Ram A. Sharma

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 Alzheimers disease. However, how sleep apnea affects longitudinal risk for Alzheimers 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 &bgr; 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 &bgr;42 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 (Alzheimers 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.

EFFECT OF OBSTRUCTIVE SLEEP APNEA (OSA) ON RATE OF CHANGE OF AD BIOMARKERS IN COGNITIVELY NORMAL, MCI AND AD ELDERLY: FINDINGS FROM THE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE (ADNI) COHORT

Background: Evidence from numerous research implicates disturbed sleep or lack of sleep as one of the risk factors for Alzheimer’s disease (AD) and in a recent meta-analysis, we confirmed the association providing an “average” magnitude of effect. However, the extent of the risk of the association of disturbed sleep with AD biomarkers remains uncertain. We conducted further subgroup meta-analyses to quantify the effect of disturbed sleep on cognitive impairment; preclinical AD and symptomatic AD respectively. Methods:PubMed, Embase, Web of Science, and the Cochrane library were used to identify original published literature for this review. Sleep problems and/or disorders were the risk factor of interest in this meta-analysis, and grouped as sleep quality, sleep duration, circadian rhythm abnormalities, insomnia, and obstructive sleep apnea (OSA) for sub-group analyses. Our target variables included the use of cognitive tests assessing cognitive impairment; the use of AD biomarkers or abnormal proteins assessing preclinical AD; and the use of ICD9/DSMIV diagnoses of symptomatic AD. Effect estimates of individual studies were pooled and relative risks (RR) and 95% confidence intervals (CI) were calculated using random effects models. Meta-regression analyses examining the effect of potential influencing factors was also conducted. Results:Twentyseven observational studies (n 1⁄4 69,216 participants) that provided 52 RR estimates were included in the meta-analysis. Subgroup meta-analytic findings showed a RR increase inverse to diagnostic confidence (e.g., 1.60, 1.70 and 3.80 for AD, Cognitive Impairment and preclinical AD, P-value <.001 for all). Relative risk for AD and/or cognitive decline was (RR: 2.37, 1.86, 1.62, 1.38 and 1.38, p<.001 for all) for OSA, sleep quantity, sleep quality, insomnia, and circadian rhythm abnormalities respectively. Meta-regression results suggested that sample size might have significantly influenced the effect size such that larger sample size studies tended to result in smaller risk and vice versa. Conclusions:Our findings suggest that disturbed sleep had a four-fold association with AD biomarkers. OSA also appeared to be a strong risk factor for AD. Since changes in AD biomarkers are predictive of persons that ultimately develop AD, these results highlight potential mechanistic relationships that are vital for potential prevention of AD.

Prevalence of Sleep Disorders in Adults With Down Syndrome: A Comparative Study of Self-Reported, Actigraphic, and Polysomnographic Findings

STUDY OBJECTIVESnSleep problems are often undetected in adults with Down syndrome (DS). Our objective was to determine the prevalence of sleep disorders in adults with DS through self-reported and objective sleep measures.nnnMETHODSnWe performed a community-based cross-sectional study of 54 adults with DS not referred for sleep disorders. Two polysomnography (PSG) sleep studies were performed. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI); daytime sleepiness was evaluated using the Epworth Sleepiness Scale (ESS) and the risk for the sleep apnea syndrome (OSA) was identified using the Berlin Questionnaire (BQ). Participants sleep/wake pattern was assessed from sleep diaries and by wrist actigraphy. PSQI, ESS, and PSG measures were compared with 35 sex-, age-, and body mass index-matched patients in the control groups.nnnRESULTSnIn PSG measures, adults with DS showed lower sleep efficiency (69 ± 17.7 versus 81.6 ± 11; P < .001), less rapid eye movement sleep (9.4 ± 5.8 versus 19.4 ± 5.1; P < .001), a higher prevalence of OSA (78% versus 14%; P < .001), and a higher apnea-hypopnea index (23.5 ± 24.5 versus 3.8 ± 10.5; P < .001) than patients in the control group. In the DS group, the questionnaires (mean PSQI 3.7 ± 2.9; mean ESS 6.3 ± 4.5 and mean BQ 1 ± 0) did not reflect the sleep disturbances detected on the PSG. Actigraphy data recorded daytime sleep that was not self-reported (118.2 ± 104.2 minutes).nnnCONCLUSIONSnAdults with DS show severe sleep disruption and a high prevalence of OSA, undetected by self-reported sleep measures. Actigraphy, PSG, and validated simplified devices for screening OSA should be routinely recommended for this population because treatment of sleep disorders can contribute to healthy aging.

SLOW WAVE SLEEP DECREASE IS ASSOCIATED WITH INCREASED LEVELS OF CSF Aβ42 IN COGNITIVELY NORMAL OLDER ADULTS

sApp-a Normal 292.30 (194.51, 390.09) 0.76 (0.62, 0.91) sApp-b Normal 184.47 (127.77, 241.18) 0.57 (0.46, 0.67) AbX-38 Gamma 146.10 (15.09, 277.11) 1.41 (1.31, 1.50) AbX-40 Normal 769.49 (297.14, 1241.85) 0.45 (0.41, 0.50) AbX-42 Normal 34.03 (-23.00, 91.06) 0.47 (0.42, 0.52) MCP-1 Normal 122.02 (92.50, 151.53) 0.53 (0.48, 0.59) YKL-40 Normal 6938.41 (-19.20, 13896.02) 0.97 (0.91, 1.02) NFL Normal -5.86 (-30.73, 19.01) 1.09 (1.04, 1.13) Ab1-42 Gamma 115.10 (75.12, 155.08) 0.32 (0.27, 0.38) T-Tau Gamma 9.79 (7.24, 12.34) 0.22 (0.21, 0.24) P-Tau Normal 16.37 (8.41, 24.32) 0.43 (0.23, 0.63) AbX-42/ AbX-40 Normal 0.0121 (-0.0018, 0.0261) 0.84 (0.71, 0.97)

SLEEP DISORDERED BREATHING AND BRAIN BETA-AMYLOID BOTH PREDICT TIME-TO-PROGRESSION FROM COGNITIVE NORMAL TO MILD COGNITIVE IMPAIRMENT WITH BRAIN BETA-AMYLOID MODIFYING THE PROGRESSION RISK

and maximally for protocol-3 at 17446687 mm. The linearregression between protocol-2-3 showed the strongest relationship (p< 0.001; r 1⁄4 0.92), while the relationship between “penumbra” volumes for Protocol-1-2 (p1⁄4 0.003; r1⁄4 0.68) and Protocol-1-3 (p 1⁄4 0.013; r 1⁄4 0.56) were less robust. In addition, protocol-3 appeared optimal for co-registration of diffusion tensor and arterial spin labeling imaging for the detection of pre-WMH pathologic changes within the “penumbra“. Conclusions: Reliable volumetric quantification methodologies are essential for the determination of longitudinal WMH change over a one-year period, amenable to use in future clinical trials of small vessel ischemic disease. Future work, validating our optimal WMH “penumbra” quantification protocol amenable to multi-site studies is underway currently.

OBSTRUCTIVE SLEEP APNEA, BRAIN BETA-AMYLOID MEASURES AND TIME-TO-PROGRESSION FROM MILD COGNITIVE IMPAIRMENT TO ALZHEIMER’S DISEASE

Age, years, mean (SD) 76.7 (8.16) Female, n (%) 82 (51.9%) White, n (%) 124 (78.5%) Education, years, mean (SD) 17.2 (2.29) APOE e4+, n (%) 35 (27.1%) PiB+, n (%) 48 (30.4%) Clinical diagnosis, n (%) Cognitively normal 153 (96.8%) Mild cognitive impairment 3 (1.90%) Dementia 2 (1.27%) Follow-up duration, years, mean (SD) 2.50 (3.15) Individuals with: 1 visit, n (%) 71 (44.9%) 2 visits 35 (22.2%) 3 visits 20 (12.7%) 4 visits 11 (6.96%) 5 visits 10 (6.33%) 6-8 visits 11 (6.96%)