Serum NfL and GFAP as biomarkers of progressive neurodegeneration in TBI.

BACKGROUND: We examined spatial patterns of brain atrophy after mild, moderate, and severe traumatic brain injury (TBI), the relationship between progression of brain atrophy with initial traumatic axonal injury (TAI), cognitive outcome, and with serum biomarkers of brain injury. METHODS: A total of 143 patients with TBI and 43 controls were studied cross-sectionally and longitudinally up to 5 years with multiple assessments, which included brain magnetic resonance imaging, cognitive testing, and serum biomarkers. RESULTS: TBI patients showed progressive volume loss regardless of injury severity over several years, and TAI was independently associated with accelerated brain atrophy. Cognitive performance improved over time. Higher baseline serum neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) were associated with greater rate of brain atrophy over 5 years. DISCUSSSION: Spatial patterns of atrophy differ by injury severity and TAI is associated with the progression of brain atrophy. Serum NfL and GFAP show promise as non-invasive prognostic biomarkers of progressive neurodegeneration in TBI. HIGHLIGHTS: In this longitudinal study of patient with mild, moderate, and severe traumatic brain injury (TBI) who were assessed with paired magnetic resonance imaging (MRI), blood biomarkers, and cognitive assessments, we found that brain atrophy after TBI is progressive and continues for many years even after a mild head trauma without signs of brain injury on conventional MRI. We found that spatial pattern of brain atrophy differs between mild, moderate, and severe TBI, where in patients with mild TBI , atrophy is mainly seen in the gray matter, while in those with moderate to severe brain injury atrophy is predominantly seen in the subcortical gray matter and whiter matter. Cognitive performance improves over time after a TBI. Serum measures of neurofilament light or glial fibrillary acidic protein are associated with progression of brain atrophy after TBI.

Clinical relevance of subthreshold PTSD versus full criteria PTSD following traumatic brain injury in U.S. service members and veterans.

BACKGROUND: The purpose of this cross-sectional study was to examine the influence of subthreshold posttraumatic stress disorder (PTSD) and full PTSD on quality of life following mild traumatic brain injury (mTBI). METHODS: Participants were 734 service members and veterans (SMV) classified into two injury groups: uncomplicated mild TBI (MTBI; n = 596) and injured controls (IC, n = 139). Participants completed a battery of neurobehavioral measures, 12-or-more months post-injury, that included the PTSD Checklist Civilian version, Neurobehavioral Symptom Inventory, and select scales from the TBI-QOL and MPAI. The MTBI group was divided into three PTSD subgroups: No-PTSD (n = 266), Subthreshold PTSD (n = 139), and Full-PTSD (n = 190). RESULTS: There was a linear relationship between PTSD severity and neurobehavioral functioning/quality of life in the MTBI sample. As PTSD severity increased, significantly worse scores were found on 11 of the 12 measures (i.e. , MTBI: Full-PTSD > Sub-PTSD > No-PTSD). When considering the number of clinically elevated scores, a linear relationship between PTSD severity and neurobehavioral functioning/quality of life was again observed in the MTBI sample (e.g., 3-or-more elevated scores: Full-PTSD = 92.1 %, Sub-PTSD = 61.9 %, No-PTSD = 19.9 %). LIMITATIONS: Limitations included the use of a self-report measure to determine diagnostic status that may under/overcount or mischaracterize individuals. CONCLUSION: PTSD symptoms, whether at the level of diagnosable PTSD, or falling short of that because of the intensity or characterization of symptoms, have a significant negative impact on one's quality of life following MTBI. Clinicians' treatment targets should focus on the symptoms that are most troubling for an individual and the individual's perception of quality of life, regardless of the diagnosis itself.

Service needs and neurobehavioral functioning following traumatic brain injury in U.S. military personnel.

OBJECTIVE: The purpose of this study was to (a) identify the prevalence and barriers of self-reported service needs in a military sample with and without traumatic brain injury (TBI), (b) evaluate the influence of the number of service needs on overall neurobehavioral functioning, and (c) examine the longitudinal trajectories of service needs over time. METHOD: Participants were 941 U.S. service members and veterans (SMVs) prospectively enrolled into four groups: uncomplicated mild TBI (MTBI; n = 455); complicated mild, moderate, severe, and penetrating TBI combined (STBI; n = 164); injured controls (IC, n = 138); and noninjured controls (NIC, n = 184). Participants completed a battery of neurobehavioral measures, as well as a self-reported service need interview, 12 or more month's postinjury. In addition, a longitudinal cohort (n = 553) was included using a subset of participants who had completed two or more evaluations. RESULTS: When examining the total number of self-reported service needs, there was a greater proportion of the MTBI and STBI groups that had a higher number of service needs compared to the NIC and IC groups (p < .001). In the MTBI and STBI groups, as the number of service needs increased, worse scores were found on all neurobehavioral measures. In the longitudinal cohort, the STBI group reported the highest number of service needs that persisted or developed over time (six needs), followed by the MTBI (three needs), IC (one need), and NIC (zero need) groups. CONCLUSIONS: These findings call for the need to enhance the provision of information given to service members and veterans following TBI regarding available services. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Gender Disparities in Neurobehavioral Symptoms and the Role of Post-Traumatic Symptoms in US Service Members Following Mild Traumatic Brain Injury.

Women are more directly involved in combat operations today than ever before, currently making up 18.6% of officers and 16.8% of enlisted personnel in the United States military. However, women continue to be under-represented in military research. Studies that do consider gender differences in traumatic brain injury (TBI) outcomes have shown that women report significantly more post-concussive symptoms than men. Conclusions for true gender differences related to TBI are hard to make without controlling for non-TBI factors. The effects previously identified in the literature may be an artifact of how men and women differ in their response to injury, unrelated to the neurological recovery process associated with TBI. The objective of this study was to examine the effects of gender specifics on mild TBI (mTBI) sequelae on injured and uninjured control groups, and to investigate the role of post-traumatic stress disorder (PTSD) on symptom reporting. It should be noted that the terms "gender" and "men/women" are used in this article in place of "sex" or "males/females" given that we are not discussing biological attributes. A total of 966 United States military service members and veterans were included in the study. Of the total sample, 455 men and 46 women were in the mTBI group, 285 men and 31 women were in the injured controls group (IC), and 111 men and 38 women in the non-injured controls group (NIC). Post-concussive and quality of life symptoms were compared for men and women while controlling for combat exposure. MTBI and IC groups were also stratified by PTSD presentation. Measures used included the Neurobehavioral Symptom Inventory (NSI), PTSD Checklist (PCL-C), Traumatic Brain Injury Quality of Life (TBI-QOL), and Combat Exposure Scale. In the mTBI group, women had worse scores on NSI total, NSI Somatosensory and Affective clusters, and the TBI-QOL Anxiety, Fatigue, and Headache scales (n2 = 0.018-0.032, small to small-medium effect sizes). When PTSD was present, women had worse scores on the NSI Somatosensory cluster only (n2 = 0.029, small-medium effect size). In contrast, when PTSD was absent, women had worse scores than men on the NSI Somatosensory and Affective clusters, and the TBI-QOL Anxiety and Headache scales (n2 = 0.032-0.063, small to medium effect sizes). In the IC group, women had worse scores on the NSI Cognitive cluster and the TBI-QOL Fatigue and Pain Interference scales (n2 = 0.024-0.042, small to small-medium effect sizes). However, group differences were no longer found when stratified by PTSD sub-groups. In the NIC group, there were no significant group differences for any analyses. We were able to identify symptoms unique to women recovering from mTBI that were not present following other forms of physical injury or in healthy controls. However, the impact of PTSD exacerbates the symptom profile and its comorbidity with mTBI equates to most of the noted gender differences.

Lifetime blast exposure is not related to cognitive performance or psychiatric symptoms in US military personnel.

Objective: The present study aimed to examine the impact of lifetime blast exposure (LBE) on neuropsychological functioning in service members and veterans (SMVs). Method: Participants were 282 SMVs, with and without history of traumatic brain injury (TBI), who were prospectively enrolled in a Defense and Veterans Brain Injury Center (DVBIC)-Traumatic Brain Injury Center of Excellence (TBICoE) Longitudinal TBI Study. A cross-sectional analysis of baseline data was conducted. LBE was based on two factors: Military Occupational Speciality (MOS) and SMV self-report. Participants were divided into three groups based on LBE: Blast Naive (n = 61), Blast + Low Risk MOS (n = 96), Blast + High Risk MOS (n = 125). Multivariate analysis of variance (MANOVA) was used to examine group differences on neurocognitive domains and the Minnesota Multiphasic Personality Inventory-2 Restructured Form. Results: There were no statistically significant differences in attention/working memory, processing speed, executive functioning, and memory (Fs < 1.75, ps > .1, ηp2s < .032) or in General Cognition (Fs < 0.95, ps > .3, ηp2s < .008). Prior to correction for covariates, lifetime blast exposure was related to Restructured Clinical (F(18,542) = 1.77, p = .026, ηp2 = .055), Somatic/Cognitive (F(10,550) = 1.99, p = .033, ηp2 = .035), and Externalizing Scales (F(8,552) = 2.17, p = .028, ηp2 = .030); however, these relationships did not remain significant after correction for covariates (Fs < 1.53, ps > .145, ηp2s < .032). Conclusions: We did not find evidence of a relationship between LBE and neurocognitive performance or psychiatric symptoms. This stands in contrast to prior studies demonstrating an association between lifetime blast exposure and highly sensitive blood biomarkers and/or neuroimaging. Overall, findings suggest the neuropsychological impact of lifetime blast exposure is minimal in individuals remaining in or recently retired from military service.

Clinical, Biomarker, and Research Tests Among US Government Personnel and Their Family Members Involved in Anomalous Health Incidents.

Importance: Since 2015, US government and related personnel have reported dizziness, pain, visual problems, and cognitive dysfunction after experiencing intrusive sounds and head pressure. The US government has labeled these anomalous health incidents (AHIs). Objective: To assess whether participants with AHIs differ significantly from US government control participants with respect to clinical, research, and biomarker assessments. Design, Setting, and Participants: Exploratory study conducted between June 2018 and July 2022 at the National Institutes of Health Clinical Center, involving 86 US government staff and family members with AHIs from Cuba, Austria, China, and other locations as well as 30 US government control participants. Exposures: AHIs. Main Outcomes and Measures: Participants were assessed with extensive clinical, auditory, vestibular, balance, visual, neuropsychological, and blood biomarkers (glial fibrillary acidic protein and neurofilament light) testing. The patients were analyzed based on the risk characteristics of the AHI identifying concerning cases as well as geographic location. Results: Eighty-six participants with AHIs (42 women and 44 men; mean [SD] age, 42.1 [9.1] years) and 30 vocationally matched government control participants (11 women and 19 men; mean [SD] age, 43.8 [10.1] years) were included in the analyses. Participants with AHIs were evaluated a median of 76 days (IQR, 30-537) from the most recent incident. In general, there were no significant differences between participants with AHIs and control participants in most tests of auditory, vestibular, cognitive, or visual function as well as levels of the blood biomarkers. Participants with AHIs had significantly increased fatigue, depression, posttraumatic stress, imbalance, and neurobehavioral symptoms compared with the control participants. There were no differences in these findings based on the risk characteristics of the incident or geographic location of the AHIs. Twenty-four patients (28%) with AHI presented with functional neurological disorders. Conclusions and Relevance: In this exploratory study, there were no significant differences between individuals reporting AHIs and matched control participants with respect to most clinical, research, and biomarker measures, except for objective and self-reported measures of imbalance and symptoms of fatigue, posttraumatic stress, and depression. This study did not replicate the findings of previous studies, although differences in the populations included and the timing of assessments limit direct comparisons.

Neuroimaging Findings in US Government Personnel and Their Family Members Involved in Anomalous Health Incidents.

Importance: US government personnel stationed internationally have reported anomalous health incidents (AHIs), with some individuals experiencing persistent debilitating symptoms. Objective: To assess the potential presence of magnetic resonance imaging (MRI)-detectable brain lesions in participants with AHIs, with respect to a well-matched control group. Design, Setting, and Participants: This exploratory study was conducted at the National Institutes of Health (NIH) Clinical Center and the NIH MRI Research Facility between June 2018 and November 2022. Eighty-one participants with AHIs and 48 age- and sex-matched control participants, 29 of whom had similar employment as the AHI group, were assessed with clinical, volumetric, and functional MRI. A high-quality diffusion MRI scan and a second volumetric scan were also acquired during a different session. The structural MRI acquisition protocol was optimized to achieve high reproducibility. Forty-nine participants with AHIs had at least 1 additional imaging session approximately 6 to 12 months from the first visit. Exposure: AHIs. Main Outcomes and Measures: Group-level quantitative metrics obtained from multiple modalities: (1) volumetric measurement, voxel-wise and region of interest (ROI)-wise; (2) diffusion MRI-derived metrics, voxel-wise and ROI-wise; and (3) ROI-wise within-network resting-state functional connectivity using functional MRI. Exploratory data analyses used both standard, nonparametric tests and bayesian multilevel modeling. Results: Among the 81 participants with AHIs, the mean (SD) age was 42 (9) years and 49% were female; among the 48 control participants, the mean (SD) age was 43 (11) years and 42% were female. Imaging scans were performed as early as 14 days after experiencing AHIs with a median delay period of 80 (IQR, 36-544) days. After adjustment for multiple comparisons, no significant differences between participants with AHIs and control participants were found for any MRI modality. At an unadjusted threshold (P < .05), compared with control participants, participants with AHIs had lower intranetwork connectivity in the salience networks, a larger corpus callosum, and diffusion MRI differences in the corpus callosum, superior longitudinal fasciculus, cingulum, inferior cerebellar peduncle, and amygdala. The structural MRI measurements were highly reproducible (median coefficient of variation <1% across all global volumetric ROIs and <1.5% for all white matter ROIs for diffusion metrics). Even individuals with large differences from control participants exhibited stable longitudinal results (typically, <±1% across visits), suggesting the absence of evolving lesions. The relationships between the imaging and clinical variables were weak (median Spearman ρ = 0.10). The study did not replicate the results of a previously published investigation of AHIs. Conclusions and Relevance: In this exploratory neuroimaging study, there were no significant differences in imaging measures of brain structure or function between individuals reporting AHIs and matched control participants after adjustment for multiple comparisons.

Cumulative Blast Exposure During a Military Career Negatively Impacts Recovery from Traumatic Brain Injury.

Sub-concussive injuries have emerged as an important factor in the long-term brain health of athletes and military personnel. The objective of this study was to explore the relationship between service member and veterans (SMVs) lifetime blast exposure and recovery from a traumatic brain injury (TBI). A total of 558 SMVs with a history of TBI were examined. Lifetime blast exposure (LBE) was based on self-report (M = 79.4, standard deviation = 392.6; range = 0-7500) categorized into three groups: Blast Naive (n = 121), Low LBE (n = 223; LBE range 1-9), and High LBE (n = 214; LBE >10). Dependent variables were the Neurobehavioral Symptom Inventory (NSI) and Post-traumatic Stress Disorder Checklist-Civilian (PCL-C) and the Traumatic Brain Injury Quality of Life (TBI-QOL). Analyses controlled for demographic factors (age, gender, and race) as well as TBI factors (months since index TBI, index TBI severity, and total number lifetime TBIs). The Blast Naive group had significantly lower NSI and PCL-C scores compared with the Low LBE group and High LBE group, with small to medium effect sizes. On the TBI-QOL, the Blast Naïve group had better quality life on 10 of the 14 scales examined. The Low LBE did not differ from the High LBE group on the PCL-C, NSI, or TBI-QOL. Blast exposure over an SMV's career was associated with increased neurobehavioral and post-traumatic stress symptoms following a TBI. The influence of psychological trauma associated with blasts may be an important factor influencing symptoms as well as the accuracy of self-reported estimates of LBE.

High Lifetime Blast Exposure Using the Blast Exposure Threshold Survey Is Associated With Worse Warfighter Brain Health Following Mild Traumatic Brain Injury.

The purpose of this study was to extend previous research by examining the relationship between lifetime blast exposure and neurobehavioral functioning after mild TBI (MTBI) by (a) using a comprehensive measure of lifetime blast exposure, and (b) controlling for the influence of post-traumatic stress disorder (PTSD). Participants were 103 United States service members and veterans (SMVs) with a medically documented diagnosis of MTBI, recruited from three military treatment facilities (74.8%) and community-based recruitment initiatives (25.2%, e.g., social media, flyers). Participants completed a battery of neurobehavioral measures 12 or more months post-injury (Neurobehavioral Symptom Inventory, PTSD-Checklist PCLC, TBI-Quality of Life), including the Blast Exposure Threshold Survey (BETS). The sample was classified into two lifetime blast exposure (LBE) groups: High (n = 57) and Low (n = 46) LBE. In addition, the sample was classified into four LBE/PTSD subgroups: High PTSD/High LBE (n = 38); High PTSD/Low LBE (n = 19); Low PTSD/High LBE (n = 19); and Low PTSD/Low LBE (n = 27). The High LBE group had consistently worse scores on all neurobehavioral measures compared with the Low LBE group. When controlling for the influence of PTSD (using ANCOVA), however, only a handful of group differences remained. When comparing measures across the four LBE/PTSD subgroups, in the absence of clinically meaningful PTSD symptoms (i.e., Low PTSD), participants with High LBE had worse scores on the majority of neurobehavioral measures (e.g., post-concussion symptoms, sleep, fatigue). When examining the total number of clinically elevated measures, the High LBE subgroup consistently had a greater number of clinically elevated scores compared with the Low LBE subgroup for the majority of comparisons (i.e., four to 15 or more elevated symptoms). In contrast, in the presence of clinically meaningful PTSD symptoms (i.e., High PTSD), there were no differences between High versus Low LBE subgroups for all measures. When examining the total number of clinically elevated measures, however, there were meaningful differences between High versus Low LBE subgroups for those comparisons that included a high number of clinically elevated scores (i.e., six to 10 or more), but not for a low number of clinically elevated scores (i.e., one to five or more). High LBE, as quantified using a more comprehensive measure than utilized in past research (i.e., BETS), was associated with worse overall neurobehavioral functioning after MTBI. This study extends existing literature showing that lifetime blast exposure, that is largely subconcussive, may negatively impact warfighter brain health and readiness beyond diagnosable brain injury.

Convergent and Discriminant Validity of the Blast Exposure Threshold Survey in United States Military Service Members and Veterans.

The Blast Exposure Threshold Survey (BETS) is a recently developed and promising new self-report measure of lifetime blast exposure (LBE). However, there are no studies that have examined the psychometric properties of the BETS, which currently limits its clinical utility. The purpose of this study was to examine the convergent and discriminant validity of the BETS by comparing the BETS Generalized Blast Exposure Value (GBEV) to six variables hypothesized to be associated with LBE (i.e., single-item LBE, combat exposure, years in the military, number of combat deployments, and military occupation specialty [MOS]) and three variables hypothesized not to be associated with LBE (i.e., age at the time of injury, estimated pre-morbid Full-Scale Intelligence Quotient [FSIQ], and resilience). Participants were 202 United States service members and veterans prospectively enrolled from three military medical treatment facilities (68.7%) and via community recruitment initiatives (31.3%). Participants completed the BETS, Combat Exposure Scale (CES), Deployment Risk and Resiliency Inventory-2 Combat Experiences (DRRI-2 CE), Traumatic Brain Injury-Quality of Life Resilience scale, and a brief structured interview. For some analyses, participants were classified into two blast risk MOS groups: high (n = 89) and low (n = 94). The BETS GBEV was not significantly correlated with all three non-blast related variables (rs = 0.01 to rs = -0.12). In contrast, GBEV was significantly (p < 0.001) associated with all blast-related variables; single-item LBE (rs = 0.76), CES (rs = 0.58), number of combat deployments (rs = 0.53), DRRI-2 CE (rs = 0.48), and high blast risk MOS (r = 0.36, medium effect size). However, a stronger relationship was found between the blast-related variables and three modified GBEV scores when excluding some small weapons categories; single-item LBE (rs = 0.80-0.82), CES (rs = 0.64-0.67), number of combat deployments (rs = 0.56), DRRI-2 CE (rs = 0.51-0.53), and high blast risk MOS (r = 0.42-0.49, medium-large effect size). This is the first study to examine the psychometric properties of the BETS. Overall, these results offer support for the convergent and discriminant validity of the BETS. In order to ensure that the BETS can be confidently used as a valid and reliable measure of LBE, more research is needed to further examine the psychometric properties of the test, particularly with regard to the establishment of test-retest reliability.

Lifetime Blast Exposure Is Not Related to White Matter Integrity in Service Members and Veterans With and Without Uncomplicated Mild Traumatic Brain Injury.

This study examines the impact of lifetime blast exposure on white matter integrity in service members and veterans (SMVs). Participants were 227 SMVs, including those with a history of mild traumatic brain injury (mTBI; n = 124), orthopedic injury controls (n = 58), and non-injured controls (n = 45), prospectively enrolled in a Defense and Veterans Brain Injury Center (DVBIC)/Traumatic Brain Injury Center of Excellence (TBICoE) study. Participants were divided into three groups based on number of self-reported lifetime blast exposures: none (n = 53); low (i.e., 1-9 blasts; n = 81); and high (i.e., ≥10 blasts; n = 93). All participants underwent diffusion tensor imaging (DTI) at least 11 months post-injury. Tract-of-interest (TOI) analysis was applied to investigate fractional anisotropy and mean, radial, and axial diffusivity (AD) in left and right total cerebral white matter as well as 24 tracts. Benjamini-Hochberg false discovery rate (FDR) correction was used. Regressions investigating blast exposure and mTBI on white matter integrity, controlling for age, revealed that the presence of mTBI history was associated with lower AD in the bilateral superior longitudinal fasciculus and arcuate fasciculus and left cingulum (ßs = -0.255 to -0.174; ps < 0.01); however, when non-injured controls were removed from the sample (but orthopedic injury controls remained), these relationships were attenuated and did not survive FDR correction. Regression models were rerun with modified post-traumatic stress disorder (PTSD) diagnosis added as a predictor. After FDR correction, PTSD was not significantly associated with white matter integrity in any of the models. Overall, there was no relationship between white matter integrity and self-reported lifetime blast exposure or PTSD.

Phosphodiesterase-5 (PDE-5) Inhibitors as Therapy for Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury.

Multiple phase III randomized controlled trials (RCTs) for pharmacologic interventions in traumatic brain injury (TBI) have failed despite promising results in experimental models. The heterogeneity of TBI, in terms of pathomechanisms and impacted brain structures, likely contributes to these failures. Biomarkers have been recommended to identify patients with relevant pathology (predictive biomarkers) and confirm target engagement and monitor therapy response (pharmacodynamic biomarkers). Our group focuses on traumatic cerebrovascular injury as an understudied endophenotype of TBI and is validating a predictive and pharmacodynamic imaging biomarker (cerebrovascular reactivity; CVR) in moderate-severe TBI. We aim to extend these studies to milder forms of TBI to determine the optimal dose of sildenafil for maximal improvement in CVR. We will conduct a phase II dose-finding study involving 160 chronic TBI patients (mostly mild) using three doses of sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor. The study measures baseline CVR and evaluates the effect of escalating sildenafil doses on CVR improvement. A 4-week trial of thrice daily sildenafil will assess safety, tolerability, and clinical efficacy. This dual-site 4-year study, funded by the Department of Defense and registered in ClinicalTrials.gov (NCT05782244), plans to launch in June 2023. Biomarker-informed RCTs are essential for developing effective TBI interventions, relying on an understanding of underlying pathomechanisms. Traumatic microvascular injury (TMVI) is an attractive mechanism which can be targeted by vaso-active drugs such as PDE-5 inhibitors. CVR is a potential predictive and pharmacodynamic biomarker for targeted interventions aimed at TMVI. (Trial registration: NCT05782244, ClinicalTrials.gov ).

Elevated Serum Tau and UCHL-1 Concentrations Within 12 Months of Injury Predict Neurobehavioral Functioning 2 or More Years Following Traumatic Brain Injury: A Longitudinal Study.

OBJECTIVE: Blood-based biomarkers have received considerable attention for their diagnostic and prognostic value in the acute and postacute period following traumatic brain injury (TBI). The purpose of this study was to examine whether blood-based biomarker concentrations within the first 12 months of TBI can predict neurobehavioral outcome in the chronic phase of the recovery trajectory. SETTING: Inpatient and outpatient wards from 3 military medical treatment facilities. PARTICIPANTS: A total of 161 service members and veterans classified into 3 groups: (a) uncomplicated mild TBI (MTBI; n = 37), (b) complicated mild, moderate, severe, penetrating TBI combined (STBI; n = 46), and (c) controls (CTRL; n = 78). DESIGN: Prospective longitudinal. MAIN MEASURES: Participants completed 6 scales from the Traumatic Brain Injury Quality of Life (ie, Anger, Anxiety, Depression, Fatigue, Headaches, and Cognitive Concerns) within 12 months (baseline) and at 2 or more years (follow-up) post-injury. Serum concentrations of tau, neurofilament light, glial fibrillary acidic protein, and UCHL-1 at baseline were measured using SIMOA. RESULTS: Baseline tau was associated with worse anger, anxiety, and depression in the STBI group at follow-up (R2 = 0.101-0.127), and worse anxiety in the MTBI group (R2 = 0.210). Baseline ubiquitin carboxyl-terminal hydrolase L1 (UCHL-1) was associated with worse anxiety and depression at follow-up in both the MTBI and STBI groups (R2Δ = 0.143-0.207), and worse cognitive concerns in the MTBI group (R2Δ = 0.223). CONCLUSIONS: A blood-based panel including these biomarkers could be a useful tool for identifying individuals at risk of poor outcome following TBI.

Efficient Estimation of the Binaural Masking Level Difference Using a Technique Based on Manual Audiometry.

PURPOSE: The Masking Level Difference (MLD) has been used for decades to evaluate the binaural listening advantage. Although originally measured using Bekesy audiometry, the most common clinical use of the MLD is the CD-based Wilson 500-Hz technique with interleaved N0S0 and N0Sπ components. Here, we propose an alternative technique based on manual audiometry as a faster way of measuring the MLD. The article describes the advantages to this administration technique and evaluates if it is a viable alternative for the Wilson technique. METHOD: Data were retrospectively analyzed on 264 service members (SMs). All SMs completed both the Wilson and Manual MLDs. Descriptive and correlational statistics were applied to evaluate the comparisons between the two techniques and highlight the differences. Equivalence measures were also completed to compare the tests using a standardized cutoff score. Analyses were also made to compare both techniques to subjective and objective measures of hearing performance. RESULTS: Moderate to high positive correlations were determined between Wilson and Manual measures of each threshold (N0Sπ and N0S0). Although the Manual and Wilson MLD techniques produced significantly different thresholds, simple linear transformations can be used to obtain approximately equivalent scores on the two tests, and agreement was high for using these transformed scores to identify individuals with substantial MLD deficits. Both techniques had moderate test-retest reliability. The Manual MLD and components had stronger correlations to the subjective and objective hearing measures than the Wilson. CONCLUSIONS: The Manual technique is a faster method for obtaining MLD scores that is just as reliable as the CD-based Wilson test. With the significant reduction in assessment time and comparable results, the Manual MLD is a viable alternative for direct use in the clinic.

Normative Ranges for, and Interrater Reliability of, Rotational Vestibular and Balance Tests in U.S. Military Service Members and Veterans.

PURPOSE: The objectives of this study were to (a) describe normative ranges-expressed as reference intervals (RIs)-for vestibular and balance function tests in a cohort of Service Members and Veterans (SMVs) and (b) to describe the interrater reliability of these tests. METHOD: As part of the Defense and Veterans Brain Injury Center (DVBIC)/Traumatic Brain Injury Center of Excellence 15-year Longitudinal Traumatic Brain Injury (TBI) Study, participants completed the following: vestibulo-ocular reflex suppression, visual-vestibular enhancement, subjective visual vertical, subjective visual horizontal, sinusoidal harmonic acceleration, the computerized rotational head impulse test (crHIT), and the sensory organization test. RIs were calculated using nonparametric methods and interrater reliability was assessed using intraclass correlation coefficients between three audiologists who independently reviewed and cleaned the data. RESULTS: Reference populations for each outcome measure comprised 40 to 72 individuals, 19 to 61 years of age, who served either as noninjured controls (NIC) or injured controls (IC) in the 15-year study; none had a history of TBI or blast exposure. A subset of 15 SMVs from the NIC, IC, and TBI groups were included in the interrater reliability calculations. RIs are reported for 27 outcome measures from the seven rotational vestibular and balance tests. Interrater reliability was considered excellent for all tests except the crHIT, which was found to have good interrater reliability. CONCLUSION: This study provides clinicians and scientists with important information regarding normative ranges and interrater reliability for rotational vestibular and balance tests in SMVs.

Cross-Walk Comparison of the DVBIC-TBICoE and LIMBIC-CENC Combat-Related Concussion Prospective Longitudinal Study Datasets.

OBJECTIVE: To describe and compare cohorts between 2 large, longitudinal, federally-funded TBI studies of Service members and veterans across demographic, self-report, and neuropsychological variables. DESIGN: Analysis of data from the DVBIC-TBICoE and LIMBIC-CENC prospective longitudinal studies (PLS). SETTING: Recruitment locations spanning Department of Defense and Veterans Affairs hospitals across the U.S. PARTICIPANTS: 1463 participants (N=1463) enrolled in the DVBIC-TBICoE study and divided among non-injured (NIC) (n=191), injured control (IC) (n=349), mild TBI (mTBI) (n=682), and (severe, moderate, penetrating, and complicated mild traumatic brain injury (smcTBI) (n=241) subgroups. 1550 participants enrolled in the LIMBIC-CENC study and divided between IC (n=285) and mTBI (n=1265) subgroups. IC and mTBI study groups were compared across demographic and military characteristics, self-reported symptoms, and neuropsychological test scores. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Neurobehavioral Symptom Inventory, PTSD Checklist-Military Version, TBI quality of life, Test of Premorbid Functioning, Wechsler Adult Intelligence Scale-IV Visual Puzzles, Symbol Search, Coding, Letter-Number Sequencing, and Digit Span, Trail Making Test, Delis-Kaplan Executive Functioning System Verbal Fluency, Letter Fluency, and Category Fluency, California Verbal Learning Test-II, and Grooved Pegboard. RESULTS: Compared with DVBIC-TBICoE, LIMBIC-CENC participants have higher enrollment age, education level, proportion of Black race, and time from injury as well as less combat deployments and are less likely to be married. The distribution of military service branches also differed. Further, symptom profiles differed between cohorts. LIMBIC-CENC participants endorsed higher posttraumatic stress disorder symptomatology. DVBIC-TBICoE study IC participants endorsed higher somatosensory and vestibular symptoms (medium effect sizes). Other symptom measure differences had very small effect sizes (≤0.2). Differences were found on many cognitive test results, but are difficult to interpret given the demographic differences and generally very small effect sizes. CONCLUSIONS: The heavy use of National Institutes of Health common data elements in both studies and collaboration with the DVBIC-TBICoE study team on development of the LIMBIC-CENC assessment battery enabled this comparative analysis. Results highlight unique differences in study cohorts and add perspective and interpretability for assimilating past and future findings.

Varying failure criteria on performance validity tests influences interpretation of cognitive outcomes.

OBJECTIVE: The present study examined the effects of applying various performance validity tests (PVT) failure criteria on the relationship between cognitive outcomes and posttraumatic stress (PTS) symptomology. METHOD: One hundred and ninety-nine veterans with a history of mild traumatic brain injury referred for clinical evaluation completed cognitive tests, PVTs, and self-report measures of PTS symptoms and symptom exaggeration. Normative T scores of select cognitive tests were averaged into memory, attention/processing speed, and executive functioning composites. Separate one way analyses of variance assessed differences among high PTS (n = 140) versus low PTS (n = 59) groups and were repeated excluding participants based on varying combinations of PVT failure criteria. RESULTS: When no PVTs were considered, the high PTS group demonstrated worse performance across all three cognitive domains. Excluding those who failed two or more stand-alone, or two or more embedded validity measures resulted in group differences across all cognitive composites. When participants were excluded based on failure of any one embedded and any one stand-alone PVT measure combined, the high PTS group performed worse on the executive functioning and attention/processing speed composites. The remaining three proposed methods to control for performance validity resulted in null PTS-cognition relationships. Results remained largely consistent after controlling for symptom exaggeration. CONCLUSIONS: Methods of defining PVT failure can greatly influence differences in cognitive function between groups defined by PTS symptom levels. Findings highlight the importance of considering performance validity when interpreting cognitive data and warrant future investigation of PVT failure criteria in other conditions. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Risk factors for the presence and persistence of posttraumatic stress symptoms following traumatic brain injury in U.S. service members and veterans.

This study aimed to identify risk factors predictive of the presence and persistence of posttraumatic stress disorder (PTSD) symptom reporting following traumatic brain injury (TBI). Participants were 1,301 U.S. service members and veterans (SMVs) divided into four groups: uncomplicated mild TBI (mTBI; n = 543); complicated mild, moderate, severe, and penetrating TBI (n = 230); injured controls (n = 340); and noninjured controls (n = 188). We examined 25 factors related to demographic, injury-related, military-specific, treatment/health care need, and mental health/social support variables. Seven factors were statistically associated with the presence of DSM-IV-TR symptom criteria for PTSD: premorbid IQ, combat exposure, depression, social participation, history of mTBI, need for managing mood and stress, and need for improving memory and attention, p < .001 (51.3% variance). When comparing the prevalence of these risk factors in a longitudinal cohort (n = 742) across four PTSD trajectory groups (i.e., asymptomatic, improved, developed, persistent), a higher proportion of participants in the persistent PTSD group reported worse depression, a lack of social participation, and history of mTBI. Additionally, a higher proportion of participants in the persistent and developed PTSD groups reported the need for managing mood/stress and improving memory/attention. When considered simultaneously, the presence of ≥ 1 or ≥ 2 risk factors was associated with a higher proportion of participants in the developed and persistent PTSD groups, ps < .001. These risk factors may be useful in identifying SMVs at risk for the development and/or persistence of PTSD symptoms who may need intervention.

White Matter Integrity Relates to Cognition in Service Members and Veterans after Complicated Mild, Moderate, and Severe Traumatic Brain Injury, But Not Uncomplicated Mild Traumatic Brain Injury.

The extant literature investigating the relationship between diffusion tensor imaging (DTI) and cognition following traumatic brain injury (TBI) is limited by small sample sizes and inappropriate control groups. The present study examined DTI metric differences between service members and veterans (SMVs) with bodily injury (Trauma Control; TC), uncomplicated mild TBI (mTBI), complicated mild TBI (compTBI), and severe-moderate TBI combined (smTBI), and how DTI metrics related to cognition within each group. Participants were 226 SMVs (56 TC, 112 mTBI, 29 compTBI, 29 smTBI) with valid neuropsychological testing and DTI at least 11 months post-injury. The smTBI group demonstrated decreased fractional anisotropy (FA) and increased axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) of the cerebral white matter (CWM) and several individual white matter tracts compared with the TC, mTBI, and compTBI groups (all ps < 0.05; rs = 0.17 to 0.49). The TC, mTBI, and compTBI groups did not differ in terms of any DTI metrics. Within the smTBI group, FA, AD, MD, and RD of the total CWM and several white matter tracts were related to Processing Speed (|rs|: 0.43 to 0.66; ps < 0.05), and/or Delayed Memory (|rs|: 0.41 to 0.67; ps < 0.05). In the compTBI group, Processing Speed was related to left arcuate fasciculus and superior longitudinal fasciculus (SLF) FA, MD, and RD, as well as left uncinate fasciculus MD and RD. In contrast, there were no significant relationships between DTI metrics and cognition/emotional functioning within the mTBI or TC groups. Overall, findings suggest a dose-response relationship between TBI severity and the strength of the relationship between white matter integrity and cognitive performance, with essentially no relationship in mTBI, some findings in compTBI, and several strongly significant relationships in smTBI. In contrast to previously reported findings, there were no differences in DTI metrics between controls, mTBI, and compTBI, and DTI metrics were unrelated to cognition in our relatively large mTBI group.

¹8F-fluorodeoxyglucose-positron emission tomography findings are not related to cognitive functioning in service members with remote history of mild traumatic brain injury.

OBJECTIVE: Determine whether glucose uptake as measured by 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging is associated with cognitive performance and cognitive deficits in active duty service members with a history of mild traumatic brain injury (mTBI). METHOD: 287 patients with a history of mTBI underwent FDG-PET scans at rest and neuropsychological testing at the National Intrepid Center of Excellence at Walter Reed National Military Medical Center. Glucose uptake in the bilateral frontal, parietal, occipital, and temporal lobes, and 58 cortical/cerebellar regions were correlated with seven neuropsychological composite scores, with and without relevant covariates. RESULTS: Perceptual reasoning correlated with bilateral hippocampi glucose uptake (rs = .141-.165, p < .03), processing speed was inversely related to glucose uptake in the left temporal lobe (r = -.134, p = .034), and working memory was related to glucose uptake in the left parietal, temporal, and occipital lobes (rs = .128-.140, p < .05); however, these findings did not survive correction for multiple comparisons. Partial correlations between cognition and the 56 cortical/cerebellar regions of interests were not significant after correction for multiple comparisons. Glucose uptake in the left hippocampus was inversely related to the likelihood of cognitive deficits (OR = .745, p = .041); however, this did not survive correction for multiple comparisons. CONCLUSIONS: After correction for multiple comparisons, there was no significant relationship between regional glucose uptake and neurocognitive performance or cognitive deficits. Glucose uptake as measured by FDG-PET is not indicative of cognitive performance in active duty service members with a remote history of mTBI. (PsycInfo Database Record (c) 2023 APA, all rights reserved).