Neurofilament Light Chain and Metabolome as Biomarkers of Disease Severity and Progression in Charcot-Marie-Tooth Disease. Summary of the Doctoral Thesis

Abstract

Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuromuscular disorder. It is clinically and genetically heterogeneous group of disorders with the phenotype of chronic and slowly progressive neuropathy affecting both the motor and the sensory nerves. Currently, there are no specific treatments for CMT available; therefore, biomarkers that could detect the effect of treatment on disease progression are crucial for successful clinical trials. Previous studies have confirmed that the plasma neurofilament light chain (NfL) concentration is significantly higher in CMT patients than in controls and reflects disease severity of CMT. However, knowledge about the plasma concentration of NfL as a disease progression marker is limited and available from small patient cohorts. Additionally, numerous studies have shown that some plasma metabolites are associated with diabetic neuropathy; however, there are no widely accepted metabolite biomarkers for CMT, and data about metabolic profiles in hereditary neuropathies are still lacking. The aim of this study is to investigate the association between NfL and metabolite biomarker concentrations with CMT clinical severity and disease progression. The study included 101 CMT patients and 64 healthy individuals. Repeated evaluation after three years was performed in 73 patients and 28 controls. Disease severity was assessed using a CMT Neuropathy Score version 2 (CMTNSv2). Plasma neurofilament light chain (NfL) concentration was measured using the Single Molecule Array (Simoa) assay. In addition, the concentrations of 33 plasma metabolites were analysed in 84 patients and 34 controls using ultra-high-performance liquid chromatography coupled with mass spectrometry. Plasma NfL concentration was elevated in the CMT patient group compared to controls (p < 0.001). Overall, NfL levels increased over the three-year period in both the CMT group (p = 0.012) and the control group (p = 0.001). However, in 22 out of 73 CMT patients and 7 out of 28 control subjects, NfL levels decreased compared to baseline. Analysis of the association between changes in plasma NfL over three years and disease severity revealed no statistically significant correlation in the CMT group (r = 0.228, p = 0.052) or within CMT subgroups. Plasma metabolome analysis revealed elevated plasma ratio of acetylcarnitine and decreased plasma ratio of glycine in the CMT group compared with controls. Additionally, reduced valine levels were detected in the CMTX1 subgroup compared with controls. However, further metabolite biomarker analysis of predictive abilities indicated poor separation ability for CMT group and CMT subgroups. In addition, no association was observed between metabolite levels and disease severity. The study confirms elevated plasma NfL concentrations in CMT patients compared to the control group; however, the longitudinal changes in NfL levels were variable. Furthermore, the data demonstrated no association between dynamic changes in plasma NfL levels and disease progression. Consequently, NfL concentration does not reflect disease severity or the rate of progression and cannot be used as a biomarker for CMT progression. Although this study identified significant differences in plasma metabolite levels between CMT patients and controls, longitudinal studies are needed to evaluate the potential of these metabolites as biomarkers for CMT progression.