Faculty Bibliography

We examined the relative contribution of pulmonary diseases (chronic obstructive pulmonary disease, asthma and sleep apnea) to mortality risks associated with Coronavirus Disease (COVID-19) independent of other medical conditions, health risks, and sociodemographic factors. Data were derived from a large US-based case series of patients with COVID-19, captured from a quaternary academic health network covering New York City and Long Island. From March 2 to May 24, 2020, 11,512 patients who were hospitalized were tested for COVID-19, with 4,446 (38.62%) receiving a positive diagnosis for COVID-19. Among those who tested positive, 959 (21.57%) died of COVID-19-related complications at the hospital. Multivariate-adjusted Cox proportional hazards modeling showed mortality risks were strongly associated with greater age (HR = 1.05; 95% CI: 1.04-1.05), ethnic minority (Asians, Non-Hispanic blacks, and Hispanics) (HR = 1.26; 95% CI, 1.10-1.44), low household income (HR = 1.29; 95% CI: 1.11, 1.49), and male sex (HR = 0.85; 95% CI: 0.74, 0.97). Higher mortality risks were also associated with a history of COPD (HR = 1.27; 95% CI: 1.02-1.58), obesity (HR = 1.19; 95% CI: 1.04-1.37), and peripheral artery disease (HR = 1.33; 95% CI: 1.05-1.69). Findings indicate patients with COPD had the highest odds of COVID-19 mortality compared with patients with pre-existing metabolic conditions, such as obesity, diabetes and hypertension. Sociodemographic factors including increased age, male sex, low household income, ethnic minority status were also independently associated with greater mortality risks.

Objective/UNASSIGNED:Compared to European Americans, research indicates that African Americans have higher white matter hyperintensity (WMH) load; however, the clinical and biological bases underlying this higher burden are poorly understood. We hypothesize that obesity may explain differences in WMH between African and European Americans. Methods/UNASSIGNED:, and WMH load, captured by FLAIR images, as sum of deep and periventricular volumes, scored using the Fazekas scale (0-6), WMH≥4 considered high. Results/UNASSIGNED:=5.3, p=0.02). Conclusion/UNASSIGNED:Results denote that age predicted WMH among European Americans, while obesity predicted WMH among African Americans. Matched sample analyses indicate that obesity increases the odds of WMH, though more pronounced in African Americans. These findings suggest that obesity may explain the differential burden of white matter hyperintensity load, signifying public health and clinical importance.

Background: Rodent model and in vitro studies suggest brain temperature has the potential to bidirectionally interact with tau pathology in Alzheimer's Disease (AD): tau phosphorylation is robustly increased by small (<1degreeC) reductions in temperature within the human physiological range, and lower brain thermoregulatory areas may be among those first affected by AD pathology. Here, we evaluated the cross-sectional association between body temperature (Tb), as a proxy for brain temperature, and clinically accessible markers of tau pathology in cognitively normal older adults.
Method(s): Tb was measured continuously over 48 hours with ingestible telemetry combined with a novel pre-processing algorithm. This period included 2 nights of nocturnal polysomnography to facilitate delineation of Tb-tau pathology relationships according to waking vs sleeping time intervals. Tau pathology was assessed with both soluble markers including plasma P-tau (P-tau 181) and cerebrospinal fluid (CSF) P-tau, both sampled the following day, and aggregated tau, namely neurofibrillary tangle (NFT) burden in early (I-III) Braak stage areas imaged with MR-PET using the [18F]MK-6240 radio tracer on average ~ one month later Results: Plasma and CSF P-tau levels were highly correlated with one another and with tau tangle radio tracer uptake (NFT burden), p < 0.05 for all comparisons. Lower Tb (quantified by lower mean Tb and a greater proportion of time Tb was under 37.0degreeC) was associated with increased NFT burden and increased plasma and CSF P-tau levels, p < 0.05 all comparisons. For aggregated tau, lower Tb - tau pathology associations were seen during for Tb recorded during waking, but not during sleeping intervals.
Conclusion(s): Preliminary results suggest that lower body temperature in older adults may be associated with increased aggregated and soluble tau pathology

Background: Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane innate immune receptor of the immunoglobulin family. In the brain, TREM2 is found exclusively on microglia and its stimulation has been associated with antiinflammatory and protective effects. Activation of TREM2 also results in the formation of a proteolytic soluble product (sTREM2). Higher baseline CSF sTREM2 concentrations have been associated with a slower rate of cognitive decline and decreased longitudinal brain amyloid deposition in Alzheimer's disease (AD). Thus, it has been proposed that CSF sTREM2 might reflect an antiinflammatory state. In a previous study by our group (ACNP presentation 2017), cognitively unimpaired individuals with latelife major depression (LLMD) which is associated with increased risk for AD, showed significant reductions in CSF sTREM2 levels and a lack of significant correlations with CSF AD biomarkers compared to controls, consistent with the aforementioned hypothesis and that TREM2- mediated anti-inflammatory microglia activation might be impaired in this disorder. In the current report, we examined the relationship between longitudinal changes in CSF sTREM2 during a 3-year period and their relationship to LLMD diagnosis and changes in AD and inflammatory markers.
Method(s): Our baseline sample consisted of 51 subjects aged 60 years and older who completed a longitudinal observational study over three years and an optional lumbar puncture (LP). 38 of these individuals completed the LP at year 3 (20 with LLMD and 18 controls). We evaluated the effects of time on CSF TREM2 with related-samples Wilcoxon Signed Rank Test and the effect diagnosis on change in CSF sTREM2 with Mann Whitney U test. Correlations between change in CSF sTREM2 and CSF markers of AD (Abeta42, Abeta40, total-tau, p-tau181), inflammation (Il-6, Il-8), and Complement component 3 (C3) markers were run with Spearman's Rank test.
Result(s): Baseline CSF sTREM2 was significantly lower in the LLMD group vs controls (p = 0.03). There were no group differences in CSF sTREM2 from baseline to Year 3 (LLMD p = 0.82, Controls p = 0.18), nor did Year 3 differ between the LLMD and control group (p = 0.35). No differences were observed between controls and LLMD for the longitudinal change in CSF sTREM2, AD biomarkers and inflammatory markers. In the whole group, change in sTREM2 was significantly moderately correlated with change in CSF Abeta40 (rho = 0.54, p < 0.001), Abeta42 (rho = 0.48, p = 0.003), and PTau181 (rho = 0.34, p = 0.04). In the control group, change in sTREM2 was significantly correlated with change in CSF Abeta40 (rho = 0.58, p = 0.01) and Abeta42 (rho = 0.56, p = 0.02). In the LLMD group, change in sTREM2 was significantly correlated with change in CSF Abeta40 (rho = 0.50, p = 0.03), Tau (rho = 0.44, p = 0.05) and P-Tau181 (rho = 0.52, p = 0.02) but not with change in CSF Abeta42, a more specific marker of cerebral amyloidosis. Change in inflammatory markers (i.e., IL-6, IL-8) were not significantly correlated with change in sTREM2 (p > 0.05) for LLMD or controls, or the whole group. Change in sTREM2 was significantly correlated with C3 (rho = 0.35, p = 0.04) in the whole group.
Conclusion(s): There were no group differences in change in CSF sTREM2 during a 3-year period, nor any difference between baseline and year 3. The longitudinal increase in CSF sTREM2 during a 3-year period and its association with CSF AD biomarkers may reflect increased anti-inflammatory microglia activation and phagocytosis in response to pathological forms of AD biomarkers Abeta, tau, and p-tau 181. Interestingly, the CSF sTREM2 increase was associated with the increase CSF Abeta42 in controls, but not in LLMD. This finding suggests that upregulation of anti-inflammatory microglia and phagocytosis of brain amyloid deposits may be less efficient in LLMD. Similarly, the positive correlation between the longitudinal increase in CSF sTREM2 and the increase in CSF T-tau and Ptau181, which we found in the LLMD group but not in controls is also consistent with an upregulation of anti-inflammatory microglia in response to increased tau and neurofibrillary tangles, markers of neurodegeneration and AD, respectively. However, the change in CSF sTREM2 was correlated with the change in CSF C3 in the whole cohort; our group and others have also found positive correlations between CSF sTREM2 and CSF neurofilament light (NFL) protein, a biomarker of neuroaxonal damage. Taken together these results suggest that higher CSF sTREM2 concentrations may reflect not only upregulation of antiinflammatory microglia and phagocytosis in response to increased brain amyloid and tau pathology, but also increased neurotoxic effects which are possibly related to its reported intrinsic proinflammatory effects

Identifying cerebral vulnerability in late life may help prevent or slow the progression of aging-related chronic diseases. However, non-invasive biomarkers aimed at detecting subclinical cerebral changes in the elderly are lacking. Here, we have examined the potential of plasma total tau (t-tau) for identifying cerebral and cognitive deficits in normal elderly subjects. Patterns of cortical thickness and cortical glucose metabolism were used as outcomes of cerebral vulnerability. We found that increased plasma t-tau levels were associated with widespread reductions of cortical glucose uptake, thinning of the temporal lobe, and memory deficits. Importantly, tau-related reductions of glucose consumption in the orbitofrontal cortex emerged as a determining factor of the relationship between cortical thinning and memory loss. Together, these results support the view that plasma t-tau may serve to identify subclinical cerebral and cognitive deficits in normal aging, allowing detection of individuals at risk for developing aging-related neurodegenerative conditions.

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.

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.