Cognitive Deficits, Apathy, and Hypersomnolence Represent the Core Brain Symptoms of Adult-Onset Myotonic Dystrophy Type 1

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.

Blood-Based Markers of Neuronal Injury in Adult-Onset Myotonic Dystrophy Type 1

“…Alterations in white matter (WM) appear to occur early in the disease, as cerebral WM FA was found to be reduced among individuals with PreDM1, who have yet to manifest clinical motor symptoms ( 10 ). Reduced WM FA is associated with motor symptoms of DM1 ( 9 ), and with other functional outcomes, such as lower IQ, apathy and hypersomnolence ( 11 ). These studies underscore the importance of tracking brain health in DM1 to gain insights into disease onset and progression.…”

Myotonic dystrophy type 1 presenting with dyspnea: A case report

“…Myotonic dystrophy type 1 (DM1) is an inherited neuromuscular disease characterized by muscle rigidity, muscle weakness, and atrophy[ 1 - 3 ], with a prevalence of 0.5-18.1 per 100000 population[ 4 ]. DM1 patients may also have concurrent multiple systemic disorders, such as lens opacity[ 5 ], abnormal cardiac conduction systems[ 6 ], insulin resistance[ 7 ], gastrointestinal dysfunction[ 8 ], and cognitive dysfunction[ 9 ].…”

“…Also, sleep disturbances, including excessive daytime sleepiness, central and obstructive sleep apnea, restless legs syndrome, and rapid eye movement sleep dysregulation, are prominent in patients with DM1[ 12 , 13 ]. Overall, the clinical phenotype of DM1 patients is highly variable[ 1 , 6 , 9 , 14 ].…”

Brain Pathogenesis and Potential Therapeutic Strategies in Myotonic Dystrophy Type 1

“…These central nervous system (CNS) deficits among DM1 individuals significantly increase the disease burden, not only affecting neuropsychological domains but also decreasing the whole quality of life. A large clinical longitudinal study of DM1 patients by Miller et al (2021) demonstrated that cognitive deficits, hypersomnolence, and apathy are critical brain symptoms of adult-onset DM1 caused by the underlying molecular mechanisms. In contrast, depression and anxiety are secondary coping symptoms with chronic physical and emotional stress ( Miller et al, 2021 ).…”

“…A large clinical longitudinal study of DM1 patients by Miller et al (2021) demonstrated that cognitive deficits, hypersomnolence, and apathy are critical brain symptoms of adult-onset DM1 caused by the underlying molecular mechanisms. In contrast, depression and anxiety are secondary coping symptoms with chronic physical and emotional stress ( Miller et al, 2021 ). In addition, Simoncini et al (2020) proved that the severity and progression rate of neurological impairments are highly variable over time, possibly attributed to underlying neuropathology ( Mazzoli et al, 2020 ).…”