Functional brain networks in DYT1 dystonia

Abstract

Early-onset idiopathic torsion dystonia (ITD) is an autosomal dominant hyperkinetic movement disorder with incomplete penetrance, associated with a 3 base-pair deletion in the DYT1 gene on chromosome 9q34. To determine the metabolic substrates of brain dysfunction in DYT1 dystonia, we scanned 7 nonmanifesting and 10 affected DYT1 carriers and 14 normal volunteers with [18F]fluorodeoxyglucose and positron emission tomography. We found that DYT1 dystonia is mediated by the expression of two independent regional metabolic covariance patterns. The first pattern, identified in an analysis of nonmanifesting gene carriers was designated movement free (MF). This abnormal pattern was characterized by increased metabolic activity in the lentiform nuclei, cerebellum, and supplementary motor areas. The MF pattern was present in DYT1 carriers with and without clinical manifestations and persisted in DYT1 dystonia patients in whom involuntary movements were suppressed by sleep. The second pattern, identified in an analysis of affected gene carriers with sustained contractions at rest, was designated movement related (MR). This pattern was characterized by increased metabolic activity in the midbrain, cerebellum, and thalamus. The expression of the MR pattern was increased in waking DYT1 patients with sustained dystonia, compared with DYT1 carriers who were unaffected or who had dystonia only on action, as well as normal controls. MR subject scores declined significantly with sleep in affected DYT1 patients but not in normal controls. These findings indicate the penetrance of the DYT1 gene is considerably greater than previously assumed. ITD is mediated through the interaction of functional brain networks relating separately to gene status and to abnormal movement.

Obsessive‐compulsive disorder is not a clinical manifestation of the DYT1 dystonia gene

“…The etiopathogenic and phenotypic differences between DYT1 dystonia and other dystonias, especially distinct involvement of fronto-striatal circuitry may explain the differences in OCD frequency among dystonia subtypes. Imaging and other functional studies may help shed light on the relationship between psychiatric and motor dysfunction for specific dystonia subtypes [Eidelberg et al, 1998;Carbon et al, 2004]. In the current study, few subjects met CIDI criteria for OCD, and the rate of OCD was not higher in gene carriers (either for the combined group of MC and NMC, or for either group alone) than in NC.…”

Neuroimaging and therapeutics in movement disorders

“…These computations were conducted using an automated routine that was blind to diagnostic category. 38,41 As in the original analysis, prospectively computed PDRP scores were significantly elevated in the disease group (p Ͻ 0.00001).…”

“…3,34 Formal multiregion, multisubject network approaches using principal components analysis (PCA) 3,35 have been employed to identify patterns of regional metabolism that are associated with PD 3,36 and other movement disorders (e.g., Huntington's Disease, 37 torsion dystonia, 38,39 Tourette syndrome). 40 PCA extracts multiple, statistically independent components that account, singly or in combination, for the majority of the variability in the regional PET data.…”

“…However, the quantification of disease-related patterns of glucose metabolism may provide unique data regarding diagnosis and treatment effects in situations in which other imaging approaches are lacking or insufficient. Indeed, we have used FDG PET to describe unique metabolic networks associated with Huntington's disease, 37,100 idiopathic torsion dystonia, 38,39 and Tourette syndrome. 40,101 …”

Developmental patterns of torsinA and torsinB expression

“…Though there is no evidence of neuronal degeneration, torsinA, laminA, and ubiquitin inclusions have been reported in midbrain of DYT1 patients (McNaught et al, 2004). Manifesting and non-manifesting carriers of DYT1 mutation show abnormal electrical excitability in the cerebral cortex and asymptomatic carriers of DYT1 mutation show altered resting glucose utilization and decreased D2 receptors in several brain areas as well as delayed motor learning (Eidelberg et al, 1998). At present, it is difficult to correlate these functional changes in the human brain with specific patterns of torsinA or torsinB expression in the different brain regions.…”