Plasma neurofilament light in Huntington's disease: A marker for disease onset, but not symptom progression

Abstract

To investigate whether plasma NfL levels correlate with clinical symptom severity in premanifest (PM) and manifest HD (HD) individuals, and whether a NfL cut-point could distinguish PM from HD patients with reasonable accuracy. Method: 98 participants (33 control, 26 PM, 39 HD), underwent blood sample collection and clinical assessment, using both UHDRS and non-UHDRS measures, at one academic HD Center. Years to onset (YTO), probability of disease onset in 5 years, and predicted years until 60% onset probability were also calculated. NfL levels were measured using a Meso Scale Discovery assay. Results: Cohorts differed by age. NfL levels differed significantly across diagnostic groups and were significantly correlated with age. Age-adjusted NfL levels were not correlated with clinical measures in either HD or PM cohorts, but were correlated when cohorts were combined. In PM subjects, NfL levels correlated with YTO, probability of onset in 5 years, and years until 60% onset probability. Using ROC analysis, a NfL cut-point of <53.15 pg/ml distinguished HD from control; <74.84 pg/ml distinguished HD from PM. Conclusions: These findings implicate plasma NfL as a peripheral prognostic marker for premanifest-HD. Notably, we show that significant correlations between NfL and clinical symptoms are detected only when PM + HD subjects are combined, but not within HD subjects alone. To date, prior studies have investigated the clinical usefulness of NfL exclusively in merged PM + HD cohorts. Our data suggests a biasing of these previous correlations, and hence potentially limited usefulness of plasma NfL in monitoring HD symptom progression, for example, in clinical trials.

Benefits of global mutant huntingtin lowering diminish over time in a Huntington’s disease mouse model

“…Although early mHtt lowering delayed an increase of NFL in the CSF, neither early nor late moderate global mHtt-lowering could prevent or reverse the increase of NFL in the CSF when measured at 12 months of age. This is consistent with CSF NFL correlating with disease onset, but not tracking with disease progression (39).…”

“…In HD patients, an increase in neurofilament light chain (NFL) levels in the plasma and CSF have been reported to correlate with the onset of clinical symptoms and to increase during disease progression (36)(37)(38)(39)(40). Previously, NFL was reported to increase in the CSF of the R6/2 mouse model (41), therefore, we examined NFL levels in the CSF from mice with and without mHtt lowering.…”

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

“…Our results correspond with work in spinocerebellar ataxia showing that NF-L was stable during the study period, despite clinical progression ( 14 ). A study in individuals with HD likewise demonstrated that NF-L was not associated with clinical outcomes in individuals with manifest disease ( 13 ). Adult-onset DM1 is characterized by slow clinical disease progression ( 30 ), indicating that longer follow-up periods may be required to detect changes in blood-based markers.…”

“…While NF-L has been studied extensively in individuals with neurodegenerative illness (12)(13)(14)(15)27); its utility as biomarker of CNS pathology in DM1 had not been determined prior to this study. 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.…”

“…Examination of a variety of relevant markers of brain injury could be beneficial in identifying outcome measures for clinical trials. Protein markers of brain injury have garnered considerable attention in the past several years as potential biomarkers of neurodegenerative illness (12)(13)(14)(15); however, their utility in tracking disease onset and progression in DM1 is largely unexplored.…”