Plasma neurofilament light chain predicts cerebellar atrophy and clinical progression in spinocerebellar ataxia

Giulia Coarelli, Frederic Darios, Emilien Petit, Karim Dorgham, Isaac Adanyeguh, Elodie Petit, Alexis Brice, Fanny Mochel, Alexandra Durr

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Neurofilament light chain (NfL) is a marker of brain atrophy and predictor of disease progression in rare diseases such as Huntington Disease, but also in more common neurological disorders such as Alzheimer's disease. The aim of this study was to measure NfL longitudinally in autosomal dominant spinocerebellar ataxias (SCAs) and establish correlation with clinical and imaging parameters. We enrolled 62 pathological expansions carriers (17 SCA1, 13 SCA2, 19 SCA3, and 13 SCA7) and 19 age-matched controls in a prospective biomarker study between 2011 and 2015 and followed for 24 months at the Paris Brain Institute. We performed neurological examination, brain 3 T MRI and plasma NfL measurements using an ultrasensitive single-molecule array at baseline and at the two-year follow-up visit. We evaluated NfL correlations with ages, CAG repeat sizes, clinical scores and volumetric brain MRIs. NfL levels were significantly higher in SCAs than controls at both time points (p < 0.001). Age-adjusted NfL levels were significantly correlated at baseline with clinical scores (p < 0.01). We identified optimal NfL cut-off concentrations to differentiate controls from carriers for each genotype (SCA1 16.87 pg/mL, SCA2, 19.1 pg/mL, SCA3 16.04 pg/mL, SCA7 16.67 pg/mL). For all SCAs, NfL concentration was stable over two years (p = 0.95) despite a clinical progression (p < 0.0001). Clinical progression between baseline and follow-up was associated with higher NfL concentrations at baseline (p = 0.04). Of note, all premanifest carriers with NfL levels close to cut off concentrations had signs of the disease at follow-up. For all SCAs, the higher the observed NfL, the lower the pons volume at baseline (p < 0.01) and follow-up (p = 0.02). Higher NfL levels at baseline in all SCAs predicted a decrease in cerebellar volume (p = 0.03). This result remained significant for SCA2 only among all genotypes (p = 0.02). Overall, plasma NfL levels at baseline in SCA expansion carriers predict cerebellar volume change and clinical score progression. NfL levels might help refine inclusion criteria for clinical trials in carriers with very subtle signs.

Original languageEnglish (US)
Article number105311
JournalNeurobiology of Disease
Volume153
DOIs
StatePublished - Jun 1 2021
Externally publishedYes

Bibliographical note

Funding Information:
This study was supported by a grant from the French Ministry of Health “Programme Hospitalier de Recherche Clinique” (PHRC BIOSCA – ID RCB: 2010- A01324 35 , AOM10094 , NCT01470729 ).

Publisher Copyright:
© 2021 The Author(s)

Keywords

  • Biomarker
  • Cerebellum
  • Neurofilament light chain
  • Spinocerebellar ataxias
  • Volumetric MRI

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