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

Abstract

ObjectiveTo 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).MethodsA 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.ResultsDM1 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.ConclusionsWM 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.

207th ENMC Workshop on chronic respiratory insufficiency in myotonic dystrophies: Management and implications for research, 27–29 June 2014, Naarden, The Netherlands

“…Fatigue is also a predictor of disrupted social participation and EDS is associated with lower employment rates [29]. Fatigue in DM1 [30] may have several facets: it may have a central component, due to central pathways [31,32] or it may relate to functional disability, which is dependent on an individual's coping ability (adaptive fatigue). It may also have an emotional component due to depression, where there is a lack of association between objective and subjective fatigue.…”

CRISPR/Cas9-Induced (CTG⋅CAG) n Repeat Instability in the Myotonic Dystrophy Type 1 Locus: Implications for Therapeutic Genome Editing

“…Myotonic dystrophy type 1 (DM1) is an inherited multisystemic disorder that manifests itself at different ages, with variable expression of progressive skeletal muscle wasting, myotonia, dysfunction of the heart, gastrointestinal problems, insulin resistance, cataract, and alterations in cognitive functions and behavior associated with white matter loss in the central nervous system 1, 2. DM1’s autosomal-dominant character, complex symptoms, and progression are caused by expansion of a (CTG⋅CAG)n-triplet repeat located in the 3′ UTR of the DMPK gene3, 4, 5 and in a partially overlapping antisense (DM1-AS) gene 6, 7.…”

Diffuse Brain Abnormalities in Myotonic Dystrophy Type 1 Detected by 3.0 T Proton Magnetic Resonance Spectroscopy

“…There are several magnetic resonance imaging (MRI) [3,4] and diffusion tensor imaging (DTI) [5,6] studies in vivo, showing diffuse brain damage among patients with DM1. Moreover, the involvement of cortical and subcortical regions among patients with DM1 is in agreement with pathological studies documenting neuronal loss and intracellular neurofibrillary tangles in the frontal and temporal lobes, thalamus, basal ganglia, and brainstem [7,8,9,10].…”