Citations

Abstract Introduction Symptoms associated with autonomic nervous system dysfunction are common to patients with neurodegenerative disorders (NDD) resulting from the accumulation of α-synuclein in the neurons and glial cells. In this study we investigate whether a novel biomarker, the autonomic activation index, can discriminate these potentially affected NDD groups. Methods After ethics review and with informed consent, patients with Lewy body disease (DLB/PDD: n=20%), Alzheimer’s disease dementia (AD: n=27), Parkinson disease (PD: n=14), mild cognitive impairment (MCI: n=37), isolated REM sleep behavior disorder (iRBD: n=15) and a control group (CG: n=58) were studied with the Sleep Profiler. AAI was based on a 6 BPM increase in pulse rate compared to the previous/subsequent 10th second. Between-group comparisons were assessed with Mann-Whitney U and Chi-square tests. Results The AAI values for the DLB/PDD patients were decreased compared to the AD, MCI (both p<0.03), and CG (p<0.0005), while the PD was less than AD and MCI (both < 0.05) and CG (p<0.002). The proportions of cases with abnormal AAI values (<10 events/h) was greatest in DLB/PDD patients, and greater than in ADem (p<0.02), MCI (p<0.02) and CG (p<0.0001), while AAI in PD and iRBD was greater than in CG (p<0.007 and 0.05 respectively). Conclusions These findings suggest that the AAI can be used to objectively confirm subjective complaints of autonomic dysfunction symptoms in patients with synucleinopathies. Longitudinal studies are needed determine factors that influence changes in the AAI.

Abstract Introduction In 2015, Lee et al. observed sleeping position influenced the efficiency of glymphatic clearance in rats. In 2018, Levendowski et al. reported supine sleep was independently associated with neurodegenerative disorders (NDD)(odds ratio=3.7). This update further evaluates the comparative frequency of the supine sleep position across a spectrum of cognitive impairment, including patients diagnosed with a Parkinsonian spectrum disorder (PSD), Alzheimer’s disease dementia (AD) and mild cognitive impairment (MCI), compared with a control group (CG) of patients without a known cognitive disorder. Methods After ethics review and with informed consent, a control group (CG: n=170), PSD (n=36), AD (n=29) and MCI group (n=41) were studied in-home with the Sleep Profiler; 89% across two-nights. Between-group comparisons were assessed with Mann-Whitney U and Chi-square tests. Results The hours of supine sleep were greater in PSD=3.0 + 1.9, AD=3.2 + 2.0 and MCI=3.0 + 2.0 vs. CG=1.9 + 1.8 (all p<0.002). The proportion of patients with >2 hours of supine sleep were PSD=69%, AD=69% and MCI=59% vs. CG=39%, with odds ratios of PSD=3.6, AD=3.5 and MCI=2.2 (all p<0.001). Conclusions Here we provide further evidence for a relatively strong association between supine sleep and neurodegenerative disease including PSD, AD and MCI cohorts. The nature of this association remains unclear from cross sectional study designs. Future prospective studies should test if there is a causal link between supine sleep and subsequent development of neurodegeneration.

Background: Adults with cardiovascular co-morbidities and risk factors are at greater risk of severe COVID-19. These same risk factors may also be associated with an attenuated antibody response to COVID-19 vaccines, although studies in diverse, U.S. population-based cohorts have been limited. Methods: The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) conducted a serosurvey for SARS-CoV-2 antibodies via dried blood spot (DBS) in 14 U.S. cohorts. IgG antibodies to SARS-CoV-2 spike subunit 1 (S1) and nucleocapsid (N) were measured from DBS using a semi-quantitative microsphere immunoassay and reported as median fluorescence intensity (MFI). Multivariable adjusted linear models regressed log-transformed anti-S1 MFI on age, sex, race/ethnicity, education attainment, self-reported diabetes, hypertension, cardiovascular disease (CVD), chronic kidney disease, smoking history, body mass index (BMI), asthma, obstructive lung diseases, DBS batch, anti-N MFI, vaccine type, time between vaccine and DBS, and vaccine dose at time of DBS collection. Results are presented as the percent difference in anti-S1 MFI compared with a reference group. Results: There were 6614 vaccinated participants prior to booster regimens and DBS collection (April 2021-July 2022) with 50%, 48%, and 2% of the cohort who received BNT162b2, mRNA-1273, or other vaccines, respectively. The mean (SD) time between vaccination and DBS was 3.8 (1.8) months. Over 10% of the cohort had self-reported a history of diabetes, 55% had hypertension, and 74% had a BMI>25 kg/m 2 . Anti-S1 MFI decreased as the time between vaccine dose and DBS collection increased. Diabetes was associated with a 16.1% lower anti-S1 MFI (95%CI:-22.4,-9.5) whereas neither hypertension (-3.8%;95%CI:-9.3,2.1), nor cardiovascular disease history (-5.3%;95%CI:-16.3,7.4) were associated with anti-S1 MFI. Former and current smoking history were each associated with a lower anti-S1 MFI: (-6.6%;95%CI:-12.1,-0.8) and (-16.1%;95%CI:-24.7,-6.6), respectively. Participants with a BMI 25-29.9 kg/m 2 had a 7.6% higher anti-S1 MFI (95%CI:0.3,15.4) whereas those with a BMI of 30-35 kg/m 2 and >35 kg/m 2 had 6.2% (95%CI:-2.4,15.5) higher and 8.9% lower (95%CI:-17.6,0.7) MFI levels, respectively. Older age and male sex were each associated with a lower anti-S1 MFI and mRNA-1273 vaccine, Asian subgroup, higher anti-N titer, and prior COVID-19 infection were each associated with higher anti-S1 MFI. Chronic kidney disease, education attainment, and lung disease were not associated with anti-S1 MFI. Conclusions: Several traditional cardiovascular disease risk factors were associated with diminished humoral responses to the initial COVID-19 vaccine regimens in a diverse U.S. population-based cohort and may have implications on strategies to improve vaccine responses.

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.

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 Background Randomized controlled trials have highlighted the importance of exercise training on the severity of obstructive sleep apnea (OSA). The primary objective of this meta-analysis was to analyze the data from these studies on the severity of OSA indices as measured by formal polysomnography. The secondary objective was to evaluate the effect of exercise on oxygen desaturation index, body mass index and several metabolic parameters associated with OSA. Methods Two independent reviewers and an experienced librarian searched MEDLINE, EMBASE, COCHRANE, and Scopus and SPORTDiscus databases from January 1, 2000, to October 21, 2021 to identify randomized controlled trials that evaluated the impact of exercise training on OSA severity. Pre-exercise and postexercise training data on the primary and secondary objectives were extracted. Results A total of 11 randomized controlled trials (533 study participants) were identified based on the inclusion criteria. The mean pre-exercise and postexercise reduction in apnea hypopnea index was −6.94 event per hour (95% confidence interval [CI]: −10.74 to −3.13, I2 = 84%). The mean changes in oxygen desaturation index and body mass index were −5.32 events per hour (95% CI: −9.65 to −0.99, I2 = 73%) and −1.21 kg·m−2 (95% CI: −1.80 to −0.62, I2 = 49%) respectively. Conclusion In adult patients with OSA, exercise training was associated with statistically significant reduction in OSA 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 Non-REM hypertonia (NRH) was recently reported to be independently associated with the synucleinopathy-mediated neurodegenerative disorders: dementia with Lewy Bodies/Parkinson Disease Dementia (DLB/PDD), Parkinson Disease (PD), and isolated REM sleep behavior disorder (iRBD). In this NRH investigation, we included progressive supranuclear palsy (PSP), a Parkinsonian-spectrum disorder caused by tau pathology. Methods In this multicenter study, patients broadly characterized as presumed Parkinsonian-spectrum disorders (PSD) included DLB/PDD (n=16), PD (n=16), iRBD (n=19), and PSP (n=13). Presumed non-PSD subjects included Alzheimer’s Disease dementia (AD=22), mild cognitive impairment (MCI=35), and normal cognition (NC=61). Sleep Profiler studies were acquired in all participants. NRH, auto-detected based on persistently elevated electromyographic (EMG) power relative to delta, theta, and sigma bands in the differential Af7-Af8 signal, was measured as a percentage of sleep time and then weight-averaged in the 75% of in-home studies with two-nights of data. A &gt;5% threshold characterized abnormal-NRH. Twenty-nine NC were longitudinally retested after 364- to 563-days. Statistical analyses included inter-class correlations (ICC), Bland-Altman plots, multiple logistic regression, and receiver-operating-characteristic curves (ROC). Results In the PSD=41 and non-PSD=95 records with two-nights of data, NRH-severity demonstrated moderate consistency (ICC=0.78, bias=0.6+/-6.2%, P&lt;0.0001). Across the two-nights, NRH was classified consistently as normal or abnormal in 59.6% and 27.2% of the records, vs. normal/abnormal=4.4% or abnormal/normal=8.8%. The test-retest reliability of NRH-severity was good (ICC=0.84, bias=0.06+/-3.8%, P&lt;0.0001), with all retest comparisons repeating as normal (73%) or abnormal (27%). The frequency of abnormal-NRH in PSP=92% was significantly greater than MCI=26%, AD=14%, and NC=16% (all P&lt;0.0001) and PD=56% (P&lt;0.05), but not DLB/PDD=81% and iRBD=74%. Abnormal-NRH was significantly associated with the PSD group (P&lt;0.0001) and it differentiated PSD versus non-PSD group with an area under the curve of 0.78 (95%CI: 0.72-0.85) based on a sensitivity of 0.75 (95%CI: 0.63-0.84) and a specificity of 0.81 (85%CI: 0.73-0.87). Conclusion NRH independently discriminated PSD patients from age-sex similar non-PSD subjects, suggesting that NRH is a common sleep motor signature across clinical PSD phenotypes. We speculate that NRH could be related to pathological changes within the key non-REM sleep motor modulating center in synucleinopathies and PSP. Support (If Any) NIA grants: R44AG050326, R44AG054256, P30AG62677 and R34AG56639.

Abstract Introduction Increased non-REM hypertonia (NRH) and decreased sleep spindle-durations were found to be independently associated with patients broadly characterized as presumed Parkinsonian-spectrum disorder [i.e., dementia with Lewy Bodies/Parkinson Disease Dementia (DLB/PDD), Parkinson Disease (PD), progressive supranuclear palsy (PSP), or isolated REM sleep behavior disorder (iRBD)] when compared to subjects with Alzheimer Disease dementia (AD), mild cognitive impairment (MCI) and normal cognition (NC). In this investigation, the NRH and spindle-duration features were combined to determine whether these biomarkers could distinguish neurodegenerative disorder subtypes. Methods This multicenter investigation included analysis of several neurodegenerative disorder patient subtypes including: DLB/PDD (n=16), PD (n=16), iRBD (n=19), PSP (n=13), AD (n=22), MCI (n=35), and NC (n=61). Sleep Profiler (SP) studies were conducted in all participants. NRH was auto-detected based on persistently elevated electromyographic (EMG) power relative to delta, theta, and sigma bands, while spindles were recognized by temporal excursions in alpha and sigma power &gt; 250-milliseconds. With NRH &gt;5% of sleep-time and spindle-duration &lt;1-minute considered abnormal, tallies were compared across neurodegenerative disorder subtypes with Fisher Exact tests. Results Combined SP features of Normal-NRH/normal-SpD were greater in the NC (56%), AD (46%), and MCI (43%) subtypes versus PSP (8%) and DLB/PDD (6%), and when iRBD (21%) was compared to NC (all P&lt;0.05). Abnormal-NRH/abnormal-SpD were more frequent in PSP (85%) and DLB/PDD (75%) subtypes versus iRBD (26%), PD (25%), MCI (11%), AD (9%), and NC (8%)(all P&lt;0.02). Abnormal-NRH/normal-SpD were greater in iRBD (47%) compared to MCI (14%), NC (8%), PSP (8%), DLB/PDD (6%), and AD (5%) subtypes, and in PD (31%) versus NC (all P&lt;0.05). Normal-NRH/abnormal-SpD occurred more often in AD (41%) than iRBD (5%) and PSP (0%)(both P&lt;0.05). Conclusion The combination of NRH and spindle-duration abnormality occurred more frequently in DLB/PDD and PSP subtypes. Abnormal NRH with normal sleep-duration was more frequent in iRBD and PD subtypes. Normal NRH and spindle-duration occurred most often in NC and MCI types. AD exhibited normal NRH with isolated cases of either normal or abnormal spindle-duration. Our preliminary findings suggest that auto-detected sleep biomarkers may aid in the characterization of neurodegenerative disorder subtypes. Larger prospective cohort studies are needed. Support (If Any) NIA grants: R44AG050326, R44AG054256, P30AG62677 and R34AG56639.