The hypothalamic-pituitary-adrenal (HPA) axis coordinates the physiological stress response by driving glucocorticoid (GC) secretion. While acute glucocorticoid signaling supports adaptive cognitive and metabolic responses, sustained activation of this system can produce hippocampal atrophy, impaired synaptic plasticity, and long-term cognitive dysfunction. Alzheimer's disease (AD), characterized by extracellular amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs), arises from interactions among genetic variants, epigenetic regulation, and environmental exposures. Here, we review clinical, epidemiological, and translational evidence implicating chronic stress and glucocorticoid exposure as a potent environmental risk factor for AD. Human observations linking stress exposure to cognitive impairment are complemented by clinical hypercortisolemia paradigms, which highlight the sensitivity of hippocampal circuits to prolonged cortisol exposure. The detrimental impact of stress on cognition is mediated by GC-responsive genes implicated in AD or, conversely, by AD genes that also respond to GCs. Animal models further support causality, showing that chronic stress or glucocorticoid exposure exacerbates Aβ accumulation, tau pathology, synaptic dysfunction, and cognition in AD-relevant systems. Finally, stress and GC exposure regulate GC or AD genes through epigenetic mechanisms, which can encode cumulative stress exposure and bias trajectories toward neurodegeneration. The involvement of stress in AD elucidates molecular mechanisms underlying its complex pathology but also provides a promising avenue of investigation for AD therapy and intervention strategies.

Importance:Circadian rest-activity rhythms (RARs) are increasingly viewed as aging-relevant behavioral phenotypes, but links to DNA methylation-based epigenetic age acceleration (EAA) are not well defined. Objective:To evaluate associations between multidimensional actigraphy-derived 24-hour RAR metrics (strength and robustness, regularity and fragmentation, and timing) and EAA across 4 epigenetic clocks. Design, Setting, and Participants:This cross-sectional study used data from the Baltimore Epidemiologic Catchment Area Study, wave 5 (2017-2022). The cohort included community-dwelling adults in eastern Baltimore, Maryland, with 7-day wrist actigraphy and blood DNA methylation data. Analyses were conducted from January to December 2025. Exposures:Seven-day wrist actigraphy-derived parametric and nonparametric RAR metrics, including rhythm strength and robustness (amplitude, mesor, relative amplitude, and mean activity during the least active continuous 5-hour period [L5] and most active continuous 10-hour period [M10]), regularity and fragmentation (interdaily stability [IS] and intradaily variability [IV]), timing (acrophase, L5 and M10 start times, and rest and sleep midpoints), and day-to-day timing variability (rest midpoint variability [RMV] and sleep midpoint variability [SMV]). Main Outcomes and Measures:Associations between EAA for 4 clocks (Horvath, Hannum, PhenoAge, and GrimAge) and each RAR metric, evaluated using linear regression models. Results:A total of 207 participants were included (mean [SD] age, 68.42 [7.48] years; 135 [65.2%] female). In fully adjusted models, each 1-SD increase in amplitude, relative amplitude, and IS was associated with lower GrimAge acceleration (amplitude: β, -0.67 [95% CI, -1.24 to -0.09]; P = .02; relative amplitude: β, -0.77 [95% CI, -1.31 to -0.23]; P = .005; IS: β, -0.65 [95% CI, -1.20 to -0.09]; P = .02). Each 1-SD increase in amplitude and IS was also associated with lower PhenoAge acceleration (amplitude: β, -1.20 [95% CI, -2.26 to -0.15]; P = .03; IS: -1.35 [95% CI, -2.36 to -0.34]; P = .009). Higher L5 activity and IV were associated with higher GrimAge acceleration (L5: β, 0.60 [95% CI, 0.06-1.13]; P = .03; IV: β, 0.72 [95% CI, 0.17-1.28]; P = .01). There were nonsignificant but directionally consistent outcomes for the Horvath and Hannum clocks. RAR-EAA effect sizes were generally larger in women than in men (amplitude, mesor, M10, RMV, and SMV; P < .05 for interaction) and in White participants compared with those in other race and ethnicity categories (mesor, IV, and M10; P < .05 for interaction); associations for rhythm-timing metrics varied with age; and Shapley additive explanations analyses identified IS, RMV, and amplitude as 3 of the most influential RAR factors in epigenetic age acceleration. Conclusions and Relevance:In this exploratory cross-sectional study, higher strength and stability of circadian RARs were associated with lower acceleration of epigenetic age (particularly GrimAge and PhenoAge), whereas greater irregularity and more variable activity timing were associated with greater acceleration, supporting the interpretation of RARs as markers of biological aging.

INTRODUCTION:Deep brain stimulation of the fornix (fx-DBS) is being investigated for treatment of Alzheimer's disease (AD). The therapy aims at alleviating memory and cognitive circuit dysfunction. In preclinical models of AD, electrical stimulation of the memory circuit has demonstrated a possible disease-modifying potential. Here we examined changes resulting from fx-DBS in hippocampal atrophy and amyloid accumulation in AD patients with fx-DBS. METHODS:Repeated magnetic resonance imaging and positron emission tomography (PET) images acquired over the course of 12 months were used to assess changes in hippocampal volume in 36 ADvance trial patients compared to 40 matched untreated AD patients from the Alzheimer's Disease Neuroimaging Initiative, and in 10 separate patients with repeated flutemetamol PET and cerebrospinal fluid (CSF) markers. RESULTS:We observed a reduction of hippocampal atrophy and amyloid beta (Aβ) PET binding, and an increase in the CSF Aβ/total-tau ratio in DBS patients. DISCUSSION:These findings highlight the potential of fornix deep brain stimulation to modify AD biomarkers and possibly progression in some patients. HIGHLIGHTS:Fornix deep brain stimulation (fx-DBS) is being investigated to treat Alzheimer's disease (AD). Results show that fx-DBS modifies imaging and cerebrospinal fluid (CSF) markers. It reduces hippocampal atrophy and increases the amyloid beta/total-tau CSF ratio. These findings highlight the potential of fx-DBS to modify AD.

Alzheimer’s disease (AD) is a leading cause of mortality and morbidity among aging populations worldwide. Despite arduous research efforts, treatment options for this devastating neurodegenerative disease are limited. Sleep disturbances, through their link to changes in neural excitability and impaired clearance of interstitial abnormal protein aggregates, are a key risk factor for the development of AD. Research also suggests that the neuroprotective effects of sleep are particularly active during slow wave sleep. Given the strong link between sleep disturbance and AD, targeting sleep in the prodromal stages of AD, such as in mild cognitive impairment (MCI), represents a promising avenue for slowing the onset of AD-related cognitive decline. In efforts to improve sleep in older individuals, several pharmacologic approaches have been employed, but many pose safety risks, concern for worsening cognitive function, and fail to effectively target slow wave sleep. Trazodone, a safe and widely used drug in the older adult population, has shown promise in inducing slow wave sleep in older adults, but requires more rigorous research to understand its effects on sleep and cognition in the prodromal stages of AD. In this review, we present the rationale and study design for our randomized, double-bind, placebo-controlled, crossover trial (NCT05282550) investigating the effects of trazodone on sleep and cognition in 100 older adults with amnestic MCI and sleep complaints.

Our finding that individuals with MCI reported experiencing lower distress than their cognitively normal peers in response to a laboratory-based stressor may help alleviate concerns regarding the risks of studying stress in this population. Future research with larger samples will be valuable in studying other determinants of the stress response in these individuals.

INTRODUCTION:Growing evidence suggests that some common infections are causally associated with cognitive impairment; however, less is known about the burden of multiple infections. METHODS:We investigated the cross-sectional association of positive antibody tests for herpes simplex virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), and Toxoplasma gondii (TOX) with Mini-Mental State Examination (MMSE) and delayed verbal recall performance in 575 adults aged 41-97 from the Baltimore Epidemiologic Catchment Area Study. RESULTS:In multivariable-adjusted zero-inflated Poisson (ZIP) regression models, positive antibody tests for CMV (p = .011) and herpes simplex virus (p = .018) were individually associated with poorer MMSE performance (p = .011). A greater number of positive antibody tests among the five tested was associated with worse MMSE performance (p = .001). DISCUSSION:CMV, herpes simplex virus, and the global burden of multiple common infections were independently associated with poorer cognitive performance. Additional research that investigates whether the global burden of infection predicts cognitive decline and Alzheimer's disease biomarker changes is needed to confirm these findings.

BACKGROUND:Alcohol use disorder (AUD) affects 283 million people worldwide and its prevalence is increasing. Despite the role of the cerebellum in executive control and its sensitivity to alcohol, few studies have assessed its involvement in AUD-relevant functional networks. The goal of this study is to compare resting-state functional connectivity (FC) patterns in abstinent adults with a history of AUD and controls (CTL). We hypothesized that group differences in cerebro-cerebellar FC would be present, particularly within the frontoparietal/executive control network (FPN). METHODS:Twenty-eight participants completed a resting-state functional magnetic resonance imaging (rsfMRI) study. CTL participants had no history of AUD, comorbid psychological conditions, or recent heavy drinking and/or drug use. AUD participants had a history of AUD, with sobriety for at least 30 days prior to data collection. Multivariate pattern analysis, an agnostic, whole-brain approach, was used to identify regions with significant differences in FC between groups. Seed-based analyses were then conducted to determine the directionality and extent of these FC differences. Associations between FC strength and executive function were assessed using correlations with Wisconsin Card Sorting Test (WCST) performance. RESULTS:There were significant group differences in FC in nodes of the FPN, ventral attention network, and default mode network. Post hoc analyses predominantly identified FC differences within the cerebro-cerebellar FPN, with AUD showing significantly less FC within the FPN. In AUD, FC strength between FPN clusters identified in the multivariate pattern analysis (MVPA) analysis (Left Crus II, Right Frontal Cortex) was positively associated with performance on the WCST. CONCLUSIONS:Our results show less engagement of the FPN in individuals with AUD than in CTL. FC strength within this network was positively associated with performance on the WCST. These findings suggest that long-term heavy drinking alters cerebro-cerebellar FC, particularly within networks that are involved in executive function.

OBJECTIVES:Multiple exposures to gadolinium-based contrast agents (GBCAs) is known to be associated with gadolinium deposition in the brain in certain patients. Such deposition has been correlated with specific brain MRI findings, although most available data is in patients with underlying neurologic disorders. We aim to prospectively evaluate brain MRI signal changes as well as neurologic and neuropsychologic testing results in women undergoing screening breast MRI.METHODS:In this IRB-approved, HIPAA-compliant prospective study, 9 women with 5 or more exposures to linear and/or macrocyclic GBCA due to screening breast MRI underwent noncontrast brain MRI, neurologic exam and neuropsychologic testing. Women with underlying neurologic, psychologic, hepatic or renal disorders were excluded.RESULTS:The mean total number of GBCA exposures was 8 (standard deviation 2.7), with 63/72 (87%) of the exposures being linear agents. There was no association between brain MRI signal changes and abnormalities on neurologic or neuropsychologic examination. There was no association between total number of GBCA exposures and abnormalities on neurologic or neuropsychologic examination.CONCLUSION:In this prospective exploratory study of 9 women with 5 or more GBCA exposures due to screening breast MRI, there was no association between brain MRI signal changes and clinical abnormalities on neurologic or neuropsychologic examination. While larger studies are needed in this patient population, the lack of clinical impact of multiple GBCA exposures in this study is reassuring.

Study objectives: Trauma exposure likely contributes to poor sleep, but relatively few studies have empirically tested this, instead focusing on posttraumatic stress disorder. Moreover, little is known about sex differences in sleep after trauma. The current study used a cross-sectional and retrospective design to test hypotheses that trauma exposure would be associated with subsequent insomnia symptoms, particularly among women, even after accounting for important covariates. Method: Data from Wave 3 (1993-1996) of the Baltimore Epidemiologic Catchment Area Study (N = 1920) were used to examine associations between remote (prior to past year) and recent (past year) trauma and current sleep disturbance (insomnia, hypersomnia symptoms) in the total sample (Mage= 55, 63.2% women, 57.7% white), and separately in men and women. Sensitivity analyses were conducted among individuals with no pretrauma sleep disturbance to examine incident sleep disturbance. Results: Among all participants, both remote (odds ratio [OR] = 1.95, 95% confidence interval [CI] [1.34, 2.85]) and recent (OR = 1.94, 95% CI [1.31, 2.87]) trauma exposure were associated with increased odds of insomnia (OR = 2.41, 95% CI [1.54, 3.76]) but not hypersomnia. Associations between trauma and insomnia were particularly strong among women, but null among men. The relationship between trauma exposure and insomnia symptoms persisted among individuals with no pretrauma history of insomnia. Conclusion: Results suggest women may be vulnerable to insomnia symptoms as sequelae of trauma. Future research should examine prospective associations between trauma and sleep in larger samples and how assessment and treatment of insomnia among women trauma survivors reduces the public health impact of trauma and poor sleep. (c) 2021 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.

BACKGROUND:Financial capacity (FC) is a complex ability commonly impaired in older individuals with cognitive impairment; however, the underlying neural mechanisms are not well understood.OBJECTIVE:To assess resting state functional connectivity using functional magnetic resonance imaging (rs-fMRI) in individuals with mild cognitive impairment (MCI) and impaired FC compared to cognitively normal older adults.METHODS:rs-fMRI scans were obtained from individuals with MCI (N = 17) and normal older adults (N = 15). All participants completed the Financial Capacity Instrument Short Form (FCI-SF) and neuropsychological assessments. Based on previous findings, the left angular gyrus (lAG) was used as the seed region. Connectivity correlation coefficients were calculated for each seed-based connection that showed significantly altered connectivity. A Pearson's correlation was calculated between the connectivity correlation values from relevant regions and FC and other cognitive measures.RESULTS:A total of 26 brain regions showed significantly increased functional connectivity with the lAG. Of these regions, 14 were identified as relevant to higher-level cognitive function for analysis. Pearson's correlations showed a significant negative correlation between the FCI-SF total score and increased connectivity between the IAG and the right temporal fusiform cortex (rTFC) (r = -0.455, p = 0.009).CONCLUSION:Results showed a significant correlation between FC and increased functional connectivity between the lAG and the rTFC in cognitively normal older adults compared to participants with MCI. These exploratory findings suggest that cognitive functions play important roles in FC as the functional connectivity between the lAG and rTFC was not associated with other tests of executive or visuospatial cognition.

Background Falls are highly common in patients with Alzheimer’s disease (AD); around two-thirds of AD patients fall annually. Fall events are major drivers of injury, early institutionalization, and shorter survival. Balance and mobility impairment are among the most important fall risk factors in AD patients. Vestibular therapy (VT) is an effective rehabilitation intervention in improving balance and fall risk through vestibular function, but not often used in AD. We want to evaluate the feasibility of using VT to reduce falls and improve balance function in patients with AD and drive use of an existing, potentially beneficial therapy in a patient population whose high level of vestibular deficits is currently unaddressed. Methods The proposed pilot clinical trial will be a parallel-group randomized controlled trial. Patients with a diagnosis of mild-moderate AD, age ≥ 60, and the presence of a caregiver will be recruited from the Johns Hopkins Memory and Alzheimer’s Treatment Center. Eligible patients will be offered vestibular testing. Patients with vestibular loss will be offered participation in the VT trial. One-hundred AD patients with vestibular loss will be enrolled and randomized 1:1 into the control and intervention arms of the trial. All patients will undergo baseline balance and cognitive assessment, followed by 8 weeks of active control therapy or VT, consisting of ~25-min office sessions with a vestibular therapist. Patients will be tracked for falls and undergo follow-up balance and cognitive assessment at 8 and 52 weeks (1 year) to assess the potential short-term and longer-term effects, respectively, of VT on balance and cognition. The main outcomes of this trial are falls, balance (using the Berg Balance Scale and the Timed Up and Go test), and cognition (using the clock drawing test, the Card Rotations test, the Money Road Map test, and the triangle completion task). Discussion As the population ages and the number of individuals with AD in the US grows to a projected 14 million in 2050, managing falls in AD will continue to grow as a critical public health concern; this trial assesses feasibility of a potential solution. Trial registration ClinicalTrial.Gov identifier — NCT03799991 . Registered 01 August 2019.

Objective: To determine whether combination antiretroviral therapy (cART) initiation alters the trajectory of cognitive performance in HIV+ men, and whether cognition prior to cART predicts postcART function. Design: Longitudinal cohort study. Multicenter AIDS Cohort Study. Methods: From an initial set of 3701 men with complete neuropsychological data, men with HIV infection were initially matched with men without infection on cognitive status, race, age, and timeline (T0 defined as cART initiation). Propensity score matching was then used to match pairs on depressive symptoms at T0, education, T0 cognitive scores, and recruitment cohort. There were 506 matched pairs of infected and uninfected men in the final analysis. Mixed effect models were constructed to analyze the trajectories of cognitive functions and to test the effect of cART and HIV on cognitive functions over time. Results: Performance in each cognitive domain did not change following the initiation of cART among HIV-infected men with prior impairment and was comparable to the performance of their matched uninfected men. However, among the infected men who were unimpaired prior to cART, motor function declined significantly faster than it did for uninfected controls. Conclusions: Cognitive dysfunction is persistent in HIV-infected men and cART does not alter the trajectory of cognitive decline in men who were impaired prior to effective therapy. This suggests that current cognitive impairment in HIV+ men results from a legacy effect, and from factors other than the HIV itself. Furthermore, motor skills may be uniquely vulnerable to the virus, cART, or age-related co-morbidities.

Background: Although combination antiretroviral therapy reduced the prevalence of HIV-associated dementia, milder syndromes persist. Our goals were to predict cognitive impairment of the Multicenter AIDS Cohort Study (MACS) participants 5 years ahead and from a large pool of factors, select the ones that mostly contributed to our predictions. Design: Longitudinal, natural and treated history of HIV infection among MSM. Methods: The MACS is a longitudinal study of the natural and treated history of HIV disease in MSM; the neuropsychological substudy aims to characterize cognitive disorders in men with HIV disease. Results: We modeled on an annual basis the risk of cognitive impairment 5 years in the future. We were able to predict cognitive impairment at individual level with high precision and overperform default methods. We found that while a diagnosis of AIDS is a critical risk factor, HIV infection per se does not necessarily convey additional risk. Other infectious processes, most notably hepatitis B and C, are independently associated with increased risk of impairment. The relative importance of an AIDS diagnosis diminished across calendar time. Conclusion: Our prediction models are a powerful tool to help clinicians address dementia in early stages for MACS paticipants. The strongest predictors of future cognitive impairment included the presence of clinical AIDS and hepatitis B or C infection. The fact that the pattern of predictive power differs by calendar year suggests a clinically critical change to the face of the epidemic.

An abstract is not available for this content so a preview has been provided. Please use the Get access link above for information on how to access this content.

BACKGROUND:Prevalence estimates of cognitive impairment in HIV disease vary widely. Here we used multivariate normative comparison (MNC) with identify individuals with impaired cognition, and to compare the results with those using the Frascati and Gisslén criteria.METHODS:The current project used data collected before October 2014 from bisexual/gay men from the Multicenter AIDS Cohort Study. A total of 2904 men (mean age 39.7 years, 52.7% seropositive) had complete data in six cognitive domains at their first neuropsychological evaluation. T-scores were computed for each domain and the MNC was applied to detect impairment among seronegative and seropositive groups.RESULTS:The MNC classified 6.26% of seronegative men as being impaired using a predetermined 5% false discovery rate. By contrast, the Frascati and the Gisslén criteria identified 24.54 and 11.36% of seronegative men as impaired. For seropositive men, the percentage impairment was 7.45, 25.73, and 11.69%, respectively, by the MNC, Frascati and Gisslén criteria. When we used seronegative men without medical comorbidities as the control group, the MNC, the Frascati and the Gisslén criteria identified 5.05, 27.07, and 4.21% of the seronegative men, and 4.34, 30.95, and 4.48% of the seropositive men as having cognitive impairment. For each method, serostatus was not associated with cognitive impairment.CONCLUSION:The MNC controls the false discovery rate and therefore avoids the low specificity that characterizes the Frascati and Gisslén criteria. More research is needed to evaluate the sensitivity of the MNC method in a seropositive population that may be sicker and older than the current study sample and that includes women.

Objectives: Despite treatment-related improvements in morbidity and mortality, HIV-1–infected (HIV+) individuals continue to face a wide range of HIV-associated medical and HIV-associated neurocognitive disorders. Little is known about the impact of cognitive impairment on patients’ health-related quality of life (HRQoL). To address this, the current study examined the longitudinal relationship between cognitive functioning and HRQoL among HIV+ individuals. Method: The sample consisted of 1,306 HIV+ men enrolled in the Multicenter AIDS Cohort Study. Participants received biannual assessments of cognitive functioning (including tests of processing speed, executive functioning, attention/working memory, motor functioning, learning, and memory) and completed questionnaires assessing HRQoL and depression. Multilevel models were used to examine the longitudinal and cross-lagged relationship between HRQoL and cognition, independent of depression and HIV disease severity. Results: There was a significant relationship between HRQoL and cognitive functioning both between and within subjects. Specifically, individuals who reported better HRQoL reported better cognitive functioning, and longitudinal change in cognition was positively related to change in HRQoL. There was a significant unidirectional-lagged relationship; cognition predicted HRQoL at subsequent visits, but HRQoL did not predict cognitive functioning at subsequent visits. Furthermore, analyses of severity of neurocognitive impairment revealed that transition to a more severe stage of cognitive impairment was associated with a decline in HRQoL. Conclusions: Overall, the current study suggests that changes in HRQoL are partially driven by changes in cognitive functioning.

Objective Obesity is a common, modifiable cardiovascular and cerebrovascular risk factor. Among people with HIV, obesity may contribute to multisystem dysregulation including cognitive impairment. We examined body mass index (BMI) and central obesity (waist circumference [WC]) in association with domain-specific cognitive function and 10-year cognitive decline in men with HIV infection (MWH) vs HIV-uninfected (HIV−) men. Methods A total of 316 MWH and 656 HIV− Multicenter AIDS Cohort Study participants ≥40 years at baseline, with neuropsychological testing every 2 years and concurrent BMI and WC measurements, were included. MWH were included if taking ≥2 antiretroviral agents and had HIV-1 RNA <400 copies/mL at >80% of visits. Mixed-effects models included all visits from 1996 to 2015, stratified by HIV serostatus, and adjusted for sociodemographic, behavioral, and clinical characteristics. At baseline and follow-up, 8% of MWH and 15% of HIV− men and 41% of MWH and 56% of HIV− men were ≥60 years, respectively. Results Cross-sectionally, higher BMI was inversely associated with motor function in MWH and HIV− men, and attention/working memory in HIV− men. WC was inversely associated with motor function in MWH and HIV− men. Longitudinal associations indicated an obese BMI was associated with a less steep decline in motor function in MWH whereas in HIV− men, obesity was associated with a greater decline in motor function, learning, and memory. WC, or central obesity, showed similar patterns of associations. Conclusion Higher adiposity is associated with lower cognition cross-sectionally and greater cognitive decline, particularly in HIV− men. Overweight and obesity may be important predictors of neurologic outcomes and avenues for prevention and intervention.

The reasons why women are at higher risk than men for developing dementia are unclear. Although studies implicate sex differences in the effect of stress on cognitive functioning, whether stressful life events are associated with subsequent cognitive decline has received scant research attention.

INTRODUCTION:Alzheimer's disease (AD) is a disabling, common cause of dementia, and agitation is one of the most common and distressing symptoms for patients with AD. Escitalopram for agitation in Alzheimer's disease (S-CitAD) tests a novel, clinically derived therapeutic approach to treat agitation in patients with AD. METHODS:S-CitAD is a NIH-funded, investigator-initiated, randomized, multicenter clinical trial. Participants receive a structured psychosocial intervention (PSI) as standard of care. Participants without sufficient response to PSI are randomized to receive 15 mg escitalopram/day or a matching placebo in addition to PSI. Primary outcome is the Modified Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (mADCS-CGIC). DISCUSSION:S-CitAD will provide information about a practical, immediately available approach to treating agitation in patients with AD. S-CitAD may become a model of how to evaluate and predict treatment response in patients with AD and agitation as a neuropsychiatric symptom (ClinicalTrials.gov Identifier: NCT03108846).