Selected CSF biomarkers indicate no evidence of early neuroinflammation in Huntington disease

Abstract

Objective: To investigate CSF biomarkers of neuroinflammation and neurodegeneration in Huntington disease (HD) gene-expansion carriers compared to controls and to investigate these biomarkers in association with clinical HD rating scales and disease burden score.

Methods: We collected CSF from 32 premanifest and 48 manifest HD gene-expansion carriers and 24 gene-expansion negative at-risk controls. We examined biomarkers of neuroinflammation (matrix metalloproteinase 9, C-X-C motif chemokine 13, terminal complement complex, chitinase-3-like-protein 1 [CHI3L1], and osteopontin [OPN]) and neurodegeneration (microtubule-associated protein tau, neurofilament light polypeptide [NFL], and myelin basic protein [MBP]). The study was approved by the Ethics Committee of the Capital Region of Denmark (H2-2011-085) and written informed consent was obtained from each participant before enrollment.

Results: NFL was the only biomarker that increased in premanifest stages and no evidence of early involvement of neuroinflammation in HD was found. However, we found that the biomarkers for neurodegeneration, MBP and tau, increased during the disease course in manifest HD gene-expansion carriers and were associated with an increase of the neuroinflammation biomarkers CHI3L1 and OPN. Tau was also increased in all gene-expansion carriers with psychiatric symptoms compared to gene-expansion carriers without psychiatric symptoms.

Conclusions: Neuroinflammation, which seems not to be an early event in our cohort, may be secondary to neurodegeneration in late HD. NFL is a possible disease burden correlate in HD, reflecting neuronal loss even before motor symptom onset, and may be useful as a dynamic biomarker in intervention studies.

Figure 1.. Concentrations of CSF markers in gene-expansion negative controls and premanifest and manifest gene-expansion carriers

Age- and sex-adjusted concentrations of CSF markers in gene-expansion negative controls (GEN C), premanifest gene-expansion carriers (P GEC), and manifest gene-expansion carriers (M GEC). Markers were adjusted to the level of a 45-year-old man. Markers of neurodegeneration: (A) neurofilament light polypeptide (NFL); (B) myelin basic protein (MBP); (C) microtubule-associated protein tau (Tau). Markers of neuroinflammation: (D) osteopontin (OPN); (E) chitinase-3-like 1 (CHI3L1): (F) terminal complement complex (TCC). Markers of oxidative stress: (G) total nitric oxide (NO_x). The p values were obtained from linear regression analysis and Bonferroni correction.

Figure 2.. Correlation between markers and disease burden expressed as CAG age product (CAP) scores in Huntington disease gene-expansion carriers

Sex- and age-adjusted log-transformed concentrations of the CSF markers as a function of CAP score ([CAG_n-33.66] × age). (A) Neurofilament light polypeptide (NFL); (B) myelin basic protein (MBP); (C) microtubule-associated protein tau (Tau) (only sex-adjusted); (D) chitinase-3 like 1 (CHI3L1); (E) osteopontin (OPN); (F) total nitric oxide (NO_x); (G) terminal complement complex (TCC). The p values were obtained from linear regression analyses including sex, age, and CAP score.

Figure 3.. Hypothesized model of the dynamics of CSF biomarkers in Huntington disease (HD)

The dynamics of CSF biomarkers over time are illustrated for gene-expansion negative controls (medium-toned lines) and the changes from gene-expansion negative controls to gene-expansion carriers are illustrated by dark-toned lines. Light-toned lines: * illustrates level of microtubule-associated protein tau (total) (Tau) in HD gene-expansion carriers with psychiatric symptoms; ** illustrates level of neurofilament light polypeptide in HD gene-expansion carriers with cognitive impairment. CHI3L1= human chitinase 3-like 1 protein; MBP = myelin basic protein; NFL = neurofilament light polypeptide; OPN = osteopontin.