A longitudinal and cross‐sectional study of plasma neurofilament light chain concentration in Charcot‐Marie‐Tooth disease

Abstract

Advances in genetic technology and small molecule drug development have paved the way for clinical trials in Charcot‐Marie‐Tooth disease (CMT); however, the current FDA‐approved clinical trial outcome measures are insensitive to detect a meaningful clinical response. There is, therefore, a need to identify sensitive outcome measures or clinically relevant biomarkers. The aim of this study was to further evaluate plasma neurofilament light chain (NFL) as a disease biomarker in CMT. Plasma NFL was measured using SIMOA technology in both a cross‐sectional study of a US cohort of CMT patients and longitudinally over 6 years in a UK CMT cohort. In addition, plasma NFL was measured longitudinally in two mouse models of CMT2D. Plasma concentrations of NFL were increased in a US cohort of patients with CMT1B, CMT1X and CMT2A but not CMT2E compared with controls. In a separate UK cohort, over a 6‐year interval, there was no significant change in plasma NFL concentration in CMT1A or HSN1, but a small but significant reduction in patients with CMT1X. Plasma NFL was increased in wild type compared to GARSC201R mice. There was no significant difference in plasma NFL in GARSP278KY compared to wild type mice. In patients with CMT1A, the small difference in cross‐sectional NFL concentration vs healthy controls and the lack of change over time suggests that plasma NFL may lack sufficient sensitivity to detect a clinically meaningful treatment response in adulthood.

A translatable RNAi-driven gene therapy silences PMP22/Pmp22 genes and improves neuropathy in CMT1A mice

“…Responsiveness of these translatable biomarkers is highly encouraging for their utility in parallel clinical trials of miRNA therapies. Although, a recent study (79) showed a lack of correlation of NF-L plasma levels with disease progression over time in patients with CMT1A, this might be due to the older age of the patients tested (mean age, 46 years). In this regard, validation of additional clinically relevant plasma and skin biomarkers as indicators for future gene therapy efficacy would be essential (19,111,112,113).…”

Blood biomarkers of peripheral neuropathy

“…40 The demonstration of significantly increased plasma NFL in patients with CMT1A, and CMT1B has been replicated by other groups, 43,4441 ; however, the correlation between plasma NFL and the CMT neuropathy and examination scores has been replicated in some but not all studies. 40,41,43 In the only longitudinal study of plasma NFL in CMT, there was no significant change over 6 years follow-up period. 41 Subgroup analysis revealed a trend towards a reduction in plasma NFL over time in CMT1A and a significant reduction in CMT1X.…”

“…31 Subsequent studies using a more sensitive SIMOA platform measuring NFL have shown a significant albeit small difference (10 pg/ml compared to 51.3 pg/ml in ATTR amyloidosis) in patients with CMT (both axonal and demyelinating) versus controls. 37,[40][41][42][43] Subgroup analyses have shown significant NFL increases in the CMT1A, CMT1X and hereditary sensory neuropathy cohorts. 40 Encouragingly, there was also a significant correlation between plasma NFL and the clinical outcome measure, the CMT examination score version 2.…”

“…The first such study measured plasma pNFH but failed to show an increase in patients with CMT versus controls 31 . Subsequent studies using a more sensitive SIMOA platform measuring NFL have shown a significant albeit small difference (10 pg/ml compared to 51.3 pg/ml in ATTR amyloidosis) in patients with CMT (both axonal and demyelinating) versus controls 37,40–43 . Subgroup analyses have shown significant NFL increases in the CMT1A, CMT1X and hereditary sensory neuropathy cohorts 40 .…”

Blood biomarkers for Alzheimer's disease and related disorders

“…36 These age-related changes are an important challenge when considering how to use the test clinically, resulting in the development of age-specific cut-points. It is also relevant that a number of common pathologies can elevate NfL, including mild traumatic brain injury, 37 cerebrovascular insults, 38 peripheral neuropathy 39 and kidney dysfunction, 40 all of which may need to be taken into account.…”