We studied the anatomic and functional changes in various brain areas during the course of Huntington's disease (HD) in a large cohort of mutation-positive individuals (n = 71) encompassing the complete range of disability (presymptomatic through stage V), and in healthy controls, for the purpose of defining both degenerative and dysfunctional brain changes in the same subjects.

Methods: We used an MRI and unsupervised multiparametric segmentation procedure based on a relaxometric approach to measure in vivo brain volumes in 71 subjects with presymptomatic to advanced HD. The same population was evaluated by 18F-FDG PET to assess variations in brain glucose metabolism. To predict age at onset in unaffected mutation carriers, we considered the estimated number of years from each subject's age to manifested HD symptoms, for a given expanded triplet number.

Results: Age-adjusted analyses confirmed that the 71 subjects as a group, as well as the subgroup of 24 unaffected presymptomatic subjects at risk for HD, had significantly smaller gray-matter and white-matter volumes and larger cerebrospinal fluid volumes than did controls (P < 0.0001). In the 24 presymptomatic subjects, we observed a significant inverse linear correlation between white-matter volume reduction and the estimated time to symptom onset (r2= 0.39; P = 0.0011). Both clinically unaffected subjects at risk for HD and symptomatic patients had significantly decreased glucose uptake in the cortex (frontal and temporal lobes) and striatum (caudate and putamen). HD subjects who were followed up longitudinally showed progressive white-matter reduction in the preclinical subjects (n = 10) and decreased glucose uptake in the cortex and striatum in affected (n = 21) and preclinical (n = 10) subjects.

Conclusion: White-matter volume loss may precede gray-matter atrophy and may be associated with neuronal dysfunction in early disease.