Postuma, Ronald B.

AbstractBackgroundREM Sleep Behavior Disorder (RBD) is a prodromal marker of α‐synucleinopathies with no standardized tool for assessing severity in clinical or research practice. RBD severity may have implications in measuring risk of phenoconversion, monitoring response to treatment and clinical trial design. This study assessed the validity of the RBD symptom severity scale (RBDSSS) and its correlation to the clinical global impression of severity (CGI‐S) in a cohort of participants enrolled in the North American Prodromal Synucleinopathy (NAPS) Consortium.MethodParticipants and their bedpartners enrolled in the NAPS cohort filled out an 8‐item questionnaire, developed by the International RBD Study Group, assessing frequency and severity of dreams, vocalizations, movements, and injuries associated with RBD, with higher scores indicating more severe symptoms. The CGI‐S is a 7‐point scale ranging from normal (1) to most severely ill (7) and was completed by a clinician based on an independent interview with the participant ± their bedpartners. Total scores for participant (RBDSSS‐PT) and bed partner (RBDSSS‐BP) questionnaires were derived by multiplying frequency and severity scores for each feature, then summing the products for possible maximum scores of 54 and 38 respectively.ResultThis cohort (n = 212) was predominantly male (82.5%) with a mean ± SE age of 65.16 ± 1.46 years. The median (interquartile range) for RBDSSS‐PT, RBDSSS‐BP and CGI‐S was 11 (4‐17), 8 (4‐14.3) and 3 (3‐4), respectively. Spearman’s rank correlation coefficients (rs) were as follows: RBDSSS‐PT vs. RBDSSS‐BP, rs = 0.579; RBDSSS‐PT vs. CGI‐S, rs = 0.642; RBDSSS‐BP vs. CGI‐S, rs = 0.487 (all P<0.0001). RBDSSS‐BP scores were significantly lower in women (6 vs. 9, Chi‐Square p = 0.009) while there were no differences in RBDSSS‐PT scores by sex. (9 vs. 11, p = 0.473).ConclusionA moderate correlation was observed between RBDSSS‐PT and RBDSSS‐BP suggesting good construct validity for the scale. CGI‐S correlated most with RBDSSS‐PT and had a weaker association with RBDSSS‐BP. Women had lower severity scores as reported by bed partners unlike their self‐reported scores, indicating possible sex differences in perceived RBD severity.

Abstract Introduction The objective of this study is to assess the validity of the REM Sleep Behavior Disorder (RBD) symptom severity scale (RBDSSS) and its correlation to the clinical global impression of severity (CGI-S) in a cohort of participants enrolled in the North American Prodromal Synucleinopathy (NAPS) study. RBD is a prodromal marker of α-synucleinopathies with no standardized tool for assessing severity in clinical or research practice. Development of a reliable scale is essential to understand risk of phenoconversion and to monitor response to treatments, particularly in future neuroprotective clinical trials. Methods Participants and their bedpartners enrolled in the NAPS cohort filled out an 8-item questionnaire, developed by the International RBD Study Group, assessing frequency and severity of dreams, vocalizations, movements, and injuries associated with RBD, with higher scores indicating more severe symptoms. The CGI-S is a 7-point scale ranging from normal (1) to most severely ill (7) and was completed by a clinician based on an independent interview with the participant ± their bedpartners. Data was included when patient (RBDSSS-PT) and bedpartner (RBDSSS-BP) responses were both available. Total scores were derived by multiplying assigned point values for frequency and severity (for each question) and summing them for individual RBDSSS-PT scores (total possible=54) and RBDSSS-BP scores (total possible=38). Results This cohort (n=212) included in this analysis was predominantly male (n=175) with a mean ± SE age of 65.16 ± 1.46 years. The median (interquartile range) for RBDSSS-PT, RBDSSS-BP and CGI-S was 11 (4-17), 8 (4-14.3) and 3 (3-4), respectively. Non-parametric Spearman’s rank correlation coefficients (rs) for each variable pair are as follows: RBDSSS-PT vs. RBDSSS-BP, rs=0.575; RBDSSS-PT vs. CGI-S, rs=0.641; RBDSSS-BP vs. CGI-S, rs=0.463 (P&lt;0.0001). Conclusion A moderate correlation was observed between RBDSSS-PT and RBDSSS-BP suggesting good construct validity for the scale. CGI-S correlated moderately with RBDSSS-PT and weakly with RBDSSS-BP. Future, larger studies are needed to explore this as a possible universal and clinically applicable scale for designation of RBD disease burden and prognostication. Support (If Any)

Abstract Introduction Introduction: Rapid Eye Movement (REM) Sleep Behavior Disorder (RBD) is characterized by a lack of muscle atonia during REM sleep with dream enactment. RBD is regarded as a prodromal synucleinopathy as a high proportion of patients eventually phenoconvert to Parkinson’s Disease and related synucleinopathies, suggesting RBD may be an early non-motor symptom of disease. Accordingly, patients with RBD are ideally situated to test potential therapeutic interventions to prevent phenoconversion to synucleinopathy. However, RBD itself, and associated patient registries, are rare. The North American Prodromal Synucleinopathy Consortium (NAPS) establishes a multisite registry of RBD patients with standardized neurological, neuropsychiatric, and neuropsychological assessments and biomarker collection. The present work reports baseline characteristics of this RBD patient database at its current state. Methods Methods: Participants &gt;18 years of age with overnight polysomnogram-confirmed RBD by ICSD-3 criteria who did not meet criteria for the diagnosis of PD, dementia, MSA, or narcolepsy were enrolled from 10 sites across North America (8/2018 to 4/2021). Data collection included family and personal history of RBD and related symptoms, as well as standardized assessments related to cognitive, motor, sensory and autonomic function. Additionally, all subjects have contributed blood, and a subset of subjects have contributed cerebrospinal fluid samples to the National Centralized Repository for Alzheimer's Disease and Related Dementias for future analysis. Results Results: A total of n=251 participants were enrolled. Outcomes are reported based on sex (n=202 male, n=49 female). Data were further examined based on participants’ history of antidepressant use (n=142 with, n=103 without) and based on participants’ extent of synucleinopathy burden (n=70 defined as isolated RBD, n=181 defined as RBD+ [i.e., exhibiting ≥1 abnormality]). Any observed sex differences among the data did not persist after correction for antidepressant use. Conclusion Conclusions: This prospective, cross-sectional data on history, demographic, cognitive, motor, sensory, and autonomic function in n=251 participants with RBD highlight the lack of sex differences and the high preponderance of concomitant neurological abnormalities with RBD, and provide a valuable registry for future longitudinal studies and neuroprotective clinical trials. Support (If Any) NIH NIA R34 AG056639 (YJ, BB)

Abstract 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.

Abstract Introduction Rapid Eye Movement (REM) Sleep Behavior Disorder (RBD) is characterized by a lack of muscle atonia during REM sleep with dream enactment. RBD is regarded as a prodromal synucleinopathy as a high proportion of patients eventually phenoconvert to Parkinson’s Disease and related synucleinopathies, suggesting RBD may be an early non-motor symptom of disease. Accordingly, patients with RBD are ideally situated to test potential therapeutic interventions to prevent phenoconversion to synucleinopathy. However, RBD itself, and associated patient registries, are rare. The North American Prodromal Synucleinopathy Consortium (formed in 2018) establishes a multisite registry of RBD patients with standardized neurological, neuropsychiatric, and neuropsychological assessments and biomarker collection. The present work reports baseline characteristics of this RBD patient database at its current state. Methods Seven participating sites have contributed n=170 polysomnographically-confirmed RBD patients. Data includes past medical and family history, self-report questionnaires, and neuropsychological, motor, sensory, and autonomic function testing. Additionally, all subjects have contributed blood, and a subset of subjects have contributed cerebrospinal fluid samples to the National Centralized Repository for Alzheimer’s Disease and Related Dementias for future analysis. A final diagnosis for each subject was determined through an adjudication process by NAPS Consortium PIs; subjects were categorized as ether: 1) isolated RBD, 2) RBD+, 3) Early Symptomatic, or 4) Phenoconverted. Results Of the n=170 subjects, there were n=39 isolated RBD, n=81 RBD+, n=45 Early Symptomatic, and n=4 Phenoconverted. Isolated RBD subjects have no other early neurodegeneration signs/symptoms, those with RBD+ have at least one other identifiable early/mild symptom. The early symptomatic group includes those with mild or subjective cognitive impairment, pure autonomic failure, or possible multiple systems atrophy. The Phenoconverted group consists of those with Dementia with Lew Bodies, Dementia NOS, Parkinson’s Disease, or Parkinson’s NOS. The distribution of impairment across the 5 major domains (motor, cognitive, autonomic, sensory, and psychiatric) for each of the 4 groups will be described. Conclusion This interim analysis presents data on n=170 subjects. The target enrollment is n=360 across the 7 original sites plus 3 new sites. Future work will follow these subjects longitudinally to assess rates and predictors of phenoconversion. Support (if any) NIH NIA R34 AG056639 (YJ, BB)

Abstract Introduction Idiopathic/isolated REM sleep behavior disorder (iRBD) is a prodromal alpha-synucleinopathy characterized by dream enactment behavior and REM sleep without atonia (RSWA). We sought to define quantitative RSWA diagnostic thresholds in the North American Prodromal Synucleinopathy (NAPS) Consortium cohort. We analyzed RSWA between iRBD patients across participating NAPS sleep centers, compared to normative controls, and hypothesized that previous diagnostic RSWA thresholds were overestimates. Methods All digital polysomnography files were converted to European Data Format and scored at a central laboratory (Mayo Clinic) which standardized display scoring montages, channel sensitivities, and filtering, and scripted computational analyses for visual scoring. RSWA was quantitatively analyzed in the submentalis (SM) and anterior tibialis (AT) muscles in iRBD (n=86) patients and controls (n=118) utilizing well validated visual (Mayo) and automated (RAI) methods. Parametric statistics were used to compare RSWA metrics, and RSWA thresholds were developed using receiver operating characteristic curves. Results RSWA was significantly higher for the RAI and all visual individual and combined muscle activity metrics in iRBD compared to controls (all p&lt;0.001). Average SM phasic measures were: 14.2% (Mayo), 17.9% (McGill), 18.5% (UCLA), and 9.4% (Washington University). Average AT phasic measures at each site were: 26.7% (Mayo), 17.1% (McGill), 23.3% (UCLA), and 17.4% (Washington University). Average SM/AT ‘any’ measures at each site were: 45.4% (Mayo), 35.9% (McGill), 53.4% (UCLA), and 23.5% (Washington University). Overall cohort RBD diagnostic thresholds (AUC, specificity/sensitivity) were: SM phasic 4.9% (90.0, 82.2%/83.7%); AT phasic 7.6% (88.7%, 82.2%/81.4%) and combined SM/AT ‘any’ 13% (94.6, 83.9%/96.5%). Conclusion RSWA thresholds in the NAPS cohort were substantially lower than previously reported, suggesting previously overestimated diagnostic RSWA thresholds due to smaller, enriched patient samples and overfit statistical modeling. Confirmation of these findings in the complete NAPS cohort (n=300 iRBD patients across all 10 NAPS centers) is planned. Support (if any):

ObjectiveThis 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).MethodsWe 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.ResultsNo 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.InterpretationAutomated 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

AbstractBackgroundIt is important to determine the natural history of individuals with RBD and generate clinical and neuropsychological data for planning disease‐modifying trials to delay or prevent phenoconversion of RBD to an overt synucleinopathy such as dementia with Lewy bodies, Parkinson’s disease, or multiple system atrophy. Our objective is to present initial neuropsychological data on 136 participants with REM sleep behavior disorder (RBD) without an overt synucleinopathy who are in the North American Prodromal Synucleinopathy (NAPS; R34AG056639) Consortium.MethodAs part of the NAPS protocol (www.naps‐rbd.org), investigators at 10 centers in North America are enrolling a target of 360 participants with RBD. A comprehensive clinical battery and a set of neuropsychological measures (using the National Alzheimer Coordinating Center Uniform Data Set version 3 or UDS3) are performed at each visit.ResultParticipants were 82% male, ranging in age from 35‐85 (Mean=65.9, SD=15.9) and education from 8‐20 years (Mean=15.9, SD=3.1). Only 17 participants (13%) were impairment‐free across all tests administered. The proportions of participants with impaired scores were tabulated as follows (< ‐1.5 SD after adjustment for age, sex, and education): global cognition – 17%; attention/executive functioning – 10‐20% across measures; language – 14‐24% across measures; visuospatial – 16%; and episodic learning/memory – 18‐25% across measures. Of all participants, 79 (58%) showed impairments < ‐2 SD. Moreover, 53% of those with cognitive impairment involved impact in 2 domains, an additional 20% in 3 domains, and another 4% was impaired in all domains. The combination of attention/executive and language was most often observed.ConclusionCollection of a comprehensive set of clinical and neuropsychological measures is feasible and tolerated in RBD patients. Using the UDS3 neuropsychological test battery, impairment in one or more measures was present in 87% of participants, and 58% showed impairments greater than 2 SD below the mean in the absence of a clinical diagnosis of dementia. Impairments in > 2 domains was common, most frequently involving attention/executive and language. Future longitudinal assessments will be required to determine the predictive utility of neuropsychological performance for phenoconversion of RBD to an overt synucleinopathy.

ABSTRACT 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