Abnormal striatal and thalamic dopamine neurotransmission

Abstract

Objective: To determine whether changes in D 2 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 [11 C] raclopride (RAC) and PET. Measures of D 2 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 D 2 receptor availability were evident in both groups of mutation carriers relative to healthy controls (p Ͻ 0.001). The changes were greater in DYT6 relative to DYT1 carriers (Ϫ38.0 Ϯ 3.0% vs Ϫ15.0 Ϯ 3.0%, p Ͻ 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 D 2 receptor availability in carriers of dystonia genes is compatible with dysfunction or loss of D 2 -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. Neurology GLOSSARY ANOVA ϭ analysis of variance; BFM ϭ Burke-Fahn-Marsden; CN ϭ caudate nucleus; FWE ϭ family-wise error rate; GPe ϭ external pallidum; GPi ϭ interal pallidum; RAC ϭ raclopride; ROI ϭ region of interest; SOR ϭ striato-occipital ratio; THX ϭ trihexyphenidyl; VL ϭ ventrolateral tier nuclei.Multiple lines of evidence support the role of altered striatal DA neurotransmission in primary dystonia. 1,2 Nonetheless, imaging studies have revealed only minimal reductions in striatal D 2 receptor binding in patients with idiopathic dystonia 3,4 and in nonmanifesting carriers of the DYT1 dystonia mutation.5 Indeed, similar reductions have been described in DYT1 dystonia patients at postmortem.1 It is not known whether similar abnormalities are also present in primary dystonia associated with other genetic mutations.Experimental models of dystonia have yielded varied results with regard to the striatal DA dynamics. Increased striatal DA turnover was found in a transgenic murine DYT1 model regardless of behavioral phenotype. 6,7 However, in this model, striatal DA levels were reduced

Pallidal deep brain stimulation for DYT6 dystonia

“…It is more likely that either the underlying pathophysiology of DYT6 dystonia and/or the stimulation parameters we are employing for therapy account for these more modest responses. Previously published positron emission tomography studies by Carbon and colleagues30 31 demonstrate both similarities and significant differences in the pathophysiologies of DYT1 and DYT6 torsion dystonia. Most significantly, these studies demonstrate decreases in striatal D2 receptor availability in both disorders that is more severe in the brains of DYT6 patients.…”

Imaging insights into basal ganglia function, Parkinson's disease, and dystonia

“…72,73 Although many factors might contribute to altered striatal processing in dystonia, changes in dopamine function might be important. 74,75 By contrast with other forms of dystonia in which D 2 receptor binding might be decreased, increases are seen in patients with dopa-responsive dystonia and in clinically unaffected mutation carriers, 76 in keeping with underlying impairment of dopamine synthesis. F-dopa uptake, which largely indicates the activity of L-aromatic aminoacid decarboxylase, is normal in dopa-responsive dystonia, in accordance with the upstream origin of the deficit in dopamine synthesis.…”

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

“…For instance, gene carriers of the autosomal dominant DYT1 and DYT6 dystonias show functional disturbances of cerebellar connections. DYT1 has a relatively low penetrance (about 30 %) that may result from an additional abnormality in thalamocortical projections, which may be protective in these cases [97,[211][212][213]. Subtle structural cerebellar pathology is suspected to occur in some forms of dystonia [214].…”