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BDNF genotype is associated with hippocampal volume in mild traumatic brain injury.

ABSTRACT: The negative long-term effects of mild traumatic brain injury (mTBI) have been a growing concern in recent years, with accumulating evidence suggesting that mTBI combined with additional vulnerability factors may induce neurodegenerative-type changes in the brain. However, the factors instantiating risk for neurodegenerative disease following mTBI are unknown. This study examined the link between mTBI and brain-derived neurotrophic factor (BDNF) genotype, which has previously been shown to regulate processes involved in neurodegeneration including synaptic plasticity and facilitation of neural survival through its expression. Specifically, we examined nine BDNF single-nucleotide polymorphisms (SNPs; rs908867, rs11030094, rs6265, rs10501087, rs1157659, rs1491850, rs11030107, rs7127507 and rs12273363) previously associated with brain atrophy or memory deficits in mTBI. Participants were 165 white, non-Hispanic Iraq and Afghanistan war veterans between the ages of 19 and 58, 110 of whom had at least one mTBI in their lifetime. Results showed that the BDNF SNP rs1157659 interacted with mTBI to predict hippocampal volume. Furthermore, exploratory analysis of functional resting state data showed that rs1157659 minor allele homozygotes with a history of mTBI had reduced functional connectivity in the default mode network compared to major allele homozygotes and heterozygotes. Apolipoprotein E (APOE) was not a significant predictor of hippocampal volume or functional connectivity. These results suggest that rs1157659 minor allele homozygotes may be at greater risk for neurodegeneration after exposure to mTBI and provide further evidence for a potential role for BDNF in regulating neural processes following mTBI.

SUBMITTER: Hayes JP

PROVIDER: S-EPMC5787402 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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BDNF genotype is associated with hippocampal volume in mild traumatic brain injury.

Hayes J P JP Reagan A A Logue M W MW Hayes S M SM Sadeh N N Miller D R DR Verfaellie M M Wolf E J EJ McGlinchey R E RE Milberg W P WP Stone A A Schichman S A SA Miller M W MW

Genes, brain, and behavior 20170830 2

The negative long-term effects of mild traumatic brain injury (mTBI) have been a growing concern in recent years, with accumulating evidence suggesting that mTBI combined with additional vulnerability factors may induce neurodegenerative-type changes in the brain. However, the factors instantiating risk for neurodegenerative disease following mTBI are unknown. This study examined the link between mTBI and brain-derived neurotrophic factor (BDNF) genotype, which has previously been shown to regul ...[more]

PMID: 28755387

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Project description:To investigate longitudinal changes in global and regional brain volume in patients 1 year after mild traumatic brain injury (MTBI) and to correlate such changes with clinical and neurocognitive metrics.This institutional review board-approved study was HIPAA compliant. Twenty-eight patients with MTBI (with 19 followed up at 1 year) with posttraumatic symptoms after injury and 22 matched control subjects (with 12 followed up at 1 year) were enrolled. Automated segmentation of brain regions to compute regional gray matter (GM) and white matter (WM) volumes was performed by using three-dimensional T1-weighted 3.0-T magnetic resonance imaging, and results were correlated with clinical metrics. Pearson and Spearman rank correlation coefficients were computed between longitudinal brain volume and neurocognitive scores, as well as clinical metrics, over the course of the follow-up period.One year after MTBI, there was measurable global brain atrophy, larger than that in control subjects. The anterior cingulate WM bilaterally and the left cingulate gyrus isthmus WM, as well as the right precuneal GM, showed significant decreases in regional volume in patients with MTBI over the 1st year after injury (corrected P < .05); this was confirmed by means of cross-sectional comparison with data in control subjects (corrected P < .05). Left and right rostral anterior cingulum WM volume loss correlated with changes in neurocognitive measures of memory (r = 0.65, P = .005) and attention (r = 0.60, P = .01). At 1-year follow-up, WM volume in the left cingulate gyrus isthmus correlated with clinical scores of anxiety (Spearman rank correlation r = -0.68, P = .007) and postconcussive symptoms (Spearman rank correlation r = -0.65, P = .01).These observations demonstrate structural changes to the brain 1 year after injury after a single concussive episode. Regional brain atrophy is not exclusive to moderate and severe traumatic brain injury but may be seen after mild injury. In particular, the anterior part of the cingulum and the cingulate gyrus isthmus, as well as the precuneal GM, may be distinctively vulnerable 1 year after MTBI.

Project description:Traumatic brain injury (TBI) is a prevalent head injury worldwide which increases the risk of neurodegenerative diseases. Increased reactive oxygen species (ROS) and inflammatory chemokines after TBI induces secondary effects which damage neurons. Targeting NADPH oxidase or increasing redox systems are ways to reduce ROS and damage. Earlier studies show that C-C motif chemokine ligand 5 (CCL5) has neurotrophic functions such as promoting neurite outgrowth as well as reducing apoptosis. Although CCL5 levels in blood are associated with severity in TBI patients, the function of CCL5 after brain injury is unclear. In the current study, we induced mild brain injury in C57BL/6 (wildtype, WT) mice and CCL5 knockout (CCL5-KO) mice using a weight-drop model. Cognitive and memory functions in mice were analyzed by Novel-object-recognition and Barnes Maze tests. The memory performance of both WT and KO mice were impaired after mild injury. Cognition and memory function in WT mice quickly recovered after 7 days but recovery took more than 14 days in CCL5-KO mice. FJC, NeuN and Hypoxyprobe staining revealed large numbers of neurons damaged by oxidative stress in CCL5-KO mice after mTBI. NADPH oxidase activity show increased ROS generation together with reduced glutathione peroxidase-1 (GPX1) and glutathione (GSH) activity in CCL5-KO mice; this was opposite to that seen in WT mice. CCL5 increased GPX1 expression and reduced intracellular ROS levels which subsequently increased cell survival both in primary neuron cultures and in an overexpression model using SHSY5Y cell. Memory impairment in CCL5-KO mice induced by TBI could be rescued by i.p. injection of the GSH precursor - N-acetylcysteine (NAC) or intranasal delivery of recombinant CCL5 into mice after injury. We conclude that CCL5 is an important molecule for GPX1 antioxidant activation during post-injury day 1-3, and protects hippocampal neurons from ROS as well as improves memory function after trauma.

Project description:Psychosis is a rare, but particularly serious sequela of traumatic brain injury. However, little is known as to the neurobiological processes that may contribute to its onset. Early evidence suggests that psychotic symptom development after traumatic brain injury may co-occur with hippocampal degeneration, invoking the possibility of a relationship. Particularly regarding the hippocampal head, these degenerative changes may lead to dysregulation in dopaminergic circuits, as is reported in psychoses due to schizophrenia, resulting in the positive symptom profile typically seen in post-injury psychosis. The objective of this study was to examine change in hippocampal volume and psychotic symptoms across time in a sample of moderate-to-severe traumatic brain injury patients. We hypothesized that hippocampal volume loss would be associated with increased psychotic symptom severity. From a database of n = 137 adult patients with prospectively collected, longitudinal imaging and neuropsychiatric outcomes, n = 24 had complete data at time points of interest (5 and 12 months post-traumatic brain injury) and showed increasing psychotic symptom severity on the Personality Assessment Inventory psychotic experiences subscale of the schizophrenia clinical scale across time. Secondary analysis employing stepwise regression with hippocampal volume change (independent variable) and Personality Assessment Inventory psychotic symptom change (dependent variable) from 5 to 12 months post-injury was conducted including age, sex, marijuana use, family history of schizophrenia, years of education and injury severity as control variables. Total right hippocampal volume loss predicted an increase in the Personality Assessment Inventory psychotic experiences subscale (F (1, 22) = 5.396, adjusted R 2 = 0.161, P = 0.030; β = -0.017, 95% confidence interval = -0.018, -0.016) as did volume of the right hippocampal head (F (1, 22) = 5.764, adjusted R 2 = 0.172, P = 0.025; β = -0.019, 95% confidence interval = -0.021, -0.017). Final model goodness-of-fit was confirmed using k-fold (k = 5) cross-validation. Consistent with our hypotheses, the current findings suggest that hippocampal degeneration in the chronic stages of moderate-to-severe traumatic brain injury may play a role in the delayed onset of psychotic symptoms after traumatic brain injury. These findings localized to the right hippocampal head are supportive of a proposed aetiological mechanism whereby atrophy of the hippocampal head may lead to the dysregulation of dopaminergic networks following traumatic brain injury; possibly accounting for observed clinical features of psychotic disorder after traumatic brain injury (including prolonged latency period to symptom onset and predominance of positive symptoms). If further validated, these findings may bear important clinical implications for neurorehabilitative therapies following traumatic brain injury.

Dataset Information

BDNF genotype is associated with hippocampal volume in mild traumatic brain injury.

Publications

BDNF genotype is associated with hippocampal volume in mild traumatic brain injury.

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