Cognitive impairment in myotonic dystrophy type 1 is associated with white matter damage

Abstract

Objective: To investigate grey (GM) and white matter (WM) abnormalities and their effects on cognitive and behavioral deficits in a large, phenotypically and genotypically well-characterized cohort of classic adult (aDM1, age at onset ≥ 20 years) or juvenile (jDM1, age at onset <20 years) patients with myotonic dystrophy type 1 (DM1).

Methods: A case-control study including 51 DM1 patients (17 jDM1 and 34 aDM1) and 34 controls was conducted at an academic medical center. Clinical, cognitive and structural MRI evaluations were obtained. Quantitative assessments of regional GM volumes, WM hyperintensities (WMHs), and microstructural WM tract damage were performed. The association between structural brain damage and clinical and cognitive findings was assessed.

Results: DM1 patients showed a high prevalence of WMHs, severe regional GM atrophy including the key nodes of the sensorimotor and main cognitive brain networks, and WM microstructural damage of the interhemispheric, corticospinal, limbic and associative pathways. WM tract damage extends well beyond the focal WMHs. While aDM1 patients had severe patterns of GM atrophy and WM tract damage, in jDM1 patients WM abnormalities exceeded GM involvement. In DM1, WMHs and microstructural damage, but not GM atrophy, correlated with cognitive deficits.

Conclusions: WM damage, through a disconnection between GM structures, is likely to be the major contributor to cognitive impairment in DM1. Our MRI findings in aDM1 and jDM1 patients support the hypothesis of a degenerative (premature aging) origin of the GM abnormalities and of developmental changes as the principal substrates of microstructural WM alterations in DM1.

Figure 1. White matter hyperintensities spatial distribution in patients with myotonic dystrophy 1.

The color scale (from 5% to 25%) represents the minimum to maximum probability of a lesion occurring in a particular spatial location. Results are overlaid on the coronal, sagittal and axial sections of the Montreal Neurological Institute standard brain in radiological convention (right is left).

Figure 2. Voxel-based morphometry results in patients with myotonic dystrophy 1 compared with age-matched healthy controls adjusting for age and total intracranial volume.

Regions of grey matter atrophy are shown in yellow-to-red and overlaid on the coronal, sagittal and axial sections of the Montreal Neurological Institute standard brain in radiological convention (right is left). Results are displayed at p<0.05 corrected for multiple comparisons.

Figure 3. Tract-based spatial statistics results in patients with myotonic dystrophy 1 compared with age-matched healthy controls and relationship between the Addenbrooke’s Cognitive Examination–Revised (ACE-R) orientation and attention subscores and mean diffusivity values.

Analyses were adjusted for age. A–C: Voxelwise group differences are shown in blue (mean diffusivity) and red (fractional anisotropy). D) Regions where MD values correlated with the ACE-R orientation and attention subscores are shown in blue. Results are overlaid on the sagittal and axial sections of the Montreal Neurological Institute standard brain in radiological convention (right is left), and displayed at p<0.05 corrected for multiple comparisons. The white matter skeleton is green.