Neuroscience
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Late-onset Alzheimer's disease is a common complex disorder of old age. Though these types of disorders can be highly heritable, they differ from single-gene (Mendelian) diseases in that their causes are often multifactorial with both genetic and environmental components. Genetic risk factors that have been firmly implicated in the cause are mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes, which are found in large multi-generational families with an autosomal dominant pattern of disease inheritance, the apolipoprotein E (APOE)epsilon4 allele and the sortilin-related receptor (SORL1) gene. ⋯ The "endophenotype" approach is an alternative method for measuring phenotypic variation that may facilitate the identification of susceptibility genes for complexly inherited traits. The usefulness of endophenotypes in genetic analyses of normal brain morphology and, in particular for Alzheimer's disease will be reviewed as will the implications of these findings for models of disease causation. Given that the pathways from genotypes to end-stage phenotypes are circuitous at best, identifying endophenotypes more proximal to the effects of genetic variation may expedite the attempts to link genetic variants to disorders.
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There has been a dramatic rise in gene x environment studies of human behavior over the past decade that have moved the field beyond simple nature versus nurture debates. These studies offer promise in accounting for more variability in behavioral and biological phenotypes than studies that focus on genetic or experiential factors alone. They also provide clues into mechanisms of modifying genetic risk or resilience in neurodevelopmental disorders. ⋯ In this paper, we describe research that focuses on the impact of a polymorphism in a brain-derived neurotrophic factor (BDNF) gene, known to be involved in learning and development. Specifically we present findings that assess the effects of genotypic and environmental loadings on neuroanatomic and behavioral phenotypes across development. The findings illustrate the use of a genetic mouse model that mimics the human polymorphism, to constrain the interpretation of gene-environment interactions across development in humans.
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Primary torsion dystonia (PTD) is a chronic movement disorder manifested clinically by focal or generalized sustained muscle contractions, postures, and/or involuntary movements. The most common inherited form of PTD is associated with the DYT1 mutation on chromosome 9q34. A less frequent form is linked to the DYT6 locus on chromosome 8q21-22. ⋯ The DTI data raise the possibility that metabolic abnormalities in mutation carriers reflect adaptive responses to developmental abnormalities in the intrinsic connectivity of the motor pathways. Moreover, findings of increased motor activation responses in these subjects are compatible with the reductions in cortical inhibition that have been observed in this disorder. Future research will focus on clarifying the relationship of these changes to clinical penetrance in dystonia mutation carriers, and the reversibility of disease-related functional abnormalities by treatment.
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Over the past few decades, behavioral, neuroimaging and molecular studies of neurogenetic conditions, such as Williams, fragile X, Turner and velocardiofacial (22q11.2 deletion) syndromes, have led to important insights regarding brain development. These investigations allow researchers to examine "experiments of nature" in which the deletion or alteration of one gene or a contiguous set of genes can be linked to aberrant brain structure or function. Converging evidence across multiple imaging modalities has now begun to highlight the abnormal neural circuitry characterizing many individual neurogenetic syndromes. ⋯ In this review, we highlight converging evidence across syndromes from multiple neuroimaging modalities, with a particular emphasis on functional imaging. In addition, we discuss the commonalities and differences pertaining to selective deficits in visuospatial processing that occur across four neurogenetic syndromes. We suggest avenues for future exploration, with the goal of achieving a deeper understanding of the neural abnormalities in these affected populations.
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In recent years, an array of brain mapping techniques has been successfully employed to link individual differences in circuit function or structure in the living human brain with individual variations in the human genome. Several proof-of-principle studies provided converging evidence that brain imaging can establish important links between genes and behaviour. ⋯ While the rapidly emerging field of imaging genetics holds great promise, the integration of genetic and neuroimaging data also poses major methodological and conceptual challenges. Therefore, this special issue also focuses on how these challenges can be met to fully exploit the synergism of genetically informed brain imaging.