Healthy Days at Home Among Older Medicare Beneficiaries With Traumatic Brain Injury Requiring Inpatient Rehabilitation.

OBJECTIVE: The objectives of this study were to characterize and identify correlates of healthy days at home (HDaH) before and after TBI requiring inpatient rehabilitation. Setting: Inpatient hospital, nursing home, and home health services. PARTICIPANTS: Average of n= 631 community-dwelling fee-for-service age 66+ Medicare beneficiaries across 30 replicate samples who were hospitalized for traumatic brain injury (TBI) between 2012 and 2014 and admitted to an inpatient rehabilitation facility (IRF) within 72 hours of hospital discharge. DESIGN: Retrospective study using data from Medicare claims supplemented with data from the National Trauma Databank. MAIN MEASURES: The primary outcome, HDaH, was calculated as time alive not using inpatient hospital, nursing home, and home health services in the year before TBI hospitalization and after IRF discharge. RESULTS: We found HDaH declined from 93.2% in the year before TBI hospitalization to 65.3% in the year after IRF discharge (73.6% among survivors only). Most variability in HDaH was: (1) in the first 3 months after discharge and (2) by discharge disposition, with persons discharged from IRF to another acute hospital having the worst prognosis for utilization and death. In negative binomial regression models, the strongest predictors of HDaH in the year after discharge were rehabilitation Functional Independence Measure mobility score (ß = 0.03; 95% CI, 0.002-0.06) and inpatient Charlson Comorbidity Index score (ß = - 0.06; 95% CI, -0.13 to 0.001). Dual Medicaid eligible was associated with less HDaH among survivors (ß = - 0.37; 95% CI, -0.66 to -0.07). CONCLUSION: In this study, among community-dwelling older adults with TBI, we found a notable decrease in the proportion of time spent alive at home without higher-level care after IRF discharge compared to before TBI. The finding that physical disability and comorbidities were the biggest drivers of healthy days alive in this population suggests that a chronic disease management model is required for older adults with TBI to manage their complex health care needs.

The Effects of Repetitive Head Impact Exposure on Mental Health Symptoms Following Traumatic Brain Injury.

OBJECTIVE: This study aimed to characterize the types and timing of repetitive head impact (RHI) exposures in individuals with moderate to severe traumatic brain injury (TBI) and to examine the effects of RHI exposures on mental health outcomes. SETTING: TBI Model Systems National Database. PARTICIPANTS: 447 patients with moderate to severe TBI who reported RHI exposure between 2015 and 2022. DESIGN: Secondary data analysis. MAIN MEASURES: RHI exposures reported on the Ohio State University TBI Identification Method (OSU TBI-ID) were characterized by exposure category, duration, and timing relative to the index TBI. Mental health outcomes were evaluated at the 5-year follow-up assessment using the Patient Health Questionnaire-9 (PHQ-9) for depression symptoms and the Generalized Anxiety Disorder-7 (GAD-7) for anxiety symptoms. RESULTS: The majority of RHI exposures were sports-related (61.1%), followed by other causes (20.8%; including falls), repetitive violence/assault (18.8%), and military exposures (6.7%). Males predominantly reported sports and military exposures, while a larger proportion of females reported violence and falls. Sports exposures were most common before the index TBI, while exposures from falls and violence/abuse were most common after TBI. RHI exposures occurring after the index TBI were associated with higher levels of depression (ß = 5.05; 95% CI, 1.59-8.50) and anxiety (ß = 4.53; 95% CI, 1.02-8.05) symptoms than exposures before the index TBI. CONCLUSION: The findings emphasize the need to consider RHI exposures and their interaction with TBI when assessing mental health outcomes. Understanding the prevalence and challenges associated with RHI post-TBI can inform targeted interventions and improve the well-being of individuals with TBI. Preventive measures and ongoing care should be implemented to address the risks posed by RHI, particularly in individuals with prior TBI, especially surrounding fall and violence/abuse prevention.

Intimate Partner Violence and Other Trauma Exposures in Females With Traumatic Brain Injury.

We examined whether females with a history of traumatic brain injury (TBI) and intimate partner violence (IPV) have greater exposure to lifetime trauma relative to females with TBI but no IPV history. Further, we assessed the effects of lifetime trauma on psychological outcomes after TBI. Female participants (n = 70; age M [standard deviation-SD] = 50.5 [15.2] years) with TBI (time since injury median [interquartile range -IQR] = 10.2 [5.3-17.8] years) completed a structured assessment of lifetime history of TBI, including an IPV module to query head injuries from physical violence by an intimate partner. We characterized lifetime trauma exposure with the Adverse Childhood Experiences (ACEs) questionnaire and Survey of Exposure to Community Violence (CV). We evaluated psychological functioning with self-report questionnaires of post-traumatic stress disorder (PTSD), depression, and anxiety symptoms. Compared with those with no IPV history (n = 51), participants reporting IPV-related head injuries (n = 19; 27.1%) reported more ACEs (M[SD] IPV: 4.5[2.9]; No IPV: 1.6[1.8], p < 0.001, d = 1.08) and greater CV (IPV: 17.5[8.4]; No IPV: 7.6[6.1], p < .0001, d = 1.26). Within the full sample, ACEs (ß = 0.21, 95% confidence interval [CI] = 0.04-0.39) and CV (ß = 0.07, 95% CI = 0.01-0.13) predicted worse PTSD symptoms, while IPV alone did not. Exposure to all three sources of trauma (ACEs, CV, and IPV) was associated with worse PTSD symptoms relative to fewer traumas. The results highlight the scope of traumatic exposures among TBI survivors and the importance of considering IPV and other lifetime trauma exposure in assessing and managing TBI. Trauma-informed interventions that are modified for TBI-related impairment may offer improved outcomes in managing psychological symptoms.

Health care utilization and costs in the years preceding dementia identification.

INTRODUCTION: There is evidence that health care utilization increases after incident dementia, particularly after dementia diagnosis and toward the end of life; however, less is known about utilization in the years before dementia identification. METHODS: In this retrospective cohort study we obtained data on n = 5547 beneficiaries from the Health and Retirement Study (HRS)-Medicare linked sample (n = 1241 with and n = 4306 without dementia) to compare longitudinal trends in health care costs and utilization in the 6 years preceding dementia identification relative to a confounder-balanced reference group without dementia. RESULTS: We found that persons with dementia had a greater prevalence of outpatient emergency department (ED), inpatient hospital, skilled nursing, and home health use, and total health care costs in the years preceding dementia identification compared to their similar counterparts without dementia across a comparable timespan in later life. CONCLUSIONS: This study provides evidence to suggest greater healthcare burden may exist well before clinical manifestation and identification of dementia. HIGHLIGHTS: Several studies have documented the tremendous healthcare-related costs of living with dementia, particularly toward the end of life. Dementia is a progressive neurodegenerative disease, which, for some, includes a prolonged pre-clinical phase. However, health services research to date has seldom considered the time before incident dementia. This study documents that health care utilization and costs are significantly elevated in the years before incident dementia relative to a demographically-similar comparison group without dementia.

Developing multidimensional participation profiles after traumatic brain injury: a TBI model systems study.

Purpose. To characterize societal participation profiles after moderate-severe traumatic brain injury (TBI) along objective (Frequency) and subjective (Satisfaction, Importance, Enfranchisement) dimensions.Materials and Methods. We conducted secondary analyses of a TBI Model Systems sub-study (N = 408). Multiaxial assessment of participation included the Participation Assessment with Recombined Tools-Objective and -Subjective questionnaires (Participation Frequency and Importance/Satisfaction, respectively) and the Enfranchisement Scale. Participants provided responses via telephone interview 1-15 years post-injury. Multidimensional participation profiles (classes) were extracted using latent profile analysis.Results. A 4-class solution was identified as providing maximal statistical separation between profiles and being clinically meaningful based on profile demographic features. One profile group (48.5% of the sample) exhibited the "best" participation profile (High Frequency, Satisfaction, Importance, and Enfranchisement) and was also the most advantaged according to socioeconomic indicators. Other profile groups showed appreciable heterogeneity across participation dimensions. Age, race/ethnicity, education level, ability to drive, and urbanicity were features that varied between profiles.Conclusions. Societal participation is a critical, but inherently complex, TBI outcome that may not be adequately captured by a single index. Our data underscore the importance of a multidimensional approach to participation assessment and interpretation using profiles. The use of participation profiles may promote precision health interventions for community integration.Implications for RehabilitationOur study found unidimensional measures of societal participation in traumatic brain injury (TBI) populations that focus exclusively on frequency indicators may be overly simplistic and miss key subjective components of participationTaking a multidimensional perspective, we documented four meaningfully distinct participation subgroups (including both objective and subjective dimensions of societal participation) within the TBI rehabilitation populationMultidimensional profiles of participation may be used to group individuals with TBI into target groups for intervention (e.g., deeper goal assessment for individuals who do not rate standard participation activities as important, but also do not participate and do not feel enfranchised).

Association of Traumatic Brain Injury with Late Life Neuropathological Outcomes in a Community-Based Cohort.

BACKGROUND: Prior studies into the association of head trauma with neuropathology have been limited by incomplete lifetime neurotrauma exposure characterization. OBJECTIVE: To investigate the neuropathological sequelae of traumatic brain injury (TBI) in an autopsy sample using three sources of TBI ascertainment, weighting findings to reflect associations in the larger, community-based cohort. METHODS: Self-reported head trauma with loss of consciousness (LOC) exposure was collected in biennial clinic visits from 780 older adults from the Adult Changes in Thought study who later died and donated their brain for research. Self-report data were supplemented with medical record abstraction, and, for 244 people, structured interviews on lifetime head trauma. Neuropathology outcomes included Braak stage, CERAD neuritic plaque density, Lewy body distribution, vascular pathology, hippocampal sclerosis, and cerebral/cortical atrophy. Exposures were TBI with or without LOC. Modified Poisson regressions adjusting for age, sex, education, and APOE ɛ4 genotype were weighted back to the full cohort of 5,546 participants. RESULTS: TBI with LOC was associated with the presence of cerebral cortical atrophy (Relative Risk 1.22, 95% CI 1.02, 1.42). None of the other outcomes was associated with TBI with or without LOC. CONCLUSION: TBI with LOC was associated with increased risk of cerebral cortical atrophy. Despite our enhanced TBI ascertainment, we found no association with the Alzheimer's disease-related neuropathologic outcomes among people who survived to at least age 65 without dementia. This suggests the pathophysiological processes underlying post-traumatic neurodegeneration are distinct from the hallmark pathologies of Alzheimer's disease.

Sex differences in associations between APOE ε2 and longitudinal cognitive decline.

INTRODUCTION: We examined whether sex modifies the association between APOE ε2 and cognitive decline in two independent samples. METHODS: We used observational data from cognitively unimpaired non-Hispanic White (NHW) and non-Hispanic Black (NHB) adults. Linear mixed models examined interactive associations of APOE genotype (ε2 or ε4 carrier vs. ε3/ε3) and sex on cognitive decline in NHW and NHB participants separately. RESULTS: In both Sample 1 (N = 9766) and Sample 2 (N = 915), sex modified the association between APOE ε2 and cognitive decline in NHW participants. Specifically, relative to APOE ε3/ε3, APOE ε2 protected against cognitive decline in men but not women. Among APOE ε2 carriers, men had slower decline than women. Among APOE ε3/ε3 carriers, cognitive trajectories did not differ between sexes. There were no sex-specific associations of APOE ε2 with cognition in NHB participants (N = 2010). DISCUSSION: In NHW adults, APOE ε2 may protect men but not women against cognitive decline. HIGHLIGHTS: We studied sex-specific apolipoprotein E (APOE) ε2 effects on cognitive decline. In non-Hispanic White (NHW) adults, APOE ε2 selectively protects men against decline. Among men, APOE ε2 was more protective than APOE ε3/ε3. In women, APOE ε2 was no more protective than APOE ε3/ε3. Among APOE ε2 carriers, men had slower decline than women. There were no sex-specific APOE ε2 effects in non-Hispanic Black (NHB) adults.

Cognitive Performance, Depression, and Anxiety 1 Year After Traumatic Brain Injury.

OBJECTIVES: To evaluate associations between depression, anxiety, and cognitive impairment among individuals with complicated mild to severe traumatic brain injury (TBI) 1 year after injury. SETTING: Multiple inpatient rehabilitation units across the United States. PARTICIPANTS: A total of 498 adults 16 years and older who completed inpatient rehabilitation for complicated mild to severe TBI. DESIGN: Secondary analysis of a prospective, multicenter, cross-sectional observational cohort study. MAIN MEASURES: Assessments of depression (Traumatic Brain Injury Quality of Life [TBI-QOL] Depression) and anxiety (TBI-QOL Anxiety) as well as a telephone-based brief screening measure of cognitive functioning (Brief Test of Adult Cognition by Telephone [BTACT]). RESULTS: We found an inverse relationship between self-reported depression symptoms and the BTACT Composite score (ß = -0.18, P < .01) and anxiety symptoms and the BTACT Composite score (ß = -0.20, P < .01). There was no evidence this relationship varied by injury severity. Exploratory analyses showed depression and anxiety were negatively correlated with both BTACT Executive Function factor score and BTACT Memory factor score. CONCLUSIONS: Both depression and anxiety have a small but significant negative association with cognitive performance in the context of complicated mild to severe TBI. These findings highlight the importance of considering depression and anxiety when interpreting TBI-related neuropsychological impairments, even among more severe TBI.

Distal and Proximal Predictors of Rehospitalization Over 10 Years Among Survivors of TBI: A National Institute on Disability, Independent Living, and Rehabilitation Research Traumatic Brain Injury Model Systems Study.

OBJECTIVE: To describe the rates and causes of rehospitalization over a 10-year period following a moderate-severe traumatic brain injury (TBI) utilizing the Healthcare Cost and Utilization Project (HCUP) diagnostic coding scheme. SETTING: TBI Model Systems centers. PARTICIPANTS: Individuals 16 years and older with a primary diagnosis of TBI. DESIGN: Prospective cohort study. MAIN MEASURES: Rehospitalization (and reason for rehospitalization) as reported by participants or their proxies during follow-up telephone interviews at 1, 2, 5, and 10 years postinjury. RESULTS: The greatest number of rehospitalizations occurred in the first year postinjury (23.4% of the sample), and the rates of rehospitalization remained stable (21.1%-20.9%) at 2 and 5 years postinjury and then decreased slightly (18.6%) at 10 years postinjury. Reasons for rehospitalization varied over time, but seizure was the most common reason at 1, 2, and 5 years postinjury. Other common reasons were related to need for procedures (eg, craniotomy or craniectomy) or medical comorbid conditions (eg, diseases of the heart, bacterial infections, or fractures). Multivariable logistic regression models showed that Functional Independence Measure (FIM) Motor score at time of discharge from inpatient rehabilitation was consistently associated with rehospitalization at all time points. Other factors associated with future rehospitalization over time included a history of rehospitalization, presence of seizures, need for craniotomy/craniectomy during acute hospitalization, as well as older age and greater physical and mental health comorbidities. CONCLUSION: Using diagnostic codes to characterize reasons for rehospitalization may facilitate identification of baseline (eg, FIM Motor score or craniotomy/craniectomy) and proximal (eg, seizures or prior rehospitalization) factors that are associated with rehospitalization. Information about reasons for rehospitalization can aid healthcare system planning. By identifying those recovering from TBI at a higher risk for rehospitalization, providing closer monitoring may help decrease the healthcare burden by preventing rehospitalization.

Association of Military Employment With Late-Life Cognitive Decline and Dementia: A Population-Based Prospective Cohort Study.

INTRODUCTION: As the number of U.S. veterans over age 65 has increased, interest in whether military service affects late-life health outcomes has grown. Whether military employment is associated with increased risk of cognitive decline and dementia remains unclear. MATERIALS AND METHODS: We used data from 4,370 participants of the longitudinal Adult Changes in Thought (ACT) cohort study, enrolled at age 65 or older, to examine whether military employment was associated with greater cognitive decline or higher risk of incident dementia in late life. We classified persons as having military employment if their first or second-longest occupation was with the military. Cognitive status was assessed at each biennial Adult Changes in Thought study visit using the Cognitive Abilities Screening Instrument, scored using item response theory (CASI-IRT). Participants meeting screening criteria were referred for dementia ascertainment involving clinical examination and additional cognitive testing. Primary analyses were adjusted for sociodemographic characteristics and APOE genotype. Secondary analyses additionally adjusted for indicators of early-life socioeconomic status and considered effect modification by age, gender, and prior traumatic brain injury with loss of consciousness TBI with LOC. RESULTS: Overall, 6% of participants had military employment; of these, 76% were males. Military employment was not significantly associated with cognitive change (difference in modeled 10-year cognitive change in CASI-IRT scores in SD units (95% confidence interval [CI]): -0.042 (-0.19, 0.11), risk of dementia (hazard ratio [HR] [95% CI]: 0.92 [0.71, 1.18]), or risk of Alzheimer's disease dementia (HR [95% CI]: 0.93 [0.70, 1.23]). These results were robust to additional adjustment and sensitivity analyses. There was no evidence of effect modification by age, gender, or traumatic brain injury with loss of consciousness. CONCLUSIONS: Among members of the Adult Changes in Thought cohort, military employment was not associated with increased risk of cognitive decline or dementia. Nevertheless, military veterans face the same high risks for cognitive decline and dementia as other aging adults.

Investigation of the association of military employment and Parkinson's disease with a validated Parkinson's disease case-finding strategy.

INTRODUCTION: Persons with military involvement may be more likely to have Parkinson's disease (PD) risk factors. As PD is rare, case finding remains a challenge, contributing to our limited understanding of PD risk factors. Here, we explore the validity of case-finding strategies and whether military employment is associated with PD. MATERIALS AND METHODS: We identified Adult Changes in Thought (ACT) study participants reporting military employment as their longest or second longest occupation. We used self-report and prescription fills to identify PD cases and validated this case-finding approach against medical record review. RESULTS: At enrollment, 6% of 5,125 eligible participants had military employment and 1.8% had prevalent PD; an additional 3.5% developed PD over follow-up (mean: 8.3 years). Sensitivity of our case-finding approach was higher for incident (80%) than prevalent cases (54%). Specificity was high (>97%) for both. Military employment was not associated with prevalent PD. Among nonsmokers, point estimates suggested an increased risk of incident PD with military employment, but the result was non-significant and based on a small number of cases. CONCLUSIONS: Self-report and prescription medications can accurately identify incident PD cases relative to the reference method of medical record review. We found no association between military employment and PD.

AD and non-AD mediators of the pathway between the APOE genotype and cognition.

INTRODUCTION: The apolipoprotein E (APOE) genotype is a driver of cognitive decline and dementia. We used causal mediation methods to characterize pathways linking the APOE genotype to late-life cognition through Alzheimer's disease (AD) and non-AD neuropathologies. METHODS: We analyzed autopsy data from 1671 individuals from the Religious Orders Study, Memory and Aging Project, and Minority Aging Research Study (ROS/MAP/MARS) studies with cognitive assessment within 5 years of death and autopsy measures of AD (amyloid beta (Aß), neurofibrillary tangles), vascular (athero/arteriolo-sclerosis, micro-infarcts/macro-infarcts), and non-AD neurodegenerative neuropathologies (TAR DNA protein 43 [TDP-43], Lewy bodies, amyloid angiopathy, hippocampal sclerosis). RESULTS: The detrimental effect of APOE ε4 on cognition was mediated by summary measures of AD and non-AD neurodegenerative neuropathologies but not vascular neuropathologies; effects were strongest in individuals with dementia. The protective effect of APOE ε2 was partly mediated by AD neuropathology and stronger in women than in men. DISCUSSION: The APOE genotype influences cognition and dementia through multiple neuropathological pathways, with implications for different therapeutic strategies targeting people at increased risk for dementia. HIGHLIGHTS: Both apolipoprotein E (APOE) ε2 and APOE ε4 effects on late-life cognition are mediated by AD neuropathology. The estimated mediated effects of most measures of AD neuropathology were similar. Non-Alzheimer's disease (AD) neurodegenerative pathologies mediate the effect of ε4 independently from AD. Non-AD vascular pathologies did not mediate the effect of the APOE genotype on cognition. The protective effect of APOE ε2 on cognition was stronger in women.

Associations of Military Service History and Health Outcomes in the First Five Years After Traumatic Brain Injury.

For many years, experts have recognized the importance of studying traumatic brain injury (TBI) among active-duty service members and veterans. A majority of this research has been conducted in Veterans Administration (VA) or Department of Defense settings. However, far less is known about military personnel who seek their medical care outside these settings. Studies that have been conducted in civilian settings have either not enrolled active duty or veteran participants, or failed to measure military history, precluding study of TBI outcomes by military history. The purpose of the present study was to determine associations between military history and medical (prevalence of 25 comorbid health conditions), cognition (Brief Test of Adult Cognition by Telephone), and psychological health (Patient Health Questionnaire-9 [PHQ-9], Generalized Anxiety Disorder-7, suicidality [9th item from PHQ-9]) in the first 5 years after TBI. In this prospective study, we analyzed data from the TBI Model Systems National Database. Participants were 7797 individuals with TBI admitted to one of 21 civilian inpatient rehabilitation facilities from April 1, 2010, to November 19, 2020, and followed up to 5 years. We assessed the relationship between military history (any versus none, combat exposure, service era, and service duration) and TBI outcomes. We found specific medical conditions were significantly more prevalent 1 year post-TBI among individuals who had a history of combat deployment (lung disorders, post-traumatic stress disorder [PTSD], and sleep disorder), served in post-draft era (chronic pain, liver disease, arthritis), and served >4 years (high cholesterol, PTSD, sleep disorder). Individuals with military history without combat deployment had modestly more favorable cognition and psychological health in the first 5 years post-injury relative to those without military history. Our data suggest that individuals with TBI with military history are heterogeneous, with some favorable and other deleterious health outcomes, relative to their non-military counterparts, which may be driven by characteristics of service, including combat exposure and era of service.

Branching out: Feasibility of examining the effects of greenspace on mental health after traumatic brain injury.

Aim: This pilot study's aim was to determine the feasibility of examining the effects of an environmental variable (i.e., tree canopy coverage) on mental health after sustaining a brain injury. Methods: A secondary data analysis was conducted leveraging existing information on mental health after moderate to severe traumatic brain injury (TBI) from the TBI Model System. Mental health was measured using PHQ-9 (depression) and GAD-7 (anxiety) scores. The data were compared with data on tree canopy coverage in the state of Texas that was obtained from the Multi-Resolution Land Characteristics (MRLC) Consortium using GIS analysis. Tree canopy coverage as an indicator of neighborhood socioeconomic status was also examined using the Neighborhood SES Index. Results: Tree canopy coverage had weak and non-significant correlations with anxiety and depression scores, as well as neighborhood socioeconomic status. Data analysis was limited by small sample size. However, there is a higher percentage (18.8%) of participants who reported moderate to severe depression symptoms in areas with less than 30% tree canopy coverage, compared with 6.6% of participants who endorsed moderate to severe depression symptoms and live in areas with more than 30% tree canopy coverage (there was no difference in anxiety scores). Conclusion: Our work confirms the feasibility of measuring the effects of tree canopy coverage on mental health after brain injury and warrants further investigation into examining tree canopy coverage and depression after TBI. Future work will include nationwide analyses to potentially detect significant relationships, as well as examine differences in geographic location.

Sex-specific effects of microglial activation on Alzheimer's disease proteinopathy in older adults.

Females show a disproportionate burden of Alzheimer's disease pathology and higher Alzheimer's disease dementia prevalences compared to males, yet the mechanisms driving these vulnerabilities are unknown. There is sexual dimorphism in immunological functioning, and neuroimmune processes are implicated in Alzheimer's disease genesis. Using neuropathology indicators from human brain tissue, we examined the mediational role of microglial activation on the relationship between amyloid and tau and how it differs by sex. 187 decedents (64% female; 89 mean age at death; 62% non-demented) from the Rush Memory and Aging Project completed neuropathological evaluations with brain tissue quantified for microglial activation, amyloid-ß and tau. Proportion of morphologically activated microglia was determined via immunohistochemistry (HLA-DP-DQ-DR) and morphological staging (stage I, II or III). Amyloid-ß and tau burden were quantified via immunohistochemistry (M00872 or AT8, respectively). Using causal counterfactual modelling, we estimated the mediational effect of microglial activation on the amyloid-ß to tau relationship in the whole sample and stratified by sex (amyloid-ß â†’ microglial activation → tau). Alternative models tested the role of microglia activation as the precipitating event (microglial activation → amyloid-ß â†’ tau). Microglial activation significantly mediated 33% [95% confidence interval (CI) 10-67] of the relationship between amyloid-ß and tau in the whole sample; stratified analyses suggested this effect was stronger and only statistically significant in females. 57% (95% CI 22-100) of the effect of amyloid-ß on tau was mediated through microglial activation in females, compared to 19% (95% CI 0-64) in males. Regional analyses suggested that mediational effects were driven by greater cortical versus subcortical microglial activation. Relationships were independent of cerebrovascular disease indices. Alternative models suggested that in females, microglial activation was a significant exposure both preceding the amyloid-ß to tau relationship (mediational effect: 50%, 95% CI 23-90) and directly related to tau burden (microglia direct effect: 50%, 95% CI 10-77). By contrast, in males, only the direct effect of microglial activation to tau reached significance (74%, 95% CI 32-100) (mediational effect: 26%, 95% CI 0-68). Our models suggest a reciprocal, bidirectional relationship between amyloid-ß and microglial activation that significantly accounts for tau burden in females. By contrast, in males, direct independent (non-mediational) relationships between microglial activation or amyloid-ß with tau were observed. Microglial activation may be disproportionately important for Alzheimer's disease pathogenesis in females. Determining sex-specific vulnerabilities to Alzheimer's disease development both inform fundamental pathophysiology and support precision health approaches for this heterogeneous disease.

Cerebral amyloid angiopathy interacts with neuritic amyloid plaques to promote tau and cognitive decline.

Accumulating data suggest that cerebrovascular disease contributes to Alzheimer's disease pathophysiology and progression toward dementia. Cerebral amyloid angiopathy is a form of cerebrovascular pathology that results from the build-up of ß-amyloid in the vessel walls. Cerebral amyloid angiopathy commonly co-occurs with Alzheimer's disease pathology in the ageing brain and increases the risk of Alzheimer's disease dementia. In the present study, we examined whether cerebral amyloid angiopathy influences tau deposition and cognitive decline independently or synergistically with parenchymal ß-amyloid burden. Secondly, we examined whether tau burden mediates the association between cerebral amyloid angiopathy and cognitive decline. We included data from autopsied subjects recruited from one of three longitudinal clinical-pathological cohort studies: the Rush Memory and Aging Project, the Religious Orders Study and the Minority Aging Research Study. Participants completed annual clinical and cognitive evaluations and underwent brain autopsy. Cerebral amyloid angiopathy pathology was rated as none, mild, moderate or severe. Bielschowsky silver stain was used to visualize neuritic ß-amyloid plaques and neurofibrillary tangles. We used linear regression and linear mixed models to test independent versus interactive associations of cerebral amyloid angiopathy and neuritic plaque burden with tau burden and longitudinal cognitive decline, respectively. We used causal mediation models to examine whether tau mediates the association between cerebral amyloid angiopathy and cognitive decline. The study sample included 1722 autopsied subjects (age at baseline = 80.2 ± 7.1 years; age at death = 89.5 ± 6.7 years; 68% females). Cerebral amyloid angiopathy interacted with neuritic plaques to accelerate tau burden and cognitive decline. Specifically, those with more severe cerebral amyloid angiopathy pathology and higher levels of neuritic plaque burden had greater tau burden and faster cognitive decline. We also found that tau mediated the association between cerebral amyloid angiopathy and cognitive decline among participants with higher neuritic plaque burden. In summary, more severe levels of cerebral amyloid angiopathy and higher parenchymal ß-amyloid burden interacted to promote cognitive decline indirectly via tau deposition. These results highlight the dynamic interplay between cerebral amyloid angiopathy and Alzheimer's disease pathology in accelerating progression toward dementia. These findings have implications for Alzheimer's disease clinical trials and therapeutic development.

Changes in alcohol use and mood during the COVID-19 pandemic among individuals with traumatic brain injury: A difference-in-difference study.

OBJECTIVE: To evaluate the impact of COVID-19 pandemic exposure on changes in alcohol use and mood from years 1 to 2 after traumatic brain injury (TBI). METHODS: We used a difference-in-difference (DiD) study design to analyze data from 1,059 individuals with moderate-to-severe TBI enrolled in the TBI Model Systems (TBIMS) National Database. We defined COVID-19 pandemic exposure as participants who received their year 1 post-injury interviews prior to January 1, 2020, and their year 2 interview between April 1, 2020 and January 15, 2021. Pandemic-unexposed participants had both year 1 and 2 follow-up interviews before January 1, 2020. We measured current alcohol use as any past month alcohol use, average number of drinks per drinking occasion, and past month binge drinking. We measured depression symptoms using Patient Health Questionnaire-9, and anxiety symptoms using the Generalized Anxiety Disorder-7. RESULTS: We found persons with TBI exposed to the pandemic had greater increases in the average number of drinks per occasion from year 1 to 2 post-injury compared to pandemic-unexposed individuals (ß = 0.36, 95% CI: 0.16, 0.57, p = 0.001), with males, adults <65 years old, and Black and Hispanic subgroups showing the greatest increases in consumption. Though average consumption was elevated, changes in rates of any alcohol use or binge drinking by pandemic exposure were not observed. Overall, there were no significant changes in depressive and anxiety symptoms over time between pandemic exposed and unexposed groups; however, pandemic-exposed Hispanics with TBI reported significant increases in anxiety symptoms from year-1 to year-2 post-injury compared to pandemic-unexposed Hispanics (ß = 2.35, 95% CI: 0.25, 4.47, p = 0.028). CONCLUSION: Among persons living with TBI, those exposed to the pandemic had significant increases in average alcohol consumption. Pandemic-exposed Hispanics with TBI had large elevations in anxiety symptoms, perhaps reflecting health inequities exacerbated by the pandemic, and suggesting a need for targeted monitoring of psychosocial distress.

Health and cognition among adults with and without Traumatic Brain Injury: A matched case-control study.

OBJECTIVES: To evaluate associations between traumatic brain injury (TBI) and presence of health conditions, and to compare associations of health and cognition between TBI cases and controls. METHODS: This matched case-control study used data from the TBI Model Systems National Database (TBI cases) and Midlife in the United States II and Refresher studies (controls).  248 TBI cases were age-, sex-, race-, and education-matched without replacement to three controls. Cases and controls were compared on prevalence of 18 self-reported conditions, self-rated health, composite scores from the Brief Test of Adult Cognition by Telephone. RESULTS: The following conditions were significantly more prevalent among TBI cases versus controls: anxiety/depression (OR = 3.12, 95% CI: 2.20, 4.43, p < .001), chronic sleeping problems (OR = 2.76, 95% CI: 1.86, 4.10, p < .001), headache/migraine (OR = 2.61, 95% CI: 1.50, 4.54, p = .0007), and stroke (OR = 6.42, 95% CI: 2.93, 14.10, p < .001). The relationship between self-rated health and cognition significantly varied by TBI (pinteraction = 0.002). CONCLUSION: Individuals with TBI have greater odds of selected neurobehavioral conditions compared to their demographically similar uninjured peers. Among persons with TBI there was a stronger association between poorer self-rated health and cognition than controls. TBI is increasingly conceptualized as a chronic disease; current findings suggest post-TBI health management requires cognitive supports.

Home, but Not Homebound: A Prospective Analysis of Persons Living With Dementia.

OBJECTIVES: Homebound persons living with dementia may have increased difficulty accessing needed care in the community. This study identifies factors associated with becoming homebound among a national sample of Medicare beneficiaries with newly identified dementia. DESIGN: Prospective cohort analysis. SETTING AND PARTICIPANTS: We used the National Health and Aging Trends Study (NHATS) 2011-2018 to identify community-dwelling older adults at the time of a new dementia diagnosis (n = 939). Dementia status was determined based on cognitive testing and self and proxy reporting. METHODS: We compared characteristics of homebound (ie, those who never or rarely left home) and non-homebound participants at the time of dementia identification. Among non-homebound participants, we used a Fine-Gray subdistribution hazard model to identify factors associated with becoming homebound over follow-up (median follow-up 4 years), accounting for competing risks of death and moving to a nursing home. RESULTS: 20% of individuals with newly identified dementia were homebound and this group was more functionally impaired, medically complex, and socioeconomically disadvantaged as compared to the non-homebound. Over time, depression [subhazard ratio (SHR) 2.19, 95% CI 1.36, 3.54], living in an assisted living facility (SHR 2.60, 95% CI 1.35, 4.97), and Hispanic ethnicity (SHR 1.91, 95% CI 1.05, 3.47) were associated with becoming homebound. CONCLUSIONS AND IMPLICATIONS: Most adults are not homebound at the time of dementia diagnosis. Identifying and addressing modifiable factors like depression may slow progression to homebound status and enable persons living with dementia to access needed care in the community. In order to accommodate diverse individual and family preferences for long-term care, robust systems of home-based clinical and long-term care are necessary for those who do become homebound.

Development and Validation of a Functionally Relevant Comorbid Health Index in Adults Admitted to Inpatient Rehabilitation for Traumatic Brain Injury.

Several studies have characterized comorbidities among individuals with traumatic brain injury (TBI); however, there are few validated TBI comorbidity indices. Widely used indices (e.g., Elixhauser Comorbidity Index [ECI]) were developed in other patient populations and anchor to mortality or healthcare utilization, not functioning, and notably exclude conditions known to co-occur with TBI. The objectives of this study were to develop and validate a functionally relevant TBI comorbidity index (Fx-TBI-CI) and to compare prognostication of the Fx-TBI-CI with the ECI. We used data from the eRehabData database to divide the sample randomly into a training sample (N = 21,292) and an internal validation sample (N = 9166). We used data from the TBI Model Systems National Database as an external validation sample (N = 1925). We used least absolute shrinkage and selection operator (LASSO) regression to narrow the list of functionally relevant conditions from 39 to 12. In internal validation, the Fx-TBI-CI explained 14.1% incremental variance over an age and sex model predicting the Functional Independence Measure (FIM) Motor subscale at inpatient rehabilitation discharge, compared with 2.4% explained by the ECI. In external validation, the Fx-TBI-CI explained 4.9% incremental variance over age and sex and 3.8% over age, sex, and Glasgow Coma Scale score,compared with 2.1% and 1.6% incremental variance, respectively, explained by the ECI. An unweighted Sum Condition Score including the same conditions as the Fx-TBI-CI conferred similar prognostication. Although the Fx-TBI-CI had only modest incremental variance over demographics and injury severity in predicting functioning in external validation, the Fx-TBI-CI outperformed the ECI in predicting post-TBI function.