Abstract
Myotonic dystrophy type 1 is the most common form of muscular dystrophy in adults, and is primarily characterized by muscle weakness and myotonia, yet some of the most disabling symptoms of the disease are cognitive and behavioral. Here we evaluated several of these non-motor symptoms from a cross-sectional time-point in one of the largest longitudinal studies to date, including full-scale intelligence quotient, depression, anxiety, apathy, sleep, and cerebral white matter fractional anisotropy in a group of 39 adult-onset myotonic dystrophy type 1 participants (27 female) compared to 79 unaffected control participants (46 female). We show that intelligence quotient was significantly associated with depression (P < 0.0001) and anxiety (P = 0.018), but not apathy (P < 0.058) or hypersomnolence (P = 0.266) in the DM1 group. When controlling for intelligence quotient, cerebral white matter fractional anisotropy was significantly associated with apathy (P = 0.042) and hypersomnolence (P = 0.034), but not depression (P = 0.679) or anxiety (P = 0.731) in the myotonic dystrophy type 1 group. Finally, we found that disease duration was significantly associated with apathy (P < 0.0001), hypersomnolence (P < 0.001), IQ (P = 0.038), and cerebral white matter fractional anisotropy (P < 0.001), but not depression (P = 0.271) or anxiety (P = 0.508). Our results support the hypothesis that cognitive deficits, hypersomnolence, and apathy, are due to the underlying neuropathology of myotonic dystrophy type 1, as measured by cerebral white matter fractional anisotropy and disease duration. Whereas elevated symptoms of depression and anxiety in myotonic dystrophy type 1 are secondary to the physical symptoms and the emotional stress of coping with a chronic and debilitating disease. Results from this work contribute to a better understanding of disease neuropathology and represent important therapeutic targets for clinical trials.
Highlights
Myotonic dystrophy type 1 (DM1) is a trinucleotide repeat disorder, classically characterized with motor symptoms of prolonged muscle contractions, progressive muscle wasting, and weakness [1]
General cognitive deficits are severe in congenital and childhood forms of myotonic dystrophy type 1 (DM1) [18], but even in adult-onset DM1, we have shown that Full Scale IQ (FSIQ) is significantly lower than unaffected healthy adults [19, 20]
We focused on cerebral white matter fractional anisotropy (FA) for the current analysis, rather than regional White matter (WM) FA, given prior research indicating lack of regional specificity of WM FA deficits in DM1
Summary
Myotonic dystrophy type 1 (DM1) is a trinucleotide repeat disorder, classically characterized with motor symptoms of prolonged muscle contractions (myotonia), progressive muscle wasting, and weakness [1]. DM1 manifests with many additional non-motor symptoms including cataracts, heart conduction abnormalities and arrythmias, gastrointestinal abnormalities, endocrine abnormalities, insulin resistance and diabetes, and respiratory failure. Other nonmotor symptoms, including cognitive deficits, sleep disturbances and affective symptoms, are thought to be due to CNS pathology in DM1, a feature of the disease that has had increasing focus over the past 5–10 years. White matter (WM) microstructure pathology is one of the most robust and reproducible observations in DM1, supported by several neuroimaging studies to date [2,3,4,5,6,7,8,9,10,11,12,13]. In DM1, FA has been shown to be globally reduced, with limited regional specificity [3,4,5,6,7,8,9,10,11,12,13,14]
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