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Abnormal striatal and thalamic dopamine neurotransmission

Genotype-related features of dystonia

From the Center for Neurosciences (M.C., M.N., S.P., V.D., T.C., Y.M., D.E.), The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, Manhasset; Departments of Neurology and Medicine (M.C., V.D., T.C., Y.M., D.E.), North Shore University Hospital and New York University School of Medicine, New York; and the Mirken Department of Neurology (D.R., S.B.), Beth Israel Medical Center, New York, NY.

Address correspondence and reprint requests to Dr. David Eidelberg, Center for Neurosciences, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, 350 Community Drive, Manhasset, NY 11030 david1{at}nshs.edu.

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 [¹¹C] 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.

Abbreviations: ANOVA = analysis of variance; BFM = Burke-Fahn-Marsden; CN = caudate nucleus; FWE = family-wise error rate; GPe = external pallidum; GPi = interal pallidum; RAC = raclopride; ROI = region of interest; SOR = striato-occipital ratio; THX = trihexyphenidyl; VL = ventrolateral tier nuclei.

Supplemental data at www.neurology.org.

Supported by the NIH (R01 NS 047668) and the General Clinical Research Center of The Feinstein Institute for Medical Research (M01 RR018535).

Disclosure: The authors report no disclosures.

Received November 21, 2008. Accepted in final form March 13, 2009.