Jauhtai Cheng

Circadian Clock Gene Polymorphisms and Sleep–Wake Disturbance in Alzheimer Disease

OBJECTIVES One of the hypothesized causes of the breakdown in sleep-wake consolidation often occurring in individuals with Alzheimer disease (AD) is the dysfunction of the circadian clock. The goal of this study is to report indices of sleep-wake function collected from individuals with AD in relation to relevant polymorphisms in circadian clock-related genes. DESIGN One week of ad libitum ambulatory sleep data collection. SETTING At-home collection of sleep data and in-laboratory questionnaire. PARTICIPANTS Two cohorts of AD participants. Cohort 1 (N = 124): individuals with probable AD recruited from the Stanford/Veterans Affairs, National Institute on Aging Alzheimers Disease Core Center (N = 81), and the Memory Disorders Clinic at the University of Nice School of Medicine (N = 43). Cohort 2 (N = 176): individuals with probable AD derived from the Alzheimers Disease Neuroimaging Initiative data set. MEASUREMENTS Determination of sleep-wake state was obtained by wrist actigraphy data for 7 days in Cohort 1 and by the Neuropsychiatric Inventory questionnaire for Cohort 2. Both cohorts were genotyped by using an Illumina Beadstation (Illumina, San Diego, CA), and 122 circadian-related single-nucleotide polymorphisms (SNPs) were examined. In Cohort 1, an additional polymorphism (variable-number tandem repeat in per3) was also determined. RESULTS Adjusting for multiple tests, none of the candidate gene SNPs were significantly associated with the amount of wake time after sleep onset (WASO), a marker of sleep consolidation. Although the study was powered sufficiently to identify moderate-sized correlations, we found no relationships likely to be of clinical relevance. CONCLUSIONS It is unlikely that a relationship with a clinically meaningful correlation exists between the circadian rhythm-associated SNPs and WASO in individuals with AD.

Modeling the effects of obstructive sleep apnea and hypertension in Vietnam veterans with PTSD

PurposeThe present work aimed to extend models suggesting that obstructive sleep apnea (OSA) is associated with worse cognitive performance in community-dwelling older adults. We hypothesized that in addition to indices of OSA severity, hypertension is associated with worse cognitive performance in such adults.MethodsThe PTSD Apnea Clinical Study recruited 120 community-dwelling, male veterans diagnosed with PTSD, ages 55 and older. The Rey Auditory Verbal Learning Test (RAVLT) and Color-Word Interference Test (CWIT) were measures of auditory verbal memory and executive function, respectively. Apnea–hypopnea index (AHI), minimum and mean pulse oximeter oxygen saturation (min SpO2, mean SpO2) indicators were determined during standard overnight polysomnography. Multivariate linear regression and receiver operating characteristic (ROC) curve analyses were performed.ResultsIn regression models, AHI (β = −4.099; p < 0.01) and hypertension (β = −4.500; p < 0.05) predicted RAVLT; hypertension alone (β = 9.146; p < 0.01) predicted CWIT. ROC analyses selected min SpO2 cut-points of 85% for RAVLT (κ = 0.27; χ² = 8.23, p < 0.01) and 80% for CWIT (κ = 0.25; χ² = 12.65, p < 0.01). Min SpO2 cut-points and hypertension were significant when added simultaneously in a regression model for RAVLT (min SpO2, β = 4.452; p < 0.05; hypertension, β = −4.332; p < 0.05), and in separate models for CWIT (min SpO2, β = −8.286; p < 0.05; hypertension, β = −8.993; p < 0.01).ConclusionsOSA severity and presence of self-reported hypertension are associated with poor auditory verbal memory and executive function in older adults.

Effects of body mass index-related disorders on cognition: preliminary results

Background Well-known risk factors for cognitive impairment are also associated with obesity. Research has highlighted genetic risk factors for obesity, yet the relationship of those risk factors with cognitive impairment is unknown. The objective of this study was to determine the associations between cognition, hypertension, diabetes, sleep-disordered breathing, and obesity. Genetic risk factors of obesity were also examined. Methods The sample consisted of 369 nondemented individuals aged 50 years or older from four community cohorts. Primary outcome measures included auditory verbal memory, as measured by the Rey Auditory Verbal Learning Test, and executive functioning, as measured by the Color–Word Interference Test of the Delis–Kaplan Executive Function System battery. Apnea–hypopnea index indicators were determined during standard overnight polysomnography. Statistical analyses included Pearson correlations and linear regressions. Results Poor executive function and auditory verbal memory were linked to cardiovascular risk factors, but not directly to obesity. Genetic factors appeared to have a small but measureable association to obesity. Conclusion A direct linkage between obesity and poor executive function and auditory verbal memory is difficult to discern, possibly because nonobese individuals may show cognitive impairment due to insulin resistance and the “metabolic syndrome”.

Longitudinal assessment of sleep disordered breathing in Vietnam veterans with post-traumatic stress disorder

Purpose Previous work has demonstrated the relatively high prevalence of risk factors for cognitive impairment, such as sleep disordered breathing (SDB) and obesity, in Vietnam War era veterans with post-traumatic stress disorder (PTSD). No data are currently available on the longitudinal stability of SDB as a risk factor for cognitive decline in that population, which this study now reports. Methods Sample consisted of 48 veterans of the Vietnam War with PTSD who completed longitudinal sleep assessments over a 3-year period. The primary outcome measure, the Apnea-Hypopnea Index (AHI) indicator, was determined during standard overnight polysomnography. Body mass index (BMI) was calculated using standard measurements. Measures of cognitive function tapped auditory verbal memory as measured by the Rey Auditory Verbal Learning Test and executive functioning as measured by the Color-Word Interference Test of the Delis–Kaplan Executive Function System battery. Statistical analyses included mixed effects modeling. Results In this sample, AHI increased significantly by 2.19 points per year (β=2.19; P<0.005). AHI worsened over the 3-year period, increasing from a mean of 18.7±15.7 to 24.7±17.4 points. Neither BMI nor cognition showed significant change over the 3-year period. Conclusion SDB worsened in a group of veterans of the Vietnam War with PTSD over a 3-year period. The worsening of SDB over time suggests the need for appropriate countermeasures in populations at risk for progression of the condition.

DTI measures identify mild and moderate TBI cases among patients with complex health problems: A receiver operating characteristic analysis of U.S. veterans

Standard MRI methods are often inadequate for identifying mild traumatic brain injury (TBI). Advances in diffusion tensor imaging now provide potential biomarkers of TBI among white matter fascicles (tracts). However, it is still unclear which tracts are most pertinent to TBI diagnosis. This study ranked fiber tracts on their ability to discriminate patients with and without TBI. We acquired diffusion tensor imaging data from military veterans admitted to a polytrauma clinic (Overall n = 109; Age: M = 47.2, SD = 11.3; Male: 88%; TBI: 67%). TBI diagnosis was based on self-report and neurological examination. Fiber tractography analysis produced 20 fiber tracts per patient. Each tract yielded four clinically relevant measures (fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity). We applied receiver operating characteristic (ROC) analyses to identify the most diagnostic tract for each measure. The analyses produced an optimal cutpoint for each tract. We then used kappa coefficients to rate the agreement of each cutpoint with the neurologists diagnosis. The tract with the highest kappa was most diagnostic. As a check on the ROC results, we performed a stepwise logistic regression on each measure using all 20 tracts as predictors. We also bootstrapped the ROC analyses to compute the 95% confidence intervals for sensitivity, specificity, and the highest kappa coefficients. The ROC analyses identified two fiber tracts as most diagnostic of TBI: the left cingulum (LCG) and the left inferior fronto-occipital fasciculus (LIF). Like ROC, logistic regression identified LCG as most predictive for the FA measure but identified the right anterior thalamic tract (RAT) for the MD, RD, and AD measures. These findings are potentially relevant to the development of TBI biomarkers. Our methods also demonstrate how ROC analysis may be used to identify clinically relevant variables in the TBI population.

The influence of physical and mental health symptoms on Veterans’ functional health status

Veterans who have been deployed to combat often have complex medical histories including some combination of traumatic brain injury (TBI); mental health problems; and other chronic, medically unexplained symptoms (i.e., chronic multisymptom illness [CMI] clusters). How these multiple pathologies relate to functional health is unclear. In the current study, 120 Veterans (across multiple combat cohorts) underwent comprehensive clinical evaluations and completed self-report assessments of mental health symptoms (Patient Health Questionnaire-2 [PHQ-2], PTSD Checklist-Civilian Version [PCL-C]) and functional health (Veterans Rand 36-Item Health Survey). Canonical correlation and regression modeling using split-sample permutation tests revealed that the PHQ-2/PCL-C composite variable (among TBI severity and number of problematic CMI clusters) was the primary predictor of multiple functional health domains. Two subscales, Bodily Pain and General Health, were associated with multiple predictors (TBI, PHQ-2/PCL-C, and CMI; and PHQ-2/PCL-C and CMI, respectively), demonstrating the multifaceted nature of how distinct medical problems might uniquely and collectively impair aspects of functional health. Apart from these findings, however, TBI and CMI were not predictors of any other aspects of functional health. Taken together, our findings suggest that mental health problems might exert ubiquitous influence over multiple domains of functional health. Thus, screening of mental health problems and education and promotion of mental health resources can be important to the treatment and care of Veterans.