Abstract
IntroductionThe 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.MethodsYearly 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).ResultsThe 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 (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).InterpretationWhile 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.
Highlights
DM1 patients than controls (Estimate = −0.62, 95% confidence interval [CI] −0.95: −0.28, P < 0.001), while glial fibrillary acidic protein (GFAP) was elevated in PreDM1 only
Cerebral white matter (WM) fractional anisotropy (FA) was significantly associated with neurofilament light (NF-L) (Estimate = −42.86, 95% CI −82.70: −3.02, P = 0.035)
Plasma NF-L was elevated among individuals with manifest DM1 relative to controls, and those with PreDM1 exhibited intermediate levels compared with controls and manifest DM1 patients
Summary
Associations between brain injury markers and cerebral white matter (WM) fractional anisotropy (FA) were identified. 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. Protein markers of brain injury have garnered considerable attention in the past several years as potential biomarkers of neurodegenerative illness [12,13,14,15]; their utility in tracking disease onset and progression in DM1 is largely unexplored
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