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. 2021 Jun:87:32-38.
doi: 10.1016/j.parkreldis.2021.04.017. Epub 2021 Apr 28.

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

Georgia M Parkin  1 , Jody Corey-Bloom  2 , Chase Snell  3 , Jordan Castleton  4 , Elizabeth A Thomas  5
Affiliations

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

Georgia M Parkin et al. Parkinsonism Relat Disord. 2021 Jun.

Abstract

Objective: 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.

Keywords: Biomarker; Blood; Huntington's disease; Neurofilament light; Plasma.

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Conflict of interest statement

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1.
Fig. 1.
Plasma NfL levels in HD patients, premanifest individuals and normal controls. Plasma NfL levels are significantly increased in manifest HD patients compared to premanifest HD (PM) individuals and normal controls (NC), as determined by Kruskal-Wallis test (p < .0001). Box plots represent median and interquartile range, with whiskers at 5–95 percentiles (A). Receiver Operating Characteristic Curves for plasma NfL in the diagnosis of manifest HD compared to NC (Area Under the Curve (AUC) = 0.92, p < .0001) (B) and PM (AUC = 0.94, p < .0001) (C).
Fig. 2.
Fig. 2.
Graphical presentation of clinical scores significantly correlated with plasma NfL in the combined PM + HD cohort. Correlation of plasma NfL levels with Symbol Digit Modality Test score (SDMT; A), Stroop Word Reading score (SWR; B), UHDRS Total Motor Score (TMS; C), UHDRS Chorea score (D), UHDRS Total Functional Capacity score (TFC; E) and composite UHDRS score (cUHDRS; F) in premanifest (PM, open circles) and manifest HD (filled circles) participants. Please refer to Table 2 for Spearman’s rho, Nonparametric Partial Correlation rho, and p values.
Fig. 3.
Fig. 3.
Association between plasma NfL levels and calculations for years to onset. Correlation of plasma NfL levels with Probability of onset in 5 years (A), Years to 60% probability of onset (B, C) and Aylward score (D) in premanifest (PM, open circles) and HD (filled circles) participants. Panel C shows NfL levels in patients who are a predicted ≤10 yrs vs. >10 yrs to onset (post-hoc Mann Whitney U test U = 14, p = .001). The dotted line in Figure C represents the optimal NfL value cut-point (45.66 pg/ml) that could distinguish PM individuals with more than 10 years until they reached 60% probability of symptom onset, ≤10 years (AUC: 0.89, sensitivity: 79%, specificity: 100%, p = .002); error bars represent median and 95% confidence intervals. Please refer to text for Spearman’s rho, Nonparametric Partial Correlation rho, and p values for Figures A, B, and D.
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