Dataset Information

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

ABSTRACT:

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; η_p ² = .039) and executive functioning (p = .010; η_p ² = .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; η_p ² < .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.

SUBMITTER: Merritt VC

PROVIDER: S-EPMC7415574 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundMild traumatic brain injury (mTBI) occurs at a higher frequency among military personnel than among civilians. A common symptom of mTBIs is cognitive dysfunction. Health care professionals use neuropsychological assessments as part of a multidisciplinary and best practice approach for mTBI management. Such assessments support clinical diagnosis, symptom management, rehabilitation, and return-to-duty planning. Military health care organizations currently use computerized neurocognitive assessment tools (NCATs). NCATs and more traditional neuropsychological assessments present unique challenges in both clinical and military settings. Many research gaps remain regarding psychometric properties, usability, acceptance, feasibility, effectiveness, sensitivity, and utility of both types of assessments in military environments.ObjectiveThe aims of this study were to explore evidence regarding the use of NCATs among military personnel who have sustained mTBIs; evaluate the psychometric properties of the most commonly tested NCATs for this population; and synthesize the data to explore the range and extent of NCATs among this population, clinical recommendations for use, and knowledge gaps requiring future research.MethodsStudies were identified using MEDLINE, Embase, American Psychological Association PsycINFO, CINAHL Plus with Full Text, Psych Article, Scopus, and Military & Government Collection. Data were analyzed using descriptive analysis, thematic analysis, and the Randolph Criteria. Narrative synthesis and the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews) guided the reporting of findings. The psychometric properties of NCATs were evaluated with specific criteria and summarized.ResultsOf the 104 papers, 33 met the inclusion criteria for this scoping review. Thematic analysis and NCAT psychometrics were reported and summarized.ConclusionsWhen considering the psychometric properties of the most commonly used NCATs in military populations, these assessments have yet to demonstrate adequate validity, reliability, sensitivity, and clinical utility among military personnel with mTBIs. Additional research is needed to further validate NCATs within military populations, especially for those living outside of the United States and individuals experiencing other conditions known to adversely affect cognitive processing. Knowledge gaps remain, warranting further study of psychometric properties and the utility of baseline and normative testing for NCATs.

Project description:Clinicians have long noticed that some Traumatic Brain Injury (TBI) patients have worse symptoms and take a longer time to recover than others, for reasons unexplained by known factors. Identifying what makes some individuals more susceptible is critical to understanding the underlying mechanisms through which TBI causes deleterious effects. We have sought to determine the effect of a single nucleotide polymorphism (SNP) in Brain-derived neurotrophic factor (BDNF) at amino acid 66 (rs6265) on recovery after TBI. There is controversy from human studies as to whether the BDNF Val66Val or Val66Met allele is the risk factor for worse outcomes after brain trauma. We therefore investigated cellular and behavioral outcomes in genetically engineered mice following repeated mild TBI (rmTBI) using a lateral fluid percussion (LFP) injury model. We found that relative to injured Val66Val carriers, injured Val66Met carriers had a larger inflammation volume and increased levels of neurodegeneration, apoptosis, p-tau, activated microglia, and gliosis in the cortex and/or hippocampus at 1 and/or 21 days post-injury (DPI). We therefore concluded that the Val66Met genetic polymorphism is a risk factor for poor outcomes after rmTBI. In order to determine the mechanism for these differences, we investigated levels of the apoptotic-inducing pro BDNF and survival-inducing mature BDNF isoforms and found that Met carriers had less total BDNF in the cortex and a higher pro/mature ratio of BDNF in the hippocampus. We then developed a personalized approach to treating genetically susceptible individuals by overexpressing wildtype BDNF in injured Val66Met mice using an AAV-BDNF virus. This intervention improved cellular, motor, and cognitive behavior outcomes at 21 DPI and increased levels of mature BDNF and phosphorylation of mature BDNF's receptor trkB. This study lays the groundwork for further investigation into the genetics that play a role in the extent of injury after rmTBI and highlights how personalized therapeutics may be targeted for recovery in susceptible individuals.

Project description:ImportanceTraumatic brain injury (TBI) is common in both veteran and civilian populations. Prior studies have linked moderate and severe TBI with increased dementia risk, but the association between dementia and mild TBI, particularly mild TBI without loss of consciousness (LOC), remains unclear.ObjectiveTo examine the association between TBI severity, LOC, and dementia diagnosis in veterans.Design, setting, and participantsThis cohort study of all patients diagnosed with a TBI in the Veterans Health Administration health care system from October 1, 2001, to September 30, 2014, and a propensity-matched comparison group. Patients with dementia at baseline were excluded. Researchers identified TBIs through the Comprehensive TBI Evaluation database, which is restricted to Iraq and Afghanistan veterans, and the National Patient Care Database, which includes veterans of all eras. The severity of each TBI was based on the most severe injury recorded and classified as mild without LOC, mild with LOC, mild with LOC status unknown, or moderate or severe using Department of Defense or Defense and Veterans Brain Injury Center criteria. International Classification of Diseases, Ninth Revision codes were used to identify dementia diagnoses during follow-up and medical and psychiatric comorbidities in the 2 years prior to the index date.Main outcomes and measuresDementia diagnosis in veterans who had experienced TBI with or without LOC and control participants without TBI exposure.ResultsThe study included 178 779 patients diagnosed with a TBI in the Veterans Health Administration health care system and 178 779 patients in a propensity-matched comparison group. Veterans had a mean (SD) age of nearly 49.5 (18.2) years at baseline; 33 250 (9.3%) were women, and 259 136 (72.5%) were non-Hispanic white individuals. Differences between veterans with and without TBI were small. A total of 4698 veterans (2.6%) without TBI developed dementia compared with 10 835 (6.1%) of those with TBI. After adjustment for demographics and medical and psychiatric comobidities, adjusted hazard ratios for dementia were 2.36 (95% CI, 2.10-2.66) for mild TBI without LOC, 2.51 (95% CI, 2.29-2.76) for mild TBI with LOC, 3.19 (95% CI, 3.05-3.33) for mild TBI with LOC status unknown, and 3.77 (95% CI, 3.63-3.91) for moderate to severe TBI.Conclusions and relevanceIn this cohort study of more than 350 000 veterans, even mild TBI without LOC was associated with more than a 2-fold increase in the risk of dementia diagnosis. Studies of strategies to determine mechanisms, prevention, and treatment of TBI-related dementia in veterans are urgently needed.

Project description:The predictability of neurocognitive outcomes in patients with traumatic brain injury is not straightforward. The extent and nature of recovery in patients with mild traumatic brain injury (mTBI) are usually heterogeneous and not substantially explained by the commonly known demographic and injury-related prognostic factors despite having sustained similar injuries or injury severity. Hence, this study evaluated the effects and association of the Brain Derived Neurotrophic Factor (BDNF) missense mutations in relation to neurocognitive performance among patients with mTBI. 48 patients with mTBI were prospectively recruited and MRI scans of the brain were performed within an average 10.1 (SD 4.2) hours post trauma with assessment of their neuropsychological performance post full Glasgow Coma Scale (GCS) recovery. Neurocognitive assessments were repeated again at 6 months follow-up. The paired t-test, Cohen's d effect size and repeated measure ANOVA were performed to delineate statistically significant differences between the groups [wildtype G allele (Val homozygotes) vs. minor A allele (Met carriers)] and their neuropsychological performance across the time point (T1 = baseline/ admission vs. T2 = 6th month follow-up). Minor A allele carriers in this study generally performed more poorly on neuropsychological testing in comparison wildtype G allele group at both time points. Significant mean differences were observed among the wildtype group in the domains of memory (M = -11.44, SD = 10.0, p = .01, d = 1.22), executive function (M = -11.56, SD = 11.7, p = .02, d = 1.05) and overall performance (M = -6.89 SD = 5.3, p = .00, d = 1.39), while the minor A allele carriers showed significant mean differences in the domains of attention (M = -11.0, SD = 13.1, p = .00, d = .86) and overall cognitive performance (M = -5.25, SD = 8.1, p = .01, d = .66).The minor A allele carriers in comparison to the wildtype G allele group, showed considerably lower scores at admission and remained impaired in most domains across the timepoints, although delayed signs of recovery were noted to be significant in the domains attention and overall cognition. In conclusion, the current study has demonstrated the role of the BDNF rs6265 Val66Met polymorphism in influencing specific neurocognitive outcomes in patients with mTBI. Findings were more detrimentally profound among Met allele carriers.