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.
Highlights
Myotonic dystrophy type 1 (DM1) is a dominantly inherited, multisystem progressive disease, caused by a trinucleotide (CTG) expansion in the 39-untranslated region of the dystrophia myotonica protein kinase gene on chromosome 19 [1]
JDM1 were younger with earlier disease onset compared with aDM1 patients
MRI showed that DM1 patients had altered structural brain measures relative to controls including regional Grey matter (GM) volumes, WM hyperintensities (WMHs), and white matter (WM) microstructural tract damage
Summary
Myotonic dystrophy type 1 (DM1) is a dominantly inherited, multisystem progressive disease, caused by a trinucleotide (CTG) expansion in the 39-untranslated region of the dystrophia myotonica protein kinase gene on chromosome 19 [1]. DM1 is the most common form of adult-onset muscular dystrophy and is characterized by limb muscle weakness, myotonia, and multiorgan involvement, including cataract, cardiac conduction defects, insulin resistance, gonadal atrophy, and central nervous system (CNS) pathology [1]. Fatigue, executive and visuospatial dysfunctions, and anxious personality traits (deteriorating with age) are common manifestations in patients with the classic adult (aDM1, age at onset $20 years) or juvenile (jDM1, age at onset ,20 years) forms of DM1 [2]. Intraneuronal neurofibrillary tangles (NFT) of the type seen in frontotemporal dementia, without plaques, have been demonstrated in the DM1 brains [3,4,5], connecting this disorder to a subset of neurodegenerative diseases termed tauopathies
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