The brain in myotonic dystrophy 1 and 2: evidence for a predominant white matter disease

Martina Minnerop, Bernd Weber, Jan-Christoph Schoene-Bake, Sandra Roeske, Sandra Mirbach, Christian Anspach, Christiane Schneider-Gold, Regina C Betz, Christoph Helmstaedter, Marc Tittgemeyer, Thomas Klockgether, Cornelia Kornblum, Martina Minnerop, Bernd Weber, Jan-Christoph Schoene-Bake, Sandra Roeske, Sandra Mirbach, Christian Anspach, Christiane Schneider-Gold, Regina C Betz, Christoph Helmstaedter, Marc Tittgemeyer, Thomas Klockgether, Cornelia Kornblum

Abstract

Myotonic dystrophy types 1 and 2 are progressive multisystemic disorders with potential brain involvement. We compared 22 myotonic dystrophy type 1 and 22 myotonic dystrophy type 2 clinically and neuropsychologically well-characterized patients and a corresponding healthy control group using structural brain magnetic resonance imaging at 3 T (T(1)/T(2)/diffusion-weighted). Voxel-based morphometry and diffusion tensor imaging with tract-based spatial statistics were applied for voxel-wise analysis of cerebral grey and white matter affection (P(corrected) < 0.05). We further examined the association of structural brain changes with clinical and neuropsychological data. White matter lesions rated visually were more prevalent and severe in myotonic dystrophy type 1 compared with controls, with frontal white matter most prominently affected in both disorders, and temporal lesions restricted to myotonic dystrophy type 1. Voxel-based morphometry analyses demonstrated extensive white matter involvement in all cerebral lobes, brainstem and corpus callosum in myotonic dystrophy types 1 and 2, while grey matter decrease (cortical areas, thalamus, putamen) was restricted to myotonic dystrophy type 1. Accordingly, we found more prominent white matter affection in myotonic dystrophy type 1 than myotonic dystrophy type 2 by diffusion tensor imaging. Association fibres throughout the whole brain, limbic system fibre tracts, the callosal body and projection fibres (e.g. internal/external capsules) were affected in myotonic dystrophy types 1 and 2. Central motor pathways were exclusively impaired in myotonic dystrophy type 1. We found mild executive and attentional deficits in our patients when neuropsychological tests were corrected for manual motor dysfunctioning. Regression analyses revealed associations of white matter affection with several clinical parameters in both disease entities, but not with neuropsychological performance. We showed that depressed mood and fatigue were more prominent in patients with myotonic dystrophy type 1 with less white matter affection (early disease stages), contrary to patients with myotonic dystrophy type 2. Thus, depression in myotonic dystrophies might be a reactive adjustment disorder rather than a direct consequence of structural brain damage. Associations of white matter affection with age/disease duration as well as patterns of cerebral water diffusion parameters pointed towards an ongoing process of myelin destruction and/or axonal loss in our cross-sectional study design. Our data suggest that both myotonic dystrophy types 1 and 2 are serious white matter diseases with prominent callosal body and limbic system affection. White matter changes dominated the extent of grey matter changes, which might argue against Wallerian degeneration as the major cause of white matter affection in myotonic dystrophies.

Figures

Figure 1
Figure 1
Neuroimaging results of the brain (VBM, group comparisons). Displayed results of VBM analyses are based on a threshold of Pfalse discovery rate < 0.05 at voxel-level with an extended cluster threshold of 10 voxels. The coordinates refer to the MNI reference space. (A) Grey matter decrease in patients with myotonic dystrophy type 1 compared with controls. (B) White matter decrease in patients with myotonic dystrophy type 1 compared with controls. (C) Grey matter decrease in patients with myotonic dystrophy type 2 compared with controls (no clusters detected). (D) White matter decrease in patients with myotonic dystrophy type 2 compared with controls.
Figure 2
Figure 2
Neuroimaging results of the brain (DTI, group comparison of fractional anisotropy values). Displayed results of tract-based spatial statistics analyses of fractional anisotropy values (group comparison) are based on a corrected threshold of Pfamily wise error < 0.05. Mean tract-based spatial statistics tract skeleton is overlaid on the mean fractional anisotropy image (display threshold of 0.1). The coordinates refer to the MNI reference space. (A) Fractional anisotropy reduction in patients with myotonic dystrophy type 1 compared with healthy controls. (B) Fractional anisotropy reduction in patients with myotonic dystrophy type 2 compared with healthy controls. (C) Fractional anisotropy reduction in patients with myotonic dystrophy type 1 compared with patients with myotonic dystrophy type 2.
Figure 3
Figure 3
Neuroimaging results of the brain (DTI, group comparison of fractional anisotropy values, axial, radial and mean diffusivity). Displayed results of tract-based spatial statistics analyses of different diffusivity indices (fractional anisotropy, axial diffusivity, radial diffusivity, mean diffusivity) are based on a corrected threshold of Pfamily wise error < 0.05. Mean tract-based spatial statistics tract skeleton is overlaid on the mean fractional anisotropy image (display threshold of 0.1). The coordinates refer to the MNI reference space. (A and E) Fractional anisotropy reduction in patients with myotonic dystrophy type 1 (A) and patients with myotonic dystrophy type 2 (E) compared with healthy controls. (B and F) Increase in axial diffusivity in patients with myotonic dystrophy type 1 (B) and patients with myotonic dystrophy type 2 (F) compared with healthy controls. (C and G) Increase in radial diffusivity in patients with myotonic dystrophy type 1 (C) and patients with myotonic dystrophy type 2 (G) compared with healthy controls. (D and H) Increase of mean diffusivity in patients with myotonic dystrophy type 1 (D) and patients with myotonic dystrophy type 2 (H) compared with healthy controls.
Figure 4
Figure 4
Neuroimaging results of the brain (DTI, correlation analyses between white matter affection (fractional anisotropy values) and clinical parameters). Correlation analyses in myotonic dystrophy type 1 (A–G) and myotonic dystrophy type 2 (H–L). Displayed results of Tract-based spatial statistics analyses of fractional anisotropy values are based on a corrected threshold of Pthreshold-free cluster enhancement < 0.05. Mean tract-based spatial statistics tract skeleton is overlaid on the mean fractional anisotropy image (display threshold of 0.1). The coordinates refer to the MNI reference space. Correlations of fractional anisotropy values in patients with myotonic dystrophy type 1 with age and disease duration (A and B), CTG repeat length (C), Muscular Impairment Rating Scale score (D), motor performance (E). Positive correlation of fractional anisotropy values in patients with myotonic dystrophy type 1 with depressed mood (BDI score, F) and fatigue (KFSS score, G). Correlations of fractional anisotropy values in patients with myotonic dystrophy type 2 with age (H), disease duration (I) and motor performance (J). Negative correlations of fractional anisotropy values in patients with myotonic dystrophy type 2 with depressed mood (BDI score, K) and fatigue (KFSS score, L).

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