Multimodal imaging: genetic and environmental effects in neuropsychiatry

点击翻译按钮获取中文摘要

The past year has seen a number of published papers and new data presented at national and international meetings. In Tost et al. 2013, an association of variation in the gene coding for the brain derived neurotrophic factor (BDNF; Val66Met polymorphism) with white matter microstructure was assessed. This polymorphism has been associated with various psychiatric conditions, including schizophrenia. It is known that the variant changes the trafficking of BDNF within neural cells, resulting in changes in hippocampal neurochemistry, fMRI activation and performance on memory tasks. Besides affecting neuronal phenotypes, BDNF has effects on other cell types, including oligodendrocytes, represented more prominently in white matter. Several studies have addressed the effect of the BDNF Val66Met polymorphism on white matter structure, with conflicting results. Our results are in line with the largest study in the literature in finding that white matter anisotropy (a measure of the coherent spatial organization of white matter bundles) was increased in Met carriers as compared to Val homozygotes. We also found that this effect was mostly due to a decrease in a measure that is usually considered a measure of myelination; however, there is no evidence supporting increased myelination in Met carriers and it is more likely that these changes reflect alterations in the architecture of white matter fibers. We also showed in this publication that in Val/Val individuals white matter microstructure (anisotropy) was positively correlated with verbal and working memory performance, while in Met carriers, the opposite was true. Along similar lines of inquiry, we found an effect of a polymorphism in the serotonin transporter promoter region (5HTT-LPR) on the white matter microstructure of the uncinate fasciculus. This polymorphism has been implicated in the causation of mood disorders and has been associated with changes in white matter microstructure in previous literature, though the results have been conflicting. We implemented a novel method to define the uncinate fasciculus that allows for automatic delineation of multiple white matter tracts and extraction of tract metrics. In Radulescu et al. 2013, genetic variants in GPR85 that were previously found to increase risk for schizophrenia, were associated with brain activation studied with fMRI. Tasks designed to produce activation in hippocampus (encoding of scenes) and amygdala (presentation of anxious or angry faces), both regions where this gene in highly expressed in adulthood, showed association with the two variants studied. The association in the amygdala was sex specific. Moreover, one of the studied gene variants was associated in a sex specific manner to brain activation during a working memory task. A similar trend occurred in our clinical, where the G allele at locus rs56080411 appeared to increase risk for schizophrenia mainly in males, while it was protective in females. Although the functions of GPR85 are still unknown, these results obtained in healthy individuals support a role of this gene in emotional and mnemonic processing, both functions that are altered in schizophrenia. The work on obstetrical complications as an environmental risk factor for schizophrenia generated a publication (Jaffe et al. 2013, Mol. Psych.) showing that it is unlikely that de novo mutations are the main cause for the known association of paternal age and schizophrenia. Obstetrical complications were associated with increased risk for schizophrenia especially for lower birth order, consistent with the fact that initial pregnancies are more likely to be problematic than later ones. In collaboration, advances have also been made in detailing the effects on white matter microstructure of the 7q11.23 hemideletion associated with Williams Syndrome, leading to the observation that white matter tracts connecting the insula to other important stations of the emotional regulation system (such as amygdala and prefrontal cortex) may be altered in this condition (Jabbi et al. 2012). Moreover, studies in this domain have revealed that people with atypical deletions of the Williams Syndrome chromosome region have an overall alteration of white matter microstructure as compared to controls. Because all the atypical deletions involved the gene LIMK1, which is important in neuronal migration and maturation, it is possible that this gene controls multiple aspects of white matter architecture. Confirmation of this hypothesis was obtained in healthy volunteers, where a genetic variant in the promoter region of LIMK1 was found to be associated with reduced gray matter volume in the intra-parietal sulcus (a characteristic of Williams Syndrome) and a global alteration of white matter microstructure with the same directionality as found in partial and full deletions of the Williams Syndrome chromosome region. Consistent with a role of LIMK1 in regulating white matter microstructure are its known biological functions, which include regulation of growth cone motility in response to axon guidance cues, synapse maturation and plasticity, axon response to myelin associated inhibitors, and appropriate myelination of peripheral nervous cells. Connected to this research, is a more methodological line of work, where we laid the groundwork for determination of white matter tract volume in large datasets of individuals for genetic studies. We focused on the inferior fronto-occipital fasciculus because preliminary work indicated that this might be the white matter tract particularly reduced in volume in participants with short deletions of the Williams syndrome chromosome region. We have also studied GABA and glutamate levels in the anterior cingulate cortex of patients with schizophrenia as compared to controls and have found that GABA levels do not differ between patients and controls, whereas glutamate levels appear to be reduced. We also found that the suspension of neuroleptic medication had no effect on GABA levels in patients with schizophrenia.