Faculty Bibliography

INTRODUCTION/BACKGROUND:Obstructive sleep apnea (OSA) is associated with Alzheimer's disease (AD) biomarkers in cognitively normal (CN) and mild cognitive impaired (MCI) participants. However, independent and combined effects of OSA, amyloid beta (Aβ) and tau-accumulation on AD time-dependent progression risk is unclear. METHODS:Study participants grouped by biomarker profile, as described by the A/T/N scheme, where "A" refers to aggregated Aβ, "T" aggregated tau, and "N" to neurodegeneration, included 258 CN (OSA-positive [OSA+] [A+TN+ n = 10, A+/TN- n = 6, A-/TN+ n = 10, A-/TN- n = 6 and OSA-negative [OSA-] [A+TN+ n = 84, A+/TN- n = 11, A-/TN+ n = 96, A-/TN- n = 36]) and 785 MCI (OSA+ [A+TN+ n = 35, A+/TN- n = 15, A-/TN+ n = 25, A-/TN- n = 16] and OSA- [A+TN+ n = 388, A+/TN- n = 28, A-/TN+ n = 164, A-/TN- n = 114]) older-adults from the Alzheimer's Disease Neuroimaging Initiative cohort. Cox proportional hazards regression models estimated the relative hazard of progression from CN-to-MCI and MCI-to-AD, among baseline OSA CN and MCI patients, respectively. Multi-level logistic mixed-effects models with random intercept and slope investigated the synergistic associations of self-reported OSA, Aβ, and tau burden with prospective cognitive decline. RESULTS:Independent of TN-status (CN and MCI), OSA+/Aβ+ participants were approximately two to four times more likely to progress to MCI/AD (P < .001) and progressed 6 to 18 months earlier (P < .001), compared to other participants combined (ie, OSA+/Aβ-, OSA-/Aβ+, and OSA-/Aβ-). Notably, OSA+/Aβ- versus OSA-/Aβ- (CN and MCI) and OSA+/TN- versus OSA-/TN- (CN) participants showed no difference in the risk and time-to-MCI/AD progression. Mixed effects models demonstrated OSA synergism with Aβ (CN and MCI [β = 1.13, 95% confidence interval (CI), 0.74 to 1.52, and β = 1.18, 95%CI, 0.82 to 1.54]) respectively, and with tau (MCI [β = 1.31, 95% CI, 0.87 to 1.47]), P < .001 for all. DISCUSSION/CONCLUSIONS:OSA acts in synergism with Aβ and with tau, and all three acting together result in synergistic neurodegenerative mechanisms especially as Aβ and tau accumulation becomes increasingly abnormal, thus leading to shorter progression time to MCI/AD in CN and MCI-OSA patients, respectively.

Here we review the impact of obstructive sleep apnea (OSA) on biomarkers of Alzheimer's disease (AD) pathogenesis, neuroanatomy, cognition and neurophysiology, and present the research investigating the effects of continuous positive airway pressure (CPAP) therapy. OSA is associated with an increase in AD markers amyloid-β and tau measured in cerebrospinal fluid (CSF), by Positron Emission Tomography (PET) and in blood serum. There is some evidence suggesting CPAP therapy normalizes AD biomarkers in CSF but since mechanisms for amyloid-β and tau production/clearance in humans are not completely understood, these findings remain preliminary. Deficits in the cognitive domains of attention, vigilance, memory and executive functioning are observed in OSA patients with the magnitude of impairment appearing stronger in younger people from clinical settings than in older community samples. Cognition improves with varying degrees after CPAP use, with the greatest effect seen for attention in middle age adults with more severe OSA and sleepiness. Paradigms in which encoding and retrieval of information are separated by periods of sleep with or without OSA have been done only rarely, but perhaps offer a better chance to understand cognitive effects of OSA than isolated daytime testing. In cognitively normal individuals, changes in EEG microstructure during sleep, particularly slow oscillations and spindles, are associated with biomarkers of AD, and measures of cognition and memory. Similar changes in EEG activity are reported in AD and OSA, such as "EEG slowing" during wake and REM sleep, and a degradation of NREM EEG microstructure. There is evidence that CPAP therapy partially reverses these changes but large longitudinal studies demonstrating this are lacking. A diagnostic definition of OSA relying solely on the Apnea Hypopnea Index (AHI) does not assist in understanding the high degree of inter-individual variation in daytime impairments related to OSA or response to CPAP therapy. We conclude by discussing conceptual challenges to a clinical trial of OSA treatment for AD prevention, including inclusion criteria for age, OSA severity, and associated symptoms, the need for a potentially long trial, defining relevant primary outcomes, and which treatments to target to optimize treatment adherence.

Beta amyloid (Aβ) accumulation is the earliest pathological marker of Alzheimer's disease (AD), but early AD pathology also affects white matter (WM) integrity. We performed a cross-sectional study including 44 subjects (23 healthy controls and 21 mild cognitive impairment or early AD patients) who underwent simultaneous PET-MR using 18F-Florbetapir, and were categorized into 3 groups based on Aβ burden: Aβ- [mean mSUVr ≤1.00], Aβi [1.00 < mSUVr <1.17], Aβ+ [mSUVr ≥1.17]. Intergroup comparisons of diffusion MRI metrics revealed significant differences across multiple WM tracts. Aβi group displayed more restricted diffusion (higher fractional anisotropy, radial kurtosis, axonal water fraction, and lower radial diffusivity) than both Aβ- and Aβ+ groups. This nonmonotonic trend was confirmed by significant continuous correlations between mSUVr and diffusion metrics going in opposite direction for 2 cohorts: pooled Aβ-/Aβi and pooled Aβi/Aβ+. The transient period of increased diffusion restriction may be due to inflammation that accompanies rising Aβ burden. In the later stages of Aβ accumulation, neurodegeneration is the predominant factor affecting diffusion.

Aims/hypothesis/UNASSIGNED:Midlife obesity is a risk factor for dementia. We investigated the impact of obesity on brain structure, metabolism, and cerebrospinal fluid (CSF) core Alzheimer's disease (AD) biomarkers in healthy elderly. Methods/UNASSIGNED:We selected controls from ADNI2 with CSF AD biomarkers and/or fluorodeoxyglucose positron emission tomography (FDG-PET) and 3T-MRI. We measured cortical thickness, FDG uptake, and CSF amyloid beta (Aβ)1-42, p-tau, and t-tau levels. We performed regression analyses between these biomarkers and body mass index (BMI). Results/UNASSIGNED:). Higher BMI was related to less cortical thickness and higher metabolism in brain areas typically not involved in AD (family-wise error [FWE] <0.05), but not to AD CSF biomarkers. It is notable that the impact of obesity on brain metabolism and structure was also found in amyloid negative individuals. Conclusions/interpretation/UNASSIGNED:In the cognitively unimpaired elderly, obesity has differential effects on brain metabolism and structure independent of an underlying AD pathophysiology.

Background and Objectives/UNASSIGNED:Sleep difficulties are common among older adults and are associated with cognitive decline. We used data from a large, nationally representative longitudinal survey of adults aged older than 50 in the United States to examine the relationship between specific sleep difficulties and cognitive function over time. Research Design and Methods/UNASSIGNED:= 16 201). Sleep difficulty measures included difficulty initiating sleep, nocturnal awakenings, early morning awakenings, and waking up feeling rested from rarely/never (1) to most nights (3). The modified Telephone Interview for Cognitive Status was used to measure cognitive function. Generalized linear mixed models were used with time-varying covariates to examine the relationship between sleep difficulties and cognitive function over time. Results/UNASSIGNED:< .05). Discussion and Implications/UNASSIGNED:Our findings highlight an association between early morning awakenings and worse cognitive function, but also an association between waking up feeling rested and better cognitive function over time.

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.

Late-life major depression (LLMD) is a risk factor for the development of mild cognitive impairment and dementia, including Alzheimer's disease (AD) and vascular dementia. Immune dysregulation and changes in innate immune responses in particular, have been implicated in the pathophysiology of both LLMD and AD. Complement system, a key component of the innate immune mechanism, is known to play an important role in synaptic plasticity and cognitive functions. However, its role in LLMD remains unknown. In the present study, we examined the levels of complement component 3 (C3, the convergence point of all complement activation pathways) in the cerebrospinal fluid (CSF) of elderly depressed subjects compared to healthy controls; as well as the relationship of CSF C3 levels with amyloid-beta (Aβ42 and Aβ40), total tau (T-tau) and phosphorylated tau (P-tau) proteins and cognition scores. CSF was obtained from 50 cognitively intact volunteers (major depression group, N = 30; comparison group, N = 20) and analyzed for levels of C3 by ELISA. C3 levels were marginally lower in the major depression group relative to the comparison group. We did not find any significant association of C3 with the AD biomarkers Aβ42 reflecting plaque pathology, P-tau related to tau pathology or the neurodegeneration biomarker T-tau. In contrast, C3 was positively correlated with CSF Aβ40, which may reflect Aβ deposition in cerebral vessel walls. We observed a negative correlation between C3 levels and Total Recall on the Buschke Selective Reminding Test (BSRT) for memory performance in the depressed subjects when controlling for education. This initial evidence on C3 status in LLMD subjects may have implications for our understanding of the pathophysiology of major depression especially in late life.

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