Value of CNS Imaging in DM1
Brain imaging has shown potential to assess progression of DM1 and thus may prove to be an important biomarker or outcome measure to assess candidate therapeutics targeted to the CNS. Consistent with neuropathologic assessments, a recent systematic review of such studies (Okkersen et al., 2017) concluded that DM1 causes broad structural changes in both white and gray matter with little evidence of specific regional involvement or sparing. This imaging data also has been correlated with individual patient cognitive or neuropsychological findings. PET and SPECT imaging did identify patterns of specificity in cortical region involvement. However, data have not yet been available to evaluate links between brain pathology and motor function in DM1. Understanding such structural/functional associations is critical to the design, conduct, and interpretation of interventional clinical trials targeting the CNS in DM1 patients.
Identification of Pathway-Specific Involvement and Linkage to Motor Function
To determine the relationship between cerebral cortical changes and motor function, Dr. Yongmin Chang (Kyungpook National University) and colleagues studied a cohort of 18 adult DM1 patients (mean CTG repeat length of 360) and 20 age-matched healthy controls using voxel-based quantitative MRI (including DTI) in conjunction with motor functional assessments (hand grip, 6-minute walk test (6MWT), and MRC sum score (MRCSS)).
The team showed that reductions in volume of specific gray matter regions correlated with CTG length, hand grip score, and disease duration. The broadest range of cortical involvement was seen in the correlation of hand grip score with pathology in specific gyri and sulci in frontal, parietal, and occipital lobes, including both precentral and postcentral gyri. DTI data established correlations between genetic and clinical parameters (CTG repeat length, MRCSS, and 6MWT) and abnormalities in the posterior limb of the internal capsule and middle section of the corticospinal tract. These white matter changes were accompanied by reduction in volume in both precentral and postcentral gyri, as measured by DTI—the authors argue that these data support a strong association between gray and white matter changes in DM1.
Overall, the research team noted strong relationships between the motor functioning of DM1 patients and abnormalities in the corticospinal tract, and specifically linked the degree of gray matter and descending motor tract changes, as measured by DTI parameters, to severity of hand grip performance. They reaffirmed prior calls for longitudinal imaging/clinical studies to better characterize the natural history of CNS changes and improve clinical trial readiness in DM1.
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Neurology. 2017 Aug 2. pii: 10.1212/WNL.0000000000004300. doi: 10.1212/WNL.0000000000004300. [Epub ahead of print] Review.
Diffusion tensor imaging and voxel-based morphometry reveal corticospinal tract involvement in the motor dysfunction of adult-onset myotonic dystrophy type 1.
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