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

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.

Blood-Based Markers of Neuronal Injury in Adult-Onset Myotonic Dystrophy Type 1

“…Details regarding image processing of the diffusion-weighted images were previously published ( 10 ). Since WM abnormalities in DM1 appear to be global rather than tract-specific ( 9 , 10 ), we limited our analyses to cerebral WM FA consisting of all supratentorial WM. Note that tract-based comparisons of WM across groups in this sample were reported previously ( 9 ).…”

“…Myotonic dystrophy type 1 (DM1) is an autosomal dominant, multisystemic disease caused by an expansion of a CTG trinucleotide repeat in the 3′ untranslated region of the dystrophia myotonica protein kinase gene ( DMPK ; OMIM 160900). Abnormalities in white matter—as measured with fractional anisotropy (FA)—are one of the most replicated findings in adult-onset DM1 ( 1 – 8 ) and appear to be a global phenomenon rather than tract specific ( 9 ). For instance, our group showed that relative to controls, DM1 patients exhibited reduced FA and increased axial diffusivity and radial diffusivity across tracts ( 9 ).…”

“…Alterations in white matter (WM) appear to occur early in the disease, as cerebral WM FA was found to be reduced among individuals with PreDM1, who have yet to manifest clinical motor symptoms ( 10 ). Reduced WM FA is associated with motor symptoms of DM1 ( 9 ), and with other functional outcomes, such as lower IQ, apathy and hypersomnolence ( 11 ). These studies underscore the importance of tracking brain health in DM1 to gain insights into disease onset and progression.…”

“…Abnormalities in white matter-as measured with fractional anisotropy (FA)-are one of the most replicated findings in adult-onset DM1 (1)(2)(3)(4)(5)(6)(7)(8) and appear to be a global phenomenon rather than tract specific (9). For instance, our group showed that relative to controls, DM1 patients exhibited reduced FA and increased axial diffusivity and radial diffusivity across tracts (9). Alterations in white matter (WM) appear to occur early in the disease, as cerebral WM FA was found to be reduced among individuals with PreDM1, who have yet to manifest clinical motor symptoms (10).…”

Altered Local Brain Amplitude of Fluctuations in Patients With Myotonic Dystrophy Type 1

“…Neurological involvement in the DM1 has aroused lots of interest in the recent years and several brain MRI studies have reported white matter lesions and brain atrophy (Minnerop et al, 2011;Baldanzi et al, 2016;Zanigni et al, 2016;Okkersen et al, 2017b;Koscik et al, 2021;Leddy et al, 2021;Lopez-Titla et al, 2021). Diffusion tensor imaging studies have demonstrated widespread white matter lesions with reduced fractional anisotropy (FA) and increased mean diffusivity in patients with DM1 compared with controls (Cabada et al, 2017;Yoo et al, 2017;van Dorst et al, 2019).…”