Understanding of the CNS Manifestations Is an Unmet Need in DM

While skeletal muscle biomarkers and clinical endpoints are rightly the current focus of interventional clinical trials in DM1, as they are most likely to inform go/no-go decisions, the CNS burden in DM is considerable and likely requires targeted therapy development programs. Pharmaceutical and biotechnology firms increasingly recognize the need for CNS biomarkers and clinically meaningful endpoint measures, but, likely due to the costs of brain imaging studies, efforts to evaluate brain structural changes with MRI are often modest. A recent review details accomplishments in brain imaging in DM and assesses the path forward to more informative studies.

CNS Imaging Studies May Yield Vital DM1 Clinical Trial Endpoint Measures

Dr. Kees Okkersen and team members at Radboud University Medical Centre and the University of Glasgow have conducted a comprehensive review of published studies that used a variety of imaging methodologies (MRI, functional MRI, MRS, ultrasound, SPECT, PET, and CT) to assess DM1. Their review article in Neurology relies upon a total of 81 cross-sectional and longitudinal studies to draw conclusions about the pattern of changes in the CNS in DM1, to show how they relate to other genetic and clinical parameters, and to provide direction to optimize future studies.

The research team followed a careful search/selection strategy that triaged publications from 1974-2016 in the Embase and MEDLINE databases to include 81 studies, reporting a total of 1,663 DM1 cases, in their analysis. Conclusions were drawn from aggregate analysis of findings from these studies and included comments on the strengths, weaknesses, and overall validity of the various imaging strategies used in DM1. The aggregate data showed widespread structural changes to gray and white matter in cerebral cortex, cerebellum, and basal ganglia, with little evidence of specific regional involvement or sparing; a finding consistent with neuropathologic observations in DM1. Substantial white matter involvement was a consistent feature across studies (with prevalence of 70% in DM1 subjects vs. 6% in controls). Specificity in cortical region involvement was seen across the 7 PET studies that met inclusion criteria; these findings were supported by SPECT studies (n = 5). Findings of fMRI studies supported personality and social cognition patterns seen in DM1.

Overall, the aggregate analysis supported some correlations between findings from brain imaging and genetic/clinical features. If clinical trial endpoints are to be developed, it is essential to understand the natural history of the structural and functional changes in the brain in DM1. The research team, however, observed that only 3 of the 81 studies that qualified for their analysis were longitudinal imaging studies. Such studies were deemed to be particularly important since some of the imaging changes in DM1 are associated with normal aging and it will be important to understand whether DM1 pathophysiology starts within specific brain regions before generalizing. 

Taken together, this review of brain imaging provides careful selection and analysis of completed studies in DM1. Sufficiently powered longitudinal studies represent a clear need for the field. Given the high costs of such studies, a consortium approach with an agreed upon data collection, sharing, and analysis protocol is likely the best path forward to understanding and developing therapies for CNS manifestations of DM1.

Brain imaging in myotonic dystrophy type 1: A systematic review.
Okkersen K, Monckton DG, Le N, Tuladhar AM, Raaphorst J, van Engelen BGM.
Neurology. 2017 Aug 2. pii: 10.1212/WNL.0000000000004300. doi: 10.1212/WNL.0000000000004300. [Epub ahead of print] Review.