Top

Journal of Neurology

Published in:

01-09-2020 | Spinocerebellar Degeneration | Original Communication

Neurofilament light chain as a potential biomarker of disease status in Friedreich ataxia

Authors: Alexandra Clay, Kristin M. Obrochta, Russell K. Soon Jr, Christopher B. Russell, David R. Lynch

Published in: Journal of Neurology | Issue 9/2020

Abstract

Background

The present study evaluates serum neurofilament light chain (NfL) as a biomarker of disease features in Friedreich’s ataxia (FRDA).

Methods

NfL levels from serum of 117 subjects (85 FRDA patients, 13 carriers, and 19 controls) were assayed and correlated with disease features such as smaller GAA repeat length (GAA1), age, sex, and level of neurological dysfunction.

Results

Mean serum NfL levels were higher in FRDA patients than in carriers or unaffected controls in two independent cohorts of subjects. In longitudinal samples from FRDA patients drawn monthly or 1 year apart, values changed minimally. No difference was noted between carriers and controls. NfL levels correlated positively with age in controls and carriers of similar age, (Rs = 0.72, p < 0.0005), whereas NfL levels inversely correlated with age in FRDA patients (Rs = − 0.63, p < 0.001). NfL levels were not associated with sex or GAA1 length in patients, and linear regression revealed a significant relationship between NfL levels in the cohort with age (coefficient = − 0.36, p < 0.001), but not sex (p = 0.64) or GAA1 (p = 0.13).

Conclusion

Because NfL is elevated in patients, but decreases with age and disease progression, our results suggest that age is the critical determinant of NfL in FRDA (rather than clinical or genetic severity).

Babady NE, Carelle N, Wells RD, Rouault TA, Hirano M, Lynch DR, Delatycki MB, Wilson RB, Isaya G, Puccio H (2007) Advancements in the pathophysiology of Friedreich's Ataxia and new prospects for treatments. Mol Genet Metab 92:23–35CrossRef

Schulz JB, Pandolfo M (2013) 150 years of Friedreich ataxia: from its discovery to therapy. J Neurochem 126(Suppl 1):1–3CrossRef

Pandolfo M (2008) Friedreich ataxia. Arch Neurol 65:1296–1303CrossRef

Campuzano V, Montermini L, Moltò MD, Pianese L, Cossée M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A, Zara F, Cañizares J, Koutnikova H, Bidichandani SI, Gellera C, Brice A, Trouillas P, De Michele G, Filla A, De Frutos R, Palau F, Patel PI, Di Donato S, Mandel JL, Cocozza S, Koenig M, Pandolfo M (1996) Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271:1423CrossRef

Dürr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, Mandel JL, Brice A, Koenig M (1996) Clinical and genetic abnormalities in patients with Friedreich's ataxia. N Engl J Med 335:1169–1175CrossRef

Cavadini P, O'Neill HA, Benada O, Isaya G (2002) Assembly and iron-binding properties of human frataxin, the protein deficient in Friedreich ataxia. Hum Mol Genet 11:217–227CrossRef

Deutsch EC, Santani AB, Perlman SL, Farmer JM, Stolle CA, Marusich MF, Lynch DR (2010) A rapid, noninvasive immunoassay for frataxin: utility in assessment of Friedreich ataxia. Mol Genet Metab 101:238–245CrossRef

Campuzano V, Montermini L, Lutz Y, Cova L, Hindelang C, Jiralerspong S, Trottier Y, Kish SJ, Faucheux B, Trouillas P, Authier FJ, Dürr A, Mandel JL, Vescovi A, Pandolfo M, Koenig M (1997) Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Hum Mol Genet 6:1771–1780CrossRef

Lazaropoulos M, Dong Y, Clark E, Greeley NR, Seyer LA, Brigatti KW, Christie C, Perlman SL, Wilmot GR, Gomez CM, Mathews KD, Yoon G, Zesiewicz T, Hoyle C, Subramony SH, Brocht AF, Farmer JM, Wilson RB, Deutsch EC, Lynch DR (2015) Frataxin levels in peripheral tissue in Friedreich ataxia. Ann Clin Transl Neurol 2:831–842CrossRef

10.

Rissin DM, Kan CW, Campbell TG, Howes SC, Fournier DR, Song L, Piech T, Patel PP, Chang L, Rivnak AJ, Ferrell EP, Randall JD, Provuncher GK, Walk DR, Duffy DC (2010) Single-Molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations. Nat Biotechnol 28:595–599CrossRef

11.

Gisslen M, Price RW, Andreasson U, Norgren N, Nilsson S, Hagberg L, Fuchs D, Spudich S, Blennow K, Zetterberg H (2016) Plasma Concentration of the Neurofilament Light Protein (NFL) is a Biomarker of CNS Injury in HIV Infection: A Cross-Sectional Study. EBioMedicine 3:135–140CrossRef

12.

Ru Y, Corado C, Soon RK, Melton AC, Harris A, Yu GK, Pryer N, Sinclair JR, Katz ML, Ajayi T, Jacoby D, Russell CB, Chandriani S (2019) Neurofilament light is a treatment-responsive biomarker in CLN2 disease. Ann Clin Transl Neurol 6:2437–2447CrossRef

13.

Hayer SN, Liepelt I, Barro C, Wilke C, Kuhle J, Martus P, Schöls L (2020) NfL and pNfH are increased in Friedreich's ataxia. J Neurol. https://doi.org/10.1007/s00415-020-09722-6

14.

Zeitlberger AM, Thomas-Black G, Garcia-Moreno H, Foiani M, Heslegrave AJ, Zetterberg H, Giunti P (2018) Plasma Markers of Neurodegeneration Are Raised in Friedreich’s Ataxia. Front Cell Neurosci 12:366CrossRef

15.

Patel M, Isaacs CJ, Seyer L, Brigatti K, Gelbard S, Strawser C, Foerster D, Shinnick J, Schadt K, Yiu EM, Delatycki MB, Perlman S, Wilmot GR, Zesiewicz T, Mathews K, Gomez CM, Yoon G, Subramony SH, Brocht A, Farmer J, Lynch DR (2016) Progression of Friedreich ataxia: quantitative characterization over 5 years. Ann Clin Transl Neurol 3:684–694CrossRef

16.

Rezende TJR, Martinez ARM, Faber I, Girotto Takazaki KA, Martins MP, de Lima FD, Lopes-Cendes I, Cendes F, França MC Jr (2019) Developmental and neurodegenerative damage in Friedreich's ataxia. Eur J Neurol 26:483–489CrossRef

17.

Parhad IM, Clark AW (1987) Griffin JW Effect of changes in neurofilament content on caliber of small axons: the beta, beta'-iminodipropionitrile model. J Neurosci 7:2256–2263CrossRef

18.

Perry GW, Burmeister DW, Grafstein B (1985) Changes in protein content of goldfish optic nerve during degeneration and regeneration following nerve crush. J Neurochem 44:1142–1151CrossRef

19.

Hoffman PN, Cleveland DW (1988) Neurofilament and tubulin expression recapitulated the developmental program during axonal regeneration: Induction of a specific β-tubulin isotype. Proc Natl Acad Sci USA 85:4530–4533CrossRef

20.

Friedman LS, Schadt KA, Regner SR, Mark GE, Lin KY, Sciascia T, St John Sutton M, Willi S, Lynch DR (2013) Elevation of serum cardiac troponin I in a cross-sectional cohort of asymptomatic subjects with Friedreich ataxia. Int J Cardiol 167:1622–1624CrossRef

Title: Neurofilament light chain as a potential biomarker of disease status in Friedreich ataxia
Authors: Alexandra Clay
Kristin M. Obrochta
Russell K. Soon Jr
Christopher B. Russell
David R. Lynch
Publication date: 01-09-2020
Publisher: Springer Berlin Heidelberg
Keywords: Spinocerebellar Degeneration
Biomarkers
Published in: Journal of Neurology / Issue 9/2020
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-020-09868-3

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Neurofilament light chain as a potential biomarker of disease status in Friedreich ataxia

Abstract

Background

Methods

Results

Conclusion

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 9/2020

Ioflupane 123I (DAT scan) SPECT identifies dopamine receptor dysfunction early in the disease course in progressive apraxia of speech

Posterior circulation stroke: machine learning-based detection of early ischemic changes in acute non-contrast CT scans

Prevalence and risk factors of silent brain infarcts in patients with AF detected by 3T-MRI

A systematic review and meta-analyses of pregnancy and fetal outcomes in women with multiple sclerosis: a contribution from the IMI2 ConcePTION project

SPG7 mutations in amyotrophic lateral sclerosis: a genetic link to hereditary spastic paraplegia

The contribution of enhancing lesions in monitoring multiple sclerosis treatment: is gadolinium always necessary?