[show abstract][hide abstract] ABSTRACT: Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association (P(combined) = 3.2 × 10(-8)). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 × 10(-9)) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the 5' UTR of GPCPD1, glycerophosphocholine phosphodiesterase GDE1 homolog (Saccharomyces cerevisiae), which in humans, is more highly expressed in occipital cortex compared with the remainder of cortex than 99.9% of genes genome-wide. Based on these findings, we conclude that this common genetic variation contributes to the proportional area of human visual cortex. We suggest that identifying genes that contribute to normal cortical architecture provides a first step to understanding genetic mechanisms that underlie visual perception.
Proceedings of the National Academy of Sciences 03/2012; 109(10):3985-90. · 9.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: Inferring causality is a fundamental feature of human cognition that allows us to predict outcomes in everyday events. Here, we use direct current stimulation (tDCS) to investigate the role of the right parietal lobe in the perception of causal events. Based on the results of a previous fMRI investigation, we hypothesized that the right parietal lobe plays a specific role in the processing of spatial attributes that contribute to judgments of causality. In line with our hypothesis, we found polarization-dependent modulation of causal judgments and corresponding reaction times (RTs) for trials with increasing violation of spatial contiguity in launching events. This effect was further modulated by temporal violations, as the effect of tDCS on the use of spatial information for causality judgements was strongest for trials with high temporal violations. Thus, especially for ambiguous trials with regard to temporal patterns, cathodal stimulation led to more liberal causality judgments for trials with high angles in movement trajectory. Furthermore, we found faster RTs after anodal stimulation of the right parietal lobe. These findings suggest a reduced influence of spatial attributes on the perception of causality after cathode stimulation of the right parietal lobe and an increased processing efficiency after anodal stimuli of the same region. These data demonstrate polarization-dependent tDCS modulation of spatial processing mechanisms within the right parietal lobe that contribute to the perception of causality.
Experimental Brain Research 12/2011; 215(3-4):315-25. · 2.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: Patients using cholinesterase inhibitors (ChEIs) have a delay in nursing home (NH) admission compared with those who were not using the medication. There are no long-term studies of the effects of memantine in combination with ChEIs use in Alzheimer disease (AD). This study was conducted to examine the effects of ChEIs and memantine on time to death and time to NH admission.
Time to NH admission and death was examined in 943 probable AD patients who had at least a 1-year follow-up evaluation. Of these patients, 140 (14.9%) used both ChEIs and memantine, 387 (41%) [corrected] used only ChEIs, and 416 (44.1%) [corrected] used neither. The mean (SD) follow-up time was 62.3 (35.8) months. The analysis was conducted with multivariable Cox proportional hazard models controlling for critical covariates (ie, age, education level, gender, severity of the dementia, hypertension, diabetes mellitus, heart disease, psychiatric symptoms and use of psychotropic medications).
Compared with those who never used cognitive enhancers, patients who used ChEIs had a significant delay in NH admission (HR: 0.37, 95% CI 0.27 to 0.49); this effect was significantly augmented with the addition of memantine (HR: 0.29, 95% CI 0.11 to 0.72) (memantine+ChEI vs ChEI alone). ChEIs alone, or in combination with memantine had no significant association on time to death.
This observational study revealed that the addition of the NMDA receptor antagonist memantine to the treatment of AD with ChEI significantly altered the treated history of AD by extending time to nursing home admission.
Journal of neurology, neurosurgery, and psychiatry 03/2009; 80(6):600-7. · 4.87 Impact Factor
[show abstract][hide abstract] ABSTRACT: The ε4 allele of the apolipoprotein E (APOE) gene is the major genetic risk factor for Alzheimer’s disease (AD), but limited work has suggested that APOE genotype may modulate disease phenotype. Carriers of the ε4 allele have been reported to have greater medial temporal lobe (MTL) pathology and poorer memory than noncarriers. Less attention has focused on whether there are domains of cognition and neuroanatomical regions more affected in noncarriers. Further, a major potential confound of prior in vivo studies is the possibility of different rates of clinical misdiagnosis for carriers vs. noncarriers. We compared phenotypic differences in cognition and topography of regional cortical atrophy of ε4 carriers (n = 67) vs. noncarriers (n = 24) with mild AD from the Alzheimer’s Disease Neuroimaging Initiative, restricted to those with a cerebrospinal fluid (CSF) molecular profile consistent with AD. Between-group comparisons were made for psychometric tests and morphometric measures of cortical thickness and hippocampal volume. Carriers displayed significantly greater impairment on measures of memory retention, whereas noncarriers were more impaired on tests of working memory, executive control, and lexical access. Consistent with this cognitive dissociation, carriers exhibited greater MTL atrophy, whereas noncarriers had greater frontoparietal atrophy. Performance deficits in particular cognitive domains were associated with disproportionate regional brain atrophy within nodes of cortical networks thought to subserve these cognitive processes. These convergent cognitive and neuroanatomic findings in individuals with a CSF molecular profile consistent with AD support the hypothesis that APOE genotype modulates the clinical phenotype of AD through influence on specific large-scale brain networks.