Faculty Bibliography

OBJECTIVE:To investigate the effects of lifestyle and vascular-related risk factors for Alzheimer's disease (AD) on in vivo MRI-based brain atrophy in asymptomatic young to middle-aged adults. DESIGN:Cross-sectional, observational. SETTING:Broader New York City area. Two research centres affiliated with the Alzheimer's disease Core Center at New York University School of Medicine. PARTICIPANTS:We studied 116 cognitively normal healthy research participants aged 30-60 years, who completed a three-dimensional T1-weighted volumetric MRI and had lifestyle (diet, physical activity and intellectual enrichment), vascular risk (overweight, hypertension, insulin resistance, elevated cholesterol and homocysteine) and cognition (memory, executive function, language) data. Estimates of cortical thickness for entorhinal (EC), posterior cingulate, orbitofrontal, inferior and middle temporal cortex were obtained by use of automated segmentation tools. We applied confirmatory factor analysis and structural equation modelling to evaluate the associations between lifestyle, vascular risk, brain and cognition. RESULTS:≥-0.22, P≤0.01). CONCLUSIONS:In cognitively normal middle-aged adults, MeDi and insulin sensitivity explained cortical thickness in key brain regions for AD, and EC thickness predicted memory performance in turn. Intellectual activity and overweight were associated with cognitive performance through different pathways. Our findings support further investigation of lifestyle and vascular risk factor modification against brain ageing and AD. More studies with larger samples are needed to replicate these research findings in more diverse, community-based settings.

Cerebrospinal fluid (CSF) studies consistently show that CSF levels of amyloid-beta 1-42 (Aβ42) are reduced and tau levels increased prior to the onset of cognitive decline related to Alzheimer's disease (AD). However, the preclinical prediction accuracy for low CSF Aβ42 levels, a surrogate for brain Aβ42 deposits, is not high. Moreover, the pathology data suggests a course initiated by tauopathy contradicting the contemporary clinical view of an Aβ initiated cascade. CSF Aβ42 and tau data from 3 normal aging cohorts (45-90 years) were combined to test both cross-sectional (n = 766) and longitudinal (n = 651) hypotheses: 1) that the relationship between CSF levels of Aβ42 and tau are not linear over the adult life-span; and 2) that non-linear models improve the prediction of cognitive decline. Supporting the hypotheses, the results showed that a u-shaped quadratic fit (Aβ2) best describes the relationship for CSF Aβ42 with CSF tau levels. Furthermore we found that the relationship between Aβ42 and tau changes with age-between 45 and 70 years there is a positive linear association, whereas between 71 and 90 years there is a negative linear association between Aβ42 and tau. The quadratic effect appears to be unique to Aβ42, as Aβ38 and Aβ40 showed only positive linear relationships with age and CSF tau. Importantly, we observed the prediction of cognitive decline was improved by considering both high and low levels of Aβ42. Overall, these data suggest an earlier preclinical stage than currently appreciated, marked by CSF elevations in tau and accompanied by either elevations or reductions in Aβ42. Future studies are needed to examine potential mechanisms such as failing CSF clearance as a common factor elevating CSF Aβxx analyte levels prior to Aβ42 deposition in brain.

A fundamental problem in the field of obstructive sleep apnea (OSA) and memory is that it has historically minimized the basic neurobiology of sleep's role in memory. Memory formation has been classically divided into phases of encoding, processing/consolidation, and retrieval. An abundance of evidence suggests that sleep plays a critical role specifically in the processing/consolidation phase, but may do so differentially for memories that were encoded using particular brain circuits. In this review, we discuss some of the more established evidence for sleep's function in the processing of declarative, spatial navigational, emotional, and motor/procedural memories and more emerging evidence highlighting sleep's importance in higher order functions such as probabilistic learning, transitive inference, and category/gist learning. Furthermore, we discuss sleep's capacity for memory augmentation through targeted/cued memory reactivation. OSA - by virtue of its associated sleep fragmentation, intermittent hypoxia, and potential brain structural effects - is well positioned to specifically impact the processing/consolidation phase, but testing this possibility requires experimental paradigms in which memory encoding and retrieval are separated by a period of sleep with and without the presence of OSA. We argue that such paradigms should focus on the specific types of memory tasks for which sleep has been shown to have a significant effect. We discuss the small number of studies in which this has been done, in which OSA nearly uniformly negatively impacts offline memory processing. When periods of offline processing are minimal or absent and do not contain sleep, as is the case in the broad literature on OSA and memory, the effects of OSA on memory are far less consistent.

 Obstructive sleep apnea (OSA) and Alzheimer's disease (AD) are highly prevalent conditions with growing impact on our aging society. While the causes of OSA are now better characterized, the mechanisms underlying AD are still largely unknown, challenging the development of effective treatments. Cognitive impairment, especially affecting attention and executive functions, is a recognized clinical consequence of OSA. A deeper contribution of OSA to AD pathogenesis is now gaining support from several lines of research. OSA is intrinsically associated with disruptions of sleep architecture, intermittent hypoxia and oxidative stress, intrathoracic and hemodynamic changes as well as cardiovascular comorbidities. All of these could increase the risk for AD, rendering OSA as a potential modifiable target for AD prevention. Evidence supporting the relevance of each of these mechanisms for AD risk, as well as a possible effect of AD in OSA expression, will be explored in this review.

[This corrects the article DOI: 10.1371/journal.pone.0185926.].

Introduction: Increasing evidence suggests sleep can influence the risk for development of Alzheimer disease (AD), but the precise features of sleep architecture influencing this risk and the role of obstructive sleep apnea (OSA) in contributing to this risk remain only partially characterized. Current models of AD suggest that pathological changes, including the accumulation of proteins beta-amyloid (Ab) and tau, can occur years to even decades before clinical symptoms of memory impairment become evident. In this study, we examined the impact of OSA severity on longitudinal changes in Ab measured both in cerebrospinal fluid (CSF) and with brain PET imaging with Pittsburgh compound B (PiB). In subsets of individuals without significant OSA, we examined the impact of features of sleep architecture such as slow wave activity (SWA) and spindles on concentrations CSF Ab and tau at cross-section. Materials and Methods: 208 cognitively normal elderly subjects (68 +/- 7 years, CDR score = 0) received medical, neurological, and psychiatric evaluations, home polysomnography (PSG) for OSA severity, structural magnetic resonance imaging (MRI) scans, a lumbar puncture (LP) and/or PiB PET scans. A subset of 109 subjects completed a second LP 2.4 +/- 0.9 years after the first LP, and a subset of 34 subjects completed a second brain PiB PET scan 2.5 +/- 0.4 years after the first. A subset of 50 subjects without significant OSA (AHI4% < 15/hour) completed in-laboratory nocturnal PSG for measurements of sleep architecture. SWA was calculated using the average power density in the 0.5-4.0 Hz range at the F4- lead during full night EEG recordings. Spindles were isolated and quantified using DETOKS in which the EEG from the C3-lead was decomposed into oscillatory and non-oscillatory components. Oscillatory components were further scored for sleep spindles using threshold values in the frequency band of 11-16 Hz and time duration of 0.5 to 3 seconds. Results: OSA increased amyloid burden over the years, as a significant association was found between longitudinal decreases in CSF Ab42 and increasing OSA severity indices AHI-all (F1,88 = 4.26, p< .05) and AHI4% (F1,87 = 4.36, p< .05). This was corroborated by a trend toward longitudinal increases in brain PiB PET uptake positively associating with increasing OSA severity by AHI-all (F1,28 = 2.96, p=.09). At cross-section, in those subjects without significant OSA, low frontal SWA was significantly associated with high concentrations of CSF Ab42 and low sleep spindle counts and density were significantly associated with high levels of total and phosphorylated tau in the CSF

OBJECTIVE: This observational multimodality brain imaging study investigates emergence of endophenotypes of late-onset Alzheimer disease (AD) risk during endocrine transition states in a cohort of clinically and cognitively normal women and age-matched men. METHODS: Forty-two 40- to 60-year-old cognitively normal women (15 asymptomatic perimenopausal by age [CNT], 13 perimenopausal [PERI], and 14 postmenopausal [MENO]) and 18 age- and education-matched men were examined. All patients had volumetric MRI, 18F-fluoro-2-deoxyglucose (FDG)-PET (glucose metabolism), and Pittsburgh compound B-PET scans (beta-amyloid [Abeta] deposition, a hallmark of AD pathology). RESULTS: As expected, the MENO group was older than the PERI and CNT groups. Otherwise, groups were comparable on clinical and neuropsychological measures and APOE4 distribution. Compared to CNT women and to men, and controlling for age, PERI and MENO groups exhibited increased indicators of AD endophenotype, including hypometabolism, increased Abeta deposition, and reduced gray and white matter volumes in AD-vulnerable regions (p < 0.001). AD biomarker abnormalities were greatest in MENO, intermediate in PERI, and lowest in CNT women (p < 0.001). Abeta deposition was exacerbated in APOE4-positive MENO women relative to the other groups (p < 0.001). CONCLUSIONS: Multimodality brain imaging indicates sex differences in development of the AD endophenotype, suggesting that the preclinical AD phase is early in the female aging process and coincides with the endocrine transition of perimenopause. These data indicate that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process.