Huntington's disease (HD) is an autosomal dominant neurodegenerative disease which is caused by an expanded CAG repeat and is characterized by progressive psychiatric, cognitive and motor disturbances. Despite tremendous recent advances in the molecular genetics of HD, the pathophysiologic steps linking the genetic defect to the clinical symptoms remain to be elucidated. We propose a scheme which links CAG repeat length, defective energy metabolism, neuronal degeneration and the clinical symptomatology. The goal of this proposal is to study each of the links in this pathophysiologic sequence using advanced MRI techniques. We hypothesize that: 1) Specific clinical symptoms of HD are due to degeneration of specific corticostriatal circuits. 2) A bioenergetic defect in HD contributes to anatomic degeneration. 3) The severity of energetic, anatomic and clinical deficits are linear functions of CAG repeat length.
The specific aims of this proposal are: 1) To determine if specific clinical symptoms correspond to degeneration of specific corticostriatal circuits. 2) To determine whether energetic defects precede anatomic volume loss and whether amelioration of energetic defects attenuate volume loss. 3) To correlate CAG repeat length with regional bioenergetic defects, rate of volume loss and clinical decline. This work will advance our understanding of the functional consequences of the genetic mutation in HD and may lead to improvements in monitoring and treating the disease.
| Tuch, David S; Salat, David H; Wisco, Jonathan J et al. (2005) Choice reaction time performance correlates with diffusion anisotropy in white matter pathways supporting visuospatial attention. Proc Natl Acad Sci U S A 102:12212-7 |
| Rosas, H D; Koroshetz, W J; Chen, Y I et al. (2003) Evidence for more widespread cerebral pathology in early HD: an MRI-based morphometric analysis. Neurology 60:1615-20 |
