Berka, Chris

Abstract Introduction Decreased sleep spindle oscillations were previously associated with cognitive decline in older adults, increased tau levels, and phenoconversion to dementia in patients with Parkinson disease (PD). We analyzed quantitative sleep spindle measures to determine if this biomarker was associated with particular neurodegenerative disorder syndromes. Methods Sleep spindle oscillations ascertained in patients broadly characterized as presumed Parkinsonian-spectrum disorders (PSD), which included the subtypes dementia with Lewy Bodies/Parkinson Disease Dementia (DLB/PDD, n=16), PD (n=16), isolated REM sleep behavior disorder (iRBD, n=19), and progressive supranuclear palsy (PSP, n=13), were compared with non-PSD subtypes Alzheimer Disease dementia (AD, n=22), mild cognitive impairment (MCI, n=35), and normal cognition (NC, n=61). Sleep Profiler studies were conducted in all participants. The automated spindle detection algorithms recognized temporal excursions in the alpha (8-12 Hz) and sigma (12-16 Hz) power of 250 milliseconds or greater, with spindle duration being the sum of all spindle elapsed times. Night-to-night variability was assessed in PSP=13, PD=16, DLB/PDD=12, AD=17, MCI=25, and NC=53. Statistical analyses included intraclass correlations (ICC) and Bland-Altman plots for two-night data, and Mann-Whitney U-tests and multiple logistic regression applied to sleep-time weight-averaged spindle-durations. Results The night-to-night spindle-duration ICC was 0.95 (P<0.0001), with a Bland-Altman bias of 0.05+/-2.83 minutes. Spindle-duration was independently associated with PSD versus non-PSD groups (P=0.017, OR 1.08, 95%-CI 1.01-1.15), but not significantly associated with age (P=0.12, OR 1.03, 95%-CI 0.99-1.07) or sex (P=0.54). When stratified by subtype, age was associated with spindle-duration when NC were compared to AD and MCI (P=0.0003, OR 1.10, 95%-CI 1.04-1.16) and when iRBD were compared to DLB/PDD, PD and PSP (P<0.05, OR 1.00, 95%-CI 0.89-1.13)Spindle-durations were reduced in PSP (0.9+/-2.1) and DLB/PDD (2.0+/-5.1) when individually compared to AD (3.2+/-7.1), iRBD (3.3+/-3.4), PD (5.3+/-6.6), MCI (5.3+/-9.7), and NC (8.0+/-11.1) subtypes (all P<0.05). AD patients also exhibited lower spindle-durations than NC (P=0.03). Conclusion Auto-detected sleep spindle-durations exhibited excellent night-to-night reliability in both NC and patients with neurologic disorders. Decreased sleep spindle-duration was independently associated with PSP and DLB/PDD, and in AD. Reduced sleep spindle duration may be a distinct sleep biomarker for those disorders likely indicating thalamocortical dysfunction. Support (If Any) NIA grants: R44AG050326, R44AG054256, P30AG62677 and R34AG56639.

Abstract Introduction The severity of REM sleep without atonia, a prodromal biomarker for synucleinopathy-related neurodegenerative disorders, is influenced by selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine retake inhibitor (SNRI) use. This study investigates whether SSRI/SNRIs similarly impacts the severity of Non-REM hypertonia (NRH), a biomarker independently associated with patients broadly characterized with presumed Parkinsonian-spectrum disorders (PSD). Methods In this multi-center study, the relationship between NRH and SSRI/SNRIs was evaluated in PSD patients [Lewy Body/Parkinson Disease Dementia (DLB/PDD=16), Parkinson Disease (PD=16), isolated REM sleep behavior disorder (iRBD=19), and progressive supranuclear palsy (PSP=12)], and non-PSD subjects [Alzheimer Disease (AD=22), mild cognitive impairment (MCI=35), and normal cognition (NC=61)]. Studies were conducted with the Sleep Profiler in all participants. NRH was auto-detected based on persistently elevated electromyographic (EMG) power relative to delta, theta, and sigma bands. Abnormal-NRH was based on a threshold of >5% of sleep time, and weight-averaged by sleep time, in the 75% of studies with two-nights of data. Statistical analyses included multiple logistic regression, Fisher Exact, and Mann-Whitney U tests. Results Across all 181 records, 38% had abnormal-NRH and 24% used SSRI/SNRIs (P<0.005). No differences were observed in the distributions of NRH for those with NRH-only vs. those with combined NRH and SSRI/SNRI use (n=45, 14.5+/-7.7% versus n=24, 18.6+/-11.6%, respectively; P=0.19). Abnormal-NRH was associated with the PSD versus non-PSD groups (P<0.0001, odds-ratio=14.0) and SSRI/SNRI use (P<0.05, odds-ratio=2.4), but not age and sex. Within the PSD and non-PSD groups, the frequency of abnormal-NRH was 75% vs. 19% (P<0.0001), and SSRI/SNRI use was 32% vs. 19% (P=0.07), respectively. The distributions of abnormal-NRH in the PSD and non-PSD subgroups ranged from PSP=92%, DLB/PDD=81%, PD=56% ,and RBD=74% versus MCI=26%, and NC=16%, AD=14%, respectively. By comparison, distributions of SSRI/SNRI use were DLB/PDD=50%, RBD=42%, PSP=33%, and PD=0% in the PSD subgroups, compared to MCI=34%, AD=23%, and NC=10% in the non-PSD subgroups. Conclusion Abnormal non-REM hypertonia exhibited a very strong association with Parkinsonian-spectrum disorder diagnoses (odds-ratio=14.0) and a relatively weaker association with selective serotonin reuptake inhibitor or serotonin-norepinephrine retake inhibitor use (odds-ratio=2.4), suggesting a finding that reflects an interactive, rather than causal inference. Support (If Any) NIA grants R44AG050326, R44AG054256, P30AG62677 and R34AG56639.

AbstractBackgroundNeurodegenerative disease (NDD) is associated with sleep disturbances, including decreased stage N3 and REM sleep and reduced spindle activity. Further, supine sleep position may impact NDD risk by altering glymphatic clearance. This study evaluated conventional and exploratory sleep metrics in the differentiation of subjects with normal cognition (NC) and patients with Alzheimer’s disease dementia (AD) and alpha‐synucleinopathies (α‐Syn).MethodHome sleep data were acquired across multiple study sites using the self‐applied Sleep ProfilerTM, including 44 NC subjects (age=69+5.0), 22 patients diagnosed with AD (age=75+7.1) and 25 with α‐Syn (Parkinson’s disease=14, Parkinson’s disease with Dementia or Dementia with Lewy Bodies=11; age=69+6.9). Recordings were auto‐staged and technically reviewed, with 86% of the records having two‐night averages. Logistic regression and Mann‐Whitney U tests were used to characterize group differences based on age, conventional sleep metrics (i.e., sleep efficiency, sleep onset (SO), awakenings, percent of sleep time (%) in REM,N1, N2 and N3, and sleep spindles) and exploratory sleep measures [i.e., % supine, % Light N2 (L2=N2 epochs absent of spindles with K‐complexes and/or alpha or EMG (>40 Hz) intrusion), % NREM sleep with hypertonia (NRSH=>4 consecutive epochs with persistently elevated EMG power relative to delta and theta power) and % atypical N3 (AN3=epochs staged N3 with low theta and sigma power relative to delta, alpha, beta and EMG)].ResultAD were older than both NC and α‐Syn patients (p<0.005). Both AD and α‐Syn had lower %REM and greater %supine than NC (p<0.005), and %NRSH was greater in α‐Syn than NC or AD (p<0.005). Based on logistic regression, AD was differentiated from NC based on age, %REM, %L2 (p<0.05) and %supine (p=0.06). α‐Syn was distinguished from NC using both conventional (%N3 and SO, p<0.05) and exploratory sleep metric (%AN3 and %NRSH, p<0.05; %supine, p=0.06). Age (p=0.05) and %NRSH (p<0.01) were the only metrics that differentiated α‐Syn from AD.ConclusionObjective home sleep profiles hold promise for differentiating NDD patients from NC. The sleep metrics that provided the greatest distinction between NDD and NC were %REM, %supine and NRSH, while only NRSH distinguished AD from α‐Syn patients. Further confirmatory studies are underway.

AbstractBackgroundResting state electroencephalography (rsEEG) is a neurophysiologic Alzheimer disease (AD) and alpha‐synucleinopathy (dementia with Lewy body (DLB) and Parkinson disease (PDD)) biomarker [1]–[5]. Background slowing (increased low frequency power, dominant rhythm (DR) slowing) is frequent in AD and DLB, more so in DLB. We sought to identify distinguishing rsEEG signatures between DLB and AD.MethodParticipants included dementia patients [AD (n=26), DLB (n=12), PD (PDD; n=5)] and controls (HC; n=56). 20‐channel rsEEG was collected in eyes‐closed/eyes‐open conditions (5‐min each). Power spectral densities and coherences were measured using established methods [6]. Individual rsEEG power (delta, 1‐3 Hz; theta, 3‐7 Hz; alpha, 8‐13 Hz), theta/alpha ratio (TAR), dominant rhythm (DR), and DR frequency domain prominence were measured and averaged across groups, and effect sizes were determined and compared using Hedges g.ResultAD, DLB, and PDD groups exhibited increased low frequency (delta‐theta, 1‐5 Hz) power and TAR compared to controls (p<4x10‐4), with higher effect sizes in the DLB and PDD groups compared to AD. DR frequency was also decreased in all patient groups (DLB>PDD>AD) compared to controls (p=3x10‐9, p=3x10‐5, p=4x10‐4).AD alpha power and DR frequency domain prominence were reduced compared to controls and PDD/DLB groups (p<0.003). Both AD patients and controls had comparable posterior power distribution predominance of DR, while DLB power of DR was more anteriorly distributed. Compared to controls, delta coherence was higher in AD, but lower in DLB. Delta power was positively correlated with cognitive fluctuation (CAF) in DLB (r(8)=+0.67, p=0.03), while negatively correlated with MMSE in AD (r(24)=‐0.64, p=10‐5).ConclusionDLB and AD had both common and distinct rsEEG signatures. Both had DR slowing and background slowing that was more severe in DLB than AD. Distinctive DLB findings included reduced posterior DR spatial dominance and decreased delta coherence. Conversely, distinct AD features were increased delta coherence, decreased alpha power, and decreased DR frequency prominence. Finally, the DLB and PDD groups had a similar magnitude of DR slowing, consistent with posteriorly dominant functional impairment in synucleinopathy reflected by corresponding regional rsEEG slowing, although future longitudinal prospective sequential rsEEG analyses are necessary to confirm these findings.

Background: The characterization of sleep in those with neurodegenerative disease (NDD) is essential in understanding the potential neurobiological mechanisms that underlie the connection between sleep disruption and NDD manifestations and progression. Objective: Explore the inter-relationships between NDD and age, sex, diagnosis of obstructive sleep apnea, snoring, and duration of sleep time with the head in the supine and non-supine positions. Methods: A case-control design was used to evaluate differences in sleep position obtained from multi-night, in-home Sleep Profiler recordings in 45 patients with diagnosed NDD (24 with mild cognitive impairment, 15 with Alzheimer’s disease, and 6 with Lewy Body, Parkinson’s, or other dementias) and 120 age-sex matched controls with normal cognition (NC). Results: The frequency of supine sleep >2 h/night was significantly greater in the NDD than in the NC group ( p < 0.001, odds ratio = 3.7), and remained significant after controlling for age, sex, snoring, and obstructive sleep apnea diagnosis ( p = 0.01). There were no group differences in nocturnal mobility i.e., number of head position changes/h. Conclusion: This study demonstrates the utility of in-home measurements of sleep in defining the association of supine sleep position with neurodegenerative disorders. Our findings warrant further investigation, particularly in light of the recent evidence suggesting that sleep may an active role in the brain’s ability to clear CNS neurotoxins and metabolites.