Dataset Information

APOE-?4 Genotype is Associated with Elevated Post-Concussion Symptoms in Military Veterans with a Remote History of Mild Traumatic Brain Injury.

ABSTRACT: OBJECTIVE:We evaluated the influence of the APOE-?4 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 ?4 status (n = 14 ?4+, n = 63 ?4-). 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 ?4 genotype on the NSI total score and somatic symptom cluster after adjusting for posttraumatic stress symptoms and mTBI history (p = .019-.028, ?p2 = .064-.073), such that ?4+ Veterans endorsed significantly greater symptoms than ?4- Veterans. CONCLUSIONS:Our findings suggest that genetic risk may help to explain the poorer long-term outcomes often observed in this population.

SUBMITTER: Merritt VC

PROVIDER: S-EPMC6659168 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Merritt Victoria C VC Lapira Kristina M KM Clark Alexandra L AL Sorg Scott F SF Werhane Madeleine L ML Jak Amy J AJ Bondi Mark W MW Schiehser Dawn M DM Delano-Wood Lisa L

Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists 20190701 5

<h4>Objective</h4>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).<h4>Method</h4>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 ( ...[more]

PMID: 30521018

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Project description:As few studies have examined the relationship between the apolipoprotein E (APOE) gene and clinical outcomes after military-related traumatic brain injury (TBI), we aimed to determine whether the ?4 allele of the APOE gene influences neuropsychiatric symptoms in veterans with a history of mild-to-moderate TBI. Participants included 133 veterans (TBI?=?79; military controls [MC]?=?54) who underwent APOE genotyping and were divided into ?4+ (TBI?=?18; MC?=?15) and ?4- (TBI?=?61; MC?=?39) groups. All participants underwent evaluation of psychological distress using the Beck Depression Inventory-II, Beck Anxiety Inventory, and PTSD Checklist-Military Version. Two-way analyses of variance were conducted to examine the effect of group (TBI vs. MC) and APOE-?4 status (?4+ vs. ?4-) across symptom measures. There was a significant main effect of group across all symptom measures (TBI > MC; all p values <0.001), no main effect of ?4 genotype (p?=?0.152-0.222), and a significant interaction of group by ?4 genotype across all measures (p?=?0.027-0.047). Specifically, for TBI participants, ?4+ veterans demonstrated significantly higher symptom scores across all measures when compared to ?4- veterans (p?=?0.007-0.015). For MC participants, ?4 status had no effect on the severity of psychiatric symptom scores (p?=?0.585-0.708). Our results demonstrate that, in our well-characterized sample of veterans with history of neurotrauma, possession of the ?4 allele conveys risk for increased symptomatology (i.e., depression, anxiety, and post-traumatic stress disorder), even well outside of the acute phase of injury. Findings suggest a meaningful relationship between APOE genotype and psychiatric distress post-TBI, and they suggest that there is a brain basis for the complex neuropsychiatric presentation often observed in this vulnerable population. Future longitudinal studies are needed in order to further our understanding of how genetic factors influence response to TBI.

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:A history of traumatic brain injury (TBI) increases the odds of developing Alzheimer's disease (AD). The long latent period between injury and dementia makes it difficult to study molecular changes initiated by TBI that may increase the risk of developing AD. MicroRNA (miRNA) levels are altered in TBI at acute times post-injury (<4 weeks), and in AD. We hypothesized that miRNA levels in cerebrospinal fluid (CSF) following TBI in veterans may be indicative of increased risk for developing AD. Our population of interest is cognitively normal veterans with a history of one or more mild TBI (mTBI) at a chronic time following TBI. We measured miRNA levels in CSF from three groups of participants: (1) community controls with no lifetime history of TBI (ComC); (2) deployed Iraq/Afghanistan veterans with no lifetime history of TBI (DepC), and (3) deployed Iraq/Afghanistan veterans with a history of repetitive blast mTBI (DepTBI). CSF samples were collected at the baseline visit in a longitudinal, multimodal assessment of Gulf War veterans, and represent a heterogenous group of male veterans and community controls. The average time since the last blast mTBI experienced was 4.7 ± 2.2 years [1.5 - 11.5]. Statistical analysis of TaqManTM miRNA array data revealed 18 miRNAs with significant differential expression in the group comparisons: 10 between DepTBI and ComC, 7 between DepC and ComC, and 8 between DepTBI and DepC. We also identified 8 miRNAs with significant differential detection in the group comparisons: 5 in DepTBI vs. ComC, 3 in DepC vs. ComC, and 2 in DepTBI vs. DepC. When we applied our previously developed multivariable dependence analysis, we found 13 miRNAs (6 of which are altered in levels or detection) that show dependencies with participant phenotypes, e.g., ApoE. Target prediction and pathway analysis with miRNAs differentially expressed in DepTBI vs. either DepC or ComC identified canonical pathways highly relevant to TBI including senescence and ephrin receptor signaling, respectively. This study shows that both TBI and deployment result in persistent changes in CSF miRNA levels that are relevant to known miRNA-mediated AD pathology, and which may reflect early events in AD.

Dataset Information

APOE-?4 Genotype is Associated with Elevated Post-Concussion Symptoms in Military Veterans with a Remote History of Mild Traumatic Brain Injury.

Publications

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

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