Citations

Abstract Introduction Quantitative rapid eye movement (REM) sleep without atonia (RSWA) recorded during polysomnography (PSG) represents loss of normal REM sleep atonia. RSWA is the neurophysiologic signature of REM sleep behavior disorder (RBD). Visually scored RSWA is a candidate biomarker for synucleinopathies. However, visual RSWA scoring requires expert scoring, limiting widespread application. We comparatively analyzed RSWA in DLB and iRBD using the automated Ferri REM Atonia Index (RAI). Methods We quantitatively analyzed the RAI in 17 DLB and 20 iRBD patients, compared to 20 controls using Hypnolab Software for Sleep Analysis (SWS Soft, Colognola ai Colli, Italy). PSG data were converted to European Data Format (.EDF), and the submentalis surface electromyogram (EMG) signal was notch-filtered at 60 Hertz and rectified. Automatically calculated RAI scores were comparatively analyzed across groups (DLB, iRBD, controls) using Kruskal Wallis H tests for group comparisons, and regression analyses determined relationships between diagnosis, age, and sex. Logistic regression ROC determined optimal RAI for distinguishing iRBD from DLB. When interpreting RAI, lower values represent greater amounts of RSWA, and higher values represent more normal REM atonia. Results Median age was no different between DLB (72.6 years), iRBD (69.4 years), and controls (68.0 years). The DLB group consisted of 16 men and one woman, the iRBD group had 18 men and 2 women, and controls were comprised of 16 men and 4 women. Median RAI was lowest in DLB (0.32), intermediate in iRBD (0.84) and highest in controls (0.96), indicating a gradient in RSWA amounts from DLB patients (highest) to controls (lowest). Regression demonstrated diagnosis independently predicted RAI, controlling for age and sex (adjusted R2=0.64, p=0.0001). The RAI that optimally distinguished iRBD from DLB was 0.48 (specificity 85%, sensitivity 76%, AUC=0.88). Conclusion The RAI demonstrated a clear gradient throughout the Lewy body spectrum; highest (indicating lowest RSWA amounts) in controls, intermediate in iRBD, and lowest (indicating greatest RSWA) in DLB. The RAI is a promising, time efficient and broadly applicable candidate biomarker for DLB and iRBD. Automated quantitative RSWA could be a valuable tool for deep phenotyping throughout the Lewy body disease spectrum. Support (if any) This study was supported by: U01NS100620, R34AG056639, U19AG071754, and P30AG62677.

Abstract Introduction Meta-analytic studies support that insomnia is a risk factor for cognitive decline and dementia, but limited accounting of confounders reduces their validity. Further, it is unclear whether these associations are driven by specific insomnia phenotypes. In this study, we aimed to assess the relationship between insomnia and longitudinal global cognitive decline in community-dwelling older adults after considering self-reported sleep duration changes and other important characteristics. Methods From the Mayo Clinic Study of Aging (MCSA) cohort, we identified all (age>=50yo) cognitively unimpaired participants at baseline without comorbid neurological disease with at least two previous comprehensive neuropsychological evaluations. Participants with at least two occurrences of insomnia ICD diagnosis (by EMR and Rochester Epidemiological Project data) at least 30 days apart were classified as having insomnia, and those without any instance of diagnosis were considered negative for insomnia. Changes in sleep duration were assessed using the question #16 of BDI-2 and categorized in reduced sleep (yes/no). We fit mixed-effect regression models to assess whether insomnia was associated with standardized global cognitive scores, after adjusting for age, sex, education, APOEe4, composite cardiovascular and metabolic conditions scores, anxiety/depression, reduced sleep, OSA (ICD diagnosis), alcoholism (CAGE≥2), and pain (NSAIDs use). Number of cognitive assessments and time from baseline were included as both fixed and random effects. Multiple interactions (e.g. insomnia*reduced sleep) were included. A backward stepwise procedure maintaining the hierarchical principal for interactions was utilized to reach the most parsimonious models. Results 3063 participants (50.24% males, aged 70±9.73 at baseline) were included. Insomnia alone was not associated with a decrease in global cognition, but when combined with subjective reduction in sleep duration at baseline it was associated with a -0.19 (95% CI: -0.32, -0.07; interaction p=0.01) reduction in global cognitive scores. This was equivalent to approximately 3 additional years of age or 6 cardiometabolic comorbidities at baseline. The effect size was greater than those associated with baseline cognition for having any APOE e4 allele (-0.12) and alcoholism (-0.15). Conclusion Insomnia with reduced sleep duration phenotype is a potentially modifiable risk factor for cognitive decline in older adults. Further studies with objective sleep measures are necessary for objective confirmation. Support (if any) NIA/NIH

Abstract Introduction In this pilot study, sleep biomarker-based neurodegenerative disorder (NDD) risk was assessed in a clinical cohort of patients diagnosed with varying severity of obstructive sleep apnea (OSA). Methods Consecutive in-home multi-night Sleep Profiler records from a community sleep clinic were screened for age >54 years old. Cases with comorbid restless leg syndrome, hypersomnia, missing apnea-hypopnea indexes (AHI), AHI< 5 or single-night recordings were excluded. The 67 remaining records were 40% female, ages 63 + 7.4 years and up to 84 years old. NDD risk was assigned using a machine-learning algorithm combining age and nine sleep biomarkers to assign group probabilities: for Alzheimer’s disease, Lewy Body disease, prodromal synucleinopathy and controls (CG). Sleep biomarkers included: time-REM, non-REM hypertonia, autonomic-activation index, spindle-duration, atypical-N3, time-supine, sleep-efficiency, relative-theta, and theta/alpha. Those with CG probability score >70% were classified as “Probably-normal”. Those with CG probability between 45 - 70% were classified as “Likely-normal”. Insomnia severity >14 and a PHQ 9 > 5 were used as cutoffs for clinical insomnia and depression. Mann-Whitney U-tests were used to evaluate group differences. Results This cohort had 37% mild, 34% moderate, and 29% severe OSA. Self-reported comorbid insomnia and depression were present in 43%. Seventy-three percent of patients were classified as “Probably-normal”, 16% “Likely-normal”, 11% “Likely-NDD” or “Probable-NDD”. The “Probably-normal” group was younger than the rest of the cohort (62 + 6.2 years vs. 68 + 8.6 years, p< 0.01). Of those classified as “Probably-normal” (n=49), OSA was mild in 16, moderate in 17 and severe in 16. Mean AHI trended higher in the “Probably-normal” group than in those with elevated NDD risk (29 + 23.9 vs. 19 + 13.6 events/h, p=0.085). Conclusion Approximately 89% of the clinical cohort was classified as “Probably-normal” or “Likely-normal”. NDD risk was age-dependent. Interactions between OSA severity and NDD risk were not apparent in these findings, possibly related to group-wide effects. NDD risk, as measured by this model, did not appear to be adversely biased by untreated OSA. These results suggest a need for longitudinal studies to compare NDD risk in untreated OSA versus controls without sleep disordered breathing. Support (if any) NIH grants R44AG050326, R44AG054256, RO1AG060477, R33AG064271, ULRR024150, and R34AG056639.

Background: Rehabilitation therapy is important to treat physical and functional impairments that may occur in individuals receiving physically taxing, yet potentially curative hematopoietic stem cell transplants (HSCTs). However, there are scarce data on how rehabilitation is delivered during HSCT in real-life setting. Our objective is to assess the rehabilitation practices for adult patients hospitalized for HSCT in the United States. Methods: We conducted a 48-question online survey with cancer centers with the top 10% HSCT volumes (per American registries). We obtained data on patient characteristics, rehabilitation therapy details (timing, indication, and administering providers), physical function objective and subjective outcome measures, and therapy activity precautions. Results: Out of 21 institutions, 14 were included. Rehabilitation therapy referrals occurred at admission for all patients at 35.7% of the centers for: functional decline (92.9%), fall risk (71.4%), and discharge planning (71.4%). Participating institutions had physical therapists (92.9%), occupational therapists (85.7%), speech-language pathologists (64.3%), and therapy aides (35.7%) in their rehabilitation team. Approximately 71% of centers used objective functional measures including sit-to-stand tests (50.0%), balance measures (42.9%), and 6-minute walk/gait speed (both 35.7%). Monitoring of blood counts to determine therapy modalities frequently occurred and therapies held for low platelet or hemoglobin values, but absolute neutrophil values were not a barrier to participate in resistance or aerobic therapies (42.9%). Conclusion: Rehabilitation practices during HSCT varied among the largest volume cancer centers in the United States, but most centers provided skilled therapy, utilized objective, clinician- and patient-reported outcomes, and monitored blood counts for safety of therapy administration.

Importance Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement. Objectives To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy. Design, Setting, and Participants This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses. Main Outcomes and Measures Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET). Results Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P < .001). Hippocampal MRI volume (Spearman ρ = −0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = −0.74; P < .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02). Conclusions and Relevance Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.