How genetics affects the brain to produce higher-level dysfunctions in myotonic dystrophy type 1

Abstract

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder dominated by muscular impairment and brain dysfunctions. Although brain damage has previously been demonstrated in DM1, its associations with the genetics and clinical/neuropsychological features of the disease are controversial. This study assessed the differential role of gray matter (GM) and white matter (WM) damage in determining higher-level dysfunctions in DM1. Ten patients with genetically confirmed DM1 and 16 healthy How genetics affects the brain to produce higher-level dysfunctions in myotonic dystrophy type 1 matched controls entered the study. The patients underwent a neuropsychological assessment and quantification of CTG triplet expansion. All the subjects underwent MR scanning at 3T, with studies including T1-weighted volumes and diffusion-weighted images. Voxel-based morphometry and tractbased spatial statistics were used for unbiased quantification of regional GM atrophy and WM integrity. The DM1 patients showed widespread involvement of both tissues. The extent of the damage correlated with CTG triplet expansion and cognition. This study supports the idea that genetic abnormalities in DM1mainly target the WM, but GM involvement is also crucial in determining the clinical characteristics of DM1.

Figure 1

Distribution of regional gray matter atrophy in DM1 patients. The figure illustrates the pattern of regional GM loss (in red) observed in DM1 patients as compared to healthy controls. The description of the regions corresponds to that summarized in table IV. Areas are overlaid on a T1-weighted template. Statistical threshold: p<0.05, family-wise error corrected at cluster level. The opposite contrast (healthy subjects less than DM1 patients) was not significant. See text for further details.

Figure 2

Associations between DM1 patients’ genetic characteristics and regional GM volumes. The green areas represent the brain regions in which patients’ gray matter volumes are directly associated with CTG triplet expansion. These areas are overlaid on a T1-weighted template. Statistical threshold: p<0.05, family-wise error corrected at cluster level. See text for further details.

Figure 3

Pattern of microscopic white matter damage in patients with DM1. The yellow-orange areas represent the white matter regions in which DM1 patients’ fractional anisotropy (FA, an index of tissue integrity) was significantly lower than in healthy controls. Statistical threshold: p<0.05, family-wise error corrected at cluster level for multiple comparisons. These areas are over-laid on a T1-weighted template. The FA skeleton resulting from the tract-based spatial statistics analyses is shown in green. The opposite contrast (healthy subjects less than DM1 patients) was not significant. See text for further details.

Figure 4

Associations between patients’ microscopic white matter integrity and genetic, clinical and neuropsychological features. DM1 patients’ fractional anisotropy (FA, an index of tissue integrity) in widespread white matter areas was found to correlate with CTG triplet expansions (panel A; shown in dark blue), MIRS scores (panel B; shown in red), and MMSE scores (panel C; shown in light blue). In all cases, the statistical threshold was set at p<0.05 cluster-level corrected for multiple comparisons. Areas of association are overlaid on a T1-weighted template. In all cases, the FA skeleton resulting from the tract-based spatial statistics analyses is shown in green. See text for further details.