Brain Structure and Clinical Endpoints in Myotonic Dystrophy Type 2

Nearly two-third of patients with myotonic dystrophy type 2 (DM2) report that impaired cognition is among the most disabling symptoms and deeply affects their quality of life. Yet, relatively little is known about how DM2 affects brain structure and cognitive function as brain imaging studies in DM2 are extremely limited. This is a prospective, cross-sectional study of brain structure and function on cognitive and motor performance in patients with DM2 \& DM1 compared to healthy controls. All participants will undergo magnetic resonance imaging (MRI) to evaluate brain structure and white matter integrity, a comprehensive battery of cognitive and motor measures, self-reported questionnaires, and blood collection for brain-based biomarker analysis. A subset of participants will undergo lumbar puncture for cerebrospinal fluid (CSF) collection for additional biomarker analysis and validation. This work is critical to inform the development of rigorous clinical trial designs and plan for a longitudinal study to evaluate MRI measures as imaging biomarkers of disease progression and therapeutic response in DM2 \& DM1.

Myotonic dystrophy type 2 (DM2), autosomal dominant muscular dystrophy, is characterized by late-onset proximal muscle weakness, myotonia, and multisystem features. Although muscle weakness is the key symptom, almost 70% of patients with DM2 report that impaired cognition is among the most disabling symptoms and affects their quality of life. This condition causes severe disability and impaired quality of life similar to those in myotonic dystrophy type 1 (DM1).Small literature describes cognitive deficits and cerebral white matter involvement in those with DM2, compared to controls. However, the mechanisms that lead to cognitive dysfunction are poorly understood. As the momentum of therapeutic development is outpacing our understanding of the central nervous system (CNS) manifestations in myotonic dystrophy, there is an urgent need to identify measures of brain imaging, cognitive function, and biomarkers of CNS pathology that are disease-specific and clinically relevant, and establish relationships of these measures to inform future clinical trial designs in DM2. This study will carry out a comprehensive baseline characterization of 50 adults with DM2 and 50 age and gender-matched controls identified from clinical populations across the US and through the national myotonic dystrophy registry. A subset of DM1 cohort (n=20), aged over 40 years and without contraindications to MRI, will be invited to participate in the full study protocol similar to the DM2 group. All participants will undergo 3 Tesla (3T)-brain MRI to obtain voxel-based morphometry and diffusion tensor imaging (DTI) sequences, a comprehensive Clinical Assessment Battery (CAB) of cognitive and motor measures, patient-reported outcomes, and blood collection for analysis of CNS biomarkers at their baseline visits. A subset of 20 participants will undergo lumbar punctures to collect cerebrospinal fluid (CSF) specimens for additional biomarker analysis and validation. Measures of MRI, CAB, and fluid biomarkers will be compared between DM2, DM1 and controls. Relationships between MRI measures, cognitive and motor endpoints, and biofluid (plasma and CSF) biomarkers will be analyzed within the DM2 \& DM1 group. Validation of plasma and CSF biomarkers will also be determined.