Nicole M. Armstrong

Cardiovascular risk factors and risk of incident depression throughout adulthood among men: The Johns Hopkins Precursors Study

BACKGROUND Modifiable cardiovascular risk factors elevate risk of subsequent depression in older adults, but the effect of their onset before or after age 65 on incident depression is unclear. METHODS Participants were 1190 male medical students without a diagnosis of depression, who matriculated in 1948-1964 and followed through 2011. Cox proportional hazards models were used to assess associations of vascular risk-factor burden, diabetes, hypertension, hyperlipidemia, smoking status, and overweight/obese status with onset of incident depression. Adjustment covariates were race, enrollment wave, baseline age, physical activity, and heavy alcohol use. RESULTS The analysis included 44,175 person-years of follow-up. Among participants depression-free until age 65, vascular risk-factor burden after age 65 (Hazard Ratio, [HR]: 2.13, 95% Confidence Interval, [CI]: 1.17, 3.90) was associated with incident depression risk after age 65. The magnitude of vascular risk-factor burden after age 65 on depression risk after age 65 is comparable to the effect of 8.2 additional years of age. Diabetes (HR: 2.79, 95% CI: 1.25, 6.26), hypertension (HR: 2.72, 95% CI: 1.52, 4.88), and hyperlipidemia (HR: 1.88, 95% CI: 1.05, 3.35) before age 65 were associated with incident depression risk after age 65. Men diagnosed with diabetes after age 65 had 2.87 times the risk of incident depression after age 65 (95% CI: 1.24, 6.62). LIMITATIONS Our findings are restricted to male former medical students, which may affect study generalizability. CONCLUSIONS Results support the vascular depression hypothesis. Depression screening in older adults with vascular risk-factor burden may provide an avenue for prevention of late-onset depression.

E pluribus unum: Harmonization of physical functioning across intervention studies of middle-aged and older adults

Common scales for physical functioning are not directly comparable without harmonization techniques, complicating attempts to pool data across studies. Our aim was to provide a standardized metric for physical functioning in adults based on basic and instrumental activities of daily living scaled to NIH PROMIS norms. We provide an item bank to compare the difficulty of various physical functioning activities. We used item response theory methods to place 232 basic and instrumental activities of daily living questions, administered across eight intervention studies of middle-aged and older adults (N = 2,556), on a common metric. We compared the scale’s precision to an average z-score of items and evaluated criterion validity based on objective measures of physical functioning and Fried’s frailty criteria. Model-estimated item thresholds were widely distributed across the range of physical functioning. From test information plots, the lowest precision in each dataset was 0.80. Using power calculations, the sample size needed to detect 25% physical functional decline with 80% power based on the physical functioning factor was less than half of what would be needed using an average z-score. The physical functioning factor correlated in expected directions with objective measurements from the Timed Up and Go task, tandem balance, gait speed, chair stands, grip strength, and frailty status. Item-level harmonization enables direct comparison of physical functioning measures across existing and potentially future studies and across levels of function using a nationally representative metric. We identified key thresholds of physical functioning items in an item bank to facilitate clinical and epidemiologic decision-making.

Late-Life Depressive Symptoms as Partial Mediators in the Associations between Subclinical Cardiovascular Disease with Onset of Mild Cognitive Impairment and Dementia

OBJECTIVE To study whether depression contributes to the association between subclinical cardiovascular disease (CVD) and dementia, and identify the contributions magnitude. METHODS Among participants from the Cardiovascular Health Study Cognition Study who did not have baseline CVD-related events (N = 2,450), causal mediation methodology was implemented to examine whether late-life depressive symptoms, defined as 10-item Center for Epidemiologic Studies-Depression (mCES-D) Scale scores ≥8 from 2 to 3 years after baseline, partially mediated the association of baseline subclinical CVD (CAC, carotid intimal medial thickness, stenosis, and ankle brachial index) with mild cognitive impairment (MCI)/dementia onset occurring between 5 and 10 years from baseline. The total effect was decomposed into direct and indirect effects (via late-life depressive symptoms), obtained from an accelerated failure time model with weights derived from multivariable logistic regression of late-life depressive symptoms on subclinical CVD. Analyses were adjusted by baseline covariates: age, race, sex, poverty status, marital status, body mass index, smoking status, ApoE4 status, and mCES-D. RESULTS Participants contributed 20,994 person-years of follow-up with a median follow-up time of 9.4 years. Subclinical CVD was associated with 12% faster time to MCI/dementia (time ratio [TR]: 0.88; 95% CI: 0.83, 0.93). The total effect of subclinical CVD on MCI/dementia onset was decomposed into a direct effect (TR: 0.95, 95% CI: 0.92, 0.98) and indirect effect (TR: 0.92, 95% CI: 0.88, 0.97); 64.5% of the total effect was mediated by late-life depressive symptoms. CONCLUSIONS These data suggest late-life depressive symptoms partially mediate the association of subclinical CVD with MCI/dementia onset.

Combined neuropathological pathways account for age‐related risk of dementia

Our objectives were to characterize the inter‐relation of known dementia‐related neuropathologies in one comprehensive model and quantify the extent to which accumulation of neuropathologies accounts for the association between age and dementia.

SEX-SPECIFIC ASSOCIATIONS OF SERUM BILE ACIDS WITH BRAIN ATROPHY DURING AGING: DIFFERENTIAL EFFECTS OF CONJUGATION AND GUT MICROBIAL METABOLISM

increased expression. The gene product is known to interact with APP, thus, its increased level could be associated with Ab deposition. Conclusions:We performed neuron-specific ChIP-seq of sporadic AD with H3K4me3 antibody and found two differentially bound regions. These regions are associated with neuronal functions or Ab metabolism, suggesting that histone modifications are deeply associated with AD pathophysiology.

APOLIPOPROTEIN E4 GENOTYPE AND LONGITUDINAL CHANGES IN BRAIN STRUCTURE IN SUBSEQUENTLY IMPAIRED AND COGNITIVELY HEALTHY OLDER ADULTS

GM gray m LONGITUDINAL CHANGES IN BRAIN STRUCTURE IN SUBSEQUENTLY IMPAIRED AND COGNITIVELY HEALTHY OLDER ADULTS Nicole Armstrong, Yang An, Lori L. Beason-Held, Jimit Doshi, Guray Erus, Luigi Ferrucci, Christos Davatzikos, Susan M. Resnick, National Institute on Aging, Baltimore, MD, USA; National Institute on Aging, National Institutes of Health, Baltimore, MD, USA; Center for Biomedical Image Computing and Analytics/University of Pennsylvania, Philadelphia, PA, USA; Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, PA, USA; National Institute on Aging/National Institutes of Health, Baltimore, MD, USA. Contact e-mail: nicole.armstrong@nih.gov

Optimal metrics for identifying long term patterns of depression in older HIV-infected and HIV-uninfected men who have sex with men

ABSTRACT Objectives: Center of Epidemiologic Studies–Depression Scale (CES-D) provides a snapshot of symptom severity at a single point in time. However, the best way of using CES-D to classify long-term depression is unclear. Method: To identify long-term depression among HIV-infected and HIV–uninfected 50+ year-old men who have sex with men (MSM) with at least 5 years of follow-up, we compared sensitivities and specificities of CES-D–based metrics (baseline CES-D; four consecutive CES-Ds; group-based trajectory models) thresholded at 16 and 20 to a clinicians evaluation of depression phenotype based on all available data including CES-D history, depression treatment history, drug use history, HIV disease factors, and demographic characteristics. Results: A positive depressive phenotype prevalence was common among HIV-infected (prevalence = 33.1%) and HIV-uninfected MSM (prevalence = 23.2%). Compared to the depressive phenotype, trajectory models of CES-D≥20 provided highest specificities among HIV-infected (specificity = 99.9%, 95% Confidence Interval [CI]:99.4%–100.0%) and HIV-uninfected MSM (specificity = 99.0%, 95% CI:97.4%–99.7%). Highest sensitivities resulted from classifying baseline CES-D ≥ 16 among HIV-infected MSM (sensitivity = 75.0%, 95% CI:67.3%–81.7%) and four consecutive CES-Ds ≥ 16 among HIV-uninfected MSM (sensitivity = 81.0%, 95% CI:73.7%–87.0%). Conclusion: Choice of method should vary, depending on importance of false positive or negative rate for long-term depression in HIV-infected and HIV-uninfected MSM.

Role of Late-Life Depression in the Association of Subclinical Cardiovascular Disease With All-Cause Mortality: Cardiovascular Health Study

Objectives: To evaluate whether late-life depression mediates the association of subclinical cardiovascular disease (CVD) with all-cause mortality. Method: Using data from 3,473 Cardiovascular Health Study participants, the Cox proportional hazards model was used to examine the direct and indirect (via late-life depression) effects of the association between baseline subclinical CVD and all-cause mortality with weights derived from multivariable logistic regression of late-life depression on subclinical CVD. Results: Subclinical CVD led to a higher risk of all-cause mortality (hazard ratio [HR] = 1.51, 95% confidence interval, [CI] = [1.42, 1.94]). Total effect of subclinical CVD on all-cause mortality was decomposed into direct (HR = 1.41, 95% CI = [1.37, 1.58]) and indirect (HR = 1.07, 95% CI = [1.01, 1.23]) effects; 16.3% of the total effect of subclinical CVD on all-cause mortality was mediated by late-life depression. Discussion: Late-life depression accounts for little, if any, of the association between subclinical CVD, a risk factor of all-cause mortality, and all-cause mortality.

METABOLIC SYNDROME AND COGNITIVE DECLINE IN THE FRAMINGHAM HEART STUDY

lower total gray matter volume (b1⁄4-0.07,p<0.01). Higher HDL variability was also associated with higher total mean diffusivity (b1⁄40.12, p<0.05) and higher regional diffusivity (e.g. b frontal region1⁄40.12,p<0.05). Higher LDL variability was not associated with hippocampul, white or gray matter volumes. Higher LDL variability was borderline associated with higher total mean diffusivity (b1⁄40.08,p1⁄40.07) andwith higher regional diffusivity (e.g. b temporal region1⁄40.09,p<0.05). There were no associations with fractional anisotropy. Conclusions:Higher visit-to-visit lipid, especially HDL, variability was associated with worse markers of brain integrity in midlife. Such midlife brain changes may portend an association between lipid variability and risk of dementia.

PERSISTENT DEPRESSIVE SYMPTOMS AS PARTIAL MEDIATORS IN THE ASSOCIATIONS BETWEEN SUBCLINICAL CARDIOVASCULAR DISEASE WITH ONSET OF MILD COGNITIVE IMPAIRMENT AND DEMENTIA

R03BA01-R03BA09, H02AB01-H02AB17). Only valid dementia diagnoses were considered; a diagnosis was found to be valid if a patient received a confirmative dementia diagnosis in the period from 2006-2013. The use of glucocorticoids (GCC) was defined by receiving at least one treatment during the observation period. We controlled for sex, age, major comorbidities at old age, beta2adrenergic agonists (ATC: R03AC02-R03AC19), and took interactions between asthmatics and GCC users into account. Results:During the observation period, 110,268 persons received at least one GCC treatment Out of 227,008 dementia-free persons, 23,075 persons developed dementia until the end of 2013. The hazard of suffering from dementia was significantly lower for GCC users compared to non-users (HR1⁄40.87; 95% CI1⁄40.85-0.90). Asthmatics were also at a slightly lower risk of having dementia in contrast to non-Asthmatics (HR1⁄40.95; 95% CI1⁄40.90-0.99). When interactions with asthma were taken into account, users of GCC among non-asthmatics showed a reduced risk of developing dementia (HR1⁄40.84; 95% CI1⁄40.82-0.87) as well as among asthmatics (GCC: HR1⁄40.79; 95% CI1⁄40.74-0.83 vs. no GCC: HR1⁄40.91; 95% CI1⁄40.84-0.99). Conclusions:Longitudinal German health claims data indicate that the use of GGCs may reduce subsequent risk of suffering from dementia. However, these results should be verified in clinical trials.