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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.

AbstractBackgroundDementia with Lewy Bodies (DLB) is the second most common cause of degenerative dementia but the evolution of the core clinical features of DLB has not been clearly defined. The objective of this study was to identify the temporal relationship between each core feature from the estimated onset of cognitive symptoms.MethodParticipants include 485 patients with probable DLB who were evaluated at the Mayo Clinic Alzheimer Disease Research Center with neurologic and neurocognitive assessment. Each core clinical feature was compared using Kaplan‐Meier (KM) curves with the sentinel event representing age at which each core feature developed, or time from estimated cognitive onset.ResultThe sample was disproportionately male (76%). Patients were followed longitudinally, with 84% followed until death. Mean MMSE at the last evaluation was 18.3 ± 7.8. KM curves for age of onset and cumulative incidence for DLB core features as time from cognitive onset are provided. REM‐sleep behavior disorder (RBD) developed earliest and in 77% of our sample with a median KM survival estimate of 69 years (95% CI: 67.6–70.8). RBD was present in greater than 50% of patients at cognitive symptom onset. The median KM survival estimate for cognitive symptom onset was 70.2 years (95% CI: 69.3‐71.0). Parkinsonism developed in 89% with a median KM survival estimate of 73.7 years (95% CI: 72.7‐74.7). 76% had fluctuations with a similar median KM survival estimate of 74.6 years (95% CI: 73.7‐75.8). Visual hallucinations (VH) were present in 70% emerging at a median KM survival estimate of 80.2 years (95% CI: 79.5‐ 81.3). Cumulative incidence estimates for median time from cognitive onset to parkinsonism, fluctuations and VH were 2 years (95% CI: 2.0‐2.5), 2.3 years (95% CI: 2.0‐3.2) and 4.3 years (95% CI: 4.0‐4.8 years), respectively.ConclusionIn this DLB cohort, RBD was most likely to precede cognitive onset. The evolution of the other core features after cognitive onset was parkinsonism and fluctuations and then VH. While VH occur about 4 years after cognitive symptom onset, parkinsonism and fluctuations occur within the first 2 years.

ObjectiveThe aim was to analyze the timeline, prevalence, and survival of rapid eye movement (REM) sleep behavior disorder (RBD) in patients who developed alpha‐synucleinopathies (Parkinson disease, dementia with Lewy bodies, and Parkinson disease dementia) compared with age‐ and sex‐matched controls in a population‐based incident‐cohort study.MethodsWe used a population‐based, 1991 to 2010 incident‐cohort study of alpha‐synucleinopathies. A movement‐disorder specialist reviewed medical records to confirm diagnoses. RBD was diagnosed by reported dream‐enactment symptoms or polysomnography. Probable RBD and polysomnographically confirmed RBD were analyzed separately and combined.ResultsAmong the 444 incident cases of alpha‐synucleinopathy, 86 were clinically diagnosed with RBD (19.8%), including 30 (35%) by polysomnography and 56 (65%) as probable. The prevalence of idiopathic RBD at alpha‐synucleinopathy diagnosis was 3.4%, increasing to 23.8% after 15 years. Cumulative lifetime incidence was 53 times greater in alpha‐synucleinopathy patients than in controls (odds ratio [OR] = 53.1, 95% confidence interval [CI]: 13.0–217.2, p < 0.0001), higher in dementia with Lewy bodies than in Parkinson disease (OR = 2.57, 95% CI: 1.50–4.40, p = 0.0004), and higher in men than in women with Parkinson disease, dementia with Lewy bodies, or Parkinson disease dementia (OR = 3.70, 95% CI: 2.07–6.62, p < 0.0001), but did not increase mortality risk.InterpretationOur cohort had RBD incidence of 3.4%. Overall RBD increased to 23.8% after 15 years, with an overall incidence of 2.5 cases per 100 person‐years. With 53 times greater lifetime incidence in alpha‐synucleinopathy patients than in controls, RBD was more likely to develop in dementia with Lewy bodies than in Parkinson disease or Parkinson disease dementia, and in men than in women, but did not increase mortality risk within our cohort. ANN NEUROL 2021;89:293–303

ABSTRACTBackgroundRapid eye movement (REM) sleep behavior disorder (RBD) occurs occasionally in essential tremor (ET), but polysomnographic REM sleep without atonia (RSWA) analyses have been sparse.ObjectiveTo characterize the amount and distribution of polysomnographic RSWA, the electrophysiologic substrate of RBD, in patients with Parkinson's disease (PD) and ET.MethodsWe analyzed quantitative RSWA in 73 patients: PD (23), ET (23), and age‐sex‐matched controls (27). None had dream‐enactment behavior history or received antidepressants. Phasic, tonic, “any,” and phasic‐burst duration RSWA measures were calculated in the submentalis (SM) and anterior tibialis (AT) muscles. The automated REM atonia index (RAI) was also determined. Statistical analysis was performed by Kruskal‐Wallis rank‐sum and Mann‐Whitney tests.ResultsSM phasic RSWA was significantly greater for PD than ET patients and controls (12.5% ± 12.8% vs. 4.9% ± 6.7%, 3.9% ± 2.6%), as was SM “any” (13.54% ± 14.30% vs. 5.2% ± 7.6%, 4.2% ± 2.6%). RAI was significantly lower in PD than in ET and controls (0.78 ± 0.23 vs. 0.92 ± 0.09 vs. 0.90 ± 0.17, P ≤ 0.005), but no different between ET and controls. AT phasic and “any” RSWA was similar between the 3 groups. ET and control RSWA was similar in all measures. Two ET patients (8.7%) had SM RSWA similar to PD patients.ConclusionsElevated SM RSWA distinguished PD from ET in patients without dream‐enactment symptoms and occurs frequently in PD patients, and in isolated tremor suggests underlying synucleinopathy. Prospective studies will further validate these findings.

Abstract Introduction Sleepiness has been associated with functional and cognitive decline, and may present with excessive daytime sleepiness (EDS) and/or increased sleep duration. We investigated whether sleepiness and changes in sleep patterns are associated with FDG-PET levels in wake-promoting regions. Methods From the Mayo Clinic Study of Aging cohort, we identified 373 cognitively-unimpaired middle-aged and older adults (mean +/- s.d. 66.1 +/- 13.2 yo) who underwent FDG-PET. EDS was defined as ESS score &gt;=10. Changes in sleep patterns (sleeping more, less, or no change) were assessed using question #16 of the Beck Depression Inventory-2. We used probabilistic maps to create regions of interest (ROIs): the locus coeruleus (LC), posterior lateral hypothalamus (PLH), and the basal forebrain divided in 1) medial septum/diagonal band of Broca (MS/DB) and 2) nucleus basalis of Meynert (nbM). FDG-PET levels were referenced to the pons (SUVR). In this cross-sectional analysis, we fit linear models to assess the association between EDS and changes in sleeping patterns with FDG SUVR in in each ROI, while controlling for age, sex, education, BMI, witnessed apneas, and cardiovascular risk factors. Results 10.5% had EDS, 15% reported sleeping more and 21% reported sleeping less than usual. 30.7% of participants with EDS reported sleeping more, 25.6% less, and 43.5% the same. EDS was associated with an elevation in FDG-PET SUVR in the MS/DB region (.035 [95% CI .008; .063], p=.012), while sleeping more was associated with a decrease in FDG-PET SUVR in the same region (-.027 [95%CI -.052; -.002], p=.036). Sleeping less was associated with an increase in FDG-PET SUVR in the PLH (.021 [95% CI .005; .03], p=.019). No associations were found in other ROIs. Conclusion Our results suggest that sleepiness and changes in sleep patterns in cognitively-unimpaired middle-aged and older adults were associated with measurable metabolic changes in areas of the brain involved in sleep and wakefulness. Further research should clarify whether these findings could represent different phenotypes of sleepiness with potential diagnostic and prognostic implications. Support NIA/NIH

Abstract Introduction Voluntary sleep curtailment decreases insulin sensitivity. However, molecular mechanisms underlying impaired insulin signaling are not completely understood. To gain molecular insights, we examined the transcription of known cellular insulin-signaling regulators in adipose tissue obtained from subjects undergoing experimental sleep restriction. Methods Nineteen healthy subjects (males: 11; age: 19 - 36 years; BMI: 24.5 ± 3.6 kg/m2) underwent a normal (9 hours/night) and a restricted sleep (4 hours/night) sequence in a random order. Each inpatient stay included a screen visit followed by 4 days of acclimation and 9 days of experimental phase consisting of a controlled sleep opportunity. Eucaloric diet was provided to ensure weight maintenance. Abdominal fat sample was obtained at the screen and end of the experimental phase. mRNA was quantified by RT-PCR. Fasting morning blood draws were obtained at the end of acclimation and experimental phases. Mixed models were used for analysis. Results mRNA expression did not differ in normal and restricted sleep condition for SOCS3 [changes in normal Vs. restricted sleep, 0.02 (0.11, -0.01) Vs. 0.01 (0.12, -0.07), p=0.33], PTEN [-0.22 (0.18, -0.39) Vs. -0.10 (0.21, -0.20), p=0.22], PTB1B [-0.003 (0.04, -0.07) Vs. -0.01 (0.06, -0.06), p=0.74] and Cav-1 [-2.45 (0.78, -8.39) Vs. -6.31 (1.68, -8.29), p=0.34]. Further, transcription of insulin-receptor also did not change [0.01 (0.07, -0.06) Vs. -0.03 (0.09, -0.07), p=0.92]. However, within group analysis show significant decreases in Cav-1 mRNA only during sleep restriction (normal: p=0.09; restricted: p=0.003). Importantly, restricting sleep duration was associated with lowering of insulin (0.6 ± 1.9 Vs. -1.6 ± 1.7 uIU/ml; p=0.003), no change in glucose (-1.5 ± 3.8 Vs. -3.7 ± 4.12 mg/dl, p=0.06) and improvement in HOMA-IR index (0.12 ± 0.44 Vs -0.42 ± 0.43, p=0.002). Conclusion Chronic sleep restriction does not alter the transcription of cell-signaling regulators in abdominal adipose tissue. Moreover, restricting sleep duration without increasing calorie intake did not seem to decrease insulin sensitivity as determined by HOMA-IR. Support NIH grants HL114676, Mayo Clinic CCaTS UL1 TR002377; AHA grant 13POST16420009 to NC

Abstract Introduction Sleep disturbances, including rapid eye movement (REM) behavior disorder (RBD), are known manifestations of voltage-gated-potassium-channel-complex VGKC-IgG seropositivity (VGKC+). Discovery of leucine-rich, glioma inactivated protein 1 (LGI1) and contactin-associated protein 2 (CASPR2) have refined our understanding of VGKC+. VGKC+ without LGI1/CASPR2-IgG (“double-negative”) has lost its clinical significance. Previous detailed sleep analysis of these subtypes has been limited. Methods We performed a retrospective study to characterize clinical and polysomnographic features of LGI1/CASPR2 seropositive (LGI1+/CASPR2+) and VGKC double-negative patients, including quantitative REM sleep without atonia (RSWA). Quantified RSWA was compared to matched controls and normative RSWA percentiles. Results Eleven LGI1+/CASPR2+ (LGI1+, 9) and twelve VGKC double-negative patients were analyzed. Insomnia was seen in 55% of LGI1+/CASPR2+ and 8% of VGKC double-negative patients (p=0.05). The LGI1+/CASPR2+ group had reduced slow wave sleep compared to the VGKC double-negative group. Five LGI1+ patients had clinical dream enactment behavior (DEB). Eight LGI1+ patients met quantitative diagnostic levels of RSWA. Higher RSWA levels were seen in the LGI1+/CASPR2+ group. Ten LGI1+/CASPR2+ patients received immunotherapy; all ten neurologically benefited with sleep benefits in 6/10. Conclusion Sleep disorders such as insomnia and RBD are part of the LGI1/CASPR2 autoimmune phenotype. Objective sleep manifestations can be seen on polysomnogram in the form of reduced N3 and elevated RSWA as compared to controls. Quantitative RSWA analysis identified RBD in more LGI1+ patients than clinical report or qualitative RSWA. In this study, RBD was only seen with LGI1+, not CASPR2+. The intermediate RSWA levels of the VGKC double-negative patients may suggest a spectrum of abnormal motor activity in these related antibodies. Additional studies are needed to further explore the biomarker potential of quantitative RSWA in autoimmune neurological conditions. Support This project was supported by the National Center forResearch Resources, National Institutes of Health, through Grant Number 1 UL1 RR024150- 01.

Abstract Introduction REM-sleep behavior disorder (RBD) is a common finding among patients with synucleinopathies. We aimed to determine the degree of autonomic dysfunction in patients presenting with idiopathic RBD (iRBD), and the predictive value of autonomic dysfunction for phenoconversion to a defined neurodegenerative disease. Methods We searched our electronic medical record for patients diagnosed with iRBD who also underwent standardized autonomic function testing within 6 months of iRBD diagnosis, and who had clinical follow-up of at least 3 years following iRBD diagnosis. Patients who received a diagnosis of phenoconversion within 3 months of autonomic testing were excluded. The composite autonomic severity score (CASS) was derived and compared between phenoconverters and non-converters using chi-square and Wilcoxon rank-sum tests. Results We identified 18 patients who fulfilled in- and exclusion criteria. Average age at autonomic testing was 67 ± 6.6 years. Twelve (67%) patients phenoconverted during the follow-up period; 6 developed PD, the other 6 DLB. Fifteen (83%) patients had at least mild autonomic dysfunction. There were no significant differences between overall converters and non-converters in total CASS or CASS subscores. However, iRBD patients who developed DLB had significantly higher total and cardiovagal CASS scores compared with those who developed PD (p &lt;0.05), and a trend for higher adrenergic CASS scores compared to those who developed PD and those who did not phenoconvert (p=0.08 for each). Conclusion Autonomic dysfunction was seen in 83% of iRBD patients, and more severe baseline cardiovagal and adrenergic autonomic dysfunction in iRBD was associated with phenoconversion to DLB but not PD. Prospective studies are needed to confirm the value of autonomic testing for predicting phenoconversion and disease phenotype in iRBD. Support