acoustic speech impairment was noted for the iRBD (p = 0.04) and PD (p = 0.03) groups. INTERPRETATION: Automated speech analysis might provide a useful additional biomarker of parkinsonism for the assessment of disease progression and therapeutic interventions. ANN NEUROL 2021;90:62-75.

Self-Report versus Clinician Examination in Early Parkinson's Disease.

BACKGROUND: Evaluating the discrepancies between patient-reported measures and clinician examination has implications for formulating individual treatment regimens. OBJECTIVE: This study investigated the association between health outcomes and level of self-reported motor-related function impairment relative to clinician-examined motor signs. METHODS: Recently diagnosed PD patients were evaluated using the Parkinson's Progression Marker Initiative (PPMI, N = 420) and the PASADENA phase II clinical trial (N = 316). We calculated the average normalized difference between each participant's part II and III MDS-UPDRS (Movement Disorder Society Unified Parkinson's Disease Rating Scale) scores. Individuals with score differences <25th or >75th percentiles were labeled as low- and high-self-reporters, respectively (those between ranges were labeled intermediate-self-reporters). We compared a wide range of clinical/biomarker readouts among these three groups, using Kruskal-Wallis nonparametric and Pearson's χ2 tests. Spearman's correlations were tested for associations between MDS-UPDRS subscales. RESULTS: In both cohorts, high-self-reporters reported the largest impairment/symptom experience for most motor and nonmotor patient-reported variables. By contrast, these high-self-reporters were similar to or less impaired on clinician-examined and biomarker measures. Patient-reported nonmotor symptoms on MDS-UPDRS part IB showed the strongest positive correlation with self-reported motor-related impairment (PPMI rs  = 0.54, PASADENA rs  = 0.52). This correlation was numerically stronger than the part II and clinician-examined MDS-UPDRS part III correlation (PPMI rs  = 0.38, PASADENA rs  = 0.28). CONCLUSION: Self-reported motor-related impairments reflect not only motor signs/symptoms but also other self-reported nonmotor measures. This may indicate (1) a direct impact of nonmotor symptoms on motor-related functioning and/or (2) the existence of general response tendencies in how patients self-rate symptoms. Our findings suggest further investigation into the suitability of MDS-UPDRS II to assess motor-related impairments. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Genetic, Structural, and Functional Evidence Link TMEM175 to Synucleinopathies.

OBJECTIVE: The TMEM175/GAK/DGKQ locus is the 3rd strongest risk locus in genome-wide association studies of Parkinson disease (PD). We aimed to identify the specific disease-associated variants in this locus, and their potential implications. METHODS: Full sequencing of TMEM175/GAK/DGKQ followed by genotyping of specific associated variants was performed in PD (n = 1,575) and rapid eye movement sleep behavior disorder (RBD) patients (n = 533) and in controls (n = 1,583). Adjusted regression models and a meta-analysis were performed. Association between variants and glucocerebrosidase (GCase) activity was analyzed in 715 individuals with available data. Homology modeling, molecular dynamics simulations, and lysosomal localization experiments were performed on TMEM175 variants to determine their potential effects on structure and function. RESULTS: Two coding variants, TMEM175 p.M393T (odds ratio [OR] = 1.37, p = 0.0003) and p.Q65P (OR = 0.72, p = 0.005), were associated with PD, and p.M393T was also associated with RBD (OR = 1.59, p = 0.001). TMEM175 p.M393T was associated with reduced GCase activity. Homology modeling and normal mode analysis demonstrated that TMEM175 p.M393T creates a polar side-chain in the hydrophobic core of the transmembrane, which could destabilize the domain and thus impair either its assembly, maturation, or trafficking. Molecular dynamics simulations demonstrated that the p.Q65P variant may increase stability and ion conductance of the transmembrane protein, and lysosomal localization was not affected by these variants. INTERPRETATION: Coding variants in TMEM175 are likely to be responsible for the association in the TMEM175/GAK/DGKQ locus, which could be mediated by affecting GCase activity. ANN NEUROL 2020;87:139-153.

Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies.

OBJECTIVE: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants. METHODS: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan-Meier survival analysis. RESULTS: A 5'-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5' risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3' of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3' variant rs356182) had an opposite direction of effect in iRBD compared to PD. INTERPRETATION: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3' of SNCA. Several 5' SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584-598.

Immunohistochemical Detection of Synuclein Pathology in Skin in Idiopathic Rapid Eye Movement Sleep Behavior Disorder and Parkinsonism.

BACKGROUND: Recent studies reported abnormal alpha-synuclein deposition in biopsy-accessible sites of the peripheral nervous system in Parkinson's disease (PD). This has considerable implications for clinical diagnosis. Moreover, if deposition occurs early, it may enable tissue diagnosis of prodromal PD. OBJECTIVE: The aim of this study was to develop and test an automated bright-field immunohistochemical assay of cutaneous pathological alpha-synuclein deposition in patients with idiopathic rapid eye movement sleep behavior disorder, PD, and atypical parkinsonism and in control subjects. METHODS: For assay development, postmortem skin biopsies were taken from 28 patients with autopsy-confirmed Lewy body disease and 23 control subjects. Biopsies were stained for pathological alpha-synuclein in automated stainers using a novel dual-immunohistochemical assay for serine 129-phosphorylated alpha-synuclein and pan-neuronal marker protein gene product 9.5. After validation, single 3-mm punch skin biopsies were taken from the cervical 8 paravertebral area from 79 subjects (28 idiopathic rapid eye movement sleep behavior disorder, 20 PD, 10 atypical parkinsonism, and 21 control subjects). Raters blinded to clinical diagnosis assessed the biopsies. RESULTS: The immunohistochemistry assay differentiated alpha-synuclein pathology from nonpathological-appearing alpha-synuclein using combined phosphatase and protease treatments. Among autopsy samples, 26 of 28 Lewy body samples and none of the 23 controls were positive. Among living subjects, punch biopsies were positive in 23 (82%) subjects with idiopathic rapid eye movement sleep behavior disorder, 14 (70%) subjects with PD, 2 (20%) subjects with atypical parkinsonism, and none (0%) of the control subjects. After a 3-year follow-up, eight idiopathic rapid eye movement sleep behavior disorder subjects phenoconverted to defined neurodegenerative syndromes, in accordance with baseline biopsy results. CONCLUSION: Even with a single 3-mm punch biopsy, there is considerable promise for using pathological alpha-synuclein deposition in skin to diagnose both clinical and prodromal PD. © 2020 International Parkinson and Movement Disorder Society.

Comprehensive Analysis of Familial Parkinsonism Genes in Rapid-Eye-Movement Sleep Behavior Disorder.

BACKGROUND: There is only partial overlap in the genetic background of isolated rapid-eye-movement sleep behavior disorder (iRBD) and Parkinson's disease (PD). OBJECTIVE: To examine the role of autosomal dominant and recessive PD or atypical parkinsonism genes in the risk of iRBD. METHODS: Ten genes, comprising the recessive genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7, and PLA2G6 and the dominant genes LRRK2, GCH1, and VPS35, were fully sequenced in 1039 iRBD patients and 1852 controls of European ancestry, followed by association tests. RESULTS: We found no association between rare heterozygous variants in the tested genes and risk of iRBD. Several homozygous and compound heterozygous carriers were identified, yet there was no overrepresentation in iRBD patients versus controls. CONCLUSION: Our results do not support a major role for variants in these genes in the risk of iRBD. © 2020 International Parkinson and Movement Disorder Society.