Traumatic Brain Injury and Long-Term Risk of Stroke Among US Military Veterans.

BACKGROUND: Traumatic brain injury (TBI) is associated with significant morbidity, but the association of TBI with long-term stroke risk in diverse populations remains less clear. Our objective was to examine the long-term associations of TBI with stroke and to investigate potential differences by age, sex, race and ethnicity, and time since TBI diagnosis. METHODS: Retrospective cohort study of US military veterans aged 18+ years receiving healthcare in the Veterans Health Administration system between October 1, 2002 and September 30, 2019. Veterans with TBI were matched 1:1 to veterans without TBI on age, sex, race and ethnicity, and index date, yielding 306 796 veterans with TBI and 306 796 veterans without TBI included in the study. In primary analyses, Fine-Gray proportional hazards models adjusted for sociodemographics and medical/psychiatric comorbidities were used to estimate the association between TBI and stroke risk, accounting for the competing risk of mortality. RESULTS: Participants were a mean age of 50 years, 9% were female, and 25% were of non-White race and ethnicity. Overall, 4.7% of veterans developed a stroke over a median follow-up of 5.2 years. Veterans with TBI had 1.69 times (95% CI, 1.64-1.73) increased risk of any stroke (ischemic or hemorrhagic) compared to veterans without TBI. This increased risk was highest in the first-year post-TBI diagnosis (hazard ratio [HR], 2.16 [95% CI, 2.03-2.29]) but remained elevated for 10+ years. Similar patterns were observed for secondary outcomes, with associations of TBI with hemorrhagic stroke (HR, 3.92 [95% CI, 3.59-4.29]) being stronger than with ischemic stroke (HR, 1.56 [95% CI, 1.52-1.61]). Veterans with both mild (HR, 1.47 [95% CI, 1.43-1.52]) and moderate/severe/penetrating injury (HR, 2.02 [95% CI, 1.96-2.09]) had increased risk of stroke compared to veterans without TBI. Associations of TBI with stroke were stronger among older compared to younger individuals (P interaction-by-age<0.001) and were weaker among Black veterans compared to other race and ethnicities (P interaction-by-race<0.001). CONCLUSIONS: Veterans with prior TBI are at increased long-term risk for stroke, suggesting they may be an important population to target for primary stroke prevention measures.

Intimate Partner Violence, Mental Health, and Aging-Related Health Among Men and Women Veterans Across the Lifespan.

BACKGROUND: A growing body of evidence suggests adverse health outcomes related to intimate partner violence (IPV), including traumatic brain injury (TBI). However, most research in this area has focused on reproductive-aged women. OBJECTIVE: To examine relationships between IPV (with and without TBI), mental health, and aging-related health outcomes among men and women Veterans across the lifespan. DESIGN: Cross-sectional analysis of Department of Veterans Affairs (VA) administrative data from fiscal years 2000-2019. Descriptive statistics and chi-square analyses were used to compare key comorbidities in matched samples of Veterans with and without IPV (gender-stratified and matched 1:3 based on demographics and index date). Comparisons between those with IPV and TBI relative to IPV alone were also examined. SUBJECTS: Veterans aged 18 + with and without documented IPV in Department of Veterans Affairs (VA) electronic health records (n = 4108 men, 2824 women). MAIN MEASURES: ICD codes were used to identify IPV, TBI, and aging-related medical (sleep disorder, hypertension, diabetes, dementia) and common psychiatric (depression, posttraumatic stress disorder, alcohol use disorder, and substance use disorder) diagnoses. KEY RESULTS: Demographic characteristics were reflective of VA-enrolled Veterans (men: mean age 66, SD 16; 72% non-Hispanic White; women: mean age 47, SD 13; 64% non-Hispanic White). Relative to Veterans without IPV, both men and women with IPV had higher rates of all examined medical (e.g., sleep disorders, men: 33% vs. 52%; women: 45% vs. 63%) and psychiatric diagnoses (e.g., depression, men 32% vs. 74%; women 59% vs. 91%; all ps < .001), with evidence of an additive effect of TBI on some psychiatric outcomes. CONCLUSIONS: IPV is broadly associated with aging-related and mental health, and TBI is a common correlate that may further contribute to psychiatric outcomes. Findings highlight the importance of trauma-informed care and recognizing the potential role of these exposures on men and women Veterans' health across the lifespan.

Traumatic brain injury, cardiovascular disease, and risk of dementia among older US Veterans.

OBJECTIVE: Traumatic brain injury (TBI) is associated with elevated rates of cardiovascular disease (CVD), and both CVD and TBI are risk factors for dementia. We investigated whether CVD and its risk factors underlie the association between TBI and dementia. MATERIALS AND METHODS: Cox proportional hazards models among 195,416 Veterans Health Administration patients age 55+ with TBI and a non-TBI, age/sex/race-matched comparison sample. RESULTS: Veterans +TBI were more likely to have any CVD diagnosis (24% vs 36% p = <0.001) or risk factor (83 vs. 90% p < .001) compared to -TBI. During follow-up (mean ~7 years), 12.0% of Veterans with TBI only (HR: 2.17 95% CI 2.09-2.25), and 10.3% with CVD only developed dementia (HR 1.21 95% CI 1.15-1.28), compared to 6.5% with neither. There was an additive association between TBI and CVD on dementia risk (HR 2.51, 95% CI 2.41-2.61). Among those +TBI (±CVD), risk was minimally attenuated by adjustment for CVD/CVD risk factors (unadjusted HR: 2.38, 95% CI: 2.31-2.45; adjusted HR: 2.17, 95% CI 2.10-2.23). CONCLUSIONS: Older veterans TBI have increased prevalence of CVD/CVD risk factors. TBI and CVD had an additive statistical association, with dementia risk increased by ~2.5-fold. However, CVD accounted for little of the association between TBI and dementia. More research is needed to understand mechanisms of TBI-dementia and inform clinical guidelines post-TBI.

Traumatic brain injury increases plasma astrocyte-derived exosome levels of neurotoxic complement proteins.

Possible involvement of complement (C) systems in the pathogenesis of traumatic brain injury (TBI) was investigated by quantifying Cproteins in plasma astrocyte-derived exosomes (ADEs) of subjects with sports-related TBI (sTBI) and TBI in military veterans (mtTBI) without cognitive impairment. All sTBI subjects (n = 24) had mild injuries, whereas eight of the mtTBI subjects had moderate, and 17 had mild injuries. Plasma levels of ADEs were decreased after acute sTBI and returned to normal within months. Cprotein levels in ADEs were from 12- to 35-fold higher than the corresponding levels in neuron-derived exosomes. CD81 exosome marker-normalized ADE levels of classical pathway C4b, alternative pathway factor D and Bb, lectin pathway mannose-binding lectin (MBL), and shared neurotoxic effectors C3b and C5b-9 terminal C complex were significantly higher and those of C regulatory proteins CR1 and CD59 were lower in the first week of acute sTBI (n = 12) than in controls (n = 12). Most C abnormalities were no longer detected in chronic sTBI at 3-12 months after acute sTBI, except for elevated levels of factor D, Bb, and MBL. In contrast, significant elevations of ADE levels of C4b, factor D, Bb, MBL, C3b and C5b-9 terminal C complex, and depressions of CR1 and CD59 relative to those of controls were observed after 1-4 years in early chronic mtTBI (n = 10) and persisted for decades except for normalization of Bb, MBL, and CD59 in late chronic mtTBI (n = 15). Complement inhibitors may be useful therapeutically in acute TBI and post-concussion syndrome.

Military Sexual Trauma in Older Women Veterans: Prevalence and Comorbidities.

BACKGROUND: Recent attention has highlighted the common occurrence and health consequences of military sexual trauma (MST) in younger women veterans. However, almost nothing is known about MST in older veterans. OBJECTIVE: To describe MST among older women veterans, including prevalence and common comorbidities. DESIGN: Cross-sectional observational study, using data from national Department of Veterans Affairs medical records. PARTICIPANTS: Population-based sample of women Veterans aged 55+ with at least one documented MST screen response and at least one clinical encounter in fiscal years 2005-2015. MAIN MEASURES: MST screen: medical diagnoses (diabetes, hypertension, hyperlipidemia, myocardial infarction, cerebrovascular disease, congestive heart failure, obesity, chronic pain conditions, back pain, dementia, insomnia, sleep apnea, menopause symptoms) and mental health diagnoses (anxiety, depression, posttraumatic stress disorder, tobacco use, alcohol use disorder, substance use disorder, opioid use disorder, suicidal ideation) from International Classification of Diseases, Ninth Revision Clinical Modification codes in the medical record. KEY RESULTS: In this cohort of older women veterans (n = 70,864, mean age 65.8 ± 10.4 years), 13% had a positive MST screen. In multivariable regression analyses adjusted for age, race/ethnicity, and marital status, MST was strongly associated with most mental health diagnoses, particularly posttraumatic stress disorder (OR 7.25, 95% CI 6.84-7.68), depression (OR 2.39, 95% CI 2.28-2.50), and suicidal ideation (OR 2.42, 95% CI 2.08-2.82). MST was also associated with multiple medical conditions, particularly sleep disorders (insomnia OR 1.61, 95% CI 1.43-1.82; sleep apnea OR 1.48, 95% CI 1.37-1.61) and pain (chronic pain OR 1.58, 95% CI 1.50-1.67; back pain OR 1.40, 95% CI 1.34-1.47). CONCLUSIONS: A history of MST is common among older women veterans and associated with a range of medical and mental health diagnoses. These findings call attention to the need for additional research in this understudied population, and the importance of trauma-informed care approaches for women across the lifespan.

Ten-Year Prevalence of Cognitive Impairment Diagnoses and Associated Medical and Psychiatric Conditions in a National Cohort of Older Female Veterans.

OBJECTIVE: Veterans are at risk for dementia because of elevated general risk factors and exposure to military risk factors; however, few studies have focused on female veterans despite their growing numbers. We sought to characterize the 10-year prevalence of cognitive impairment (i.e., mild cognitive impairment and dementia) and associated conditions in older female veterans. METHODS: Data were extracted from Veterans Health Administration medical records of 168,111 female veterans aged 65 and older. Cognitive impairment (CI) diagnoses were defined using International Classification of Diseases, Ninth Revision (ICD-9) codes or dementia medication prescriptions. Medical comorbidities and psychiatric conditions were determined using ICD-9 codes occurring within 2years of CI diagnosis or the last recorded medical encounter for veterans without CI. RESULTS: Ten-year prevalence was 1.8% (3,075) for mild cognitive impairment (MCI) diagnoses and 8.1% (13,653) for dementia diagnoses. Prevalence increased with age (MCI age 65: 1.4%; age 85+: 2.7%; dementia age 65: 2.5%; age 85+: 17.7%); 37.3% had dementia subtype diagnoses, with Alzheimer's disease being the most prevalent (72.7%). 47.7% of veterans with CI had at least one medical comorbidity, whereas 22.5% had at least one psychiatric condition. CONCLUSION: Few studies have characterized the prevalence of cognitive impairment in female veterans despite the expected increases in CI and impending demographic shifts in the military. The high prevalence of medical and psychiatric conditions in female veterans with CI highlights their healthcare burden and emphasizes the need for further investigations into the prevention, treatment, and care of cognitive impairment in this understudied population.

Neuropsychological Profile of Lifetime Traumatic Brain Injury in Older Veterans.

OBJECTIVES: The aim of this study was to characterize the neuropsychological profile of lifetime traumatic brain injury (TBI) in older Veterans. METHODS: Participants were 169 older Veterans [mean age=79.1 years (range, 51-97 years), 89% male, 92% Caucasian], 88 with lifetime TBI and 81 without TBI, living in Veterans' retirement homes in independent residence. TBI history was ascertained with the Ohio State TBI Identification Method structured interview. Cognition was assessed with neuropsychological tests: Raw scores were converted to Z-scores compared to age-corrected normative data and combined into five domain composite Z-scores (attention/working memory, learning/memory, language, processing speed, executive functioning). We investigated the association between TBI and performance in each cognitive domain in linear mixed effects models, with and without adjustment for demographics, medical comorbidities, and psychiatric variables. RESULTS: Compared to those without TBI, older Veterans with TBI had greater deficits in processing speed (estimate=-.52; p=.01; f 2=.08 in fully adjusted model) and executive functioning (estimate=-.41; p=.02; f 2=.06 in fully adjusted model) but performed similarly in the attention/working memory, learning/memory, and language domains (all p>.05). TBI-associated deficits were most prominent among individuals with multiple mild TBIs and those with any moderate-to-severe TBI, but were not clearly present among those with single mild TBI. CONCLUSIONS: The neuropsychological profile of lifetime TBI in older Veterans is characterized by slowed processing speed and executive dysfunction, especially among those with greater injury burden. This pattern may reflect long-standing deficits or a TBI-associated cognitive decline process distinct from Alzheimer's disease. (JINS, 2017, 23, 56-64).

Neurobehavioral Characteristics of Older Veterans With Remote Traumatic Brain Injury.

OBJECTIVE: While traumatic brain injury (TBI) is common across the life span, the detailed neurobehavioral characteristics of older adults with prior TBI remain unclear. Our goal was to compare the clinical profile of older independently living veterans with and without prior TBI. SETTING: Two veterans' retirement communities. PARTICIPANTS: Seventy-five participants with TBI and 71 without (mean age = 78 years). DESIGN: Cross-sectional. MAIN MEASURES: TBI history was determined by the Ohio State University TBI Questionnaire. We assessed psychiatric and medical history via interviews and chart review and conducted measures assessing functional/lifestyle, psychiatric, and cognitive outcomes. Regression analyses (adjusted for demographics, diabetes, prior depression, substance abuse, and site) were performed to compare between TBI and non-TBI participants. RESULTS: Compared with veterans without TBI, those with TBI had greater functional impairment (adjusted P = .05), endorsed more current depressive (adjusted P = .04) and posttraumatic stress disorder symptoms (adjusted P = .01), and had higher rates of prior depression and substance abuse (both adjusted Ps < .01). While composite memory and language scores did not differ between groups, participants with TBI performed worse on tests of executive functioning/processing speed (adjusted P = .01). CONCLUSIONS: Our results suggest that TBI may have adverse long-term neurobehavioral consequences and that TBI-exposed adults may require careful screening and follow-up.

Neurovascular coupling in normal aging: a combined optical, ERP and fMRI study.

Brain aging is characterized by changes in both hemodynamic and neuronal responses, which may be influenced by the cardiorespiratory fitness of the individual. To investigate the relationship between neuronal and hemodynamic changes, we studied the brain activity elicited by visual stimulation (checkerboard reversals at different frequencies) in younger adults and in older adults varying in physical fitness. Four functional brain measures were used to compare neuronal and hemodynamic responses obtained from BA17: two reflecting neuronal activity (the event-related optical signal, EROS, and the C1 response of the ERP), and two reflecting functional hemodynamic changes (functional magnetic resonance imaging, fMRI, and near-infrared spectroscopy, NIRS). The results indicated that both younger and older adults exhibited a quadratic relationship between neuronal and hemodynamic effects, with reduced increases of the hemodynamic response at high levels of neuronal activity. Although older adults showed reduced activation, similar neurovascular coupling functions were observed in the two age groups when fMRI and deoxy-hemoglobin measures were used. However, the coupling between oxy- and deoxy-hemoglobin changes decreased with age and increased with increasing fitness. These data indicate that departures from linearity in neurovascular coupling may be present when using hemodynamic measures to study neuronal function.

Understanding Racial Disparities in Dementia Prevalence Among Veterans.

Background: Black and Hispanic older adults have greater incidence of Alzheimer's disease and related dementias relative to White adults, but factors underlying these disparities are not well understood, limiting the ability to address them. Objective: To determine the impact of demographics, cardiovascular disease (CVD) and risk factors, social determinants of health (SDOH), and neuropsychiatric risk factors on racial/ethnic disparities in dementia risk among Veterans. Methods: We examined a random sample of 1,579,919 older Veterans (age ≥55) without dementia who received care from the VHA from October 1, 1999 to September 30, 2021. All variables were extracted from national VHA data. We used Cox proportional hazard regression models to examine change in variance in risk of dementia across racial/ethnic groups. Results: During follow up (mean 11.1 years), 13% of Veterans developed dementia. Relative to White Veterans, the adjusted hazard ratios (AHRs) for developing dementia in sex-adjusted models with age as timescale were 1.65 (95% CI, 1.63-1.67) for Black Veterans and 1.50 (95% CI, 1.44-1.56) for Hispanic Veterans. In the model examining CVD and risk factors, AHRs were 1.53 (95% CI, 1.50-1.55) for Black Veterans and 1.38 (95% CI, 1.33-1.44) for Hispanic Veterans. In the model examining SDOH, AHRs were 1.46 (95% CI, 1.43-1.49) for Black Veterans and 1.34 (95% CI, 1.29-1.40) for Hispanic Veterans. Conclusions: SDOH and CVD and risk factors accounted for the greatest amount of variance in racial/ethnic disparities in dementia risk. Cardiovascular disease and SDOH are strong possible targets for interventions designed to reduce these disparities.

The Impact of Pandemic-Related Restrictions on Dementia Risk Factors in Older Adults.

Adults aged 65+ are at highest risk for severe COVID-19 outcomes, and prior to the distribution of vaccines in the U.S., were strongly advised to quarantine at home to reduce risk of infection. This study examines how COVID-19 restrictions impacted various dementia risk factors and social determinants of health among older adults. Data came from the Systematic Multi-Domain Alzheimer's Risk Reduction Trial, a randomized controlled trial of a multi-domain intervention in higher-risk older adults (aged 70-89). A questionnaire was administered to participants (n = 156; 90.7% response rate) between May 2020 and March 2021. The data show a significant decline in social activity, physical activity, and mood among respondents. Compared to living with others, living alone was associated with worsened physical activity, diet, and subjective memory/thinking, adjusted for sex and age. These results suggest that the COVID-19 pandemic exacerbated several risk factors for dementia in older adults, particularly in those living alone.

Effect of Personalized Risk-Reduction Strategies on Cognition and Dementia Risk Profile Among Older Adults: The SMARRT Randomized Clinical Trial.

Importance: Modifiable risk factors are hypothesized to account for 30% to 40% of dementia; yet, few trials have demonstrated that risk-reduction interventions, especially multidomain, are efficacious. Objective: To determine if a personalized, multidomain risk reduction intervention improves cognition and dementia risk profile among older adults. Design, Setting, and Participants: The Systematic Multi-Domain Alzheimer Risk Reduction Trial was a randomized clinical trial with a 2-year personalized, risk-reduction intervention. A total of 172 adults at elevated risk for dementia (age 70-89 years and with ≥2 of 8 targeted risk factors) were recruited from primary care clinics associated with Kaiser Permanente Washington. Data were collected from August 2018 to August 2022 and analyzed from October 2022 to September 2023. Intervention: Participants were randomly assigned to the intervention (personalized risk-reduction goals with health coaching and nurse visits) or to a health education control. Main Outcomes and Measures: The primary outcome was change in a composite modified Neuropsychological Test Battery; preplanned secondary outcomes were change in risk factors and quality of life (QOL). Outcomes were assessed at baseline and 6, 12, 18, and 24 months. Linear mixed models were used to compare, by intention to treat, average treatment effects (ATEs) from baseline over follow-up. The intervention and outcomes were initially in person but then, due to onset of the COVID-19 pandemic, were remote. Results: The 172 total participants had a mean (SD) age of 75.7 (4.8) years, and 108 (62.8%) were women. After 2 years, compared with the 90 participants in the control group, the 82 participants assigned to intervention demonstrated larger improvements in the composite cognitive score (ATE of SD, 0.14; 95% CI, 0.03-0.25; P = .02; a 74% improvement compared with the change in the control group), better composite risk factor score (ATE of SD, 0.11; 95% CI, 0.01-0.20; P = .03), and improved QOL (ATE, 0.81 points; 95% CI, -0.21 to 1.84; P = .12). There were no between-group differences in serious adverse events (24 in the intervention group and 23 in the control group; P = .59), but the intervention group had greater treatment-related adverse events such as musculoskeletal pain (14 in the intervention group vs 0 in the control group; P < .001). Conclusions and Relevance: In this randomized clinical trial, a 2-year, personalized, multidomain intervention led to modest improvements in cognition, dementia risk factors, and QOL. Modifiable risk-reduction strategies should be considered for older adults at risk for dementia. Trial Registration: ClinicalTrials.gov Identifier: NCT03683394.

Disability in the oldest-old: incidence and risk factors in the 90+ study.

OBJECTIVES: : To measure the incidence of disability in individuals aged 90 years and older and examine factors that may increase risk of disability. DESIGN AND SETTING: : The 90+ Study, a longitudinal study of aging, initiated in January 2003 with follow-up through May 2009. PARTICIPANTS: : A total of 216 nondisabled, prospectively followed participants who were aged 90 years or older at baseline. MEASUREMENTS: : The incidence of disability was measured as needing help on one or more activities of daily living and calculated using person years. Risk factors were examined by using a Cox proportional hazards analysis. RESULTS: : The overall incidence of disability was 16.4% per year (95% confidence interval: 13.3-20.0) and did not differ by gender. Disability incidence increased with age from 8.3% in the 90-94 age group to 25.7% in the 95 years and older age group. Several factors were associated with increased risk of disability, including history of congestive heart failure, depression, poor self-rated quality of life, and cognitive impairment. CONCLUSION: : Disability incidence is high and increases rapidly with age in the oldest-old, with rates essentially tripling between ages 90-94 years and 95+ years. Some factors associated with increased risk of disability in younger elderly continue to be risk factors in the oldest-old. Because of the tremendous social and financial impact of disability and the rapid growth of the oldest-old, the development of strategies to delay disability in the elderly should be a priority for healthcare research.

Cognitive impairment in nondemented oldest-old: prevalence and relationship to cardiovascular risk factors.

OBJECTIVE: To determine the prevalence and types of cognitive impairment in a sample of nondemented participants aged ≥90 (the oldest-old) and to examine the relationships between cognitive impairment and cardiovascular risk factors. PARTICIPANTS: The participants were 420 nondemented individuals from The 90+ Study, a study of aging and dementia in the oldest-old. These participants were categorized into four nonoverlapping groups: normal cognition, amnestic mild cognitive impairment (aMCI), nonamnestic MCI (naMCI), and other cognitive impairment (OCI). History of cardiovascular risk factors was assessed through self-report. RESULTS: The overall prevalence of cognitive impairment in nondemented participants was 34.0% (95% CI: 29.5-38.5). The prevalence of OCI was highest (17.4%; 95% CI: 13.9-21.4), followed by aMCI (8.3%; 95% CI: 5.9-11.4) and naMCI (8.3%; 95% CI: 5.9-11.4). Normal cognition was present in 66.0% (95% CI: 61.2-70.5) of participants. History of hypertension and stroke were the only risk factors that varied between the groups, occurring more frequently in participants with naMCI (χ(2) = 3.82; P < .05) and OCI (χ(2) = 5.51; P < .05). CONCLUSIONS: This study found a high prevalence of cognitive impairment in a sample of nondemented oldest-old. We did not find a strong relationship between cardiovascular risk factors and the cognitive impairment groups, other than between hypertension and naMCI and stroke and OCI. Future studies comparing the incidence of dementia in these groups will ultimately determine their predictive utility in the oldest-old.

TBI and risk of death in military veterans over 14 years: Injury severity, timing, and cause of death.

The objective of this study was to determine the association of traumatic brain injury (TBI) with mortality in military veterans and whether this association differs as a function of TBI severity, timing, and cause of death. This national cohort study used U.S. Department of Veterans Affairs' (VA) data of patients 18 years and older with TBI diagnoses (N = 213,290) and 1:1 propensity-matched comparison random sample of patients without TBI (N = 213,290). The main outcome measure was mortality within 6 months of TBI diagnosis and longer-term (after 6 months). Cox proportional hazards models were used to examine risk of all-cause mortality according to TBI severity and Fine-Gray proportional hazards regression to examine time to cause-specific mortality, accounting for competing risk of other deaths. For patients with moderate-to-severe TBI (compared with no TBI), hazard ratios (HRs) for mortality were highest within first 6 months of injury (fully-adjusted HR: 2.42, 95% CI: 2.32-2.53); for mild TBIs, HRs for mortality were lower and relatively constant over time (fully-adjusted HR within first 6 months: 1.33, 95% CI: 1.26-1.39). Veterans with mild and moderate-to-severe TBI had higher risk of future death over short term for 9 out 10 of the U.S. leading causes of death, with only unintentional injury, stroke, and suicide showing differences by TBI severity. Associations attenuated significantly from within to after 6 months TBI diagnosis. These findings indicate that adults with TBI are at increased risk of majority of leading causes of death, with differential risk by TBI severity and timing of death.

Traumatic Brain Injury and Incidence Risk of Sleep Disorders in Nearly 200,000 US Veterans.

OBJECTIVE: To test the hypothesis that veterans with traumatic brain injury (TBI) have an increased subsequent risk of sleep disorders, we studied the longitudinal association between TBI and incident sleep disorders in nearly 200,000 veterans. METHODS: We performed a cohort study of all patients diagnosed with a TBI in the Veterans Health Administration system from October 1, 2001, to September 30, 2015, who were age-matched 1:1 to veterans without TBI. Veterans with prevalent sleep disorders at baseline were excluded. Development of sleep disorders was defined as any inpatient or outpatient diagnosis of sleep apnea, hypersomnia, insomnia, or sleep-related movement disorders based on ICD-9 codes after the first TBI diagnosis or the random selection date for those without TBI. We restricted the analysis to those with at least 1 year of follow-up. We used Cox proportional hazards models to examine the association between TBI and subsequent risk of sleep disorders. RESULTS: The study included 98,709 veterans with TBI and 98,709 age-matched veterans without TBI (age 49 ± 20 years). After an average follow-up of 5 (1-14) years, 23,127 (19.6%) veterans developed sleep disorders. After adjustment for demographics, education, income, and medical and psychiatric conditions, those who had TBI compared to those without TBI were 41% more likely to develop any sleep disorders (hazard ratio 1.41 [95% confidence interval 1.37-1.44]), including sleep apnea (1.28 [1.24-1.32]), insomnia (1.50 [1.45-1.55]), hypersomnia (1.50 [1.39-1.61]), and sleep-related movement disorders (1.33 [1.16-1.52]). The association was stronger for mild TBIs, did not differ appreciably by presence of posttraumatic stress disorder, and remained after a 2-year time lag. CONCLUSION: In 197,418 veterans without sleep disorders, those with diagnosed TBI had an increased risk of incident sleep disorders over 14 years. Improved prevention and long-term management strategies for sleep are needed for veterans with TBI.

Agent Orange Exposure and Dementia Diagnosis in US Veterans of the Vietnam Era.

Importance: Agent Orange is a powerful herbicide that contains dioxin and was used during the Vietnam War. Although prior studies have found that Agent Orange exposure is associated with increased risk of a wide range of conditions, including neurologic disorders (eg, Parkinson disease), metabolic disorders (eg, type 2 diabetes), and systemic amyloidosis, the association between Agent Orange and dementia remains unclear. Objective: To examine the association between Agent Orange exposure and incident dementia diagnosis in US veterans of the Vietnam era. Design, Setting, and Participants: This cohort study included Veterans Health Administration data from October 1, 2001, and September 30, 2015, with up to 14 years of follow-up. Analyses were performed from July 2018 to October 2020. A 2% random sample of US veterans of the Vietnam era who received inpatient or outpatient Veterans Health Administration care, excluding those with dementia at baseline, those without follow-up visits, and those with unclear Agent Orange exposure status. Exposures: Presumed Agent Orange exposure documented in electronic health record. Main Outcomes and Measures: Fine-Gray competing risk models were used to compare the time to dementia diagnosis (with age as the time scale) for veterans with vs without presumed Agent Orange exposure (as per medical records), adjusting for demographic variables and medical and psychiatric comorbidities. Results: The total sample was 511 189 individuals; after exclusions, 316 351 were included in analyses. Veterans were mostly male (n = 309 889 [98.0%]) and had a mean (SD) age of 62 (6.6) years; 38 121 (12.1%) had presumed Agent Orange exposure. Prevalence of most conditions, including Parkinson disease, diabetes, and amyloidosis, was similar at baseline among veterans with and without Agent Orange exposure. After adjusting for demographic variables and comorbidities, veterans exposed to Agent Orange were nearly twice as likely as those not exposed to receive a dementia diagnosis over a mean (SD) of 5.5 (3.8) years of follow-up (1918 of 38 121 [5.0%] vs 6886 of 278 230 [2.5%]; adjusted hazard ratio: 1.68 [95% CI, 1.59-1.77]). Veterans with Agent Orange exposure developed dementia at a mean of 1.25 years earlier (at a mean [SD] age of 67.5 [7.0] vs 68.8 [8.0] years). Conclusions and Relevance: Veterans with Agent Orange exposure were nearly twice as likely to be diagnosed with dementia, even after adjusting for the competing risk of death, demographic variables, and medical and psychiatric comorbidities. Additional studies are needed to examine potential mechanisms underlying the association between Agent Orange exposure and dementia.

Span, CRUNCH, and beyond: working memory capacity and the aging brain.

Neuroimaging data emphasize that older adults often show greater extent of brain activation than younger adults for similar objective levels of difficulty. A possible interpretation of this finding is that older adults need to recruit neuronal resources at lower loads than younger adults, leaving no resources for higher loads, and thus leading to performance decrements [Compensation-Related Utilization of Neural Circuits Hypothesis; e.g., Reuter-Lorenz, P. A., & Cappell, K. A. Neurocognitive aging and the compensation hypothesis. Current Directions in Psychological Science, 17, 177-182, 2008]. The Compensation-Related Utilization of Neural Circuits Hypothesis leads to the prediction that activation differences between younger and older adults should disappear when task difficulty is made subjectively comparable. In a Sternberg memory search task, this can be achieved by assessing brain activity as a function of load relative to the individual's memory span, which declines with age. Specifically, we hypothesized a nonlinear relationship between load and both performance and brain activity and predicted that asymptotes in the brain activation function should correlate with performance asymptotes (corresponding to working memory span). The results suggest that age differences in brain activation can be largely attributed to individual variations in working memory span. Interestingly, the brain activation data show a sigmoid relationship with load. Results are discussed in terms of Cowan's [Cowan, N. The magical number 4 in short-term memory: A reconsideration of mental storage capacity. Behavioral and Brain Sciences, 24, 87-114, 2001] model of working memory and theories of impaired inhibitory processes in aging.

Sex, race, and risk of dementia diagnosis after traumatic brain injury among older veterans.

OBJECTIVE: To investigate whether sex and race differences exist in dementia diagnosis risk associated with traumatic brain injury (TBI) among older veterans. METHODS: Using Fine-Gray regression models, we investigated incident dementia diagnosis risk with TBI exposure by sex and race. RESULTS: After the exclusion of baseline prevalent dementia, the final sample (all veterans ≥55 years of age diagnosed with TBI during the 2001-2015 study period and a random sample of all veterans receiving Veterans Health Administration care) included nearly 1 million veterans (4.3% female; 81.8% White, 11.5% Black, and 1.25% Hispanic), 96,178 with TBI and 903,462 without TBI. Compared to those without TBI, Hispanic veterans with TBI were almost 2 times more likely (17.0% vs 10.3%; hazard ratio [HR] 1.74, 95% confidence interval [CI] 1.51-2.01), Black veterans with TBI were >2 times more likely (11.2% vs 6.4%; HR 2.15, 95% CI 2.02-2.30), and White veterans with TBI were nearly 3 times more likely to receive a dementia diagnosis (12.0% vs 5.9%; HR 2.71, 95% CI 2.64-2.77). A significant interaction between TBI and race for dementia diagnosis was observed (p < 0.001). Both male and female veterans with TBI were more than twice as likely (men 11.8% vs 5.9%, HR 2.60, 95% CI 2.54-2.66; women 6.3% vs 3.1%, HR 2.36, 95% CI 2.08-2.69) to receive a diagnosis of dementia compared to those without. There was a significant interaction effect between sex and TBI (p = 0.02), but the magnitude of differences was small. CONCLUSIONS: In this large, nationwide cohort of older veterans, all race groups with TBI had increased risk of dementia diagnosis, but there was an interaction effect such that White veterans were at greatest risk for dementia after TBI. Further research is needed to understand the mechanisms for this discrepancy. Differences in dementia diagnosis risk for men and women after TBI were significant but small, and male and female veterans had similarly high risks of dementia diagnosis after TBI.

Neuron-Derived Plasma Exosome Proteins after Remote Traumatic Brain Injury.

To identify long-term effects of traumatic brain injury (TBI) on levels of plasma neuron-derived exosome (NDE) protein biomarkers of cognitive impairment (CI), plasmas were obtained from four groups of older veterans, who were matched for age and sex: no TBI or CI (n = 42), no TBI with CI (n = 19), TBI without CI (n = 21), and TBI with CI (n = 26). The TBI was sustained 12 to 74 years before the study in 75%. The NDEs were enriched by sequential precipitation and anti-L1CAM antibody immunoabsorption, and extracted protein biomarkers were quantified by enzyme-linked immunosorbent assays. Chronic NDE biomarkers known to increase for three to 12 months after TBI, including cellular prion protein (PrPc), synaptogyrin-3, P-T181-tau, P-S396-tau, Aß42, and interleukin (IL)-6, were elevated significantly in subjects who had TBI and CI compared with controls with TBI but no CI. Chronic NDE biomarker levels in subjects without TBI showed significantly higher levels of PrPc, synaptogyrin-3, P-T181-tau, and Aß42, but not P-S396-tau and IL-6, in those with CI compared with controls without CI. The acute NDE biomarkers claudin-5, annexin VII, and aquaporin-4 were not increased in either group with CI. The NDE biomarkers P-S396-tau and IL-6, which are increased distinctively with CI after TBI, may prove useful in evaluating CI in older patients. Aß42 and P-tau species, as well as their respective putative receptors, PrPc and synaptogyrin-3, remain elevated for decades after TBI and may mediate TBI-associated CI and be useful targets for development of drugs.