Abnormal structure-function relationships in hereditary dystonia

Abstract

Primary torsion dystonia (PTD) is a chronic movement disorder manifested clinically by focal or generalized sustained muscle contractions, postures, and/or involuntary movements. The most common inherited form of PTD is associated with the DYT1 mutation on chromosome 9q34. A less frequent form is linked to the DYT6 locus on chromosome 8q21-22. Both forms are autosomal dominant with incomplete (approximately 30%) clinical penetrance. Extensive functional and microstructural imaging with positron emission tomography (PET) and diffusion tensor MRI (DTI) has been performed on manifesting and non-manifesting carriers of these mutations. The results are consistent with the view of PTD as a neurodevelopmental circuit disorder involving cortico-striatal-pallido-thalamocortical (CSPTC) and related cerebellar-thalamo-cortical pathways. Studies of resting regional metabolism have revealed consistent abnormalities in PTD involving multiple interconnected elements of these circuits. In gene carriers, changes in specific subsets of these regions have been found to relate to genotype, phenotype, or both. For instance, genotypic abnormalities in striatal metabolic activity parallel previously reported reductions in local D(2) receptor availability. Likewise, we have identified a unique penetrance-related metabolic network characterized by increases in the pre-supplementary motor area (SMA) and parietal association areas, associated with relative reductions in the cerebellum, brainstem, and ventral thalamus. Interestingly, metabolic activity in the hypermetabolic areas has recently been found to be modified by the penetrance regulating D216H polymorphism. The DTI data raise the possibility that metabolic abnormalities in mutation carriers reflect adaptive responses to developmental abnormalities in the intrinsic connectivity of the motor pathways. Moreover, findings of increased motor activation responses in these subjects are compatible with the reductions in cortical inhibition that have been observed in this disorder. Future research will focus on clarifying the relationship of these changes to clinical penetrance in dystonia mutation carriers, and the reversibility of disease-related functional abnormalities by treatment.

Fig. 1

(A) Increased resting state glucose metabolism in the putamen (top) and cerebellum (bottom) of non-manifesting (nm) DYT1 carriers and gene negative controls (C). (B) Reduced metabolism in the thalamus (top) and cerebellum (bottom) of nm DYT6 carriers (see text). [Statistical parametric maps (SPMs) (left) comparing normalized regional glucose metabolism (adjusted rCMRGlc) in non-manifesting mutation carriers with controls. The maps were superimposed on a single-subject T1-weighted MRI template. The color stripe represents T values thresholded at 2.6, p<0.005. Bar graphs (right) illustrate regional metabolic values (mean ± SE) from each significant cluster (arrows)]

Fig. 1

(A) Increased resting state glucose metabolism in the putamen (top) and cerebellum (bottom) of non-manifesting (nm) DYT1 carriers and gene negative controls (C). (B) Reduced metabolism in the thalamus (top) and cerebellum (bottom) of nm DYT6 carriers (see text). [Statistical parametric maps (SPMs) (left) comparing normalized regional glucose metabolism (adjusted rCMRGlc) in non-manifesting mutation carriers with controls. The maps were superimposed on a single-subject T1-weighted MRI template. The color stripe represents T values thresholded at 2.6, p<0.005. Bar graphs (right) illustrate regional metabolic values (mean ± SE) from each significant cluster (arrows)]

Fig. 2

(A) Spatial covariance analysis of 42 FDG PET scans from manifesting and non-manifesting DYT1 and DYT6 mutation carriers (see text). The analysis disclosed a significant covariance pattern (PC1, accounting for 18.7% of the subject×voxel variance in the derivation sample) that correlated with clinical penetrance. This dystonia-related pattern (DYT-RP) was characterized by increased metabolic activity in the pre-SMA and parietal regions, associated with decreases in the inferior cerebellum, brainstem and ventral thalamic nuclei. Voxel weights on this pattern were demonstrated to be stable by bootstrap estimation (p<0.01). [The voxel weights were thresholded at Z<2 for positive weights (yellow-red) and Z<−2 for negative weights (blue), reflecting significant (p<0.01) metabolic contributions of these regions to network activity] (B) Bar graph of DYT-RP expression in manifesting (MAN; black) and non-manifesting (NM; gray) dystonia mutation carriers and gene-negative controls (C; open). Network computations were performed on FDG PET scans from 18 MAN-DYT1, 17 NM-DYT1, 11 MAN-DYT6, 11 NM-DYT6, and 22 control subjects. Analysis of variance (ANOVA) revealed a significant effect of phenotype (F[1;79]=23.8; p<0.001), but not genotype.

Fig. 3

(A) Abnormal metabolic increases in the left pre-supplementary motor area (preSMA, left), dorsal premotor cortex (middle), and parietal association cortex (right) in “unprotected” D216-DYT1 non-manifesting carriers (see text). [The color stripe represents T values thresholded at 2.0, p<0.01]. (B) Bar graphs illustrating regional metabolic activity (adjusted rCMRGlu) in each of the significant clusters (arrows) for healthy controls (C, open), “protected” 216H-DYT1 non-manifesting carriers (NM-P, light gray), “unprotected” D216-DYT1 non-manifesting carriers (NM-U, dark gray), and manifesting DYT1 carriers (MAN, black). [Bars indicate mean ± SE]

Fig. 4

Left: Regions in which motor activation in manifesting and non-manifesting DYT1 carriers differed with respect to controls (see text). [The color stripe represents T-values thresholded at 3.5, p<0.001] Right: Bar graphs of adjusted regional cerebral blood flow (rCBF) during motor activation (mean ± SE) measured in each of the significant regions (arrows) for manifesting (MAN, black) and non-manifesting (gray) carriers, and gene-negative controls (C, open). (A) Abnormally increased motor activation (p<0.05) was present in the left supplementary motor area (SMA) in DYT1 carriers, regardless of phenotype. (B) Abnormally increased activation in the left sensorimotor cortex (SMC) was present in manifesting but not non-manifesting DYT1 carriers.