Bliwise, Donald L.

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)

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<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):

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 Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are widespread and disabling. This has been known since Dr. Alois Alzheimer's first case, Frau Auguste D., presented with emotional distress and delusions of infidelity/excessive jealousy, followed by cognitive symptoms. Being cognizant of this, in 2010 the Alzheimer's Association convened a research roundtable on the topic of NPS in AD. A major outcome of the roundtable was the founding of a Professional Interest Area (PIA) within the International Society to Advance Alzheimer's Research and Treatment (ISTAART). The NPS‐PIA has prepared a series of documents that are intended to summarize the literature and provide more detailed specific recommendations for NPS research. This overview paper is the first of these living documents that will be updated periodically as the science advances. The overview is followed by syndrome‐specific synthetic reviews and recommendations prepared by NPS‐PIA workgroups on depression, apathy, sleep, agitation, and psychosis.