Myotonic dystrophy type 1 (DM1), the most common form of muscular dystrophy in adults, is a multi-faceted genetic disease caused by CTG repeat expansion in the dystrophia myotonica protein kinase (DMPK) gene. Some of the primary symptoms are muscle myotonia and weakness, yet patients and family members report that some of the most disabling symptoms of the disease are cognitive and behavioral. Therefore, the involvement of the brain has recently come to attention and has prompted the scientific community to better understand the role of the brain in this disease. Neuroimaging studies in DM1 are very limited. Results of these studies are quite variable, however what is consistent is that, compared to controls, white matter is particularly affected in DM1 subjects with decrements in cerebral white matter volume (WM), an increased number of white matter lesions (WML), and Diffusion Weighted Imaging (DWI) measures, which appear to be the most abnormal. Although these studies represent an increased interest in brain aspects of DM1, understanding the effects of DM1 on brain structure and function is still in its infancy. Lacking from the literature is a lage brain imaging study with a homogenous sample (adult onset only) combined with a comprehensive assessment of cognition, motor, and behavioral measures. In addition, the neuromuscular aspects of DM1 are progressive and there is some evidence to suggest that the cognitive changes in DM1 are also progressive. However, there is not one single study evaluating longitudinal changes in brain structure. This dearth of knowledge about the CNS effects of DM1 is in sharp contrast to where the field is moving in regard to therapeutics. The effectiveness of gene therapy using Antisense Oligonucleotides (ASOs) in treatment of an animal model of DM1 has been shown, setting the stage for human trials which have already begun. In order for the field to be ready to begin any trials of CNS treatment in DM1, a substantial amount of work needs to be done. There is an urgent need for comprehensive baseline characterization of brain structure and function in order to identify biomarkers that are: 1) disease-specific and clinically relevant; and 2) can track CNS disease progression. The overall aim of this study is to investigate the use of MRI measures of white matter health (WM, WML, DWI) as biomarkers of DM1 CNS disease. Subjects will undergo MRI scans and a comprehensive battery of cognitive, motor, and behavioral tests. Compared to matched healthy controls, the DM1 subjects are hypothesized to have specific changes in measures of white matter health in brain imaging, as well as cognitive and behavioral deficits. All subjects will be assessed at baseline and again at 1 and 2 year follow-ups. Evaluating brain measures over time will help to establish them as useful biomarkers of CNS progression, making them vital tools for clinical trials in DM1.
This study is a comprehensive, prospective longitudinal study of brain structure and function in Myotonic Dystrophy (DM1). MRI measures of white matter health are expected to be identified as reliable and valid biomarkers that can track CNS disease progression. This work is vital for any clinical trial targeting either restorative or neuroprotectve treatment of the CNS in DM1.
