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Objective: To examine and validate changes in striatal dopaminergic function and regional brain metabolism during phenocoversion of preclinical Huntington''s disease (pHD). Background: Our recent PET study (Feigin et al., 2007) found progressive declines in striatal D2-receptor binding in pHD subjects over 44 months, correlating with decreased metabolism in the striatum. During this period, thalamic metabolism was initially elevated above normal and then fell to subnormal levels in the subjects who developed symptoms. To validate these findings, we extended the previous study two years, to 68 months, and now report the preliminary results. Design/Methods: Twelve presymptomatic HD gene carriers (CAG repeat length: 41.6 ± 1.7; estimated years-to-onset: 10.3 ± 8.6 years) underwent PET scanning with both 11C-raclopride and [18F]fluorodeoxyglucose at baseline, 18, and 44 months. Of these, four subjects were diagnosed with HD during the first 44 months of the study. At 68 months, two symptomatic and two asymptomatic subjects were additionally scanned. Results: In the four subjects at 68 months, both the caudate and putamen D2 binding were further decreased relative to values at the first three time points. The decrease in striatal D2 binding was more pronounced in the two symptomatic subjects than the two pHD subjects, with greater progressive declines in striatal metabolism in the symptomatic subjects. However, thalamic metabolism at 68 months was similar to 44 months, i.e., thalamic metabolism was close to the lower limit of normal in the two symptomatic subjects, but remained above normal in the two pHD subjects. Conclusion: At the extended 68-month time point, concurrent decreases in striatal D2 binding and metabolism indicate steady focal loss of striatal projection neurons in pHD. Further, the findings at 68 months support our prior hypothesis that persistently elevated thalamic metabolism is an essential compensatory feature of the preclinical state, with normalization of thalamic metabolism as subjects approach phenoconversion. [Copyright &y& Elsevier]