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 MCImultiple 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.

Offspring from multiplex families for AD manifest genetic susceptibility by having larger cerebellar volume, which seems to be related to lesser grey matter pruning for age. Larger cerebellar volumes in adult obsessive compulsive disorder (OCD) patients have been reported. This suggests a possible similarity in structural underpinnings for alcohol dependence and OCD.

Post traumatic seizures (PTS) are a significant complication from traumatic brain injury (TBI). Adenosine, a major neuroprotective and neuroinhibitory molecule, is important in experimental epilepsy models. Thus, we investigated the adenosine A1 receptor (A1AR) gene and linked it with clinical data extracted for 206 subjects with severe TBI. Tagging SNPs rs3766553, rs903361, rs10920573, rs6701725, and rs17511192 were genotyped, and variant and haplotype associations with PTS were explored. We investigated further genotype, grouped genotype, and allelic associations with PTS for rs3766553 and rs10920573. Multivariate analysis of rs3766553 demonstrated an association between the AA genotype and increased early PTS incidence. In contrast, the GG genotype was associated with increased late and delayed onset PTS rates. Multivariate analysis of rs10920573 revealed an association between the CT genotype and increased late PTS. Multiple risk genotype analysis shows subjects with both risk genotypes have a 46.7% chance of late PTS. To our knowledge, this is the first report implicating genetic variability in the A1AR with PTS, or any type of seizure disorder. These results provide a rationale for further studies investigating how adenosine neurotransmission impacts PTS, evaluating anticonvulsant in Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript preventing and treating PTS, and developing and testing targeted adenosinergic therapies aimed at reducing PTS. KeywordsA1AR; adenosine; ADORA1; brain injury; genetic susceptibility; post-traumatic seizure 1.INTRODUCTION5.3 million American civilians have disabilities after traumatic brain injury (TBI), and the national cost is estimated at $48.3 billion per year (Thurman et al., 1999). Post-traumatic seizures (PTS) are a significant complication after TBI. PTS accounts for 20% of symptomatic seizures and 5% of all seizures in the general population (Englander et al., 2003a). Up to 86% of patients with one late seizure after TBI will have a second within 2 years (Haltiner et al., 1997). Despite recommendations supporting limited treatment for seizure prophylaxis (Temkin, 2002), people with TBI often receive PTS prophylaxis on a long term basis with anticonvulsant medications that require regular monitoring and are associated with unwanted side effects, including sedation. Patients who go on to develop PTS also experience similar issues with long term treatment (Dikmen et al., 1991;Smith Jr. et al., 1994). Importantly, the impact of these dr...

Objective To conduct a detailed analysis of DTI parameters [fractional anisotropy (FA) and radial diffusivity (RD)] to evaluate white matter integrity in the corpus callosum (CC), and to examine correlations between DTI data and performance on multiple measures of cognitive functioning. Method 12 participants with a history of complicated mild, moderate, or severe TBI, and 12 control participants completed both standardized and experimental neuropsychological testing and an FMRI session, including DTI. Measures Detailed DTI analysis examined between-group and within-group comparisons of DTI parameters and demographic information, as well as measures of episodic memory and executive functioning. Results Differences were found between groups such that the TBI group demonstrated DTI values suggesting decreased white matter integrity, and correlations with injury severity. 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 DTI parameters suggesting disruptions in white matter may be implicated in impaired performance, both in terms of cognitive tasks and reaction time, after 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 <1wk. The tSNP rs769391and the functional SNP rs3791878 in the GAD1 gene were associated with increased PTS risk occurring 1wk-6mo 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 1wk-6mo 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.