Faculty Bibliography

Increasing evidence links cognitive-decline and Alzheimer's disease (AD) to various sleep disorders, including obstructive sleep apnea (OSA). With increasing age, there are substantial differences in OSA's prevalence, associated comorbidities and phenotypic presentation. An important question for sleep and AD researchers is whether OSA's heterogeneity results in varying cognitive-outcomes in older-adults compared to middle-aged adults. In this review, we systematically integrated research examining OSA and cognition, mild cognitive-impairment (MCI) and AD/AD biomarkers; including the effects of continuous positive airway pressure (CPAP) treatment, particularly focusing on characterizing the heterogeneity of OSA and its cognitive-outcomes. Broadly, in middle-aged adults, OSA is often associated with mild impairment in attention, memory and executive function. In older-adults, OSA is not associated with any particular pattern of cognitive-impairment at cross-section; however, OSA is associated with the development of MCI or AD with symptomatic patients who have a higher likelihood of associated disturbed sleep/cognitive-impairment driving these findings. CPAP treatment may be effective in improving cognition in OSA patients with AD. Recent trends demonstrate links between OSA and AD-biomarkers of neurodegeneration across all age-groups. These distinct patterns provide the foundation for envisioning better characterization of OSA and the need for more sensitive/novel sleep-dependent cognitive assessments to assess OSA-related cognitive-impairment.

Introduction: The phenomena of a 'first-night effect' (worse sleep) or the 'reverse first-night' effect (better sleep) has ensured that many sleep research protocols employ multiple nights' of in-lab polysomnography (PSG), at the cost of increased financial and participant burden. Although previous investigations in healthy and sleep disordered populations show high night-to-night variability of PSG macrostructure metrics, it is suggested that there is considerable stability in EEG microstructure and respiratory measures. Findings relating NREM EEG microstructure measures to Alzheimer's disease (AD) pathology (tau and beta-amyloid burden) make sleep a potential biomarker of AD risk. Given that variability is always a major concern, we assessed the night-to-night variability of sleep macro and microstructure, respiratory and psychomotor vigilance test (PVT) measures in a group of normal elderly participating in aging and memory studies.
Material(s) and Method(s): 39 participants (66+/- 6.4 years-old and 72% female) attended 2 consecutive nights PSG and completed a 20-minute morning time PVT. 78 PSGs were scored according to AASM guidelines for sleep staging and sleep disordered breathing (S

STUDY OBJECTIVES/OBJECTIVE:To determine the effect of self-reported clinical diagnosis of Obstructive Sleep Apnea (OSA) on longitudinal changes in brain amyloid-PET and CSF-biomarkers (Aβ42, T-tau and P-tau) in cognitively normal (NL), mild cognitive impairment (MCI) and Alzheimer's Disease (AD) elderly. METHODS:Longitudinal study with mean follow-up time of 2.52±0.51 years. Data was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Participants included 516 NL, 798 MCI and 325 AD elderly. Main Outcomes were annual rate-of-change in brain amyloid-burden (i.e. longitudinal increases in florbetapir-PET uptake or decreases in CSF-Aβ42 levels); and tau-protein aggregation (i.e. longitudinal increases in CSF total-tau (T-tau) and phosphorylated-tau (P-tau)). Adjusted multi-level mixed effects linear regression models with randomly varying intercepts and slopes was used to test whether the rate-of-biomarker-change differed between participants with and without OSA. RESULTS:In NL and MCI groups, OSA+ subjects experienced faster annual increase in florbetapir uptake (B=.06, 95% CI .02, .11 and B=.08, 95% CI .05, .12 respectively) and decrease in CSF-Aβ42 levels (B=-2.71, 95% CI -3.11, -2.35 and B=-2.62, 95% CI -3.23, -2.03, respectively); as well as increases in CSF T-tau (B=3.68, 95% CI 3.31, 4.07 and B=2.21, 95% CI 1.58, 2.86, respectively) and P-tau (B=1.221, 95% CI, 1.02, 1.42 and, B=1.74, 95% CI 1.22, 2.27, respectively); compared to OSA- participants. No significant variations in the biomarker changes over time were seen in the AD group. CONCLUSIONS:In both NL and MCI, elderly, clinical interventions aimed to treat OSA are needed to test if OSA treatment may affect the progression of cognitive impairment due to AD.

Introduction: Obstructive sleep apnea (OSA) is a common sleep disorder associated with inconsistent cognitive consequences. Spatial disorientation increases with age and is an early sign of cognitive dysfunction in Alzheimer disease (AD). Sleep and related EEG oscillations, slow wave activity (SWA) and slow oscillations (SOs), are important for processing spatial memories, however it is not known if OSA-related sleep disruption effects spatial navigational memory processing in older adults.
Method(s): 42 older (age=66.5+/-7.9 years, 54.8% female) cognitively normal adults were recruited from the community. Participants performed timed trials on a 3D spatial maze navigational task and psychomotor vigilance test (PVT), before and after polysomnography (PSG). Maze completion time, PVT, sleep EEG macro and microstructure measures were compared between participants with and without OSA (AHI4%>=5.0/hour). Associations between sleep EEG microstructure (relative SWA (0.5-4Hz) & SOs (<1Hz) spectral power) and maze completion times were explored separately according to OSA diagnosis.
Result(s): Median AHI4% was 0.5/hour in those without OSA(n=30) and 10.7/hour in OSA(n=12). N1 sleep was significantly increased and N2 significantly decreased with OSA. No significant group differences in SWS, REM sleep or PVT performance were observed. There were no significant groups differences in pre-sleep maze completion time, whereas post-sleep maze performance was significantly different. On average participants without OSA continued to improve maze completion time across 3 morning trials whereas participants with OSA performed best on the first morning trial and performed worse on average with each subsequent trial (significant interaction between OSA group and morning trial number, p=0.016, Two Way Repeated Measures ANOVA). There were no significant differences in EEG microstructure observed between groups but in OSA, post-sleep maze performance showed a significant negative association with <1Hz spectral power at frontal (-0.78, p=0.007), central (-0.8, p=0.005) and occipital EEG (-0.71, p=0.02) during SWS.
Conclusion(s): Cognitively normal older adults with mild OSA demonstrated significantly worse morning spatial navigation performance compared to individuals without OSA after equivalent evening encoding. The associations between greater SOs and worse morning maze performance in OSA require replication

Introduction: We determined whether Obstructive Sleep Apnea (OSA) and beta-Amyloid Burden (Abeta) act additively or synergistically to promote conversion from cognitive normal (CN) to mild cognitive impairment (MCI) and from MCI to AD.
Method(s): In this longitudinal observational study, we examined CN (n=298) and MCI (n=418) older adults from the ADNI database (adni.loni.usc.edu). OSA was self-reported during a clinical interview. Brain Abeta was assessed using Florbetapir-PET imaging. The primary outcome of the analysis was conversion from CN to MCI (CN participants) and from MCI to AD (MCI participants). Participants were required to have a baseline and at least one follow-up clinical visit that identified their cognitive status. Logistic mixed-effects models with random intercept and slope were used to assess associations between OSA, Abeta, and risk of conversion from CN to MCI, and MCI to AD. All models included age at baseline, sex, APOE4 status, years of education, and their interactions with time.
Result(s): Of the 716 participants, 329 (46%) were women. The overall mean (SD) age was 74.7 (5.0) years, and the overall mean (SD) follow-up time was 5.5 (1.7) years (Range: 2.7 - 10.9 years). In CN participants at baseline, conversion to MCI was associated with both OSA (beta = 0.418; 95% CI, 0.133 to 0.703; P < .001) and higher Abeta-burden (beta = 0.554; 95% CI, 0.215 to 0.892; P < .001). The interaction of OSA and Abeta burden with time was significant (beta = 1.169, 95% CI, 0.776 to 1.562; P < .001), suggesting a synergistic effect. In MCI participants at baseline, conversion to AD was associated with both OSA (beta = 0.637; 95% CI, 0.291 to 0.982; P < .001) and higher Abeta-burden (beta = 1.061; 95% CI, 0.625 to 1.497; P < .001). The interaction of OSA and Abeta burden with time was significant (beta = 1.312, 95% CI, 0.952 to 1.671; P < .001), suggesting a synergistic effect.
Conclusion(s): In both CN and MCI elderly, Abeta modified the risk of progression to AD in OSA participants. OSA patients maybe more physiologically susceptible as Abeta load becomes increasingly abnormal

Introduction: We determined whether the co-occurrence of OSA and hypertension interact synergistically to promote beta-Amyloid burden and cognitive decline in clinically normal older adults Methods: Prospective longitudinal study utilizing NYU cohort of community-dwelling cognitively-normal elderly, with baseline and at least one follow-up of CSF-Abeta42 (measured using ELISA), and neuropsychological visits. OSA was defined using AHI4%. Hypertension diagnosis was according to AHA-guidelines. Cognitive variables assessed included Logic-2, Animal-Fluency [AF], Vegetable-Fluency [VF]), Boston-Naming-Test [BNT], Digit-Symbol-Substitution-Test [DSST], Trails Making Test-A and B [TMT-A and B]). Linear mixed-effects models with random intercept and slope were used to assess associations between OSA, hypertension, and longitudinal changes in CSF-Abeta and cognition, controlling for age-at-baseline, sex, APOE4-status, years-of-education, and their interactions with time.
Result(s): Of the 98 participants, 63 (64.3%) were women. The mean (SD) age was 69.6 (7.3) years and follow-up time was 2.46 (0.64) years. OSA and hypertension were each associated with faster rate-of-change in CSF-Abeta42 (beta = -3.11; 95%CI, -3.71, -2.51; and beta= -2.82, 95% CI -3.29, -2.35, P < .01 for both respectively). The interaction of OSA and hypertension with time was significant (beta= -1.28, 95% CI -1.78 to -0.78, P < .01) suggesting a synergistic effect. No significant associations were seen between annual-changes in CSF-Abeta42 and cognitive-decline. However, faster decline in VF, and DSST were associated with OSA (beta = -0.054; 95%CI, -0.094, -0.013; P = .02; beta = -0.058; 95%CI, -0.084, -0.033; P < .05 for both respectively), and with hypertension (beta = -0.048; 95%CI, -0.079, -0.017; P = .04; beta = -0.078; 95%CI, -0.098, -0.057; P = .002; respectively). The interaction of OSA and hypertension with time was significant for both VF and DSST (beta = -0.033, 95%CI, -0.048, -0.018; P < .001 and beta = -0.040, 95%CI, -0.064, -0.016; P < .001, respectively), suggesting a synergistic effect.
Conclusion(s): In cognitive-normal elderly OSA individuals, vascular risk may complement AD-biomarkers in assessing risk of prospective cognitive-decline in preclinical AD

Introduction: Assessment of habitual sleep duration and obstructive sleep apnea (OSA) severity and their relationships with subjective sleepiness and vigilance in cognitively normal older subjects is limited.
Method(s): Data are from subjects participating in an ongoing longitudinal study of sleep and Alzheimer's disease biomarkers in cognitively normal elderly subjects (CDR=0, MMSE>=24). Demographic data, comorbidities, medications and Apolipoprotein E4 (ApoE4) genotype were collected. Habitual nocturnal sleep duration was measured by 7-day actigraphy. OSA was evaluated from in-laboratory nocturnal polysomnography (NPSG) and/or 2-night home-sleep test (HST). Excessive daytime sleepiness (EDS) was determined from Epworth Sleep Scale (ESS), and vigilance by 20-min psychomotor vigilance test (PVT). OSA was defined by Apnea hypopnea Index 4 (AHI4)>=5 and/or respiratory disturbance index (RDI)>=15.
Result(s): Among 267 subjects (age 68.4+/-8.1 years, BMI 26.3+/-5 kg/ m2, 36.4% male), 185 underwent HST alone, 11 NPSG alone, and 71 both HST and NPSG. 58.7% of subjects had OSA. Of these, 67.3% had AHI4<15/hr and 32.7% had AHI4>=15/hr. Sleep duration was 7+/-1.1 hours. Median ESS was 5 (IQR 5), with 16.4% subjects having ESS>=10. Median PVT lapses was 3.2 (IQR 2.7). ESS and PVT showed no relationship (rho=0.093, p-value 0.14). There was a significant inverse correlation between actigraphy sleep duration and ESS (rho=-0.348, p-value<0.01), but not lapses. AHI4 (rho=0.188, p-value<0.01) and RDI (rho=0.166, p-value 0.01) from HST were correlated with ESS but not PVT. Sleep duration explained 12% of variance in ESS even after adjusting for AHI4. In 82 subjects with NPSG, we found no correlation between ESS or PVT and in-lab total sleep time, sleep stages or OSA severity. No differences in sleepiness were seen in ApoE4 carriers compared to others.
Conclusion(s): Our data confirm that OSA is highly prevalent in cognitively normal elderly subjects. We found limited subjective sleepiness, even in those with OSA. Typical sleep duration measured in the home was the main predictor of sleepiness. To date, conventional NPSG metrics do not explain the lack of EDS in OSA in this group

Study Objective/UNASSIGNED:To better understand the inter-individual differences in neurobehavioral impairment in obstructive sleep apnea (OSA) and its treatment with continuous positive airway pressure (CPAP), we examined how changes in sleep electroencephalography (EEG) slow waves were associated with next-day psychomotor vigilance test (PVT) lapses. Methods/UNASSIGNED:Data from 28 OSA subjects (AHI3A>15/hr.; AHI3A=sum of all apneas and hypopneas with 3% O2 desaturation and/or an EEG arousal, divided by total sleep time [TST]) who underwent three full in-lab nocturnal polysomnographies (NPSGs: chronic OSA, CPAP-treated OSA, and acute OSA), and 19 healthy-sleepers were assessed. Four 20-min PVT's were performed after each NPSG along with subjective and objective assessment of sleepiness. Three EEG metrics were calculated: K-complex (KC) density (#/min of N2 sleep), change in slow wave activity in 1-second envelopes surrounding KC's (ΔSWAK), and relative frontal slow wave activity during NREM (%SWA). Results/UNASSIGNED:CPAP treatment of OSA resulted in a decrease in KC density (chronic: [3.9 ± 2.2] vs. treated: [2.7 ± 1.1]; p < 0.01; mean ± SD) and an increase in ΔSWAK (chronic: [2.6 ± 2.3] vs. treated: [4.1 ± 2.4]; p < 0.01) and %SWA (chronic: [20.9 ± 8.8] vs. treated: [26.6 ± 8.6]; p < 0.001). Cross-sectionally, lower ΔSWAK values were associated with higher PVT Lapses (chronic: rho = -0.55, p < 0.01; acute: rho = -0.46, p = 0.03). Longitudinally, improvement in PVT Lapses with CPAP was associated with an increase in SWAK (chronic-to-treated: rho = -0.48, p = 0.02; acute-to-treated: rho = -0.5, p = 0.03). In contrast, OSA severity or global sleep quality metrics such as arousal index, non-REM, REM or TST were inconsistently associated with PVT Lapses. Conclusion/UNASSIGNED:Changes in EEG slow waves, in particular ∆SWAK, explain inter-individual differences in PVT performance better than conventional NPSG metrics, suggesting that ΔSWAK is a night-time correlate of next-day vigilance in OSA.

BACKGROUND:, 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:, P-tau and T-tau. Seven days of actigraphy were collected to assess habitual total sleep time. RESULTS:, 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.