Abnormal striatal and thalamic dopamine neurotransmission: Genotype-related features of dystonia

OBJECTIVE: To determine whether changes in D2 receptor availability are present in carriers of genetic mutations for primary dystonia. METHODS: Manifesting and nonmanifesting carriers of the DYT1 and DYT6 dystonia mutations were scanned with [C] raclopride (RAC) and PET. Measures of D2 receptor availability in the caudate nucleus and putamen were determined using an automated region-of-interest approach. Values from mutation carriers and healthy controls were compared using analysis of variance to assess the effects of genotype and phenotype. Additionally, voxel-based whole brain searches were conducted to detect group differences in extrastriatal regions. RESULTS: Significant reductions in caudate and putamen D2 receptor availability were evident in both groups of mutation carriers relative to healthy controls (p < 0.001). The changes were greater in DYT6 relative to DYT1 carriers (-38.0 ± 3.0% vs -15.0 ± 3.0%, p < 0.001). By contrast, there was no significant difference between manifesting and nonmanifesting carriers of either genotype. Voxel-based analysis confirmed these findings and additionally revealed reduced RAC binding in the ventrolateral thalamus of both groups of mutation carriers. As in the striatum, the thalamic binding reductions were more pronounced in DYT6 carriers and were not influenced by the presence of clinical manifestations. CONCLUSIONS: Reduced D2 receptor availability in carriers of dystonia genes is compatible with dysfunction or loss of D2-bearing neurons, increased synaptic dopamine levels, or both. These changes, which may be present to different degrees in the DYT1 and DYT6 genotypes, are likely to represent susceptibility factors for the development of clinical manifestations in mutation carriers.