The influence of genetic variants on striatal dopamine transporter and D2 receptor binding after TBI.

Dopamine (DA) neurotransmission influences cognition and recovery after traumatic brain injury (TBI). We explored whether functional genetic variants affecting the DA transporter (DAT) and D2 receptor (DRD2) impacted in vivo dopaminergic binding with positron emission tomography (PET) using [(11)C]ßCFT and [(11)C]raclopride. We examined subjects with moderate/severe TBI (N=12) ∼1 year post injury and similarly matched healthy controls (N=13). The variable number of tandem repeat polymorphism within the DAT gene and the TaqI restriction fragment length polymorphism near the DRD2 gene were assessed. TBI subjects had age-adjusted DAT-binding reductions in the caudate, putamen, and ventral striatum, and modestly increased D2 binding in ventral striatum versus controls. Despite small sample sizes, multivariate analysis showed lower caudate and putamen DAT binding among DAT 9-allele carriers and DRD2 A2/A2 homozygotes with TBI versus controls with the same genotype. Among TBI subjects, 9-allele carriers had lower caudate and putamen binding than 10/10 homozygotes. This PET study suggests a hypodopaminergic environment and altered DRD2 autoreceptor DAT interactions that may influence DA transmission after TBI. Future work will relate these findings to cognitive performance; future studies are required to determine how DRD2/DAT1 genotype and DA-ligand binding are associated with neurostimulant response and TBI recovery.

Corpus callosum integrity and neuropsychological performance after traumatic brain injury: a diffusion tensor imaging study.

OBJECTIVES: (1) Detailed analysis of diffusion tensor imaging (DTI) parameters (fractional anisotropy and radial diffusivity) to evaluate white matter integrity in the corpus callosum (CC), and (2) examine correlations between DTI data and performance on multiple measures of cognitive functioning. PARTICIPANTS: Twelve individuals with a history of complicated mild, moderate, or severe traumatic brain injury (TBI) who were an average of 1.7 years postinjury and 12 control participants. MAIN MEASURES: Standardized and experimental neuropsychological tests; detailed analysis of DTI parameters. RESULTS: The TBI group demonstrated DTI values suggesting decreased white matter integrity and correlations with severity of injury. Both groups showed correlations between DTI parameters and cognitive measures, with more significant correlations observed for the TBI group. White matter changes in the CC were evident chronically and were related to severity of injury. CONCLUSIONS: Diffusion tensor imaging parameters suggesting disruptions in white matter in the CC may be implicated in impaired performance, both in terms of cognitive tasks and reaction time, after TBI.

Variants of SLC6A4 in depression risk following severe TBI.

BACKGROUND: Post-traumatic depression (PTD) may be a result of several factors like secondary injury chemical cascades as well as psycho-social factors following traumatic brain injury (TBI). While the role of serotonin in the pathology and treatment of idiopathic major depression may be somewhat controversial, it is unclear what role serotonin may play in PTD following a TBI. OBJECTIVE: To assess serotonergic function and genetic risk for PTD development over 1 year following TBI. RESEARCH DESIGN: Examination of variation in the serotonin transporter gene [SLC6A4 (5-HTTLPR, rs25331, and a variable number of tandem repeats variant in Intron 2)] in 109 subjects with moderate-severe injury. Depression was assessed using the Patient Health Questionnaire (PHQ-9) at 6 and/or 12 months post-injury. MAIN OUTCOMES AND RESULTS: At 6 months post-injury, subjects with a history of pre-morbid mood disorders and 5-HTTLPR L-homozygotes were at greater risk for PTD. Contrary to major depression, subjects without pre-morbid mood disorders (n = 80) and S-carriers were 2.803-times less likely to be depressed compared to L-homozygotes. At 12 months post-injury, LG-carriers were also less likely to experience PTD. Temporal analysis also showed 5-HTTLPR associations in PTD development across recovery. CONCLUSIONS: This study suggests a unique injury- and temporally-specific interaction between TBI and genetic risk for depression.

Genetic variability in glutamic acid decarboxylase genes: associations with post-traumatic seizures after severe TBI.

Post traumatic seizures (PTS) occur frequently after traumatic brain injury (TBI). Since gamma-amino butyric acid (GABA) neurotransmission is central to excitotoxicity and seizure development across multiple models, we investigated how genetic variability for glutamic acid decarboxylase (GAD) influences risk for PTS. Using both a tagging and functional single nucleotide polymorphism (SNP) approach, we genotyped the GAD1 and GAD2 genes and linked them with PTS data, regarding time to first seizure, obtained for 257 adult subjects with severe TBI. No significant associations were found for GAD2. In the GAD1 gene, the tagging SNP (tSNP) rs3828275 was associated with an increased risk for PTS occurring <1 wk. The tSNP rs769391 and the functional SNP rs3791878 in the GAD1 gene were associated with increased PTS risk occurring 1 wk-6 mo post-injury. Both risk variants conferred an increased susceptibility to PTS compared to subjects with 0-1 risk variant. Also, those with haplotypes having both risk variants had a higher PTS risk 1 wk-6 mo post-injury than those without these haplotypes. Similarly, diplotype analysis showed those with 2 copies of the haplotype containing both risk alleles were at the highest PTS risk. These results implicate genetic variability within the GABA system in modulating the development of PTS.

Association of KIBRA rs17070145 polymorphism and episodic memory in individuals with severe TBI.

BACKGROUND: Studies implicate single nucleotide polymorphism (SNP) rs17070145, a common T → C polymorphism on the KIBRA gene, in mediating differences in episodic memory. In healthy adults, T-allele carriers perform better than non-carriers on episodic memory measures. However, this association is reversed in adults with subjective memory complaints and populations vulnerable to memory deficits, a problem common in traumatic brain injury (TBI). METHODS: This study assessed associations between variation in the KIBRA gene and cognitive function in 129 adults with severe TBI. In addition to other executive functioning and functional/global outcomes, the Buschke Selective Reminding Test (SRT), Rey-Osterrieth Complex Figure Test and California Verbal Learning Test-II (CVLT-II) were administered 6 and 12 months post-injury. RESULTS: T-allele non-carriers performed better than carriers on multiple episodic memory measures. At 6 months, T-allele non-carriers performed better for delayed recall measures on the SRT. At 12 months, T-allele non-carriers performed better on multiple SRT measures and on List-B learning with CVLT-II. No associations occurred with executive function or global outcome measures. CONCLUSION: These results suggest that rs17070145 T-allele effects are specific to episodic memory and support the hypothesis that associations between rs17070145 variation and memory are disparate between healthy and impaired populations.

Hemispheric and executive influences on low-level language processing after traumatic brain injury.

OBJECTIVE: The purpose of this study was to examine whether minor high-level language deficits found after traumatic brain injury (TBI) might be due to low-level language processing issues or executive control influences. A possible mechanism was also investigated. METHOD: Nineteen age- and education-matched healthy controls (16 M, 3 F) and 19 persons who had experienced a complicated mild, moderate or severe TBI between 1-3 years prior (16 M, 3 F; mean GCS = 9.44) participated in two computerized behavioural experiments utilizing two paradigms standard in the psycholinguistic literature (priming with lexical decision and verb generation), which included trials of greater and lesser executive demand. RESULTS: Response time and accuracy differences were found in both experiments, indicating deficits in single-word processing for the patient group. Disproportionate difficulty was found for trials which included an executive component. Right visual field (left hemisphere) preferences were found to be stronger in the TBI group than in controls. CONCLUSIONS: Results suggest that persons with TBI may have difficulties in processing single words alone, especially under conditions of increased executive demand, and that atypical patterns of hemispheric recruitment may be associated with these difficulties.

Encoding and recognition after traumatic brain injury: neuropsychological and functional magnetic resonance imaging findings.

Although impairment of episodic memory is common after traumatic brain injury (TBI), the complex nature of human memory suggests the need to study more than recall alone. For this reason, we are presenting an extension with additional analyses of persons reported in a previous publication ( Russell, Arenth, Scanlon, Kessler, & Ricker, 2011 ). We examined both the encoding and recognition components of an episodic memory paradigm containing both word and letter string blocks using functional magnetic resonance imaging (fMRI) and neuropsychological testing. This paradigm was completed by 12 persons with complicated mild, moderate, or severe TBI and 12 matched uninjured controls. Comparisons were made between groups and stimulus types. While task behavioral performance was not significantly different between groups, imaging results showed greater activation for the TBI group during the encoding portion of the task, while the control group exhibited more activation on the recognition portion. Observed areas of activation suggest that the TBI group may have used a less effective, but more automatic verbal strategy for encoding the nonpronounceable letter strings, while controls may have opted for more of a recognition-focused strategy. Group differences in California Verbal Learning Test-Second Edition (CVLT-II) performance supported these ideas, and further neuropsychological testing also suggested limitations in executive functioning in the TBI group that may have influenced performance. Implications for intervention are discussed.

A functional magnetic resonance imaging investigation of episodic memory after traumatic brain injury.

Traumatic brain injury often negatively impacts episodic memory; however, studies of the neural substrates of this impairment have been limited. In this study, both encoding and recognition of visually presented stimuli were examined with functional magnetic resonance imaging. Twelve adults with chronic complicated mild, moderate, and severe injuries were compared with a matched group of 12 controls. Behavioral task performance did not differentiate the groups. During neuroimaging, however, the group of individuals with traumatic brain injury exhibited increased activation, as well as increased bilaterality and dispersion as compared to controls. Findings are discussed in terms of increased resource recruitment.

APOE genetic associations with seizure development after severe traumatic brain injury.

PRIMARY OBJECTIVE: The purpose of the current study is to assess the role of the APOE genotype in post-traumatic seizure (PTS) development. RESEARCH DESIGN: A retrospective study of 322 adult Caucasians with a severe TBI and APOE genotype. METHODS AND PROCEDURES: Medical records were searched for PTS. Time to first seizure was categorized as early, late or delayed-onset PTS. Potential PTS associations by genotype, grouped genotype and allele were investigated. MAIN OUTCOME AND RESULTS: No statistically significant associations were found. However, two out of the four individuals (50%) with the E4/E4 genotype had late/delayed-onset PTS. Furthermore, none with a E2/E2 or E2/E4 genotype seized in the late periods. CONCLUSIONS: The results of this study may suggest 4/4 as a risk genotype for late/delayed onset PTS and a potential neuroprotective role of the E2 allele. However, this study did not definitively support a role for the APOE genotype in PTS susceptibility and indicates that larger populations are needed to fully evaluate the potential impact of APOE on PTS.

The relation of white matter hyperintensities to cognitive performance in the normal old: education matters.

This study examined whether the severity of cerebral white matter abnormalities (evident on MR images as white matter hyperintensities (WMH)) was related to the cognitive performance of 141 high-functioning older adults. The elderly showed the typical age decrement on measures of processing speed, working memory, and inhibition; however WMH severity was significantly related only to processing speed. The strength of this relationship was, however, influenced by the educational level of the participants, such that processing speed was more associated with WMH severity in less-educated than in well-educated participants. This is consistent with recent concepts of cognitive reserve, but does raise a question as to the underlying source of the cognitive decrement found in the sort of well-educated elders typically used in cognitive-aging studies.

Differential cortical atrophy in subgroups of mild cognitive impairment.

OBJECTIVE: To compare gray matter brain volumes in patients diagnosed with subtypes of mild cognitive impairment (MCI) (those with a focal amnestic disorder and those with more diffuse cognitive dysfunction) with those of elderly controls. DESIGN: Magnetic resonance imaging volumetric study of MCI subgroups (MCI-amnestic [MCI-A], and MCI-multiple cognitive domain [MCI-MCD]) using a whole brain voxel-based analysis. SETTING: Referral dementia clinic. Patients Thirty-seven patients with MCI (age range, 49-85 years; MCI-A, n = 9; MCI-MCD, n = 28) and 47 control subjects (age range, 55-81 years). MAIN OUTCOME MEASURES: Volumetric anatomical magnetic resonance imaging differences between MCI subgroups and normal controls, and between patients with MCI who progressed to dementia. Magnetic resonance imaging scans were analyzed using statistical software SPM99. RESULTS: Overall, the patients with MCI had significantly decreased volume in the hippocampus and middle temporal gyrus, bilaterally, compared with control subjects. Compared with patients with MCI-MCD, patients with MCI-A had significant volume loss of the left entorhinal cortex and inferior parietal lobe. Compared with patients with MCI-A, patients with MCI-MCD had significantly reduced volume of the right inferior frontal gyrus, right middle temporal gyrus, and bilateral superior temporal gyrus. Patients with MCI who progressed to Alzheimer disease during follow-up (mean interval 2 years, maximum 4.5 years), showed greater atrophy in the left entorhinal cortex, bilateral superior temporal gyri, and right inferior frontal gyrus compared with those who did not progress. CONCLUSIONS: These data provide evidence of distinct brain structural abnormalities in 2 groups of patients with MCI. While both have mesial temporal and cortical volume loss, those with a focal memory deficit have more involvement of the mesial temporal structures and less involvement of the neocortical heteromodal association areas than those patients with MCI with diffuse cognitive dysfunction. Thus, MCI may represent a more heterogeneous group than currently conceived, possibly reflecting 2 different etiological processes to dementia. These data also suggest that these structural abnormalities precede the development of Alzheimer disease.