Blood-based markers of neuronal injury in adult-onset myotonic dystrophy type 1

van der Plas, E., Long, J. D., Koscik, T. R., Magnotta, V., Monckton, D. G. , Cumming, S. A., Gottschalk, A. C., Hefti, M., Gutmann, L. and Nopoulos, P. C. (2022) Blood-based markers of neuronal injury in adult-onset myotonic dystrophy type 1. Frontiers in Neurology, 12, 791065. (doi: 10.3389/fneur.2021.791065) (PMID:35126292) (PMCID:PMC8810511)

Abstract

Introduction: The present study had four aims. First, neuronal injury markers, including neurofilament light (NF-L), total tau, glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1), were compared between individuals with and without adult-onset myotonic dystrophy type 1 (DM1). Second, the impact of age and CTG repeat on brain injury markers was evaluated. Third, change in brain injury markers across the study period was quantified. Fourth, associations between brain injury markers and cerebral white matter (WM) fractional anisotropy (FA) were identified. Methods: Yearly assessments, encompassing blood draws and diffusion tensor imaging on a 3T scanner, were conducted on three occasions. Neuronal injury markers were quantified using single molecule array (Simoa). Results: The sample included 53 patients and 70 controls. NF-L was higher in DM1 patients than controls, with individuals in the premanifest phases of DM1 (PreDM1) exhibiting intermediate levels (χ(2)2=38.142, P < 0.001). Total tau was lower in DM1 patients than controls (Estimate = −0.62, 95% confidence interval [CI] −0.95: −0.28, P < 0.001), while GFAP was elevated in PreDM1 only (Estimate = 30.37, 95% CI 10.56:50.19, P = 0.003). Plasma concentrations of UCH-L1 did not differ between groups. The age by CTG interaction predicted NF-L: patients with higher estimated progenitor allelege length (ePAL) had higher NF-L at a younger age, relative to patients with lower CTG repeat; however, the latter exhibited faster age-related change (Estimate = −0.0021, 95% CI −0.0042: −0.0001, P = 0.045). None of the markers changed substantially over the study period. Finally, cerebral WM FA was significantly associated with NF-L (Estimate = −42.86, 95% CI −82.70: −3.02, P = 0.035). Interpretation: While NF-L appears sensitive to disease onset and severity, its utility as a marker of progression remains to be determined. The tau assay may have low sensitivity to tau pathology associated with DM1.

• Item Type: Articles
• Additional Information: This work was supported by the National Institute of Neurological Disorders and Stroke (R01 NS094387, PN). The MRI instrument was funded by 1S10OD025025-01.
• Keywords: Neurology, NF-L protein, myotonic dystrophy 1, central nervous system, diffusion magnetic resonance imaging, tau proteins.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Monckton, Professor Darren and Cumming, Dr Sarah
• Authors: van der Plas, E., Long, J. D., Koscik, T. R., Magnotta, V., Monckton, D. G., Cumming, S. A., Gottschalk, A. C., Hefti, M., Gutmann, L., and Nopoulos, P. C.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Frontiers in Neurology
• Publisher: Frontiers Media
• ISSN: 1664-2295
• ISSN (Online): 1664-2295
• Copyright Holders: Copyright © 2022 van der Plas, Long, Koscik, Magnotta, Monckton, Cumming, Gottschalk, Hefti, Gutmann and Nopoulos
• First Published: First published in Frontiers in Neurology 12: 791065
• Publisher Policy: Reproduced under a Creative Commons License