Prospective memory performance in veterans with and without histories of mild traumatic brain injury: effect of the apolipoprotein E (APOE) ε4 genotype.

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, ηp2 =.160), Time Cue (p = .003, ηp2 =.157), and PM Total (p = .016, ηp2 =.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, ηp2 =.113) and PM Total (p = .048, ηp2 = .071). No significant interactions were observed between mTBI and APOE-ε4 status on MIST outcomes (ps>.25). Within the mTBI group, APOE-ε4+ Veterans performed worse than APOE-ε4- Veterans on the MIST 15-min delay subscale (p = .031, ηp2 = .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.

Subjective memory complaints are associated with decreased cortical thickness in Veterans with histories of mild traumatic brain injury.

Objective: Memory problems are frequently endorsed in Veterans following mild traumatic brain injury (mTBI), but subjective complaints are poorly associated with objective memory performance. Few studies have examined associations between subjective memory complaints and brain morphometry. We investigated whether self-reported memory problems were associated with objective memory performance and cortical thickness in Veterans with a history of mTBI. Methods: 40 Veterans with a history of remote mTBI and 29 Veterans with no history of TBI completed the Prospective-Retrospective Memory Questionnaire (PRMQ), PTSD Checklist (PCL), California Verbal Learning Test-2nd edition (CVLT-II), and 3 T T1 structural magnetic resonance imaging. Cortical thickness was estimated in 14 a priori frontal and temporal regions. Multiple regressions adjusting for age and PCL scores examined associations between PRMQ, CVLT-II scores, and cortical thickness within each Veteran group. Results: Greater subjective memory complaints on the PRMQ were associated with lower cortical thickness in the right middle temporal gyrus (ß = 0.64, q = .004), right inferior temporal gyrus (ß = 0.56, q = .014), right rostral middle frontal gyrus (ß = 0.45, q = .046), and right rostral anterior cingulate gyrus (ß = 0.58, q = .014) in the mTBI group but not the control group (q's > .05). These associations remained significant after adjusting for CVLT-II learning. CVLT-II performance was not associated with PRMQ score or cortical thickness in either group. Conclusions: Subjective memory complaints were associated with lower cortical thickness in right frontal and temporal regions, but not with objective memory performance, in Veterans with histories of mTBI. Subjective complaints post-mTBI may indicate underlying brain morphometry independently of objective cognitive testing.

Sex moderates the association between age and myelin water fraction in the cingulum and fornix among older adults without dementia.

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 (ps < 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.

HIV peripheral neuropathy-related degeneration of white matter tracts to sensorimotor cortex.

Human immunodeficiency virus-associated distal sensory polyneuropathy (HIV-DSP) affects up to 50% of people with HIV and is associated with depression, unemployment, and generally worsened quality of life. Previous work on the cortical mechanism of HIV neuropathy found decreased gray matter volume in the bilateral midbrain, thalamus, and posterior cingulate cortex, but structural connectivity in this context remains under-studied. Here we examine alterations in white matter microstructure using diffusion imaging, hypothesizing that cortical white matter degeneration would be observed in continuation of the peripheral white matter atrophy previously observed in HIV-DSP. Male HIV seropositive patients (n = 57) experiencing varying degrees of HIV neuropathy underwent single-shell diffusion tensor imaging with 51 sampling directions. The scans were pooled using tractography and connectometry to create a quantitative map of white matter tract integrity, measured in generalized fractional anisotropy (GFA). The relationship between GFA and neuropathy severity was evaluated with linear regression. Correction for multiple comparisons was done using false discovery rate (FDR), a statistical method commonly used in genomics and imaging to minimize false positives when thousands of individual comparisons are made. Neuropathy severity was associated with decreased GFA along thalamocortical radiations leading along the lateral thalamus to sensorimotor cortex, with r = -0.405 (p < 0.001; FDR), as well as with the superior bilateral cingulum (r = -0.346 (p < 0.05; FDR)). Among a population of HIV neuropathy patients, greater neuropathy severity was correlated with lower white matter integrity running from midbrain to somatosensory cortex. This suggests ascending deafferentation extending from damaged peripheral nerves further downstream than seen previously, into the axons of third-order neurons. There is also evidence of cingulum degeneration, implying some more complex mechanism beyond the ascending atrophy observed here.

The Effects of Nicotine and Cannabis Co-Use During Late Adolescence on White Matter Fiber Tract Microstructure.

OBJECTIVE: Co-use of cannabis and nicotine and tobacco products (NTPs) in adolescence/young adulthood is common and associated with worse outcomes than the use of either substance in isolation. Despite this, little is known about the unique contributions of co-use to neurostructural microstructure during this neurodevelopmentally important period. This study sought to investigate the interactive effects of nicotine and cannabis co-use on white matter fiber tract microstructure in emerging adulthood. METHOD: A total of 111 late adolescent (16-22 years old) nicotine (NTP; n = 55, all past-year cannabis users) and non-nicotine users (non-NTP; n = 56, 61% reporting cannabis use in the past year) completed demographic and clinical interviews and a neuroimaging session comprising anatomical and diffusion-weighted imaging scans. Group connectometry analysis identified white matter tracts significantly associated with the interaction between nicotine group and past-year cannabis use according to generalized fractional anisotropy (GFA). RESULTS: Nicotine Group × Cannabis Use interactions were observed in the right and left cingulum and left fornix tracts (false discovery rate = 0.053), where greater cannabis use was associated with increased GFA in the cingulum and left fornix, but only when co-used with nicotine. CONCLUSIONS: This report represents the first group connectometry analysis in late adolescent/young adult cannabis and/or NTP users. Results suggest that co-use of cannabis and NTPs results in a structurally distinct white matter phenotype as compared with cannabis use only, although to what extent this may change over time with more chronic nicotine and cannabis use remains to be examined in future work.

Elevated Neuropsychological Intraindividual Variability Predicts Poorer Health-Related Quality of Life in Veterans with a History of Mild Traumatic Brain Injury.

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.

Diffusion MRI tractography of the locus coeruleus-transentorhinal cortex connections using GO-ESP.

PURPOSE: The locus coeruleus (LC) is implicated as an early site of protein pathogenesis in Alzheimer's disease (AD). Tau pathology is hypothesized to propagate in a prion-like manner along the LC-transentorhinal cortex (TEC) white matter (WM) pathway, leading to atrophy of the entorhinal cortex and adjacent cortical regions in a progressive and stereotypical manner. However, WM damage along the LC-TEC pathway may be an earlier observable change that can improve detection of preclinical AD. THEORY AND METHODS: Diffusion-weighted MRI (dMRI) allows reconstruction of WM pathways in vivo, offering promising potential to examine this pathway and enhance our understanding of neural mechanisms underlying the preclinical phase of AD. However, standard dMRI analysis tools have generally been unable to reliably reconstruct this pathway. We apply a novel method, geometric-optics based entropy spectrum pathways (GO-ESP) and produce a new measure of connectivity: the equilibrium probability (EP). RESULTS: We demonstrated reliable reconstruction of LC-TEC pathways in 50 cognitively normal older adults and showed a negative association between LC-TEC EP and cerebrospinal fluid tau. Using Human Connectome Project data, we demonstrated replicability of the method across acquisition schemes and scanners. Finally, we compared our findings with the only other existing LC-TEC tractography template, and replicated their pathway as well as investigated the source of these discrepant findings. CONCLUSIONS: AD-related tau pathology may be detectable within GO-ESP-identified LC-TEC pathways. Furthermore, there may be multiple possible routes from LC to TEC, raising important questions for future research on the LC-TEC connectome and its role in AD pathogenesis.

Severities in persistent mild traumatic brain injury related headache is associated with changes in supraspinal pain modulatory functions.

Emerging evidence suggests mild traumatic brain injury related headache (MTBI-HA) is a form of neuropathic pain state. Previous supraspinal mechanistic studies indicate patients with MTBI-HA demonstrate a dissociative state with diminished levels of supraspinal prefrontal pain modulatory functions and enhanced supraspinal sensory response to pain in comparison to healthy controls. However, the relationship between supraspinal pain modulatory functional deficit and severity of MTBI-HA is largely unknown. Understanding this relationship may provide enhanced levels of insight about MTBI-HA and facilitate the development of treatments. This study assessed pain related supraspinal resting states among MTBI-HA patients with various headache intensity phenotypes with comparisons to controls via functional magnetic resonance imaging (fMRI). Resting state fMRI data was analyzed with self-organizing-group-independent-component-analysis in three MTBI-HA intensity groups (mild, moderate, and severe) and one control group (n = 16 per group) within a pre-defined supraspinal pain network based on prior studies. In the mild-headache group, significant increases in supraspinal function were observed in the right premotor cortex (T = 3.53, p < 0.001) and the left premotor cortex (T = 3.99, p < 0.0001) when compared to the control group. In the moderate-headache group, a significant (T = -3.05, p < 0.01) decrease in resting state activity was observed in the left superior parietal cortex when compared to the mild-headache group. In the severe-headache group, significant decreases in resting state supraspinal activities in the right insula (T = -3.46, p < 0.001), right premotor cortex (T = -3.30, p < 0.01), left premotor cortex (T = -3.84, p < 0.001), and left parietal cortex (T = -3.94, p < 0.0001), and an increase in activity in the right secondary somatosensory cortex (T = 4.05, p < 0.0001) were observed when compared to the moderate-headache group. The results of the study suggest that the increase in MTBI-HA severity may be associated with an imbalance in the supraspinal pain network with decline in supraspinal pain modulatory function and enhancement of sensory/pain decoding.

Unemployment Status Is Associated With Greater Cognitive Intraindividual Variability in Veterans With a History of Remote Mild TBI.

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 (ß = -.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.

Research Letter: PTSD Symptom Severity and Multiple Traumatic Brain Injuries Are Associated With Elevated Memory Complaints in Veterans With Histories of Mild TBI.

OBJECTIVE: The evaluation of memory complaints in mild traumatic brain injury (mTBI) remains an important clinical consideration, especially in the context of comorbid psychiatric symptoms such as posttraumatic stress disorder (PTSD). We compared subjective memory complaints in veterans with and without a history of mTBI, examined ratings between those with single versus multiple mTBIs, and investigated associations between memory complaints and PTSD symptom severity. METHODS: 117 outpatient veterans (mTBI: n = 79 [single mTBI: n = 22, multiple mTBI: n = 57], military controls [MCs]: n = 38) completed a TBI history assessment, the Prospective-Retrospective Memory Questionnaire (PRMQ), and the PTSD Checklist-Military Version (PCL-M). RESULTS: Hierarchical multiple regression showed that greater PCL-M scores significantly predicted elevated PRMQ-Total scores, accounting for 38% of the variance explained (P < .001). mTBI status predicted an additional 5% of variance in memory complaints (P < .01). The multiple-mTBI group endorsed more memory complaints than either MCs (P < .01) or the single-mTBI group (P < .05), who did not differ from MCs (P > .50). CONCLUSIONS: Comorbid PTSD symptoms are an important factor when considering memory complaints in veterans with a reported history of mTBI. However, independent of comorbid PTSD symptoms, mTBI status-particularly in the context of repetitive neurotrauma-uniquely contributes to memory complaints. Findings suggest that veterans with a history of multiple mTBIs may be a particularly vulnerable group in need of specialized interventions and/or psychoeducation.

Decreased myelin content of the fornix predicts poorer memory performance beyond vascular risk, hippocampal volume, and fractional anisotropy in nondemented older adults.

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 (ß = 0.405, p = .007) across our sample of older adults. Notably, fornix MWF remained a significant predictor of memory functioning (ß = 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.

Greater Severity and Functional Impact of Post-traumatic Headache in Veterans With Comorbid Neck Pain Following Traumatic Brain Injury.

BACKGROUND: Post-traumatic headache (PTH) is a commonly experienced symptom after mild traumatic brain injury (mTBI). Blast injury- or blunt injury-related mechanisms for mTBI in veterans can also affect musculoskeletal structures in the neck, resulting in comorbid neck pain (NP). However, it is unknown whether the presence of comorbid NP may be associated with a different pattern of headache symptoms, physical functioning, or emotional functioning compared to those without comorbid NP. The purpose of this study is to examine the role of comorbid NP in veterans with mTBI and PTH. DESIGN AND METHODS: This was a cross-sectional investigation of an existing dataset that included 33 veterans who met inclusion criteria for PTH after mTBI. Standardized measures of headache severity and frequency, insomnia, fatigue, mood disorders, and physical and emotional role function were compared between groups with and without comorbid NP. RESULTS: The majority of participants with PTH reported comorbid NP (n = 22/33, 67%). Those with comorbid NP experienced more headache symptoms that were severe or incapacitating, as compared to mild or moderate for those without NP (φ = 0.343, P = .049); however, no differences in headache frequency (φ = 0.231, P = .231) or duration (φ = 0.129, P = .712) were observed. Participants with comorbid NP also reported greater insomnia (d = 1.16, P = .003) and fatigue (d = 0.868, P = .040) as well as lower physical functioning (d = 0.802, P = .036) and greater bodily pain (d = 0.762, P = .012). There were no differences in anxiety, depression, mental health, emotional role limitations, vitality, or social functioning between those with and without comorbid NP (d ≤ 0.656, P ≥ .079). CONCLUSIONS: A majority of veterans with mTBI and PTH in our sample reported comorbid NP that was associated with greater headache symptom severity and physical limitations, but not with mood or emotional limitations. Preliminary findings from this small convenience sample indicate that routine assessment of comorbid NP and associated physical limitations should be considered in veterans with mTBI and PTH.

Elevated Intraindividual Variability in Executive Functions and Associations with White Matter Microstructure in Veterans with Mild Traumatic Brain Injury.

OBJECTIVE: We examined whether intraindividual variability (IIV) across tests of executive functions (EF-IIV) is elevated in Veterans with a history of mild traumatic brain injury (mTBI) relative to military controls (MCs) without a history of mTBI. We also explored relationships among EF-IIV, white matter microstructure, and posttraumatic stress disorder (PTSD) symptoms. METHOD: A total of 77 Veterans (mTBI = 43, MCs = 34) completed neuropsychological testing, diffusion tensor imaging (DTI), and PTSD symptom ratings. EF-IIV was calculated as the standard deviation across six tests of EF, along with an EF-Mean composite. DSI Studio connectometry analysis identified white matter tracts significantly associated with EF-IIV according to generalized fractional anisotropy (GFA). RESULTS: After adjusting for EF-Mean and PTSD symptoms, the mTBI group showed significantly higher EF-IIV than MCs. Groups did not differ on EF-Mean after adjusting for PTSD symptoms. Across groups, PTSD symptoms significantly negatively correlated with EF-Mean, but not with EF-IIV. EF-IIV significantly negatively correlated with GFA in multiple white matter pathways connecting frontal and more posterior regions. CONCLUSIONS: Veterans with mTBI demonstrated significantly greater IIV across EF tests compared to MCs, even after adjusting for mean group differences on those measures as well as PTSD severity. Findings suggest that, in contrast to analyses that explore effects of mean performance across tests, discrepancy analyses may capture unique variance in neuropsychological performance and more sensitively capture cognitive disruption in Veterans with mTBI histories. Importantly, findings show that EF-IIV is negatively associated with the microstructure of white matter pathways interconnecting cortical regions that mediate executive function and attentional processes.

Response inhibition in Veterans with a history of mild traumatic brain injury: The role of self-reported complaints in objective performance.

INTRODUCTION: Although objective deficits in response inhibition (RI) have been detected in civilians with mild traumatic brain injury (mTBI), it remains unclear whether objective RI is worse in military Veterans with mTBI despite the prevalence of self-reported disinhibition. Assessing RI in Veterans is critical due to their unique characteristics, including combat and blast exposure, in addition to the prevalence of psychiatric comorbidity. Therefore, the aims of this study were to (1) examine RI performance in Veterans with mTBI compared to non-mTBI Veterans and (2) compare RI performance in well-defined subgroups of mTBI Veterans with and without self-reported complaints of disinhibition to non-mTBI Veterans. METHOD: 53 mTBI Veterans and 37 non-mTBI Veterans completed a Go/No-Go RI task and measures of self-reported disinhibition (Frontal Systems Behavior Scale) and psychiatric symptoms. ANCOVAs covarying for mood and demographics compared RI performances of the non-mTBI Veterans to (1) the total sample of mTBI Veterans (n= 53) and to (2) mTBI Veterans with elevated (t-score ≥ 60; mTBI-SubjDis; n= 23) and low (t-score < 60; mTBI-NoSubjDis; n= 30) levels of self-reported disinhibition. RESULTS: There were no significant differences in RI between the mTBI group as a whole and the non-mTBI Veterans group. However, when Veterans with mTBI were divided into groups by clinically-significant concern about their disinhibition, the mTBI-SubjDis group demonstrated significantly worse RI than the mTBI-NoSubjDis and non-mTBI Veteran groups. No significant differences in RI performance were observed between the mTBI-NoSubjDis and non-mTBI Veteran groups. CONCLUSIONS: Results indicate that mTBI Veterans with elevated levels of self-reported disinhibition show diminished performance on objective measures of RI, independent of mood. Findings highlight the unique contribution of subjective complaints on executive functioning in mTBI, and they underscore the importance of assessing cognitive complaints in order to identify those most at risk for poor-long term outcomes.

Dissociation of BDNF Val66Met polymorphism on neurocognitive functioning in military veterans with and without a history of remote mild traumatic brain injury.

OBJECTIVE: Since neurocognitive functioning following mild traumatic brain injury (mTBI) may be influenced by genetic factors that mediate synaptic survival and repair, we examined the influence of a common brain-derived neurotrophic factor (BDNF) polymorphism (Val66Met) on cognition using a well-defined sample of military Veterans with and without a history of mTBI. METHOD: Participants included 138 Veterans (mTBI = 75; military controls [MCs] = 63) who underwent neuropsychological testing, including completion of self-report measures assessing psychiatric distress, and BDNF genotyping. The mTBI group was tested roughly 66.7 months following their most recent mTBI. Veterans were divided into two groups-Met+ (Met/Met and Met/Val; n = 49) and Met- (Val/Val; n = 89) and compared on domain-specific cognitive composite scores representing memory, executive functioning, and visuospatial speed. RESULTS: ANCOVAs adjusting for psychiatric distress, sex, years of education, and ethnicity/race revealed a significant group (mTBI vs. MC) by BDNF genotype (Met + vs. Met-) interaction for the memory (p = .024; ηp2 = .039) and executive functioning (p = .010; ηp2 = .050) composites, such that Met+ mTBI Veterans demonstrated better performance than Met- mTBI Veterans on the cognitive measures, whereas Met+ MCs demonstrated worse performance relative to Met- MCs on the cognitive measures. No significant interaction was observed for the visuospatial speed composite (p = .938; ηp2 < .001). CONCLUSIONS: These findings offer preliminary evidence to suggest that the Met allele may be protective in the context of remote mTBI. Findings need to be replicated using larger samples, and future studies are necessary to elucidate the precise mechanisms and neural underpinnings of this interaction.

PTSD, but not history of mTBI, is associated with altered myelin in combat-exposed Iraq and Afghanistan Veterans.

OBJECTIVE: To investigate the biological, cognitive, and psychological presentations of combat-exposed Veterans with a history of mild traumatic brain injury (mTBI) and/or posttraumatic stress disorder (PTSD) using a novel white matter imaging technique and comprehensive neuropsychological assessment. METHOD: 74 Iraq and Afghanistan Veterans (mean age 33.89, 90.5% male) with history of mTBI (average 7.25 years since injury), PTSD, both, or neither underwent magnetic resonance imaging (MRI) exams including acquisition of a novel imaging technique, multicomponent-driven equilibrium single-pulse observation of T1/T2 (mcDESPOT) to quantify myelin water fraction (MWF), a surrogate measure of myelin content. Participants also underwent comprehensive neuropsychological assessment and three cognitive composite scores (memory, working memory/processing speed, and executive functioning) were created. RESULTS: There were no significant group differences on the neuropsychological composite scores. ANCOVAs revealed a main effect of PTSD across all a priori regions of interest (ROI) in which PTSD was associated with higher MWF. There was no main effect of mTBI history or TBI by PTSD interaction on any ROI. Significant positive associations were observed between myelin and PTSD symptoms, but no significant associations were found between myelin and neurobehavioral symptoms. No significant associations were found between myelin in the a priori ROIs and the cognitive composite scores. CONCLUSION: This study did not find neuropsychological or MWF differences in combat Veterans with a remote history of mTBI but did find myelin alterations related to PTSD. Psychological trauma should be a primary target for intervention in Veterans with comorbid PTSD and mTBI reporting subjective complaints, given its salience.

APOE-ε4 Genotype is Associated with Elevated Post-Concussion Symptoms in Military Veterans with a Remote History of Mild Traumatic Brain Injury.

OBJECTIVE: We evaluated the influence of the APOE-ε4 allele on post-concussive symptoms in military Veterans with a remote history of mild traumatic brain injury (mTBI). METHOD: Participants (N = 77) were administered neuropsychiatric measures, on average, approximately 5 years following their most recent mTBI and provided a DNA sample for APOE genotyping. Veterans were divided into two groups based on their ε4 status (n = 14 ε4+, n = 63 ε4-). The Neurobehavioral Symptom Inventory (NSI) was the primary outcome measure, from which a total score was derived, as well as three symptom clusters (somatic, cognitive, and affective). RESULTS: ANCOVAs showed a significant main effect of ε4 genotype on the NSI total score and somatic symptom cluster after adjusting for posttraumatic stress symptoms and mTBI history (p = .019-.028, ηp2 = .064-.073), such that ε4+ Veterans endorsed significantly greater symptoms than ε4- Veterans. CONCLUSIONS: Our findings suggest that genetic risk may help to explain the poorer long-term outcomes often observed in this population.

Blast-Exposed Veterans With Mild Traumatic Brain Injury Show Greater Frontal Cortical Thinning and Poorer Executive Functioning.

Objective: Blast exposure (BE) and mild traumatic brain injury (mTBI) have been independently linked to pathological brain changes. However, the combined effects of BE and mTBI on brain structure have yet to be characterized. Therefore, we investigated whether regional differences in cortical thickness exist between mTBI Veterans with and without BE while on deployment. We also examined whether cortical thickness (CT) and cognitive performance differed among mTBI Veterans with low vs. high levels of cumulative BE. Methods: 80 Veterans with mTBI underwent neuroimaging and completed neuropsychological testing and self-report symptom rating scales. Analyses of covariance (ANCOVA) were used to compare blast-exposed Veterans (mTBI+BE, n = 51) to those without BE (mTBI-BE, n = 29) on CT of frontal and temporal a priori regions of interest (ROIs). Next, multiple regression analyses were used to examine whether CT and performance on an executive functions composite differed among mTBI Veterans with low (mTBI+BE Low, n = 22) vs. high (mTBI+BE High, n = 26) levels of cumulative BE. Results: Adjusting for age, numer of TBIs, and PTSD symptoms, the mTBI+BE group showed significant cortical thinning in frontal regions (i.e., left orbitofrontal cortex [p = 0.045], left middle frontal gyrus [p = 0.023], and right inferior frontal gyrus [p = 0.034]) compared to the mTBI-BE group. No significant group differences in CT were observed for temporal regions (p's > 0.05). Multiple regression analyses revealed a significant cumulative BE × CT interaction for the left orbitofrontal cortex (p = 0.001) and left middle frontal gyrus (p = 0.020); reduced CT was associated with worse cognitive performance in the mTBI+BE High group but not the mTBI+BE Low group. Conclusions: Findings show that Veterans with mTBI and BE may be at risk for cortical thinning post-deployment. Moreover, our results demonstrate that reductions in CT are associated with worse executive functioning among Veterans with high levels of cumulative BE. Future longitudinal studies are needed to determine whether BE exacerbates mTBI-related cortical thinning or independently negatively influences gray matter structure.

Repetitive mild traumatic brain injury in military veterans is associated with increased neuropsychological intra-individual variability.

Although across-test intra-individual variability (IIV), or dispersion, has been shown to be a valuable marker of neurological health in a variety of clinical samples, IIV has not been well examined in the context of mild traumatic brain injury (mTBI). In the present study, we examined measures of IIV in military Veterans with and without a history of mTBI. Secondly, we examined how measures of IIV relate to traditional indices of mean cognitive performance, TBI characteristics, and neuropsychiatric symptoms in mTBI. Participants included 120 Veterans (67 mTBI, 53 military controls [MCs]) who completed a comprehensive neuropsychological assessment. Two dispersion indices were calculated using 13 norm-referenced variables: an average standard deviation (ASD) score and a maximum discrepancy (MD) score. Compared to MCs, Veterans with a history of mTBI demonstrated greater IIV as indicated by the MD index after adjusting for relevant demographic variables, PTSD symptoms, and mean-level cognitive performance (p = 0.027; ηp2 = 0.043), and there was a trend finding in the same direction for the ASD index (p = 0.091; ηp2 = 0.025). Among the mTBI participants, the two IIV indices were positively correlated with each other (p < 0.001, r = 0.921) and negatively correlated with mean cognitive performance (p = 0.017-0.022, r = -[0.279-0.291]). In contrast, ASD and MD scores were not associated with a measure of premorbid intellectual functioning or neuropsychiatric symptoms (all p's > 0.05). However, higher ASD scores were positively related to lifetime number of mTBIs, such that greater cognitive variability was observed in Veterans with a history of multiple mTBIs (i.e., ≥3 mTBIs; p = 0.037, r = 0.255). Overall, our results demonstrate that Veterans with mTBI show greater IIV relative to MCs, and that repetitive mTBI is associated with increased cognitive performance variability. Findings indicate that, in the context of mTBI-which is considerably heterogeneous in nature-measures of dispersion may be more appropriate indicators of cognitive dysfunction when compared to traditional mean neuropsychological scores, especially in those with remote mTBI histories. Future longitudinal studies are needed to further establish the long-term clinical implications and brain-based correlates of these findings.

Pilot investigation of a novel white matter imaging technique in Veterans with and without history of mild traumatic brain injury.

OBJECTIVE: The objective of this study is to assess utility of in vivo myelin imaging in combat Veterans with and without history of mild traumatic brain injury (mTBI). We hypothesized that those with history of mTBI would have lower myelin water fraction (MWF), a marker of myelin integrity and content, than those without, and lower MWF would be associated with worse speeded attention/processing speed. RESEARCH DESIGN: Combat Veterans (N = 70) with (n = 42) and without history of mTBI (n = 28) underwent neuroimaging including a novel myelin-sensitive magnetic resonance imaging technique (multicomponent-driven equilibrium single-pulse observation of T1/T2; mcDESPOT) and comprehensive neuropsychological assessment. RESULTS: There were no group differences in MWF using a region-of-interest approach. An exploratory analysis applying limited spatial constraints, however, revealed significantly more 'potholes' (clusters of low MWF) in Veterans with history of mTBI compared to those without. Lower MWF across several ROIs was associated with worse performance on a speeded attention task across groups. CONCLUSION: Veterans in the post-acute period following mTBI showed limited and spatially heterogeneous MWF changes and myelin integrity was significantly related to processing speed. This preliminary evidence for usefulness of mcDESPOT in combat Veterans with history of mTBI warrants future research to determine mcDESPOT's relative utility compared to techniques such as diffusion tensor imaging.