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Objective: The authors examined the interaction between apolipoprotein E (APOE) ε4 and brain-derived neurotrophic factor (BDNF) Val66Met alleles on neuropsychological functioning among veterans with histories of mild traumatic brain injury (mTBI)., Methods: Participants were 78 veterans with mTBI (85% males; mean±SD age=32.95±7.00 years; mean time since injury=67.97±34.98 months) who completed a structured clinical interview and underwent a comprehensive neuropsychological assessment. Participants also provided a buccal swab for determination of their APOE and BDNF genotypes. Three cognitive composite scores were calculated from the neuropsychological assessment, reflecting visuospatial speed (seven variables), executive functioning (10 variables), and memory (eight variables). Two-way analyses of covariance (ANCOVAs) adjusted for age, sex, and race-ethnicity were used to assess the effects of APOE (ε4+ vs. ε4-) and BDNF (Met+ vs. Met-) on cognitive functioning., Results: ANCOVAs revealed no significant main effects of APOE or BDNF genotypes on cognitive functioning; however, there was a significant APOE-by-BDNF genotype interaction for all three cognitive composite measures (visuospatial speed: η p 2 =0.055; executive functioning: η p 2 =0.064; and memory: η p 2 =0.068). Specifically, the ε4+/Met+ (N=8) subgroup demonstrated the poorest cognitive functioning relative to all other allele subgroups (ε4+/Met-: N=12, ε4-/Met+: N=23, and ε4-/Met-: N=35)., Conclusions: This exploratory study is the first to show that, compared with other allele subgroups assessed, veterans with both ε4 and Met alleles demonstrated the poorest cognitive functioning across several cognitive domains known to be negatively affected in the context of mTBI. Further research with larger sample sizes is needed to replicate these findings., Competing Interests: This article does not necessarily represent the views of the VA or the U.S. government.

Objective: Neuropsychological criteria for mild cognitive impairment (MCI) more accurately predict progression to Alzheimer's disease (AD) and are more strongly associated with AD biomarkers and neuroimaging profiles than ADNI criteria. However, research to date has been conducted in relatively healthy samples with few comorbidities. Given that history of traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) are risk factors for AD and common in Veterans, we compared neuropsychological, typical (Petersen/Winblad), and ADNI criteria for MCI in Vietnam-era Veterans with histories of TBI or PTSD., Method: 267 Veterans (mean age = 69.8) from the DOD-ADNI study were evaluated for MCI using neuropsychological, typical, and ADNI criteria. Linear regressions adjusting for age and education assessed associations between MCI status and AD biomarker levels (cerebrospinal fluid [CSF] p -tau 181 , t -tau, and A β 42 ) by diagnostic criteria. Logistic regressions adjusting for age and education assessed the effects of TBI severity and PTSD symptom severity simultaneously on MCI classification by each criteria., Results: Agreement between criteria was poor. Neuropsychological criteria identified more Veterans with MCI than typical or ADNI criteria, and were associated with higher CSF p -tau 181 and t -tau. Typical and ADNI criteria were not associated with CSF biomarkers. PTSD symptom severity predicted MCI diagnosis by neuropsychological and ADNI criteria. History of moderate/severe TBI predicted MCI by typical and ADNI criteria., Conclusions: MCI diagnosis using sensitive neuropsychological criteria is more strongly associated with AD biomarkers than conventional diagnostic methods. MCI diagnostics in Veterans would benefit from incorporation of comprehensive neuropsychological methods and consideration of the impact of PTSD.

Objective: Identifying factors that moderate cognitive outcomes following mild traumatic brain injury (mTBI) is crucial. Prospective memory (PM) is a cognitive domain of interest in mTBI recovery as it may be especially sensitive to TBI-related changes. Since studies show that genetic status - particularly possession of the apolipoprotein E (APOE) ε4 allele - can modify PM performance, we investigated associations between mTBI status and APOE-ε4 genotype on PM performance in a well-characterized sample of Veterans with neurotrauma histories., Methods: 59 Veterans (mTBI = 33, Military Controls [MCs] = 26; age range: 24-50; average years post-injury = 10.41) underwent a structured clinical interview, neuropsychological assessment, and genotyping. The Memory for Intentions Test (MIST) measured PM across multiple subscales. ANCOVAs, adjusting for age and posttraumatic stress symptoms, tested the effects of mTBI status (mTBI vs. MC) and ε4 status (ε4+ vs. ε4-) on MIST scores., Results: Veterans with mTBI history performed more poorly compared to MCs on the MIST 15-min delay ( p =.002, η p 2 =.160), Time Cue ( p = .003, η p 2 =.157), and PM Total ( p = .016, η p 2 =.102). Those with at least one copy of the ε4 allele performed more poorly compared to ε4- Veterans on the MIST 15-min delay ( p = .011, η p 2 =.113) and PM Total ( p = .048, η p 2 = .071). No significant interactions were observed between mTBI and APOE-ε4 status on MIST outcomes ( p s>.25). Within the mTBI group, APOE-ε4+ Veterans performed worse than APOE-ε4- Veterans on the MIST 15-min delay subscale ( p = .031, η p 2 = .150)., Conclusions: mTBI history and APOE-ε4 genotype status were independently associated with worse PM performance compared to those without head injury histories or possession of the APOE-e4 genotype. Performance on the MIST 15-min delay was worse in Veterans with both risk factors (mTBI history and APOE-ε4 positivity). Findings suggest that genetic status may modify outcomes even in relatively young Veterans with mTBI histories. Future research examining longitudinal associations and links to neuroimaging and biomarker data are needed.

Introduction: Data-driven neuropsychological methods can identify mild cognitive impairment (MCI) subtypes with stronger associations to dementia risk factors than conventional diagnostic methods., Methods: Cluster analysis used neuropsychological data from participants without dementia (mean age = 71.6 years) in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (n = 26,255) and the "normal cognition" subsample (n = 16,005). Survival analyses examined MCI or dementia progression., Results: Five clusters were identified: "Optimal" cognitively normal (oCN; 13.2%), "Typical" CN (tCN; 28.0%), Amnestic MCI (aMCI; 25.3%), Mixed MCI-Mild (mMCI-Mild; 20.4%), and Mixed MCI-Severe (mMCI-Severe; 13.0%). Progression to dementia differed across clusters (oCN < tCN < aMCI < mMCI-Mild < mMCI-Severe). Cluster analysis identified more MCI cases than consensus diagnosis. In the "normal cognition" subsample, five clusters emerged: High-All Domains (High-All; 16.7%), Low-Attention/Working Memory (Low-WM; 22.1%), Low-Memory (36.3%), Amnestic MCI (16.7%), and Non-amnestic MCI (naMCI; 8.3%), with differing progression rates (High-All < Low-WM = Low-Memory < aMCI < naMCI)., Discussion: Our data-driven methods outperformed consensus diagnosis by providing more precise information about progression risk and revealing heterogeneity in cognition and progression risk within the NACC "normal cognition" group., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

This study assessed whether the effect of vascular risk on cerebral blood flow (CBF) varies by gene dose of apolipoprotein (APOE) ε4 alleles. 144 older adults without dementia from the Alzheimer's Disease Neuroimaging Initiative underwent arterial spin labeling and T1-weighted MRI, APOE genotyping, fluorodeoxyglucose positron emission tomography (FDG-PET), lumbar puncture, and blood pressure (BP) assessment. Vascular risk was assessed using pulse pressure (systolic BP - diastolic BP). CBF was examined in six AD-vulnerable regions: entorhinal cortex, hippocampus, inferior temporal cortex, inferior parietal cortex, rostral middle frontal gyrus, and medial orbitofrontal cortex. Linear regressions tested the interaction between APOE ε4 dose and pulse pressure on CBF in each region, adjusting for age, sex, cognitive classification, antihypertensive medication use, FDG-PET, reference CBF region, and AD biomarker positivity. There was a significant interaction between pulse pressure and APOE ɛ4 dose on CBF in the entorhinal cortex, hippocampus, and inferior parietal cortex, such that higher pulse pressure was associated with lower CBF only among ε4 homozygous participants. These findings demonstrate that the association between pulse pressure and regional CBF differs by APOE ε4 dose, suggesting that targeting modifiable vascular risk factors may be particularly important for those genetically at risk for AD., Competing Interests: Dr. Bondi receives royalties from Oxford University Press. No other authors have competing interests to declare.

Large-scale genetic studies of traumatic brain injury (TBI) are lacking; thus, our understanding of the influence of genetic factors on TBI risk and recovery is incomplete. This study aimed to conduct a genome-wide association study (GWAS) of TBI in VA Million Veteran Program (MVP) enrollees. Participants included a multi-ancestry cohort (European, African, and Hispanic ancestries; N = 304,485; 111,494 TBI cases, 192,991 controls). TBI was assessed using MVP survey data and International Classification of Diseases (ICD) codes from the Veterans Health Administration's electronic health record. GWAS was performed using logistic regression in PLINK, and meta-analyzed in METAL. FUMA was used for post-GWAS analysis. Genomic structural equation modeling (gSEM) was conducted to investigate underlying genetic associations with TBI, and bivariate MiXeR was used to estimate phenotype specific and shared polygenicity. SNP-based heritability was 0.060 (SE = 0.004, p = 7.83×10 -66 ). GWAS analysis identified 15 genome-wide significant (GWS) loci at p < 5×10 -8 . Gene-based analyses revealed 14 gene-wide significant genes; top genes included NCAM1, APOE, FTO, and FOXP2. Gene tissue expression analysis identified the brain as significantly enriched, particularly in the frontal cortex, anterior cingulate cortex, and nucleus accumbens. Genetic correlations with TBI were significant for risk-taking behaviors and psychiatric disorders, but generally not significant for the neurocognitive variables investigated. gSEM analysis revealed stronger associations with risk-taking traits than with psychiatric traits. Finally, the genetic architecture of TBI was similar to polygenic psychiatric disorders. Neurodegenerative disorders including Alzheimer's and Parkinson's disease showed much less polygenicity, however, the proportion of shared variance with TBI was high. This first well-powered GWAS of TBI identified 15 loci including genes relevant to TBI biology, and showed that TBI is a heritable trait with comparable genetic architecture and high genetic correlation with psychiatric traits. Our findings set the stage for future TBI GWASs that focus on injury severity and diversity and chronicity of symptom sequelae., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Decreasing white matter integrity in limbic pathways including the fornix and cingulum have been reported in Alzheimer's disease (AD), although underlying mechanisms and potential sex differences remain understudied. We therefore sought to explore sex as a moderator of the effect of age on myelin water fraction (MWF), a measure of myelin content, in older adults without dementia ( N  = 52)., Methods: Participants underwent neuropsychological evaluation and 3 T MRI at two research sites. Multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) quantified MWF in 3 a priori regions including the fornix, hippocampal cingulum (CgH), and cingulate cingulum (CgC). The California Verbal Learning Test-Second Edition assessed learning and delayed recall. Multiple linear regressions assessed for (1) interactions between age and sex on regional MWF and (2) associations of regional MWF and memory., Results: (1) There was a significant age by sex interaction on MWF of the fornix ( p  = 0.002) and CgC ( p  = 0.005), but not the CgH ( p  = 0.192); as age increased, MWF decreased in women but not men. (2) Fornix MWF was associated with both learning and recall ( p s < 0.01), but MWF of the two cingulum regions were not ( p  > 0.05). Results were unchanged when adjusting for hippocampal volume., Conclusion: The current work adds to the literature by illuminating sex differences in age-related myelin decline using a measure sensitive to myelin and may help facilitate detection of AD risk for women., Competing Interests: MB receives royalties from Oxford University Press. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Brenner, Bangen, Clark, Delano-Wood, Evangelista, Edwards, Sorg, Jak, Bondi, Deoni and Lamar.)

Objective: The purpose of this study was to explore racial/ethnic differences in neurobehavioral symptom reporting and symptom validity testing among military veterans with a history of traumatic brain injury (TBI)., Method: Participants of this observational cross-sectional study (N = 9,646) were post-deployed Iraq-/Afghanistan-era veterans enrolled in the VA's Million Veteran Program with a clinician-confirmed history of TBI on the Comprehensive TBI Evaluation (CTBIE). Racial/ethnic groups included White, Black, Hispanic, Asian, Multiracial, Another Race, American Indian or Alaska Native, and Native Hawaiian or Other Pacific Islander. Dependent variables included neurobehavioral symptom domains and symptom validity assessed via the Neurobehavioral Symptom Inventory (NSI) and Validity-10, respectively., Results: Chi-square analyses showed significant racial/ethnic group differences for vestibular, somatic/sensory, and affective symptoms as well as for all Validity-10 cutoff scores examined (≥33, ≥27, ≥26, >22, ≥22, ≥13, and ≥7). Follow-up analyses compared all racial/ethnic groups to one another, adjusting for sociodemographic- and injury-related characteristics. These analyses revealed that the affective symptom domain and the Validity-10 cutoff of ≥13 revealed the greatest number of racial/ethnic differences., Conclusions: Results showed significant racial/ethnic group differences on neurobehavioral symptom domains and symptom validity testing among veterans who completed the CTBIE. An enhanced understanding of how symptoms vary by race/ethnicity is vital so that clinical care can be appropriately tailored to the unique needs of all veterans. Results highlight the importance of establishing measurement invariance of the NSI across race/ethnicity and underscore the need for ongoing research to determine the most appropriate Validity-10 cutoff score(s) to use across racially/ethnically diverse veterans., (Published by Oxford University Press 2023.)

American football players and other individuals exposed to repetitive head impacts can exhibit a constellation of later-life cognitive and neuropsychiatric symptoms. While tau-based diseases such as chronic traumatic encephalopathy can underpin certain symptoms, contributions from non-tau pathologies from repetitive head impacts are increasingly recognized. We examined cross-sectional associations between myelin integrity using immunoassays for myelin-associated glycoprotein and proteolipid protein 1 with risk factors and clinical outcomes in brain donors exposed to repetitive head impacts from American football. Immunoassays for myelin-associated glycoprotein and proteolipid protein 1 were conducted on dorsolateral frontal white matter tissue samples of 205 male brain donors. Proxies of exposure to repetitive head impacts included years of exposure and age of first exposure to American football play. Informants completed the Functional Activities Questionnaire, Behavior Rating Inventory of Executive Function-Adult Version (Behavioral Regulation Index), and Barratt Impulsiveness Scale-11. Associations between myelin-associated glycoprotein and proteolipid protein 1 with exposure proxies and clinical scales were tested. Of the 205 male brain donors who played amateur and professional football, the mean age was 67.17 (SD = 16.78), and 75.9% ( n = 126) were reported by informants to be functionally impaired prior to death. Myelin-associated glycoprotein and proteolipid protein 1 correlated with the ischaemic injury scale score, a global indicator of cerebrovascular disease ( r = -0.23 and -0.20, respectively, P s < 0.01). Chronic traumatic encephalopathy was the most common neurodegenerative disease ( n = 151, 73.7%). Myelin-associated glycoprotein and proteolipid protein 1 were not associated with chronic traumatic encephalopathy status, but lower proteolipid protein 1 was associated with more severe chronic traumatic encephalopathy ( P = 0.03). Myelin-associated glycoprotein and proteolipid protein 1 were not associated with other neurodegenerative disease pathologies. More years of football play was associated with lower proteolipid protein 1 [beta = -2.45, 95% confidence interval (CI) [-4.52, -0.38]] and compared with those who played <11 years of football ( n = 78), those who played 11 or more years ( n = 128) had lower myelin-associated glycoprotein (mean difference = 46.00, 95% CI [5.32, 86.69]) and proteolipid protein 1 (mean difference = 24.72, 95% CI [2.40, 47.05]). Younger age of first exposure corresponded to lower proteolipid protein 1 (beta = 4.35, 95% CI [0.25, 8.45]). Among brain donors who were aged 50 or older ( n = 144), lower proteolipid protein 1 (beta = -0.02, 95% CI [-0.047, -0.001]) and myelin-associated glycoprotein (beta = -0.01, 95% CI [-0.03, -0.002]) were associated with higher Functional Activities Questionnaire scores. Lower myelin-associated glycoprotein correlated with higher Barratt Impulsiveness Scale-11 scores (beta = -0.02, 95% CI [-0.04, -0.0003]). Results suggest that decreased myelin may represent a late effect of repetitive head impacts that contributes to the manifestation of cognitive symptoms and impulsivity. Clinical-pathological correlation studies with prospective objective clinical assessments are needed to confirm our findings., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: The uncompetitive NMDA antagonist, memantine (MEM), enhances prepulse inhibition of startle (PPI) across species. MEM is used to treat Alzheimer's disease (AD); conceivably, its acute impact on PPI might be used to predict a patient's sensitivity to MEM's therapeutic effects., Objective: To begin to test this possibility, we studied MEM effects on PPI and related measures in AD patients., Methods: 18 carefully screened individuals with AD (mean age = 72.8 y; M:F=9 : 9) completed double-blind order-balanced testing with MEM (placebo versus 20 mg), assessing acoustic startle magnitude, habituation, PPI, and latency., Results: Fifteen out of 18 participants exhibited reliable startle responses. MEM did not significantly impact startle magnitude or habituation. Compared to placebo responses, PPI was significantly increased after MEM (p < 0.04; d = 0.40); this comparison reached a large effect size for the 60 ms interval (d = 0.62), where maximal MEM effects on PPI were previously detected. Prepulses reduced peak startle latency ("latency facilitation") and this effect was amplified after MEM (p = 0.03; d = 0.41; for 60 ms intervals, d = 0.69). No effects of MEM were detected on cognition, nor were MEM effects on startle associated with cognitive or clinical measures., Conclusion: MEM enhances prepulse effects on startle magnitude and latency in AD; these changes in PPI and latency facilitation with MEM suggest that these measures can be used to detect an AD patient's neural sensitivity to acute MEM challenge. Studies in progress will determine whether such a "biomarker" measured at the outset on treatment can predict sensitivity to MEM's therapeutic effects.

Objective: Given that several non-cognitive factors can contribute to difficulties with everyday functioning, examining the extent to which cognition is associated with brain-related changes in everyday functioning is critical to accurate characterization of cognitive disorders. In this study, we examined neuropsychological correlates of the shared variance between everyday functioning and pathological indicators of cognitive aging using MRI brain volumetrics., Participants and Methods: Participants were 600 adults aged 55 and older without dementia [432 cognitively normal; 168 mild cognitive impairment (MCI)] from the National Alzheimer's Coordinating Center cohort who underwent neuropsychological testing, informant-rated everyday functioning, and brain MRI scanning at baseline. The shared variance between everyday functioning and brain volumetrics (i.e., hippocampal volume, white matter hyperintensity volume) was extracted using the predicted value from multiple regression. The shared variance was used as an indicator of pathological everyday functional impairment. The residual variance from the regression analysis was used to examine functional reserve., Results: Larger white matter hyperintensity volumes ( p  = 0.002) and smaller hippocampal volumes ( p  < 0.001) were significantly correlated with worse informant-rated everyday functioning. Among individuals with MCI, worse performances on delayed recall ( p  = 0.013) and category fluency ( p  = 0.012) were significantly correlated with pathological functional impairment in multiple regression analysis. In the cognitively normal group, only worse auditory working memory (i.e., digit span backward; p  = 0.025) significantly correlated with pathological functioning. Functional reserve was inversely related to anxiety ( p  < 0.001) in the MCI group and was associated with depressive symptoms ( p  = 0.003) and apathy ( p  < 0.001) in the cognitively normal group., Conclusion: Subtle brain-related everyday functioning difficulties are evident in MCI and track with expected preclinical Alzheimer's disease cognitive phenotypes in this largely amnestic sample. Our findings indicate that functional changes occur early in the disease process and that interventions to target neuropsychiatric symptoms may help to bolster functional reserve in those at risk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fellows, Bangen, Graves, Delano-Wood and Bondi.)

Using a diverse sample of military Veterans enrolled in the VA's Million Veteran Program (N=14,378; n=1,361 females [9.5%]; all previously deployed), we examined sex differences on the Comprehensive Traumatic Brain Injury Evaluation (CTBIE), a structured traumatic brain injury (TBI) interview routinely administered within the VA. Confirmed TBI diagnoses were more frequent among males than females (65% vs. 58%). Additionally, when compared to females, a greater proportion of males with CTBIE-confirmed TBI histories experienced blast-related injuries and were employed. In contrast, a greater proportion of females reported experiencing falls, sustaining a TBI since deployment, and having more severe neurobehavioral symptoms (particularly affective-related symptoms). Results indicate that males and females experience differential clinical and functional outcomes in the aftermath of military TBI. Findings underscore the need to increase female representation in TBI research to increase understanding of sex-specific experiences with TBI and to improve the clinical care targeted to this vulnerable population., Competing Interests: Conflicts of Interest Conflicts of Interest: None

Objective: To examine measures of social support and associations with neurobehavioral, psychiatric, and cognitive symptoms in Veterans who underwent the Veterans Health Administration's Traumatic Brain Injury (TBI) Screening and Evaluation Program., Setting: Nationally representative sample of U.S. Veterans enrolled in the Veterans Affairs Million Veteran Program., Participants: Veterans (N = 9,837) were classified into the following three diagnostic groups based on results from the TBI Screening and Evaluation Program: (1) negative TBI screen (Screen-; n = 6,523), (2) positive TBI screen but no TBI diagnosis (Screen+/TBI-; n = 1,308), or (3) positive TBI screen and TBI diagnosis (Screen+/TBI+; n = 2,006)., Design: Epidemiological cross-sectional study., Main Measures: Medical Outcomes Study Social Support Survey Instrument (MOS-SSSI), with subscales representing emotional, tangible, and affectionate support and positive social interaction; Neurobehavioral Symptom Inventory (NSI); PTSD Checklist (PCL); Patient Health Questionnaire-4 (PHQ-4); and Medical Outcomes Study Cognitive Functioning-Revised Scale (MOS-Cog-R)., Results: ANCOVAs showed significant associations between diagnostic group and all aspects of social support. Pairwise comparisons revealed that Veterans in the two Screen+ groups (Screen+/TBI+ and Screen+/TBI-) reported comparable levels of social support, but that both Screen+ groups reported significantly lower levels of social support compared to the Screen- group. Among the Screen+ groups, adjusted linear regression models controlling for age, sex, and race/ethnicity showed significant associations between social support indices and all symptom measures, such that lower levels of social support were associated with more severe neurobehavioral and psychiatric symptoms and worse cognitive functioning. Finally, mediation analyses showed that psychiatric symptoms mediated the association between TBI screen group and social support., Conclusions: Our results are clinically informative and suggest (1) that the relationship between TBI screen status and social support is influenced by psychiatric symptoms and (2) that implementing distress reduction techniques before social support interventions may be most beneficial for Veterans screening positive for TBI., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to report., (Published by Elsevier Ltd.)

White matter hyperintensities (WMH), a marker of small vessel cerebrovascular disease, increase risk of developing mild cognitive impairment (MCI) and Alzheimer's disease (AD). Less is known about the extent and pattern of WMH in pre-MCI stages, such as among those with objectively-defined subtle cognitive decline (Obj-SCD). Five hundred and fifty-nine Alzheimer's Disease Neuroimaging Initiative participants (170 cognitively unimpaired [CU]; 83 Obj-SCD; 306 MCI) free of clinical dementia or stroke completed neuropsychological testing and MRI exams. ANCOVA models compared cognitive groups on regional WMH adjusting for age, sex, and apolipoprotein E (APOE) ɛ4 frequency. Compared with the CU group, those with Obj-SCD had greater temporal, occipital, and frontal WMH whereas those with MCI had higher WMH volume across all regions (p's < 0.01). No differences in WMH volume were observed between the Obj-SCD and MCI groups (p's > 0.05). Findings add to growing evidence of associations between Obj-SCD and imaging biomarkers, providing support for utility of these criteria to capture subtle cognitive changes that are biologically based., (Published by Elsevier Inc.)

The purpose of this study was to examine subjective cognitive and psychiatric functioning in post-deployed military Veterans who underwent the Veterans Health Administration's Traumatic Brain Injury (TBI) Screening and Evaluation Program and enrolled in the VA's Million Veteran Program (MVP). Veterans (N = 7483) were classified into three groups based on outcomes from the TBI Screening and Evaluation Program: (1) negative TBI screen ('Screen-'), (2) positive TBI screen but no TBI diagnosis ('Screen+/TBI-'), or (3) positive TBI screen and TBI diagnosis ('Screen+/TBI+'). Chi-square analyses revealed significant group differences across all self-reported cognitive and psychiatric health conditions (e.g., memory loss, depression), and ANCOVAs similarly showed a significant association between group and subjective symptom reporting. Specifically, the relationship between TBI group and clinical outcome (i.e., health conditions and symptoms) was such that the Screen+/TBI+ group fared the worst, followed by the Screen+/TBI- group, and finally the Screen- group. However, evaluation of effect sizes suggested that Veterans in the two Screen+ groups (Screen+/TBI+ and Screen+/TBI-) are faring similarly to one another on subjective cognitive and psychiatric functioning, but that both Screen+ groups are faring significantly worse than the Screen- group. Our results have meaningful clinical implications and suggest that Veterans who screen positive for TBI, regardless of ultimate TBI diagnosis, be eligible for similar clinical services so that both groups can benefit from valuable treatments and therapeutics. Finally, this research sets the stage for follow-up work to be conducted within MVP that will address the neurobiological underpinnings of cognitive and psychiatric distress in this population., (Published by Elsevier Ltd.)

We examined the association between cognitive functioning and health-related quality of life (HR-QOL) in military veterans with a history of mild traumatic brain injury (mTBI) using two methods to assess cognition: mean performance on cognitive composite scores and across-test intraindividual variability (IIV). The sample included 73 veterans (84.9% male; age, mean = 32.47 years) who completed neuropsychological testing and self-report questionnaires ∼7 years post-injury. Three cognitive composite scores representing mean performance were computed, including memory, attention/processing speed (A/PS), and executive functioning (EF). Three IIV indices were also calculated reflecting degree of dispersion across the same cognitive domains: memory-IIV, A/PS-IIV, and EF-IIV. The Posttraumatic Stress Disorder (PTSD) Checklist-Military Version (PCL-M) was used to assess current PTSD symptoms, and the World Health Organization Quality of Life Short Version Physical Health domain was used to assess HR-QOL. Hierarchical linear regressions adjusting for PTSD symptoms demonstrated that IIV indices, but not mean cognitive composite scores, significantly predicted HR-QOL. Specifically, memory-IIV, A/PS-IIV, and EF-IIV, when taken together, made an independent and significant contribution to the prediction of HR-QOL. Examination of the standardized coefficients showed that the A/PS-IIV index was uniquely associated with HR-QOL, such that higher A/PS-IIV scores significantly predicted poorer HR-QOL. Our results are the first to show that, in veterans with remote mTBI histories, greater fluctuations in cognitive performance significantly contribute to poorer HR-QOL, even after accounting for PTSD symptom severity. Moreover, findings suggest that, compared to traditional mean cognitive performance scores, measures of IIV may represent more sensitive indicators of clinical outcome and better align with subjective experiences of distress.

The purpose of this study was to examine neurobehavioral symptom reporting in a large sample of military veterans (N = 12,144) who completed the Comprehensive Traumatic Brain Injury Evaluation (CTBIE) and enrolled in the VA's Million Veteran Program (MVP). The CTBIE is a clinician-administered interview that assesses for historical, deployment-related traumatic brain injury (TBI) and evaluates symptoms using the Neurobehavioral Symptom Inventory (NSI). Clinicians completing the CTBIE made clinical determinations about participants' (1) TBI diagnostic status (i.e., CTBIE+ or CTBIE-) and (2) current symptom etiology (i.e., Symptom Resolution, TBI, Behavioral Health, Comorbid TBI + Behavioral Health [Comorbid], or Other). We evaluated the association of TBI diagnostic status and symptom etiology group with neurobehavioral symptoms. Results showed a significant association between TBI diagnostic status and all NSI variables, with CTBIE+ veterans endorsing greater symptoms than CTBIE- veterans. There was also a significant association between symptom etiology group and all NSI variables; specifically, the Comorbid and Behavioral Health groups generally endorsed significantly greater symptoms compared to the other groups. Follow-up analyses showed that relative to the Symptom Resolution group, the Comorbid and Behavioral Health groups had increased odds of severe/very severe cognitive and affective symptoms, whereas the TBI and Other groups did not. Finally, presence of psychiatric symptoms, pain, post-traumatic amnesia, loss of consciousness, and blast exposure significantly predicted Comorbid symptom etiology group membership. Findings from this large epidemiologic MVP study have relevant clinical implications and further highlight the importance of prioritizing integrated behavioral health interventions for this vulnerable population., (Published by Elsevier Ltd.)

White matter alterations in frontolimbic circuits and poorer cognitive functioning have been observed in individuals endorsing suicidality across numerous psychiatric conditions. However, relationships between white matter integrity, cognition, and suicidality in Veterans are poorly understood, particularly for those at increased risk for suicide due to mental health conditions (e.g., posttraumatic stress disorder, depression) and traumatic brain injury history. We (1) examined white matter alterations in combat-exposed Iraq/Afghanistan Veterans with and without suicidal ideation (SI) and (2) investigated relationships between white matter integrity and neuropsychological functioning in regions that differed between SI groups. No group differences were found regarding psychiatric diagnoses. Participants with SI had lower fractional anisotropy (FA) in the posterior corona radiata, superior corona radiata, and superior longitudinal fasciculus relative to those without SI. Worse processing speed/attention performance was associated with lower FA in the superior longitudinal fasciculus, while worse executive functioning performance was associated with lower FA in the superior corona radiata and superior longitudinal fasciculus. Memory performance was not associated with FA. These findings suggest that white matter integrity may be involved in cognitive dysfunction and increased risk for SI. Interventions that target cognitive dysfunction may ameliorate SI, and in turn, reduce risk for suicide among Veterans., (Copyright © 2021. Published by Elsevier B.V.)

Purpose/objective: To examine health-related quality of life (HR-QOL) in Veterans with and without a history of mild traumatic brain injury (mTBI) and investigate correlates and predictors of HR-QOL within the mTBI sample. Research Method/Design: Participants ( N = 144) included 81 Veterans with a history of mTBI and 63 Veteran controls (VCs) without a history of mTBI. Primary outcomes of interest were the 8 subscales of the 36-Item Short Form Survey (SF-36). Participants also completed questionnaires measuring combat exposure, depressive and posttraumatic stress disorder (PTSD) symptoms, and neurobehavioral symptoms., Results: ANCOVAs adjusting for age found that, relative to VCs, the mTBI group demonstrated poorer HR-QOL across all SF-36 subscales ( p 's = ≤.001-.006; η p ² = .05-.21). After adjusting for age, combat exposure, and depressive and PTSD symptoms, the mTBI group endorsed poorer HR-QOL on the Physical Role Functioning, General Health, and Social Functioning subscales ( p 's = .011-.032; η p ² = .03-.05). Within the mTBI sample, employment status, lifetime number of mTBIs, depression, PTSD, and neurobehavioral symptoms collectively predicted all 8 SF-36 subscales ( p 's < .001), accounting for 29-65% of the total variance. Although depression and neurobehavioral symptoms tended to be the strongest predictors of HR-QOL, lifetime number of mTBIs and employment status were also important predictors of specific HR-QOL domains., Conclusions: Results suggest that, above and beyond depression, PTSD, and combat exposure, history of remote mTBI contributes to aspects of HR-QOL-particularly in perceptions of physical health and social functioning. Furthermore, different combinations of predictor variables are associated with different HR-QOL domains, highlighting the need for multimodal treatments within this vulnerable population. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Objective: To examine the association between employment status and neuropsychological functioning in veterans with a history of remote mild traumatic brain injury (mTBI) using 2 approaches to assess cognitive performance: (a) standard, traditional mean cognitive performance; and (b) across-test intraindividual variability (IIV)., Setting: Outpatient Veterans Affairs (VA) hospital., Participants: Eligibility criteria included veterans with a history of mTBI who performed adequately on performance validity tests. Participants (N = 75; 37 employed, 38 unemployed) were evaluated, on average, about 5.5 years after their most recent mTBI., Design: Observational cohort study; all participants completed a clinical interview and a comprehensive neuropsychological assessment., Main Measures: Primary outcomes of interest included mean cognitive composite test scores and IIV scores on tasks of memory, attention/processing speed, and executive functioning., Results: Logistic regression models showed that mean cognitive performance was not predictive of employment status; however, IIV indices were ( = 7.88, P = .048) and accounted for 13% of the variance. Greater memory-IIV was significantly associated with being unemployed (β = -.16, SE = .07, P = .020, Exp(B) = 0.85; 95% CI, 0.74-0.98)., Conclusion: These findings build upon prior work showing that IIV, or cognitive dispersion, is associated with important functional outcomes following mTBI, including employment status. Future studies are needed to verify these findings, but the present study suggests that IIV indices offer a clinically meaningful marker of cognitive functioning and should be considered when evaluating functional outcomes following head trauma., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Cerebrovascular dysfunction has been proposed as a possible mechanism underlying cognitive impairment in the context of type 2 diabetes mellitus (DM). Although magnetic resonance imaging (MRI) evidence of cerebrovascular disease, such as white matter hyperintensities (WMH), is often observed in DM, the vascular dynamics underlying this pathology remain unclear. Thus, we assessed the independent and combined effects of DM status and different vascular hemodynamic measures (i.e., systolic, diastolic, and mean arterial blood pressure and pulse pressure index [PPi]) on WMH burden in cognitively unimpaired (CU) older adults and those with mild cognitive impairment (MCI). Methods: 559 older adults (mean age: 72.4 years) from the Alzheimer's Disease Neuroimaging Initiative were categorized into those with diabetes (DM+; CU = 43, MCI = 34) or without diabetes (DM-; CU = 279; MCI = 203). Participants underwent BP assessment, from which all vascular hemodynamic measures were derived. T2-FLAIR MRI was used to quantify WMH burden. Hierarchical linear regression, adjusting for age, sex, BMI, intracranial volume, CSF amyloid, and APOE ε4 status, examined the independent and interactive effects of DM status and each vascular hemodynamic measure on total WMH burden. Results: The presence of DM ( p = 0.046), but not PPi values ( p = 0.299), was independently associated with greater WMH burden overall after adjusting for covariates. Analyses stratified by cognitive status revealed a significant DM status x PPi interaction within the MCI group ( p = 0.001) such that higher PPi values predicted greater WMH burden in the DM + but not DM- group. No significant interactions were observed in the CU group (all p s > 0.05). Discussion: Results indicate that higher PPi values are positively associated with WMH burden in diabetic older adults with MCI, but not their non-diabetic or CU counterparts. Our findings suggest that arterial stiffening and reduced vascular compliance may have a role in development of cerebrovascular pathology within the context of DM in individuals at risk for future cognitive decline. Given the specificity of these findings to MCI, future exploration of the sensitivity of earlier brain markers of vascular insufficiency (i.e., prior to macrostructural white matter changes) to the effects of DM and arterial stiffness/reduced vascular compliance in CU individuals is warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Werhane, Thomas, Bangen, Weigand, Edmonds, Nation, Sundermann, Bondi and Delano-Wood.)

Introduction:  Our goal was to determine whether cognitive and cerebrospinal fluid (CSF) markers of tau and amyloid beta 1-42 (Aβ 42 ) differ between Vietnam-era veterans with and without history of traumatic brain injury (TBI) and whether TBI moderates the association between CSF markers and neurocognitive functioning., Methods:  A total of 102 male participants (52 TBI, 50 military controls [MCs]; mean age = 68) were included. Levels of CSF Aβ 42 , tau phosphorylated at the threonine 181 position (p-tau), and total tau (t-tau) were quantified. Group differences in CSF markers and cognition as well as the moderating effect of TBI on CSF and cognition associations were explored., Results:  Relative to MCs, the TBI group showed significantly higher p-tau ( P  = .01) and t-tau ( P  = .02), but no differences in amyloid ( P  = .09). TBI history moderated the association between CSF tau and performance on a measure of processing speed (t-tau:  P   = .04; p-tau:  P   = .02)., Discussion:  Tau accumulation may represent a mechanism of dementia risk in older veterans with remote TBI., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: Neurofilament light (NFL) reflects neuroaxonal damage and is implicated in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Little is known about NFL in pre-MCI stages, such as in individuals with objectively-defined subtle cognitive decline (Obj-SCD)., Methods: Two hundred ninety-four participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent baseline blood draw and serial neuropsychological testing over 5 years of follow-up., Results: Individuals with Obj-SCD and MCI showed elevated baseline plasma NFL relative to the cognitively normal (CN) group. Across the sample, elevated NFL predicted faster rate of cognitive and functional decline. Within the Obj-SCD and MCI groups, higher NFL levels predicted faster rate of decline in memory and preclinical AD composite score compared to the CN group., Discussion: Findings demonstrate the utility of plasma NFL as a biomarker of early AD-related changes, and provide support for the use of Obj-SCD criteria in clinical research to better capture subtle cognitive changes., (© 2021 the Alzheimer's Association.)

Alterations to cerebral white matter tracts have been associated with cognitive decline in aging and Alzheimer's disease (AD). In particular, the fornix has been implicated as especially vulnerable given that it represents the primary outflow tract of the hippocampus. Despite this, little work has focused on the fornix using a potential early marker of white matter degeneration-myelin water fraction (MWF; an in vivo marker of myelin content). Therefore, we sought to (1) clarify associations between MWF in the fornix and memory functioning, and (2) examine whether fornix MWF relates to memory performance above and beyond hippocampal volume and conventional imaging measures of white matter that may not be as specific to alterations in myelin content. Forty nondemented older adults (mean age = 72.9 years) underwent an MRI exam and neuropsychological assessment. Multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) was used to quantify fornix MWF and diffusion tensor imaging (DTI) was used to measure fornix fractional anisotropy (FA). Adjusting for age, sex, education, and vascular risk factors, linear regression models revealed that, lower fornix MWF was significantly associated with poorer memory functioning (β = 0.405, p = .007) across our sample of older adults. Notably, fornix MWF remained a significant predictor of memory functioning (β = 0.380, p = .015) even after adjusting for fornix DTI FA and hippocampal volume (in addition to the above covariates). Given the observed associations between myelin and memory in older adults without dementia, MWF may be a useful early marker of dementia risk., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Background and Objectives: Given prior work demonstrating that mild cognitive impairment (MCI) can be empirically differentiated into meaningful cognitive subtypes, we applied actuarial methods to comprehensive neuropsychological data from the University of California San Diego Alzheimer's Disease Research Center (ADRC) in order to identify cognitive subgroups within ADRC participants without dementia and to examine cognitive, biomarker, and neuropathologic trajectories., Methods: Cluster analysis was performed on baseline neuropsychological data (n = 738; mean age 71.8). Survival analysis examined progression to dementia (mean follow-up 5.9 years). CSF Alzheimer disease (AD) biomarker status and neuropathologic findings at follow-up were examined in a subset with available data., Results: Five clusters were identified: optimal cognitively normal (CN; n = 130) with above-average cognition, typical CN (n = 204) with average cognition, nonamnestic MCI (naMCI; n = 104), amnestic MCI (aMCI; n = 216), and mixed MCI (mMCI; n = 84). Progression to dementia differed across MCI subtypes (mMCI > aMCI > naMCI), with the mMCI group demonstrating the highest rate of CSF biomarker positivity and AD pathology at autopsy. Actuarial methods classified 29.5% more of the sample with MCI and outperformed consensus diagnoses in capturing those who had abnormal biomarkers, progressed to dementia, or had AD pathology at autopsy., Discussion: We identified subtypes of MCI and CN with differing cognitive profiles, clinical outcomes, CSF AD biomarkers, and neuropathologic findings over more than 10 years of follow-up. Results demonstrate that actuarial methods produce reliable cognitive phenotypes, with data from a subset suggesting unique biological and neuropathologic signatures. Findings indicate that data-driven algorithms enhance diagnostic sensitivity relative to consensus diagnosis for identifying older adults at risk for cognitive decline., (© 2021 American Academy of Neurology.)