White matter microstructure relates to motor outcomes in myotonic dystrophy type 1 independently of disease duration and genetic burden

Timothy R Koscik,Vincent Magnotta,Peggy C Nopoulos,Sarah A Cumming,Laurie Gutmann,Richard K Shields,Darren G Monckton,Ellen Van Der Plas

doi:10.1038/s41598-021-84520-2

Timothy R Koscik, Vincent Magnotta + Show 6 more

Open Access

https://doi.org/10.1038/s41598-021-84520-2

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Journal: Scientific Reports	Publication Date: Mar 1, 2021
Citations: 7	License type: open-access

Affiliation: University of Iowa, University of Glasgow

Abstract

Deficits in white matter (WM) integrity and motor symptoms are among the most robust and reproducible features of myotonic dystrophy type 1 (DM1). In the present study, we investigate whether WM integrity, obtained from diffusion-weighted MRI, corresponds to quantifiable motor outcomes (e.g., fine motor skills and grip strength) and patient-reported, subjective motor deficits. Critically, we explore these relationships in the context of other potentially causative variables, including: disease duration, elapsed time since motor symptom onset; and genetic burden, the number of excessive CTG repeats causing DM1. We found that fractional anisotropy (a measure of WM integrity) throughout the cerebrum was the strongest predictor of grip strength independently of disease duration and genetic burden, while radial diffusivity predicted fine motor skill (peg board performance). Axial diffusivity did not predict motor outcomes. Our results are consistent with the notion that systemic degradation of WM in DM1 mediates the relationship between DM1 progression and genetic burden with motor outcomes of the disease. Our results suggest that tracking changes in WM integrity over time may be a valuable biomarker for tracking therapeutic interventions, such as future gene therapies, for DM1.

Highlights

Deficits in white matter (WM) integrity and motor symptoms are among the most robust and reproducible features of myotonic dystrophy type 1 (DM1)
There were 2 individuals with DM1 and 3 unaffected individuals who reported prior diagnosis of Attention Deficit/Hyperactivity disorder (ADHD), but this was unrelated to all of the motor outcomes we measured except for potentially self reports of myotonia, the small number of individuals reporting ADHD precludes testing the possibility that ADHD is a contributing factor
As follow-up analyses, we explored whether these cognitive variables were related to motor outcomes and whether these potential relationships were mediated by white matter integrity

Summary

Introduction

Deficits in white matter (WM) integrity and motor symptoms are among the most robust and reproducible features of myotonic dystrophy type 1 (DM1). We investigate whether WM integrity, obtained from diffusion-weighted MRI, corresponds to quantifiable motor outcomes (e.g., fine motor skills and grip strength) and patient-reported, subjective motor deficits. We explore these relationships in the context of other potentially causative variables, including: disease duration, elapsed time since motor symptom onset; and genetic burden, the number of excessive CTG repeats causing DM1. Significant and widespread FA decrements are seen in samples as small as nine and ten subjects illustrating the large effect size of FA reduction in D M17,11 Several of these studies have shown correlations between FA and muscle impairment as defined by clinical scales such as the Scientific Reports | (2021) 11:4886. It has not been evaluated whether subjective measures of muscle or motor dysfunction are related to measures of brain pathology

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Conclusion