Cognitive Impairment in Myotonic Dystrophy Type 1 Is Associated with White Matter Damage

<div><p>Objective</p><p>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).</p><p>Methods</p><p>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.</p><p>Results</p><p>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.</p><p>Conclusions</p><p>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.</p></div

Neuropsychological and behavioural data of DM1 patients.

<p>Values are means ± standard deviations (% of subjects with abnormal test score compared with normative data of reference, see text for further details).</p>#<p>p<0.05 in aDM1 <i>vs</i> jDM1 patients (Poisson model, false-discovery rate adjusted for multiple comparisons;</p><p>*age-adjusted p values). Abbreviations: ACE-R, Addenbrooke’s Cognitive Examination–Revised; aDM1, Myotonic dystrophy type 1 with adult onset (≥20 years); BNT, Boston Naming Test; DM1, Myotonic dystrophy type 1; HDRS, Hamilton Depression Rating Scale; HARS, Hamilton Anxiety Rating Scale; jDM1, Myotonic dystrophy type 1 with early onset (<20 years); ns, not significant; RAVLT, Rey Auditory Verbal Learning test; TMT, Trials Making Test; VOT, Visual Organization Test; WAIS, Wechsler-Adult Intelligence Scale.</p

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.

<p>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.</p

Main demographic, clinical and conventional MRI data from healthy controls and DM1 patients.

<p>Values are means ± standard deviations (range or % of subjects with pathological scores relative to cut off values) or number of subjects. P values refer to Pearson chi-square or Mann-Whitney U test (see text for further details). Abbreviations: aDM1, Myotonic dystrophy type 1 with adult onset (≥20 years); DM1, Myotonic dystrophy type 1; DSS, Daytime Sleepiness Scale; KFSS, Krupp’s Fatigue Severity Scale; HC, Healthy controls; jDM1, Myotonic dystrophy type 1 with childhood onset (<20 years); ns, not significant; MIRS, Muscular impairment rating scale; MRI, magnetic resonance imaging; WMH, white matter hyperintensity.</p

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

<p>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.</p

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

<p>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).</p