Videnovic, Aleksandar

Abstract Objective Rapid eye movement (REM) sleep behavior disorder (RBD) is widely considered a prodromal synucleinopathy, as most with RBD develop overt synucleinopathy within ~10 years. Accordingly, RBD offers an opportunity to test potential treatments at the earliest stages of synucleinopathy. The North American Prodromal Synucleinopathy (NAPS) Consortium has created a multisite RBD participant, primarily clinic‐based cohort to better understand characteristics at diagnosis, and in future work, identify predictors of phenoconversion, develop synucleinopathy biomarkers, and enable early stage clinical trial enrollment. Methods Participants ≥18 years of age with overnight polysomnogram‐confirmed RBD without Parkinson's disease, dementia, multiple system atrophy, or narcolepsy were enrolled from nine sites across North America (8/2018 to 4/2021). Data collection included family/personal history of RBD and standardized assessments of cognitive, motor, sensory, and autonomic function. Results Outcomes are primarily reported based on sex (361 total: n = 295 male, n = 66 female), and secondarily based on history of antidepressant use ( n = 200 with, n = 154 without; with correction for sex differences) and based on extent of synucleinopathy burden ( n = 56 defined as isolated RBD, n = 305 defined as RBD+ [i.e., exhibiting ≥1 abnormality]). Overall, these participants commonly demonstrated abnormalities in global cognition (MoCA; 38%), motor function (alternate tap test; 48%), sensory (BSIT; 57%), autonomic function (orthostatic hypotension, 38.8%), and anxiety/depression (BAI and PHQ‐9; 39.3% and 31%, respectively). Interpretation These RBD participants, assessed with extensive history, demographic, cognitive, motor, sensory, and autonomic function demonstrated a lack of sex differences and high frequency of concomitant neurological abnormalities. These participants will be valuable for future longitudinal study and neuroprotective clinical trials.

AbstractAlpha-synucleinopathies can be identified in their prodromal phase, raising several ethical issues. In this review, we first provide definitions of prodromal α-synucleinopathies and discuss the importance of distinguishing between prodromes and risk factors. Next, we discuss the implications of a diagnosis of prodromal α-synucleinopathy and considerations regarding prognostic counseling in both clinical and research settings. We review available data on patient preferences regarding disclosure as well as providers' perspectives. We examine the pros and cons of disclosing a diagnosis of prodromal α-synucleinopathy, taking into consideration the differences between clinical and research settings. Asking about willingness to know in clinical and research settings and the shared decision-making process applied to prognostic counseling is discussed. Concerning research settings, ethical aspects regarding clinical trials are addressed. Availability of direct-to-consumer technologies will likely lead to novel contexts requiring prognostic counseling, and future neuroprotective or neuromodulating treatments may require further considerations on the timing, role, and importance of prognostic counseling. Recommendations on how to address ethical gaps should be a priority for patients, medical professional societies, and research workgroups. Ethical issues must be considered as an integral part of the overall clinical and research approach to prodromal synucleinopathies.

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 >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 Video-polysomnography (v-PSG) is essential for diagnosing rapid eye movement (REM) sleep behavior disorder (RBD). Although there are current American Academy of Sleep Medicine standards to diagnose RBD, several aspects need to be addressed to achieve harmonization across sleep centers. Prodromal RBD is a stage in which symptoms and signs of evolving RBD are present, but do not yet meet established diagnostic criteria for RBD. However, the boundary between prodromal and definite RBD is still unclear. As a common effort of the Neurophysiology Working Group of the International RBD Study Group, this manuscript addresses the need for comprehensive and unambiguous v-PSG recommendations to diagnose RBD and identify prodromal RBD. These include: (1) standardized v-PSG technical settings; (2) specific considerations for REM sleep scoring; (3) harmonized methods for scoring REM sleep without atonia; (4) consistent methods to analyze video and audio recorded during v-PSGs and to classify movements and vocalizations; (5) clear v-PSG guidelines to diagnose RBD and identify prodromal RBD. Each section follows a common template: The current recommendations and methods are presented, their limitations are outlined, and new recommendations are described. Finally, future directions are presented. These v-PSG recommendations are intended for both practicing clinicians and researchers. Classification and quantification of motor events, RBD episodes, and vocalizations are however intended for research purposes only. These v-PSG guidelines will allow collection of homogeneous data, providing objective v-PSG measures and making future harmonized multicentric studies and clinical trials possible.

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)

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.