Abstract
ObjectiveTo 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. Method98 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. ResultsCohorts 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. ConclusionsThese 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.
Highlights
Huntington’s Disease (HD) is a progressive, genetic neurodegenera tive disorder caused by unstable CAG repeat expansions in the first exon of the Huntingtin gene (HTT)
We found that plasma neurofilament light (NfL) levels can strongly distin guish manifest HD patients from both PM and control groups, and were significantly correlated with several disease and clinical measures in the PM + HD cohort
The significant correlations between plasma NfL and Stroop word reading test (SWR), Symbol Digit Modalities test (SDMT), Chorea, Unified Huntington’s Disease Rating Scale (UHDRS) TMS and Total Functional Capacity (TFC) scores observed in our PM + HD cohort were not present in either PM or HD patients alone, with the possible exception of SDMT in PM and SWR in HD
Summary
Huntington’s Disease (HD) is a progressive, genetic neurodegenera tive disorder caused by unstable CAG repeat expansions in the first exon of the Huntingtin gene (HTT). This mutation translates into a poly glutamine repeat in the Huntingtin protein, the length of which varies by CAG expansion number. Pathogenesis in HD arises largely from the expression of the mutant Huntingtin protein (mHtt), leading to the formation of soluble protein oligomers as well as insoluble aggregates that contribute to the disruption of many, predominantly cortical and striatal, intracellular pathways. The expression of mHtt subsequently contributes to the development of a spectrum of clinical signs and symptoms, including chorea, deteriorations in cognition and mood, and changes in personality, leading to a premature death around 20 years after onset. It has been estimated that up to 40% of the variation in onset age can be attributed to genes exclusive of HTT, with the remaining disparity attributed to environmental factors [1,2,3]
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