Huntington's disease (HD) is an autosomal dominant disease manifested in a triad of cognitive, psychiatric, and motor signs and symptoms. This disease has classically been conceptualized as a "neurodegenerative disease of the striatum". However, recent evidence challenges this concept. Several lines of evidence have suggested that in addition to the degenerative process, there may be an important developmental component to the etiology of this disease. For example, studies in our laboratory show that adult subjects who are gene positive for HD but have not yet manifested the illness (presymptomatic gene carriers or PSGCs) have significant changes in the structure of their brain, specifically, decreased intracranial volume, decreased volume of cerebral white matter, and increased volume of cerebral cortex. These changes support the possibility that these subjects may have had abnormal brain development. A growing body of research evaluating PSGCs compared to Non-Gene Carriers (NGCs) supports the notion that PSGCs not only have structural brain changes as described above, they also have subtle but significant deficits in cognitive, motor, and psychiatric symptoms. Thus, although brain changes and symptoms are present prior to diagnosis, when do they begin? Is it possible that these changes are present from birth and then progress during the course of the disease process? In an effort to better understand the developmental aspects of this brain disease, the current study proposes to evaluate brain structure and function in children (ages 6-12) who are at risk for developing HD. Brain structure will be evaluated using Magnetic Resonance Imaging (MRI) with quantitative measures of the entire brain, including general measures such as cerebrum and cerebellar volume as well as regional measures such as cerebral cortex, cerebral white matter, and subcortical nuclei (caudate, putamen, thalamus). Brain function will be assessed by cognitive tests, neurologic evaluation, and behavioral assessment. Subjects that are PSGCs will be compared to subjects who are NGCs. Changes in brain structure and/or function in the PSGCs would lend significant support to the notion that this disease has an important developmental component. If proven, a developmental model of HD could identify disease pathways that are dysfunctional prior to degeneration. This could lead to intervention techniques that could target and protect these pathways, preventing the disease.
This is a revised application for the proposal "Brain Structure and Function in Children at Risk for Huntington's Disease (1RO1 NS055903-01). The study is designed to evaluate the brain structure (using Magnetic Resonance Imaging) and brain function (using cognitive and behavioral assessment) of children (ages 6 - 12 years) at risk for Huntington's Disease. Changes in brain structure and/or function in the gene positive group would lend significant support to the notion that this disease has an important developmental component.
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