Mazeika, Gandis

Abstract Introduction In a recent study, most patients diagnosed with isolated REM sleep behavior disorder (iRBD) preferred their physician discussed their risk for developing a future neurodegenerative disorder (NDD) such as parkinsonism or dementia (PD). In the Mayo Clinic email survey, 75% would lose trust in their physician if PD-risk was not discussed following an iRBD diagnosis. For this survey, questions were designed to investigate preferences for how sleep physicians might communicate to community-based adults about risk of a NDD. Methods A survey was administered to Rotary Club attendees prior to a sleep and neurodegenerative disease presentation, with options for responses being either strongly disagree, disagree, neutral, agree, or strongly agree. Thirty-four surveys were obtained from approximately equal numbers of men and women with estimated ages above 50 years. Personal information were not obtained (i.e., sex and age). Results The vast majority of respondents wanted their physician to ask their preference prior to sharing NDD risk (86% strongly agreed or agreed), while virtually all would lose trust in their physician if he/she did not discuss their NDD risk (97% strongly agreed/agreed). If identified with NDD risk, responders would seek out information about medications and adaptive therapies that could delay onset (97% strongly agreed/agreed), while only about half currently had a good understanding of lifestyle patterns that might help delay onset (47% strongly agreed/agreed and 47% disagreed/strongly disagreed). Not knowing when memory problems might begin would cause most responders to feel anxious (85% strongly agreed/agreed). Conclusion Those surveyed wanted their physician to ask their preference prior to sharing NDD risk, but virtually all would lose trust in their health care provider if the information was known but not shared. There appears to be a role for physicians in educating those who may be at NDD risk about interventions that could delay onset of NDD, given approximately half have a limited understanding of lifestyle patterns that could help delay onset. Further, routine follow-up for changes in prodromal NDD biomarker severity might help to reduce anxiety in the 85% of those concerned about when memory problems might begin. Support (if any) NIA-R44AG050326

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 >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<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<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<0.0001) and PD=56% (P<0.05), but not DLB/PDD=81% and iRBD=74%. Abnormal-NRH was significantly associated with the PSD group (P<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 > 250-milliseconds. With NRH >5% of sleep-time and spindle-duration <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<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<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<0.05). Normal-NRH/abnormal-SpD occurred more often in AD (41%) than iRBD (5%) and PSP (0%)(both P<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.

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.

Abstract Purpose Compare agreements between polysomnography-based (PSG) diagnosis of isolated REM-sleep-behavior-disorder (iRBD) and Non-REM-Hypertonia (NRH), a novel biomarker independently associated with synucleinopathy-related neurodegenerative diseases. Methods Sixteen patients with histories of dream-enactment-behavior (DEB)(women=38%; age:64.6±13.0) underwent PSG with simultaneously-recorded Sleep Profiler (SP). Two boarded sleep neurologists independently characterized iRBD. Physician1 combined abnormal qualitative REM-sleep-without-atonia (RSWA) by submental electromyography, with video-confirmation of probably DEB. Physician2 relied solely on qualitative RSWA. SP was auto-staged, technically reviewed, and reprocessed for automated abnormal NRH detection. Kappa scores measured physician and NRH agreements. Results In the 14 records with REM sleep, iRBD was characterized in: Physician1=64%, Physician2=79%, NRH=71% of the records. Across the three methods, unanimous iRBD agreement occurred in 57% of the records (positive=7, negative=1). The between-physician agreement in iRBD classifications was fair (kappa=0.32). The agreement between NRH and Physician1 was moderate (kappa=0.52) versus slight with Physician2 (kappa=0.05). NRH comparisons to consensus physician agreement yielded one false-positive and one false-negative iRBD finding. Physician2 classified: a) iRBD in two cases that were negative by Physician1 and NRH, and b) one negative case that Physician1 and NRH characterized as iRBD. Physician1 identified one negative case that was classified iRBD by Physician2 and NRH. Additionally, NRH was abnormal in one of the two records with no REM sleep. Discussion NRH may assist in iRBD risk assessment, given it agreed with at least one physician in 86% of the cases and the between-physician iRBD agreement was only fair. NRH also characterized iRBD-risk in patients with insufficient REM sleep for RSWA assessment.

Abstract Purpose Evaluate the sleep staging agreement between polysomnography (PSG) and Sleep Profiler (SP) in patients with suspected isolated REM-sleep-behavior-disorder. Methods Twenty-six patients with reported dream-enactment-behavior (Site1=16, Site2=10; 27% women; age 64±13 years) underwent a diagnostic PSG with simultaneously recorded SP. A registered sleep-technologist at each site performed PSG-staging, while SP was auto-staged and technically reviewed/edited. Across technicians, the initial staging was blinded. Site1 then performed unblinded restaging of PSG=N3(N2) vs. SP=N2(N3) epochs, while Site2 conducted a blinded, carefully-targeted restaging of N3. Statistics included Cohen’s kappa and Chi-square analyses. Results Agreement between SP and Site1 vs. Site2 were significantly different for Wake (kappa:Site1=0.816;Site2=0.650;combined=0.736), stage N1 (kappa:Site1=0.149;Site2=0.228;combined=0.188), stage N2 (kappa:Site1=0.632;Site2=0.718;combined=0.659), stage N3 (kappa:Site1=0.715;Site2=0.368;combined=0.525) and REM (kappa:Site1=0.827;Site2=0.719;combined=0.766)(all P&lt;0.001). After restaging of N3, the kappa values improved at Site1 (unblinded:N2=0.659/N3=0.883) and Site2 (blinded:N2=0.775/N3=0.736)(combined:N2=0.735/N3=0.851). The proportion of PSG-epochs restaged from N3 to N2 was 17% at Sites1 and 38% at Site2 (P&lt;0.001), while Site1 had fewer remaining PSG=N3 vs. SP=N2 conflicts (5.6% vs. 20.8%, P&lt;0.001). Compared to Site2, Site1 had a superior: REM kappa due to fewer SP=N2 disagreements (8.5% vs. 16.8%, P&lt;0.001), and Wake kappa resulting from fewer SP=N1 (6.6 vs. 15.6%, P&lt;0.001) and SP=N2 conflicts (5.9 vs. 12.0%, P&lt;0.001). Conversely, the Site1 N1 kappa was inferior due to greater SP=wake disagreement (41.6% vs. 19.8%, P&lt;0.001). Discussion N3 was excessively stage by both PSG technicians before restaging. At Site1, Wake, N3, and REM had almost-perfect-agreement with SP, while N2 had substantial-agreement. At Site2 and across-site, substantial-agreement was observed for Wake, N2, N3, and REM.