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Background: We aimed to determine if burden of cerebral small vessel disease (CSVD) modifies the relationship of plasma amyloid‐beta (Abeta) 42/40 ratio and/or plasma p‐tau 181 with amyloid PET. Method: We studied N = 100 participants from the Alzheimer's Disease Neuroimaging Initiative with 1) Abeta‐42/40 biomarker levels using Quanterix SIMOA (Quanterix), Washington University Mass Spectroscopy (WashU), Simoa HD‐X 4Plex, Roche Elecsys, Shimadzu Mass Spectroscopy, and Gothenburg Mass Spectroscopy, 2) p‐tau181 plasma biomarker levels using Lumipluse G, Roche Elecsys, Simoa p‐tau181V2 Advantage (Simoa Advntage), Simoa p‐tau181, 3) MRI brain, and 4) amyloid‐PET. We stratified by CSVD bruden tertile (calculated from total white matter FLAIR hyperintensity volume). Amyloid positivity was defined as standardized uptake value ratio ≥ 1.11 for florbetapir PET scans. We used box plots to visualize plasma Abeta‐42/40 and p‐tau181 levels stratified by Amyloid‐PET positivity and CSVD tertile. Using logistic regression models, we tested for an interaction between CSVD and plasma Abeta‐42/40 ratio or p‐tau181 on amyloid PET positivity in unadjusted models and models adjusted for age, Clinical Dementia Rating, and presence of ≥1 apolipoprotein E4 allele (ApoE4+). Result: The cohort had an average age of 77 years, was 56% female, 50% cognitively normal, and 42% ApoE4+ (Table1). We found significant interactions between CSVD and plasma Abeta‐42/40 ratio on amyloid‐PET positivity for Quanterix (raw/adjusted: p = 0.035/p = 0.049), Simoa HD‐Plex (p = 0.047/p = 0.047), and Gothenburg assays (p = 0.026/p = 0.030), with worst discrimination between amyloid‐PET positivity among participants with highest CSVD burden (Figure1A). The Quanterix and Gothenburg assay demonstrated near total overlap between amyloid‐PET positive vs. negative groups at the highest tertile of CSVD. No significant interaction was found between CSVD and any plasma p‐tau181 assay on amyloid‐PET positivity (all p>0.2, Figure1B). Conclusion: Our findings suggest that individuals with a high burden of CSVD are at risk for incorrect Abeta‐42/40 ratio on certain assay platforms but not others. No interaction was found between CSVD and any plasma p‐tau181 assay on amyloid‐PET positivity. Further research in diverse cohorts with a high burden of CSVD is warranted to inform appropriate use of these blood assays and unravel mechanisms of this unexpected finding. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) increases risk for cognitive decline and Alzheimer's disease/related dementias (ADRD), and Veterans may be at increased risk of both TBI and cognitive decline due to combat/training related exposures and other risk factors. However, it is unknown whether older Veterans are more likely to experience a poor cognitive outcome after acute TBI compared to civilians. Method: We examined 112 male Veterans and 320 male civilians (55+) who experienced an acute TBI and enrolled in Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK‐TBI). Data were collected at baseline (i.e., emergency room visit) on demographic and injury characteristics. Cognitive and TBI recovery data (i.e., Rivermead Postconcussive Questionnaire, Brief Symptom Inventory, Satisfaction with Life Scale, and Glascow Outcome Scale‐Extended) were collected at 2 weeks, 6 months, and 12 months. We calculated descriptive statistics and compared across Veterans and civilians. 12‐month cognitive outcome was defined as performance <9th percentile on 2+ cognitive tests, and/or decline from 2‐week or 6‐month score >90% reliable change index on two+ tests. We used propensity weighting to address missing cognitive outcome data and conducted a logistic regression analysis to examine association of Veteran status with classification of cognitive outcome. Result: Veterans were older and less likely to be Hispanic compared to civilians but did not differ on race, education, history of head injury, or injury severity. At 12 months post‐TBI, Veterans endorsed worse mood and satisfaction with life (p's = 0.05), but these results were attenuated by adjustment for prior TBI and injury severity. In adjusted models Veterans did not differ from civilians on a measure of overall TBI outcome (p = 0.45) or postconcussive symptoms (p = 0.32). Moreover, there was no association between Veteran status and cognitive outcome (Wald chi square = 2.66, p = 0.45). Conclusion: Risk of poor cognitive outcome following TBI does not differ between older male Veterans and civilians, and mood and life satisfaction outcomes were worse for Veterans but impacted by injury severity and prior head injury. These findings have implications for understanding risk for cognitive decline and ADRD among older men who experience an acute TBI as well as tailoring care, including provision of psychosocial support, for these patients. [ABSTRACT FROM AUTHOR]

Background: Pre‐injury brain reserve may contribute to the substantial heterogeneity observed in cognitive outcome after mild traumatic brain injury (mTBI), including risk for cognitive decline and dementia. However, no tools exist to quantify pre‐injury brain reserve in an acute trauma setting, thereby limiting research. We aimed to develop and validate a visually‐rated Brain Reserve Score (BRS) to quantify baseline brain reserve on head CTs obtained to rule out intracranial trauma in adults presenting acutely with mTBI. Methods: Data are from the Transforming Research And Clinical Knowledge in Traumatic Brain Injury (TRACK‐TBI) and TRACK‐Geriatric TBI (TRACK‐GERI) studies, multi‐center prospective cohort studies of adults age 18+ presenting within 24 hours (TRACK‐TBI) or adults age 65y+ presenting within 72 hours (TRACK‐GERI) of TBI who received head CT and multi‐domain clinical follow‐up for one year. BRS was developed by adapting existing MRI visual rating scales of global cortical atrophy, hippocampal atrophy, and white matter change for use in trauma head CTs and then by refining the scoring guide to optimize rater reliability. To establish concurrent validity, we assessed correlation of BRS with pre‐injury cognitive status (measured in TRACK‐GERI using informant‐reported Clinical Dementia Rating interviews). To establish predictive validity, we assessed association of BRS with good versus poor 12‐month cognitive outcome in TRACK‐TBI using logistic regression adjusted for baseline demographics, medical/psychiatric comorbidities, injury characteristics, and trauma severity on CT. Results: Final BRS score ranged from 0‐10 (10 is highest burden of neuropathology); inter‐ and intra‐rater reliability were moderate‐substantial (weighted kappa 0.54‐0.80). Among N = 100 TRACK‐GERI participants BRS was significantly correlated with pre‐injury CDR (r = 0.37, p<0.01). Among N = 656 TRACK‐TBI participants, BRS of 6+ was independently associated with poor 12‐month cognitive outcome (fully adjusted odds ratio 4.35, 95% confidence interval 1.35‐13.99, p = 0.01). Conclusion: BRS is a reliable visually rated score of brain reserve on acute trauma head CT that correlates with pre‐injury cognitive status and independently predicts poor cognitive outcome one year post‐mTBI. BRS may be a useful tool to facilitate inclusion of older adults in acute TBI research thereby advancing clinical care and research on mechanisms of accelerated post‐TBI cognitive decline and dementia. [ABSTRACT FROM AUTHOR]

Background: Post‐mortem human brain tissue is the gold‐standard for neurodegenerative disease diagnosis and is invaluable for elucidating cellular and molecular mechanisms. Therefore, neurodegenerative disease brain banks are a critical component of research to advance diagnosis and develop effective disease modifying therapies. The Israel National Brain Repository (INBR) was established in 2018 at the Sheba Medical Center via a collaboration with the Mount Sinai Neuropathology Brain Bank in New York. Israel is a unique country with a diverse population including substantial populations of individuals of European descent, Middle‐Eastern North African (MENA) descent, and combinations of both. Method: INBR predominantly recruits from two prospective longitudinal cohort studies whose participants are at high dementia risk: older adults with type 2 diabetes (the Israel Diabetes and Cognitive Decline study) and middle‐aged offspring of people with Alzheimer's Disease (The Israel Registry for Alzheimer's Prevention). Participants in both cohorts are phenotyped for cognition, lifestyle, brain imaging, blood biomarkers, and genetics. Biospecimen collection and processing protocols are aligned with other Neurobiobanks in the USA (see flowchart). Additionally, all participants in both cohorts are members of the second largest healthcare provider in Israel, the Maccabi Healthcare Services, permitting linkage to longitudinal medical records dating from 1998. Result: N = 450 participants have signed intent to autopsy. Among the N = 285 with race/ethnicity data available, 30% are MENA. 14 brain and 6 spinal cord donations have been completed. At time of death, donors had an average age of 81.1 years, 10 had normal cognition, 3 had dementia, and one had amyotrophic lateral sclerosis. Conclusion: The potential strengths of the INBR is in the population characteristics of Israel, the ethnic diversity and admixture, the linkage to 25‐years of medical records data, and the small size of the country allowing donations to be received from anywhere in the country. The main challenge we face is cultural barriers to brain donation that exist among some segments of Israeli society. The ultimate goal is to capitalize on the strengths and uniqueness of INBR to develop novel therapies for dementia. [ABSTRACT FROM AUTHOR]

Background: Prior studies have reported a link between traumatic brain injury (TBI) and risk of adverse neuropsychiatric outcomes including dementia. However it is unclear how prevalent these conditions are prior to TBI and if they are predisposing factors in addition to sequalae. Methods: We studied older (age >55 years) US veterans who were followed for care at Veterans Affairs Medical Centers across the nation from 2000 to 2019. We first identified all veterans with an incident TBI diagnoses defined as no prior TBI diagnosis, having been seen in an emergency department (ED), having a brain imaging scan (primarily CT) within one day of ED visit and with a subsequent new TBI diagnosis in the electronic medical record (EMR). We then determined 2‐year age‐adjusted prevalence rates (rate per 1000 person‐years and 95% confidence interval or CI) for dementia and mild cognitive impairment (MCI) prior to and post incident TBI. We also compared prior TBI prevalence to prevalence among 1:3 matched (on age and index date) veterans without TBI. Results: There were 13,709 primarily male veterans with incident TBI with mean age of 77.7 sd 9.1 years, 81% were non‐Hispanic White. Compared to the 41,127 veterans without TBI (mean age = 77.9, sd 9.1), veterans prior to having an incident TBI had almost a six‐fold greater pre‐TBI age‐adjusted prevalence of dementia (104.9; 95% CI 100.8‐109.0 vs 18.6; 95% CI 17.6‐19.7, p<0.001) and MCI (48.0; 95% CI 45.2‐50.7 vs 8.1; 95% CI 7.4‐8.8, p<0.001). After the incident TBI diagnosis, the age‐adjusted prevalence rates were even higher: dementia (193.5; 95% CI 187.7‐199.2) and MCI (59.3; 95% CI 56.0‐62.6). Conclusions: Among older US veterans, there is a bidirectional association with dementia/ MCI and TBI with very high prevalence prior to TBI (compared to those without TBI) and even greater prevalence after TBI. These findings highlight the importance of prevention strategies for both pre‐ and post‐TBI cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) is an important risk factor for dementia and is especially common among Veterans. It is unknown whether TBI exposure moderates the effect of other common medical/psychiatric comorbidities that are also important risk factors for dementia in Veterans. If treatable or preventable comorbidities are either especially common or risky in TBI‐exposed Veterans, then this may have important public health implications for dementia prevention. Method: We conducted a retrospective cohort study using the Nationwide Veterans Health Administrative inpatient and outpatient data (2001‐2019). We identified all Veterans age 55 years with prior TBI and without baseline dementia (N = 95,139) and age/sex/race‐matched 1:2 with Veterans without prior TBI or baseline dementia (N = 190,278). We compared prevalence of seven common medical/psychiatric comorbidities (hypertension, coronary artery disease (CAD), diabetes, cerebrovascular disease (CVD), epilepsy, depression, and post‐traumatic stress disorder (PTSD)) and associated risk of incident dementia among Veterans with versus without prior TBI. We tested for interaction of each comorbidity with TBI on risk of dementia. We calculated risk of dementia associated with each comorbidity using multivariable hazard ratios (adjusting for demographics and all other comorbidities) and Fine‐Grey competing risk of death. We estimated population attributable risk (PAR) of dementia due to each comorbidity. Result: All comorbidities were more prevalent among Veterans with TBI compared to those without TBI: hypertension +12.5%, CAD +13.6%, diabetes +7.9%, CVD +10.8%, epilepsy +5.7%, depression +21.5%, PTSD +14.9%). All comorbidities were associated with elevated risk for dementia among Veterans with and without TBI. However, there was a significant interaction with TBI such that point estimates were slightly lower among Veterans with TBI (adjusted HRs 1.02‐1.31) versus Veterans without TBI (adjusted HRs 1.03‐1.82). However, the overall PARs for dementia were higher in Veterans with versus without TBI for several comorbidities (depression 8.7% vs. 7.4%; hypertension 3.8% vs. 1.6%; CVD 3.7% vs. 2.0%; epilepsy 2.1% vs. 1.1%), due to their higher prevalence in Veterans with TBI. Conclusion: While treating or preventing medical/psychiatric comorbidities among all Veterans remains a high public health priority, targeting depression, hypertension, CVD, and epilepsy may be especially important for dementia risk reduction among Veterans with prior TBI. [ABSTRACT FROM AUTHOR]

Background: Older adults have the highest and fastest rising incidence of traumatic brain injury (TBI) compared to all other age groups. Few studies have examined the prevalence of pre‐injury dementia among older adults presenting with TBI. None have examined injury characteristics and outcomes specifically among those with pre‐injury dementia. Our aim was to describe prevalence of pre‐injury dementia among older adults hospitalized with TBI in Israel and to examine features of those with versus without pre‐injury dementia. Method: We identified all TBIs recorded in the Israel National Trauma Registry from 2015‐2020 among adults age 65 years and older who were admitted to one of 15 trauma centers. We determined the prevalence of a diagnosis of pre‐injury dementia recorded in the registry and compared baseline demographics, injury features, and hospital outcomes among those with versus without pre‐injury dementia. Result: Among N = 7,788 identified cases of geriatric TBI, 9.8% (N = 762) had pre‐injury dementia. Compared to those without pre‐injury dementia, those with pre‐injury dementia were significantly older (90% vs. 70% age >75 years), more female (58% vs. 47%), had higher rates of injury location of residential institution (24% vs. 7%) or home (63% vs. 58%), and higher rates of injury mechanism of fall (95% vs. 84%; all p<0.01). No differences were identified in Injury Severity Score (ISS) across groups (p = 0.19). However, those with pre‐injury dementia had lower rates of severe TBI (4% vs. 7% Glasgow Coma Scale <9), lower rates of polytrauma (10% vs. 13%), and lower rates of surgical intervention (9% vs. 13%), yet had higher rates of in‐hospital mortality (10% vs. 8%) and new institutionalization post‐discharge (11% vs. 4%; all p<0.02). Conclusion: Approximately 10% of older adults admitted to hospitals in Israel with TBI have dementia compared to only 7% of older adults in the general population (per 2019 national health service data), suggesting that dementia is likely a risk factor for TBI in the elderly. Additionally, admission for a TBI resulted in 10% in‐hospital mortality and 11% new institutionalization post‐discharge among those with pre‐injury dementia. Geriatric TBI prevention, primarily through fall‐prevention, is of high public health importance in Israel. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) is an established risk factor for dementia. Risk estimates have varied substantially across studies with recent studies reporting higher risk in veterans, men, or at the extremes of age. We performed the largest and most comprehensive systematic review of risk of post‐TBI dementia with the aim of specifically investigating contributors to heterogeneity including age, sex, and veteran status. Method: We performed a systematic review and meta‐analysis of all‐cause dementia after all‐severity TBI (search window 1/1990‐1/2019). We identified observational studies reporting age‐adjusted risk for all‐cause dementia after TBI among individuals with average age ≥40 years. Data were pooled using random‐effects models. Between study variability was assessed using the I2 index. We further evaluated sources of heterogeneity according to covariates including mean age, sex distribution (majority male vs. majority female), veteran status, design (case‐control vs. cohort), outcome/exposure ascertainment (ICD‐9 vs. other) and publication year using sub‐groups and meta‐regression analysis. Funnel plot inspection and Egger and Begg statistics were used to evaluate publication bias. Result: Data from 41 studies representing N=7,736,173 individuals were included in the analysis. Overall pooled risk ratio (RR) for dementia after TBI was 1.71 (95% confidence interval [CI] 1.47,1.98) with no evidence of publication bias. There was substantial heterogeneity (I2= 98.6%; Q test p<0.001). Removal of each study in turn did not reduce heterogeneity. No significant differences were observed in risk estimates for dementia after TBI according to veteran status, study design, outcome/exposure ascertainment, or publication year (all p's >0.09). However, risk estimates were significantly higher in studies with lower mean age (mean age <50y RR 2.52 [1.80,3.53]; 50‐70y RR 1.73 [1.34,2.24]; >70y RR 1.41 [1.17,1.71]; p=0.01; see Figure) and in studies that were majority male (majority male RR 2.16 [1.74‐2.69]; majority female RR 1.44 [1.22,1.70]; p=0.01). Mean age and sex distribution accounted for 27.5% and 27.9%, respectively, of the observed heterogeneity. Conclusion: TBI is associated with a 71% increased risk for dementia. While risk was not modified by veteran status, risk was significantly higher in studies with younger mean age and majority male populations. These findings may inform targeted TBI prevention efforts. [ABSTRACT FROM AUTHOR]