Necessity of Sleep for Motor Gist Learning in Mice

With respect to behavior, the term memory “consolidation” has canonically been used to describe increased fidelity during testing to a learned behavior shaped during training. While the sleeping brain appears to certainly aid in consolidation by this definition for a variety of memories, including motor memories, growing evidence suggests that sleep allows for much more flexible use of the information encountered during prior wakefulness. Sleep has been shown to augment the extraction of gist or patterns from wake experience in human subjects, but this has been difficult to recapitulate in animal models owing to the semantic requirements in many such tasks. Here we establish a model of motor gist learning in mice in which two bouts of exclusive forward running on the rotarod significantly augments the first experience of exclusive backward running. This augmentation does not occur if sleep is disrupted following the forward running template behavior or if a period of natural wakefulness follows one of the two bouts of exclusive forward running. This suggests that sleep is required for the extraction of the motor gist of forward running to apply to backward running

Sleep oscillation-specific associations with Alzheimer’s disease CSF biomarkers : novel roles for sleep spindles and tau

Background: Based on associations between sleep spindles, cognition, and sleep-dependent memory processing, here we evaluated potential relationships between levels of CSF Aβ42, P-tau, and T-tau with sleep spindle density and other biophysical properties of sleep spindles in a sample of cognitively normal elderly individuals. Methods: One-night in-lab nocturnal polysomnography (NPSG) and morning to early afternoon CSF collection were performed to measure CSF Aβ42, P-tau and T-tau. Seven days of actigraphy were collected to assess habitual total sleep time. Results: Spindle density during NREM stage 2 (N2) sleep was negatively correlated with CSF Aβ42, P-tau and T-tau. From the three, CSF T-tau was the most significantly associated with spindle density, after adjusting for age, sex and ApoE4. Spindle duration, count and fast spindle density were also negatively correlated with T-tau levels. Sleep duration and other measures of sleep quality were not correlated with spindle characteristics and did not modify the associations between sleep spindle characteristics and the CSF biomarkers of AD. Conclusions: Reduced spindles during N2 sleep may represent an early dysfunction related to tau, possibly reflecting axonal damage or altered neuronal tau secretion, rendering it a potentially novel biomarker for early neuronal dysfunction. Given their putative role in memory consolidation and neuroplasticity, sleep spindles may represent a mechanism by which tau impairs memory consolidation, as well as a possible target for therapeutic interventions in cognitive decline

Obstructive Sleep Apnea Severity Affects Amyloid Burden in Cognitively Normal Elderly. A Longitudinal Study

Rationale: Recent evidence suggests that obstructive sleep apnea (OSA) may be a risk factor for developing mild cognitive impairment and Alzheimer’s disease. However, how sleep apnea affects longitudinal risk for Alzheimer’s disease is less well understood. Objectives: To test the hypothesis that there is an association between severity of OSA and longitudinal increase in amyloid burden in cognitively normal elderly. Methods: Data were derived from a 2-year prospective longitudinal study that sampled community-dwelling healthy cognitively normal elderly. Subjects were healthy volunteers between the ages of 55 and 90, were nondepressed, and had a consensus clinical diagnosis of cognitively normal. Cerebrospinal fluid amyloid β was measured using ELISA. Subjects received Pittsburgh compound B positron emission tomography scans following standardized procedures. Monitoring of OSA was completed using a home sleep recording device. Measurements and Main Results: We found that severity of OSA indices (AHIall [F1,88 = 4.26; P < 0.05] and AHI4% [F1,87 = 4.36; P < 0.05]) were associated with annual rate of change of cerebrospinal fluid amyloid β42 using linear regression after adjusting for age, sex, body mass index, and apolipoprotein E4 status. AHIall and AHI4% were not associated with increases in ADPiB-mask (Alzheimer’s disease vulnerable regions of interest Pittsburg compound B positron emission tomography mask) most likely because of the small sample size, although there was a trend for AHIall (F1,28 = 2.96, P = 0.09; and F1,28 = 2.32, not significant, respectively). Conclusions: In a sample of cognitively normal elderly, OSA was associated with markers of increased amyloid burden over the 2-year follow-up. Sleep fragmentation and/or intermittent hypoxia from OSA are likely candidate mechanisms. If confirmed, clinical interventions for OSA may be useful in preventing amyloid build-up in cognitively normal elderly

On neuronal hyperexcitability in a mouse model of B-amyloid neuropathology

At present, Alzheimer’s disease (AD) is an incurable neurodegenerative dementia. It has been suggested that neuronal hyperexcitability contributes to AD, so we asked how hyperexcitability develops in a common mouse model of β-amyloid neuropathology - Tg2576 mice. These mice overexpress the Swedish familial mutation of human-amyloid precursor protein (hAPP). Using video-EEG recordings, we found synchronized, large amplitude potentials resembling interictal spikes (IIS) in epilepsy at just 5 weeks of age, long before memory impairments or β-amyloid deposition. Seizures were uncommon, but occurred later in life, suggesting that IIS are possibly the earliest form of hyperexcitability. Interestingly, IIS primarily occurred during rapid-eye movement (REM) sleep prior to the deposition of β-amyloid. The interests are twofold. First, REM sleep is associated with increased cholinergic tone. Second, cholinergic impairments as well as degeneration are implicated in AD. Although previous studies suggest that cholinergic antagonists would worsen pathophysiology, the muscarinic antagonist atropine but not nicotinic antagonists reduced IIS frequency in animals prior to β-amyloid deposition. In addition, we found a role for brain hyperexcitability during general anesthesia. Epileptiform discharges are both hyperexcitable and hypersynchronous across age in Tg2576 mice and wildtypes. Our findings identify that epileptiform discharges elicited during anesthesia mediates cognitive dysfunction and is exacerbated in Aβ depositing brains. Taken together with results from prior studies, the data suggest that surprising and multiple mechanisms contribute to neural hyperexcitability. The data also suggest that IIS during sleep may be a biomarker for early detection of AD

Candidate mechanisms underlying the association between sleep-wake disruptions and Alzheimer's disease

During wakefulness, extracellular levels of metabolites in the brain increase. These include amyloid beta (Aβ), which contributes to the pathogenesis of Alzheimer's disease (AD). Counterbalancing their accumulation in the brain, sleep facilitates the removal of these metabolites from the extracellular space by convective flow of the interstitial fluid from the para-arterial to the para-venous space. However, when the sleep-wake cycle is disrupted (characterized by increased brain levels of the wake-promoting neuropeptide orexin and increased neural activity), the central nervous system (CNS) clearance of extracellular metabolites is diminished. Disruptions to the sleep-wake cycle have furthermore been linked to increased neuronal oxidative stress and impaired blood-brain barrier function - conditions that have also been proposed to play a role in the development and progression of AD. Notably, recent human and transgenic animal studies have demonstrated that AD-related pathophysiological processes that occur long before the clinical onset of AD, such as Aβ deposition in the brain, disrupt sleep and circadian rhythms. Collectively, as proposed in this review, these findings suggest the existence of a mechanistic interplay between AD pathogenesis and disrupted sleep-wake cycles, which is able to accelerate the development and progression of this disease

0645 Associations of Objective Sleep Parameters and Gray Matter Microstructure in community dwelling cognitive normal older adults

Abstract Introduction Disturbed sleep measures differentially alter white-matter microstructure. We examined whether obstructive sleep apnea (OSA)-severity, sleep fragmentation and duration measures were associated with gray-matter diffusion tensor-imaging metrics (DTI) (i.e., fractional anisotropy [FA], mean diffusivities [MD] and kurtoses [MK]) in community-dwelling cognitive-normal older-adults. Methods Gray-matter DTI metrics from MRI including mean FA, MD and MK measures of the hippocampus, thalamus, medial prefrontal-cortex (mPC) and Alzheimer’s Disease (AD) vulnerable regions (temporal [inferior, middle, and superior], parietal [inferior and superior], entorhinal cortex, and precuneus) were determined from 85 subjects. OSA-severity measures included AHI3a and AHI4%. Other sleep measures included sleep efficiency (SE), non-rapid eye movement (NREM) slow wave sleep (SWS) duration, percent time spent in SWS (%SWS), slow wave activity (SWA), total sleep time (TST), and wake after sleep onset (WASO). To analyze the data, first, we utilized factor analysis using varimax rotation to account for the DTI metrics as multivariate outcomes. Using factor loadings, we anticipated a two or three-factor model was sufficient to explain the variance of the DTI metrics. Second, we investigated predictive associations between the sleep parameters and the loaded DTI factors, and explored age, sex, BMI, education and APOE4 as covariates underlying any differences. Results Of the 85 participants, 60 (70.6%) were women, 67 (78.8%) were non-Hispanic Whites. Mean (SD) age, BMI and education was 66.7 (5.3) years, 27.9 (6.1) kg/m2 and 16.8 (2.4) years respectively. We selected the two primary loadings’ factor model based on AIC criteria. FA metrics of the investigated brain regions except thalamus, loaded on one factor, conceptualized as manifest indicators for FA. MD and MK metrics of all the investigated brain regions loaded on the second factor, conceptualized as manifest indicators for MD/MK. SWS, %SWS, TST were predictors of FA (P ≤0.01 for all). AHI3a, AHI4%, and SWA were predictors of MD/MK (P ≤0.05 for all). Additionally, sex, age, APOE4 and education were predictors of FA (P ≤0.01 for all). Conclusion In this limited sample of cognitively-normal older-adults, sleep duration measures predicted gray-matter FA, OSA-severity measures predicted gray matter MD and MK. Demographic, genetic and SES factors explained the differences in these relationships. Support (If Any) AASM 231-BS-20, AARGD-21-8488397, NIH/NIA/NHLBI (K23AG068534, L30-AG064670, CIRAD P30AG059303 Pilot, NYU ADRC P30AG066512 Developmental Grant, R25HL105444, SRG, R01AG12101, R01AG022374, R01AG13616, RF1AG057570, R01HL118624, R01AG056031

791 Association of Obstructive Sleep Apnea Severity and Novel Plasma Biomarkers of Alzheimer’s Disease Pathology

Abstract Introduction Recent evidence suggests novel plasma Alzheimer’s Disease (AD) pathology biomarkers have high potential for AD risk prediction. We determined whether obstructive sleep apnea (OSA) severity is associated with plasma levels of Aβ40, Aβ42, Aβ42/Aβ40, Tau, tau/Aβ42 and NfL and whether this relationship is dependent of amyloid burden. Methods Cross-sectional analysis of baseline data from 120 community-dwelling, cognitively normal older-adults, selected from ongoing NYU prospective longitudinal studies on memory, sleep and aging. Of the 120 participants, 70 had baseline CSF-Aβ42 (measured using ELISA). OSA-severity was defined using AHI4% criteria. Levels of plasma Aβ40, Aβ42, Tau and NfL were determined using single molecule array technology ultra-sensitive assays. Associations of OSA-severity and plasma AD-biomarker levels (n=120) were assessed using Pearson correlation analysis. The association of OSA-severity and AD plasma biomarkers dependent on CSF-Aβ42 levels (n=70) was assessed using generalized linear models. Analyses were adjusted for age, sex, BMI, race, education and APOE4. Results Of the 120 participants, 80 (67%) were women. Mean (SD) age was 69.1 (7.2) years. Mean (SD) AHI was 14.3/hr. (16.3) {48 (40%) had AHI 30}. Independent of amyloid-burden, OSA-severity was associated with higher levels of plasma Aβ40 (r=.21, p-value=.02), plasma Aβ42 (r=.26, p-value=.01), plasma Aβ42/Aβ40 (r=.20, p-value=.05), but not plasma Tau, plasma tau/Aβ42 or plasma NfL. The association of OSA-severity and plasma levels of Tau, Tau/Aβ42 or NfL dependent on CSF-Aβ42 levels revealed significant interactions between CSF-Aβ42 levels and AHI (p-value <.05 for all), with β-estimates suggesting that with combined increases in AHI and decreases in CSF-Aβ42 levels, there were corresponding increases in plasma levels of Tau, plasma Tau/Aβ42 or plasma NfL. The analysis was not powered for generating dichotomized strata specific (i.e. OSA+/Aβ+, OSA+/Aβ-, OSA-/Aβ+ and OSA-/Aβ-) estimates. Conclusion In this sample of cognitively-normal older- adults, OSA-severity was associated with levels of plasma Aβ40, Aβ42, Aβ42/Aβ40 and showed a synergistic effect with CSF Aβ42 on plasma levels of tau and NfL. Larger cohorts are necessary to delineate mechanisms and examine for OSA/Aβ strata-specific estimates. Support (if any) NIH/NIA/NHLBI (L30-AG064670, CIRAD-P30AG059303-Pilot, NYU-ADRC-P30AG066512-Developmental-Grant, AASM#231-BS-20

0887 Divergent Slow wave sleep and Alzheimer's disease Plasma Biomarkers’ Associations in Black and White Cognitive Normal Older-Adults

Abstract Introduction We determined whether slow wave sleep is associated with plasma levels of Aβ40, Aβ42, Aβ42/Aβ40, Tau, tau/Aβ42 and NfL and whether this relationship differed between Blacks/African-Americans and non-Hispanic Whites. Methods This was a cross-sectional analysis of baseline data from 171 community-dwelling cognitively normal older-adults, participating in ongoing NYU studies on memory, sleep and aging. Non-rapid eye movement sleep (NREM) slow wave sleep (SWS) duration was calculated from 2 nights of in-lab NPSGs. Plasma Aβ40, Aβ42, Tau and NfL were determined using single molecule array (SIMOA). Associations of NREM SWS duration and plasma AD biomarker levels were assessed using adjusted generalized linear models and Pearson correlation analysis after data normalization. Analyses were adjusted for age, sex, BMI, race, and education. Results Of the 171 subjects (128 non-Hispanic Whites and 43 Blacks/African-Americans), 112 (65.5%) were females, and mean (SD) age was 68.6 (6.6) years, BMI was 27.6 (6.1) kg/m**2, and education was 16.9 (2.1). There were no racial differences in age, sex, BMI, NREM SWS and AHI4%. Compared to non-Hispanic Whites, Blacks/African-Americans had significantly lower years of education (14.2 vs. 17.2, p .05 for all). NREM SWS duration was not associated with plasma Aβ42, Aβ40 or tau in the overall sample (p>.05 for all). However, in non-Hispanic Whites, NREM SWS negatively correlated with plasma Aβ42 (r=-0.28, p<=0.05), plasma Aβ40 (r=-0.087, p=0.72), though not significant, and plasma Tau (r=-0.153, p=0.27), though not significant. In Black/African-Americans, NREM SWS positively correlated with plasma Aβ42 (r=0.48, p=0.05), plasma Aβ40 levels (r=0.32, p=0.04), and plasma Tau levels (r=0.52, p=0.04). NREM SWS was not associated with plasma tau/Aβ42, plasma tau/Aβ40 or plasma NfL in the overall sample and across racial subgroups. Conclusion Race-specific divergent associations between NREM SWS and plasma Aβ42, Aβ40 & Tau may suggest differences in SDOH factors and mechanisms that could influence sleep and AD-risk in older-adults. Support (if any) AASMBTS#231-BS-20, NIAK23AG068534A, AARG-D- 21-848397, BFFA2022033

0734 Examining the diagnostic validity of the WatchPAT in a preliminary sample of cognitive normal Black/African-American older adults

Abstract Introduction The WatchPAT®️ is an innovative Home Sleep Apnea Device (HSAT) that utilizes the peripheral arterial signal (PAT®️) for OSA diagnosis. We examined the diagnostic validity of the WatchPAT and assessed the correlation between its sleep indices and those measured by PSG in a cognitive normal predominantly older Black/African-American sample. Methods Preliminary data analysis on a limited sample of 26 participants without a prior diagnosis of OSA who underwent HSAT and 2-nights of nocturnal polysomnography (NPSG). An apnea-hypopnea index (AHI) ≥ 15 events/h characterized moderate to severe OSA. Pearson correlation statistics (Fisher's z Transformation) for PAT/NPSG indices including respiratory disturbance index (RDI), oxygen desaturation index (ODI), mean oxygen saturation (Spo2), REM Latency (min), awake period during sleep (WASO), and sleep onset latency (SOL) were determined. Results Of the 26 participants, 17 (65.4%) were Black/African-American, 9 (34.6%) were non-Hispanic White, and 19 (73.1% [13/19 (68.4%) Black/African-American]) were female. Mean (SD) age, BMI and education was 66.3 (4.5) vs. 69.9 (3.7) years, 29.6 (6.4) vs. 26.6 (5.5) kg/m2 and 15.6 (3.1) vs. 17.6 (1.3) years for Black/African-American vs. non-Hispanic White, respectively. 35.3% vs. 33.3% and 17.7% vs. 22.2% of participants met criteria for moderate to severe OSA based on HSAT and NPSG, for Black/African-American vs. non-Hispanic White, respectively. The HSAT had a sensitivity and negative predictive value of 100% for both races, specificity of 78.6% vs. 85.7%, and positive predictive value (PPV) of 50% vs. 66.7%, for Black/African-American vs. non-Hispanic White, respectively. Analyses stratified by sex suggested that the WatchPAT had better diagnostic validity in Black/African-American women than men, with specificity of 83.3% vs. 75.0%. Among Blacks/African-Americans, the correlation for PAT/NPSG AHI, ODI and RDI were modest ranging from r = 0.65 to 0.70 P = .004, and mild for Spo2 and Nadir oxygen desaturation (r = 0.53 [95%CI, 0.04-0.79]; P = .03 for both). WASO, REM Latency and SOL showed no significant correlations. Conclusion Our preliminary data show HSAT having lower specificity, PPV, insights on sleep architecture for OSA diagnosis, and respiratory indices’ correlations with those from PSG, in Blacks/African-Americans compared to general population samples. The measure performed better among women. Support (If Any) AASM 231-BS-20, AARGD-21-8488397, NIH/NIA/NHLBI (K23AG068534, L30-AG064670, CIRAD P30AG059303 Pilot, NYU ADRC P30AG066512 Developmental Grant, R25HL105444 SRG, R01AG12101, R01AG022374, R01AG13616, RF1AG057570, R01HL118624, R01AG056031

0885 Alzheimer’s disease progression risk in Cognitive Normal Older Adults with Obstructive Sleep Apnea using NIA-AA Research Framework

Abstract Introduction We determined risk profiles of strata-specific cognitive-normal (NL) older-adults with obstructive sleep apnea (OSA) characterized by their Aβ, P-Tau & T-tau (ATN) burden, on prospective AD stage-transition Methods Longitudinal study utilizing data from 167 community-dwelling NL older-adults participating in NYU studies on memory, sleep and aging. Subjects had baseline CSF AD-biomarker data and at least two follow-up clinical and neuropsychological data. OSA was defined using AHI4%. Using the NIA-AA Research Framework, data-driven, clinically relevant thresholds for CSF-Aβ42 (≤375pg/ml), P-tau (≥53.7pg/ml) and T-tau (≥367 pg/ml) indicated ATN status respectively. Twenty-four participants with suspected non-AD pathologic change defined as A-T+ were excluded leaving 143 for the analysis. Main outcome was AD stage-transition (i.e., change from Global Deterioration Scale (GDS) 1 or 2 [NL] at baseline to ≥3 [≥ MCI] during follow-up). Logistic mixed-effects models with random intercept and slope were used to assess associations between ATN characterized OSA subjects, and longitudinal AD stage transition, controlling for age-at-baseline, sex, APOE4-status, years-of-education, and their interactions with time. Results Of the 143 participants, 91 (63.8%) were women. The mean (SD) age was 69.6 (7.3) years and follow-up time was 4.73 (3.45) years. Sixteen (11.2%) were OSA+/A+/TN-, and 21 (14.7%) were OSA-/A+/TN-. Ninety-two (64.3%) had normal AD biomarkers (OSA+/A-/T- [n=45] and OSA-/A-/T- [N=47]). To generate strata-specific risks, subjects were combined into groups: (i) OSA subjects with AD pathologic change OSA+/A+/TN [n=25] consisting of OSA+/A+/TN+ [n=9] plus OSA+/A+/TN- [n=16] (ii) non-OSA subjects with AD pathologic change OSA-/A+/TN [n=26]) consisting of OSA-/A+/TN+ [n=5] and OSA-/A+/TN- [n=21] Fourteen subjects (9.8%) transitioned from NL to MCI (i.e., OSA+/A+/TN [6/25], OSA-/A+/TN [3/26], OSA+/A-/TN- [4/45] and OSA-/A-/TN- [3/47]). OSA+/A+/TN subjects were at higher risk of AD stage-transition relative to OSA-/A-/TN- (β = 1.31, 95%CI, 1.02, 1.62); OSA+/A-/TN- (β = 0.89, 95%CI, 0.42, 1.37); and OSA-/A+/TN subjects, (β = 0.71, 95%CI, 0.38, 1.04); P < .01 for all. OSA+/A-/T- vs. OSA-/A-/T- participants did not show differences in cognitive change over time (β = 0.22, 95%CI, -0.15, 0.39, P =.17). Conclusion Among ATN characterized NL older-adults with OSA, those with evidence of AD pathologic change have the greatest risk of developing AD. Support (if any) AASMBTS#231-BS-20, NIAK23AG068534A, AARG-D- 21-848397, BFFA2022033