Characterizing 1991 Gulf War women veterans from the Boston Biorepository and Integrative Network for Gulf War Illness: demographics, exposures, neuroimaging and cognitive outcomes.

Objective: Gulf War Illness (GWI) is a debilitating multisymptom condition that affects nearly a third of 1990-91 Gulf War (GW) veterans. Symptoms include pain, fatigue, gastrointestinal issues, and cognitive decrements. Our work has shown that GWI rates and potential causes for symptoms vary between men and women veterans. Studies have documented neuropsychological and neuroimaging findings mostly in men or combined sex datasets. Data are lacking for women veterans due to lack of power and repositories of women veteran samples. Methods: We characterized GW women veterans in terms of demographics, exposures, neuropsychological and neuroimaging outcomes from the newly collated Boston, Biorepository and Integrative Network (BBRAIN) for GWI. Results: BBRAIN women veterans are highly educated with an average age of 54 years. 81% met GWI criteria, 25% met criteria for current PTSD, 78% were white, and 81% served in the Army. Exposure to combined acetylcholinesterase inhibitors (AChEi) including skin pesticides, fogs/sprays and/or pyridostigmine bromide (PB) anti-nerve gas pill exposure resulted in slower processing speed on attentional tasks and a trend for executive impairment compared with non-exposed women. Brain imaging outcomes showed lower gray matter volumes and smaller caudate in exposed women. Conclusions: Although subtle and limited findings were present in this group of women veterans, it suggests that continued follow-up of GW women veterans is warranted. Future research should continue to evaluate differences between men and women in GW veteran samples. The BBRAIN women sub-repository is recruiting and these data are available to the research community for studies of women veterans.

Rostral-middle locus coeruleus integrity and subjective cognitive decline in early old age.

OBJECTIVES: Abnormal tau, a hallmark Alzheimer's disease (AD) pathology, may appear in the locus coeruleus (LC) decades before AD symptom onset. Reports of subjective cognitive decline are also often present prior to formal diagnosis. Yet, the relationship between LC structural integrity and subjective cognitive decline has remained unexplored. Here, we aimed to explore these potential associations. METHODS: We examined 381 community-dwelling men (mean age = 67.58; SD = 2.62) in the Vietnam Era Twin Study of Aging who underwent LC-sensitive magnetic resonance imaging and completed the Everyday Cognition scale to measure subjective cognitive decline along with their selected informants. Mixed models examined the associations between rostral-middle and caudal LC integrity and subjective cognitive decline after adjusting for depressive symptoms, physical morbidities, and family. Models also adjusted for current objective cognitive performance and objective cognitive decline to explore attenuation. RESULTS: For participant ratings, lower rostral-middle LC contrast to noise ratio (LCCNR) was associated with significantly greater subjective decline in memory, executive function, and visuospatial abilities. For informant ratings, lower rostral-middle LCCNR was associated with significantly greater subjective decline in memory only. Associations remained after adjusting for current objective cognition and objective cognitive decline in respective domains. CONCLUSIONS: Lower rostral-middle LC integrity is associated with greater subjective cognitive decline. Although not explained by objective cognitive performance, such a relationship may explain increased AD risk in people with subjective cognitive decline as the LC is an important neural substrate important for higher order cognitive processing, attention, and arousal and one of the first sites of AD pathology.

Erectile Function, Sexual Satisfaction, and Cognitive Decline in Men From Midlife to Older Adulthood.

BACKGROUND AND OBJECTIVES: Vascular theories of cognitive aging have focused on macrovascular changes and cognitive decline. However, according to the artery-size hypothesis, microvascular changes, such as those that underlie changes in erectile function, may also play an important role in contributing to cognitive decline. Thus, we examined associations between erectile function, sexual satisfaction, and cognition starting in middle age because this represents a transition period where declines in these areas emerge. RESEARCH DESIGN AND METHODS: We examined 818 men from the Vietnam Era Twin Study of Aging across three waves at mean ages 56, 61, and 68. Erectile function and sexual satisfaction were measured using the International Index of Erectile Function. Cognitive performance was measured using factor scores for episodic memory, executive function, and processing speed. We tested multilevel models hierarchically, adjusting for demographics, frequency of sexual activity, and physical and mental health confounders to examine how changes in erectile function and sexual satisfaction related to changes in cognitive performance. RESULTS: Lower erectile function at baseline was related to poorer performance in all cognitive domains at baseline and faster declines in processing speed over time. However, baseline sexual satisfaction was unrelated to cognitive performance. Decreases in erectile function and sexual satisfaction were both associated with memory decline. DISCUSSION AND IMPLICATIONS: Decreasing sexual health may signal an increased risk for cognitive decline. We discuss potential mechanisms, including microvascular changes and psychological distress. Discussing and tracking sexual health in middle-aged men may help to identify those likely to face memory decline.

Alcohol use and cognitive aging in middle-aged men: The Vietnam Era Twin Study of Aging.

OBJECTIVE: To determine associations of alcohol use with cognitive aging among middle-aged men. METHOD: 1,608 male twins (mean 57 years at baseline) participated in up to three visits over 12 years, from 2003-2007 to 2016-2019. Participants were classified into six groups based on current and past self-reported alcohol use: lifetime abstainers, former drinkers, very light (1-4 drinks in past 14 days), light (5-14 drinks), moderate (15-28 drinks), and at-risk drinkers (>28 drinks in past 14 days). Linear mixed-effects regressions modeled cognitive trajectories by alcohol group, with time-based models evaluating rate of decline as a function of baseline alcohol use, and age-based models evaluating age-related differences in performance by current alcohol use. Analyses used standardized cognitive domain factor scores and adjusted for sociodemographic and health-related factors. RESULTS: Performance decreased over time in all domains. Relative to very light drinkers, former drinkers showed worse verbal fluency performance, by -0.21 SD (95% CI -0.35, -0.07), and at-risk drinkers showed faster working memory decline, by 0.14 SD (95% CI 0.02, -0.20) per decade. There was no evidence of protective associations of light/moderate drinking on rate of decline. In age-based models, light drinkers displayed better memory performance at advanced ages than very light drinkers (+0.14 SD; 95% CI 0.02, 0.20 per 10-years older age); likely attributable to residual confounding or reverse association. CONCLUSIONS: Alcohol consumption showed minimal associations with cognitive aging among middle-aged men. Stronger associations of alcohol with cognitive aging may become apparent at older ages, when cognitive abilities decline more rapidly.

Preliminary Findings from the Gulf War Women's Cohort: Reproductive and Children's Health Outcomes among Women Veterans.

Reproductive outcomes, such as preterm birth, miscarriage/stillbirth, and pre-eclampsia, are understudied in veterans, particularly among Gulf War veterans (GWVs). During deployment, women GWVs were exposed to toxicant and nontoxicant exposures that may be associated with adverse reproductive and developmental outcomes. The data come from a survey of 239 participants from northeastern and southern U.S. cohorts of women veterans. The questionnaire collected information about the service history, current and past general health, reproductive and family health, demographic information, and deployment exposures. Odds ratios were computed with 95% confidence intervals between exposures in theater and reproductive/children's health outcomes. GWVs experienced adverse reproductive outcomes: 25% had difficulty conceiving, and 31% had a pregnancy that ended in a miscarriage or stillbirth. Pregnancy complications were common among GWVs: 23% had a high-risk pregnancy, and 16% were diagnosed with pre-eclampsia. About a third of GWVs reported their children (38%) had a developmental disorder. Use of pesticide cream during deployment was associated with higher odds of all reproductive and developmental outcomes. The results demonstrate that GWVs experienced reproductive and children's health outcomes at potentially high rates, and exploratory analyses suggest pesticide exposure as associated with higher odds of adverse reproductive outcomes. Future longitudinal studies of women veterans should prioritize examining reproductive and children's health outcomes.

Long-term associations of cigarette smoking in early mid-life with predicted brain aging from mid- to late life.

BACKGROUND AND AIMS: Smoking is associated with increased risk for brain aging/atrophy and dementia. Few studies have examined early associations with brain aging. This study aimed to measure whether adult men with a history of heavier smoking in early mid-life would have older than predicted brain age 16-28 years later. DESIGN: Prospective cohort observational study, utilizing smoking pack years data from average age 40 (early mid-life) predicting predicted brain age difference scores (PBAD) at average ages 56, 62 (later mid-life) and 68 years (early old age). Early mid-life alcohol use was also evaluated. SETTING: Population-based United States sample. PARTICIPANTS/CASES: Participants were male twins of predominantly European ancestry who served in the United States military between 1965 and 1975. Structural magnetic resonance imaging (MRI) began at average age 56. Subsequent study waves included most baseline participants; attrition replacement subjects were added at later waves. MEASUREMENTS: Self-reported smoking information was used to calculate pack years smoked at ages 40, 56, 62, and 68. MRIs were processed with the Brain-Age Regression Analysis and Computation Utility software (BARACUS) program to create PBAD scores (chronological age-predicted brain age) acquired at average ages 56 (n = 493; 2002-08), 62 (n = 408; 2009-14) and 68 (n = 499; 2016-19). FINDINGS: In structural equation modeling, age 40 pack years predicted more advanced age 56 PBAD [ß = -0.144, P = 0.012, 95% confidence interval (CI) = -0.257, -0.032]. Age 40 pack years did not additionally predict PBAD at later ages. Age 40 alcohol consumption, but not a smoking × alcohol interaction, predicted more advanced PBAD at age 56 (ß = -0.166, P = 0.001, 95% CI = -0.261, -0.070) with additional influences at age 62 (ß = -0.115, P = 0.005, 95% CI = -0.195, -0.036). Age 40 alcohol did not predict age 68 PBAD. Within-twin-pair analyses suggested some genetic mechanism partially underlying effects of alcohol, but not smoking, on PBAD. CONCLUSIONS: Heavier smoking and alcohol consumption by age 40 appears to predict advanced brain aging by age 56 in men.

Paradoxical cognitive trajectories in men from earlier to later adulthood.

Because longitudinal studies of aging typically lack cognitive data from earlier ages, it is unclear how general cognitive ability (GCA) changes throughout the life course. In 1173 Vietnam Era Twin Study of Aging (VETSA) participants, we assessed young adult GCA at average age 20 and current GCA at 3 VETSA assessments beginning at average age 56. The same GCA index was used throughout. Higher young adult GCA and better GCA maintenance were associated with stronger specific cognitive abilities from age 51 to 73. Given equivalent GCA at age 56, individuals who had higher age 20 GCA outperformed those whose GCA remained stable in terms of memory, executive function, and working memory abilities from age 51 to 73. Thus, paradoxically, despite poorer maintenance of GCA, high young adult GCA still conferred benefits. Advanced predicted brain age and the combination of elevated vascular burden and APOE-ε4 status were associated with poorer maintenance of GCA. These findings highlight the importance of distinguishing between peak and current GCA for greater understanding of cognitive aging.

Associations between depression and cardiometabolic health: A 27-year longitudinal study.

BACKGROUND: Clarifying the relationship between depression symptoms and cardiometabolic and related health could clarify risk factors and treatment targets. The objective of this study was to assess whether depression symptoms in midlife are associated with the subsequent onset of cardiometabolic health problems. METHODS: The study sample comprised 787 male twin veterans with polygenic risk score data who participated in the Harvard Twin Study of Substance Abuse ('baseline') and the longitudinal Vietnam Era Twin Study of Aging ('follow-up'). Depression symptoms were assessed at baseline [mean age 41.42 years (s.d. = 2.34)] using the Diagnostic Interview Schedule, Version III, Revised. The onset of eight cardiometabolic conditions (atrial fibrillation, diabetes, erectile dysfunction, hypercholesterolemia, hypertension, myocardial infarction, sleep apnea, and stroke) was assessed via self-reported doctor diagnosis at follow-up [mean age 67.59 years (s.d. = 2.41)]. RESULTS: Total depression symptoms were longitudinally associated with incident diabetes (OR 1.29, 95% CI 1.07-1.57), erectile dysfunction (OR 1.32, 95% CI 1.10-1.59), hypercholesterolemia (OR 1.26, 95% CI 1.04-1.53), and sleep apnea (OR 1.40, 95% CI 1.13-1.74) over 27 years after controlling for age, alcohol consumption, smoking, body mass index, C-reactive protein, and polygenic risk for specific health conditions. In sensitivity analyses that excluded somatic depression symptoms, only the association with sleep apnea remained significant (OR 1.32, 95% CI 1.09-1.60). CONCLUSIONS: A history of depression symptoms by early midlife is associated with an elevated risk for subsequent development of several self-reported health conditions. When isolated, non-somatic depression symptoms are associated with incident self-reported sleep apnea. Depression symptom history may be a predictor or marker of cardiometabolic risk over decades.

Brain-Immune Interactions as the Basis of Gulf War Illness: Clinical Assessment and Deployment Profile of 1990-1991 Gulf War Veterans in the Gulf War Illness Consortium (GWIC) Multisite Case-Control Study.

The Boston University-based Gulf War Illness Consortium (GWIC) is a multidisciplinary initiative developed to provide detailed understanding of brain and immune alterations that underlie Gulf War illness (GWI), the persistent multisymptom disorder associated with military service in the 1990-1991 Gulf War. The core GWIC case-control clinical study conducted in-depth brain and immune evaluation of 269 Gulf War veterans (223 GWI cases, 46 controls) at three U.S. sites that included clinical assessments, brain imaging, neuropsychological testing, and analyses of a broad range of immune and immunogenetic parameters. GWI cases were similar to controls on most demographic, military, and deployment characteristics although on average were two years younger, with a higher proportion of enlisted personnel vs. officers. Results of physical evaluation and routine clinical lab tests were largely normal, with few differences between GWI cases and healthy controls. However, veterans with GWI scored significantly worse than controls on standardized assessments of general health, pain, fatigue, and sleep quality and had higher rates of diagnosed conditions that included hypertension, respiratory and sinus conditions, gastrointestinal conditions, and current or lifetime depression and post-traumatic stress disorder. Among multiple deployment experiences/exposures reported by veterans, multivariable logistic regression identified just two significant GWI risk factors: extended use of skin pesticides in theater (adjusted OR = 3.25, p = 0.005) and experiencing mild traumatic brain injury during deployment (OR = 7.39, p = 0.009). Gulf War experiences associated with intense stress or trauma (e.g., participation in ground combat) were not associated with GWI. Data and samples from the GWIC project are now stored in a repository for use by GWI researchers. Future reports will present detailed findings on brain structure and function, immune function, and association of neuroimmune measures with characteristics of GWI and Gulf War service.

Lifestyle and the aging brain: interactive effects of modifiable lifestyle behaviors and cognitive ability in men from midlife to old age.

We examined the influence of lifestyle on brain aging after nearly 30 years, and tested the hypothesis that young adult general cognitive ability (GCA) would moderate these effects. In the community-dwelling Vietnam Era Twin Study of Aging (VETSA), 431 largely non-Hispanic white men completed a test of GCA at mean age 20. We created a modifiable lifestyle behavior composite from data collected at mean age 40. During VETSA, MRI-based measures at mean age 68 included predicted brain age difference (PBAD), Alzheimer's disease (AD) brain signature, and abnormal white matter scores. There were significant main effects of young adult GCA and lifestyle on PBAD and the AD signature (ps ≤ 0.012), and a GCA-by-lifestyle interaction on both (ps ≤ 0.006). Regardless of GCA level, having more favorable lifestyle behaviors predicted less advanced brain age and less AD-like brain aging. Unfavorable lifestyles predicted advanced brain aging in those with lower age 20 GCA, but did not affect brain aging in those with higher age 20 GCA. Targeting early lifestyle modification may promote dementia risk reduction, especially among lower reserve individuals.

12-year prediction of mild cognitive impairment aided by Alzheimer's brain signatures at mean age 56.

Neuroimaging signatures based on composite scores of cortical thickness and hippocampal volume predict progression from mild cognitive impairment to Alzheimer's disease. However, little is known about the ability of these signatures among cognitively normal adults to predict progression to mild cognitive impairment. Towards that end, a signature sensitive to microstructural changes that may predate macrostructural atrophy should be useful. We hypothesized that: (i) a validated MRI-derived Alzheimer's disease signature based on cortical thickness and hippocampal volume in cognitively normal middle-aged adults would predict progression to mild cognitive impairment; and (ii) a novel grey matter mean diffusivity signature would be a better predictor than the thickness/volume signature. This cohort study was part of the Vietnam Era Twin Study of Aging. Concurrent analyses compared cognitively normal and mild cognitive impairment groups at each of three study waves (ns = 246-367). Predictive analyses included 169 cognitively normal men at baseline (age = 56.1, range = 51-60). Our previously published thickness/volume signature derived from independent data, a novel mean diffusivity signature using the same regions and weights as the thickness/volume signature, age, and an Alzheimer's disease polygenic risk score were used to predict incident mild cognitive impairment an average of 12 years after baseline (follow-up age = 67.2, range = 61-71). Additional analyses adjusted for predicted brain age difference scores (chronological age minus predicted brain age) to determine if signatures were Alzheimer-related and not simply ageing-related. In concurrent analyses, individuals with mild cognitive impairment had higher (worse) mean diffusivity signature scores than cognitively normal participants, but thickness/volume signature scores did not differ between groups. In predictive analyses, age and polygenic risk score yielded an area under the curve of 0.74 (sensitivity = 80.00%; specificity = 65.10%). Prediction was significantly improved with addition of the mean diffusivity signature (area under the curve = 0.83; sensitivity = 85.00%; specificity = 77.85%; P = 0.007), but not with addition of the thickness/volume signature. A model including both signatures did not improve prediction over a model with only the mean diffusivity signature. Results held up after adjusting for predicted brain age difference scores. The novel mean diffusivity signature was limited by being yoked to the thickness/volume signature weightings. An independently derived mean diffusivity signature may thus provide even stronger prediction. The young age of the sample at baseline is particularly notable. Given that the brain signatures were examined when participants were only in their 50 s, our results suggest a promising step towards improving very early identification of Alzheimer's disease risk and the potential value of mean diffusivity and/or multimodal brain signatures.

A cohort study of neuropsychological functioning in spouses of U.S. Gulf War veterans.

AIMS: Veterans of the 1991 Gulf War reported symptoms in their spouses that mirrored veterans' symptoms following their return from the war, including problems with attention and memory. Neuropsychological functioning in these spouses has not been examined with objective tests. This study sought to determine if these spouses exhibited deficits in neuropsychological functioning. MAIN METHODS: Spouses of a national cohort of 1991 Gulf War deployed (n = 470) and non-deployed veterans (n = 524) were examined with neuropsychological tests in 1999-2001. KEY FINDINGS: Neuropsychological tests were factor analyzed yielding five factors: verbal memory, visual memory, attention/working memory, visual organization, and motor speed. Spouses of deployed and nondeployed veterans did not differ on mean factor scores, percentage of impaired factors, or individual test scores. Spouse attention/working memory was related to their having diagnoses of PTSD or anxiety disorders, or self-reported symptoms of current anxiety. Spouse visual memory was related to a diagnosis of current depression. Spouse motor speed was related to their own status of having chronic multisymptom illness (CMI). SIGNIFICANCE: Spouses of Gulf War deployed and nondeployed veterans demonstrated similar neuropsychological functioning, although spouses with psychiatric diagnoses and symptoms, or CMI demonstrated neuropsychological impairments characteristic of those conditions, suggesting that monitoring spouses for these conditions and impairments may be warranted. This pattern of relative weaknesses mirrors some of the previously reported findings for Gulf War veterans, although the veterans displayed neuropsychological impairments beyond what was accounted for by these conditions.

How Well Does Subjective Cognitive Decline Correspond to Objectively Measured Cognitive Decline? Assessment of 10-12 Year Change.

BACKGROUND: Although not strongly correlated with current objective cognitive ability, subjective cognitive decline (SCD) is a risk factor for Alzheimer's disease. Most studies focus on SCD in relation to future decline rather than objective prior decline that it purportedly measures. OBJECTIVE: We evaluated whether self-report of cognitive decline-as a continuous measure-corresponds to objectively-assessed episodic memory and executive function decline across the same period. METHODS: 1,170 men completed the Everyday Cognition Questionnaire (ECog) at mean age 68 assessing subjective changes in cognitive ability relative to 10 years prior. A subset had mild cognitive impairment (MCI), but MCI was diagnosed without regard to subjective decline. Participants completed up to 3 objective assessments of memory and executive function (M = 56, 62, and 68 years). Informant-reported ECogs were completed for 1,045 individuals. Analyses controlled for depression and anxiety symptoms assessed at mean age 68. RESULTS: Participant-reported ECog scores were modestly associated with objective decline for memory (ß= -0.23, 95%CI [-0.37, -0.10]) and executive function (ß= -0.19, 95%CI [-0.33, -0.05]) over the same time period. However, these associations were nonsignificant after excluding MCI cases. Results were similar for informant ratings. Participant-rated ECog scores were more strongly associated with concurrent depression and anxiety symptoms, (ß= 0.44, 95%CI [0.36, 0.53]). CONCLUSION: Continuous SCD scores are correlated with prior objective cognitive changes in non-demented individuals, though this association appears driven by individuals with current MCI. However, participants' current depression and anxiety ratings tend to be strongly associated with their SCD ratings. Thus, what primarily drives SCD ratings remains unclear.

MRI-assessed locus coeruleus integrity is heritable and associated with multiple cognitive domains, mild cognitive impairment, and daytime dysfunction.

INTRODUCTION: The locus coeruleus (LC) undergoes extensive neurodegeneration in early Alzheimer's disease (AD). The LC is implicated in regulating the sleep-wake cycle, modulating cognitive function, and AD progression. METHODS: Participants were 481 men (ages 62 to 71.7) from the Vietnam Era Twin Study of Aging. LC structural integrity was indexed by neuromelanin-sensitive magnetic resonance imaging (MRI) contrast-to-noise ratio (LCCNR ). We examined LCCNR , cognition, amnestic mild cognitive impairment (aMCI), and daytime dysfunction. RESULTS: Heritability of LCCNR was .48. Participants with aMCI showed greater daytime dysfunction. Lower LCCNR was associated with poorer episodic memory, general verbal fluency, semantic fluency, and processing speed, as well as increased odds of aMCI and greater daytime dysfunction. DISCUSSION: Reduced LC integrity is associated with widespread differences across cognitive domains, daytime sleep-related dysfunction, and risk for aMCI. These findings in late-middle-aged adults highlight the potential of MRI-based measures of LC integrity in early identification of AD risk.

Neuroimaging Markers for Studying Gulf-War Illness: Single-Subject Level Analytical Method Based on Machine Learning.

Gulf War illness (GWI) refers to the multitude of chronic health symptoms, spanning from fatigue, musculoskeletal pain, and neurological complaints to respiratory, gastrointestinal, and dermatologic symptoms experienced by about 250,000 GW veterans who served in the 1991 Gulf War (GW). Longitudinal studies showed that the severity of these symptoms often remain unchanged even years after the GW, and these veterans with GWI continue to have poorer general health and increased chronic medical conditions than their non-deployed counterparts. For better management and treatment of this condition, there is an urgent need for developing objective biomarkers that can help with simple and accurate diagnosis of GWI. In this study, we applied multiple neuroimaging techniques, including T1-weighted magnetic resonance imaging (T1W-MRI), diffusion tensor imaging (DTI), and novel neurite density imaging (NDI) to perform both a group-level statistical comparison and a single-subject level machine learning (ML) analysis to identify diagnostic imaging features of GWI. Our results supported NDI as the most sensitive in defining GWI characteristics. In particular, our classifier trained with white matter NDI features achieved an accuracy of 90% and F-score of 0.941 for classifying GWI cases from controls after the cross-validation. These results are consistent with our previous study which suggests that NDI measures are sensitive to the microstructural and macrostructural changes in the brain of veterans with GWI, which can be valuable for designing better diagnosis method and treatment efficacy studies.

Alterations in high-order diffusion imaging in veterans with Gulf War Illness is associated with chemical weapons exposure and mild traumatic brain injury.

The complex etiology behind Gulf War Illness (GWI) has been attributed to the combined exposure to neurotoxicant chemicals, brain injuries, and some combat experiences. Chronic GWI symptoms have been shown to be associated with intensified neuroinflammatory responses in animal and human studies. To investigate the neuroinflammatory responses and potential causes in Gulf War (GW) veterans, we focused on the effects of chemical/biological weapons (CBW) exposure and mild traumatic brain injury (mTBI) during the war. We applied a novel MRI diffusion processing method, Neurite density imaging (NDI), on high-order diffusion imaging to estimate microstructural alterations of brain imaging in Gulf War veterans with and without GWI, and collected plasma proinflammatory cytokine samples as well as self-reported health symptom scores. Our study identified microstructural changes specific to GWI in the frontal and limbic regions due to CBW and mTBI, and further showed distinctive microstructural patterns such that widespread changes were associated with CBW and more focal changes on diffusion imaging were observed in GW veterans with an mTBI during the war. In addition, microstructural alterations on brain imaging correlated with upregulated blood proinflammatory cytokine markers TNFRI and TNFRII and with worse outcomes on self-reported symptom measures for fatigue and sleep functioning. Taken together, these results suggest TNF signaling mediated inflammation affects frontal and limbic regions of the brain, which may contribute to the fatigue and sleep symptoms of the disease and suggest a strong neuroinflammatory component to GWI. These results also suggest exposures to chemical weapons and mTBI during the war are associated with different patterns of peripheral and central inflammation and highlight the brain regions vulnerable to further subtle microscale morphological changes and chronic signaling to nearby glia.

Association of baseline semantic fluency and progression to mild cognitive impairment in middle-aged men.

OBJECTIVE: To test the hypothesis that individual differences in episodic memory and verbal fluency in cognitively normal middle-aged adults will predict progression to amnestic mild cognitive impairment (MCI) after 6 years. METHOD: The cohort analyzed included 842 male twins who were cognitively normal at baseline (mean 56 years) and completed measures of episodic memory and verbal fluency at baseline and again 6 years later (mean 62 years). RESULTS: Poor episodic memory predicted progression to both amnestic MCI (odds ratio [OR], 4.42; 95% confidence interval [CI], 2.44-10.60) and nonamnestic MCI (OR, 1.92; 95% CI, 1.32-3.44). Poor semantic verbal fluency also independently predicted progression to amnestic MCI (OR, 1.86; 95% CI, 1.12-3.52). In the full sample, a semantic-specific fluency latent variable at wave 1 (which controls for letter fluency) predicted change in episodic memory at wave 2 (ß = 0.13), but not vice versa (ß = 0.04). Associations between episodic memory and verbal fluency factors were primarily explained by genetic, rather than environmental, correlations. CONCLUSIONS: Among individuals who were cognitively normal at wave 1, episodic memory moderately to strongly predicted progression to MCI at average age 62, emphasizing the fact that there is still meaningful variability even among cognitively normal individuals. Episodic memory, which is typically a primary focus for Alzheimer disease (AD) risk, declined earlier and more quickly than fluency. However, semantic fluency at average age 56 predicted 6-year change in memory as well as progression to amnestic MCI even after accounting for baseline memory performance. These findings emphasize the utility of memory and fluency measures in early identification of AD risk.

Genetic Underpinnings of Increased BMI and Its Association With Late Midlife Cognitive Abilities.

Objectives: First, we test for differences in various cognitive abilities across trajectories of body mass index (BMI) over the later life course. Second, we examine whether genetic risk factors for unhealthy BMIs-assessed via polygenic risk scores (PRS)-predict cognitive abilities in late-life. Methods: The study used a longitudinal sample of Vietnam veteran males to explore the associations between BMI trajectories, measured across four time points, and later cognitive abilities. The sample of 977 individuals was drawn from the Vietnam Era Twin Study of Aging. Cognitive abilities evaluated included executive function, abstract reasoning, episodic memory, processing speed, verbal fluency, and visual spatial ability. Multilevel linear regression models were used to estimate the associations between BMI trajectories and cognitive abilities. Then, BMI PRS was added to the models to evaluate polygenic associations with cognitive abilities. Results: There were no significant differences in cognitive ability between any of the BMI trajectory groups. There was a significant inverse relationship between BMI-PRS and several cognitive ability measures. Discussion: While no associations emerged for BMI trajectories and cognitive abilities at the phenotypic levels, BMI PRS measures did correlate with key cognitive domains. Our results suggest possible polygenic linkages cutting across key components of the central and peripheral nervous system.

Posttraumatic stress symptom persistence across 24 years: association with brain structures.

Posttraumatic stress disorder (PTSD) is known to persist, eliciting early medical co-morbidity, and accelerated aging. Although PTSD diagnosis has been found to be associated with smaller volume in multiple brain regions, posttraumatic stress (PTS) symptoms and their associations with brain morphometry are rarely assessed over long periods of time. We predicted that persistent PTS symptoms across ~24 years would be inversely associated with hippocampal, amygdala, anterior cingulate volumes, and hippocampal occupancy (HOC = hippocampal volume/[hippocampal volume + inferior lateral ventricle volume]) in late middle age. Exploratory analyses examined prefrontal regions. We assessed PTS symptoms in 247 men at average ages 38 (time 1) and 62 (time 2). All were trauma-exposed prior to time 1. Brain volumes were assessed at time 2 using 3 T structural magnetic resonance imaging. Symptoms were correlated over time (r = 0.46 p < .0001). Higher PTS symptoms averaged over time and symptoms at time 1 were both associated with lower hippocampal, amygdala, rostral middle frontal gyrus (MFG), and medial orbitofrontal cortex (OFC) volumes, and a lower HOC ratio at time 2. Increased PTS symptomatology from time 1 to time 2 was associated with smaller hippocampal volume. Results for hippocampal, rostral MFG and medial OFC remained significant after omitting individuals above the threshold for PTSD diagnosis. Even at sub-diagnostic threshold levels, PTS symptoms were present decades after trauma exposure in parallel with highly correlated structural deficits in brain regions regulating stress responsivity and adaptation.