Nacmias, Benedetta

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EDITORIALNeurofilaments as Decay Rate Biomarker inSpinocerebellar Ataxia Type 1Highlighting Key Questions of Application and Future ChallengesBenedetta Nacmias, PhDNeurology® 2022;98:821-822. doi:10.1212/WNL.0000000000200360CorrespondenceDr. Nacmiasnacmias@unifi.itA major challenge in the study of neurodegenerative diseases is obtaining objective and easilyaccessible serum biomarkers for early detection of neurodegeneration. Having them wouldallow early diagnosis and detection of the effects of disease-modifying therapies. Neurofilamentlight (NfL) is a candidate biomarker that may address this challenge. NfLs are neuron-specificcytoskeletal proteins that are released on neuronal damage and, as a result of rapid advances inthe development of ultrasensitive assays, are reliably quantifiable in peripheral blood. Recentstudies provide evidence of the prognostic use of NfL in a variety of neurodegenerativediseases,1 including amyotrophic lateral sclerosis,2 dementia,3,4 Huntington disease,5 andneuroinflammatory conditions such as multiple sclerosis.6Spinocerebellar ataxia (SCA) refers to a group of rare autosomal dominant inherited conditionscaused by repeat expansions or variations in several SCA genes. These conditions are slowlyprogressive and are associated with atrophy of the cerebellum that is evident on a brain scan.Most of the SCAs are caused by triplet repeat expansions. People carrying a pathogenicexpansion have a high probability of developing the symptoms of the disease, and each of theirchildren has a 50% chance of inheriting the expansion in the pathogenic range, regardless of thesex of the parent or the child. A genetic test can confirm the diagnosis of SCA. For most people,it is obtained after the classic symptoms appear, but it can be requested in those at risk becauseof their family history.SCA type 1 (SCA1) is a severe neurodegenerative disease characterized by rapid and irre-versible decline of motor function starting in midlife. It is caused by a translated CAG repeatexpansion in the ATXN1 gene, leading to a polyglutamine expansion in the ATAXIN-1(ATXN1) protein. It is one of the most common SCAs. Recent studies in mice show thatantisense oligonucleotide therapies lead to targeted reductions of ATXN1 and may suggest atherapeutic approach for preventing SCA1.7 As new preventive medications that can prevent ordelay the onset of the disease become available, it will be important to identify those carrying apathogenic expansion in the preataxic stage.In this issue ofNeurology®,Wilke et al.8 publish the results of a study in which they evaluated thepotential use of serum NfL (sNfL) as a readily accessible biomarker of the disease. The mainfinding was that in preataxic individuals with SCA1, sNfL correlated with the time to clinicalonset, allowing early detection of neurodegeneration even before volumetric atrophy of cer-ebellum or pons was evident on MRI. They reported significant sNfL elevations 5 years beforeonset of symptoms. Their results suggest that sNfL elevations may be more sensitive thatvolumetric MRI in the preataxic stage.8 The authors propose sNfL as a candidate serumbiomarker for clinical trial inclusion. This could extend the number of CAG repeat-expansiondiseases that could benefit from a peripheral blood biomarker.In patients with neurodegenerative diseases, changes in the brain may begin several years beforesymptoms appear. Waiting for symptoms to appear may delay treatments until after damage to thebrain is advanced. The results of the study by Wilke et al.8 highlight the value of sNfL as aFrom the Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Italy.Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.RELATED ARTICLEResearch ArticleLevels of NeurofilamentLight at the Preataxic andAtaxic Stages ofSpinocerebellar AtaxiaType 1Page 827Copyright © 2022 American Academy of Neurology 821Copyright © 2022 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.biomarker of neurodegeneration that may be useful to de-termine when therapies may be started. The study has potentialclinical implications and offers a first step to fill the gap betweenclinical and research work in the field of biomarkers and SCA1.Limitations of the study, as pointed out by the authors, are thatadditional longitudinal measurements of NfL levels in preataxicindividuals are needed to model the early intraindividual dy-namics of NfL levels in SCA1 in more detail. In addition, vali-dation of their findings (in particular, for example, of the MRIfindings) is needed in independent larger multicentric cohortsof individuals with SCA1.A recent study provided evidence for elevated NfL levels as-sociated with clinical disease severity in individuals withSCA2,9 thus confirming the growing interest in NfL as abiomarker. Key questions remain. How can these results beextended to the >48 different forms of SCA? Are we at thethreshold of a biomarker-based precision medicine approachto SCA? The growing number of diseases caused by expan-sion of triplets could benefit from NfL.Study FundingThe author reports no targeted funding.DisclosureThe author reports no disclosures relevant to the manuscript.Go to Neurology.org/N for full disclosures.References1. Ashton NJ, Janelidze S, Al Khleifat A, et al. A multicentre validation study ofthe diagnostic value of plasma neurofilament light. Nat Commun. 2021;12(1):3400.2. Masrori P, De Schaepdryver M, Floeter MK, et al. Prognostic relationship of neu-rofilaments, CHIT1, YKL-40 and MCP-1 in amyotrophic lateral sclerosis. J NeurolNeurosurg Psychiatry. Epub 2021 Dec 20.3. Preische O, Schultz SA, Apel A, et al; Dominantly Inherited Alzheimer Network.Serum neurofilament dynamics predicts neurodegeneration and clinical progressionin presymptomatic Alzheimer’s disease. Nat Med. 2019;25(2):277-283.4. van der Ende EL, Meeter LH, Poos JM, et al; Genetic Frontotemporal DementiaInitiative (GENFI). Serum neurofilament light chain in genetic frontotemporal de-mentia: a longitudinal, multicentre cohort study. Lancet Neurol. 2019;18(12):1103-1111.5. Byrne LM, Rodrigues FB, Blennow K, et al. Neurofilament light protein in blood as apotential biomarker of neurodegeneration in Huntington’s disease: a retrospectivecohort analysis. Lancet Neurol. 2017;16(8):601-609.6. Kapoor R, Smith KE, Allegretta M, et al. Serum neurofilament light as a biomarker inprogressive multiple sclerosis. Neurology. 2020;95(10):436-444.7. O’Callaghan B, Hofstra B, Handler HP, et al. Antisense oligonucleotide therapeuticapproach for suppression of ataxin-1 expression: a safety assessment.Mol Ther NucleicAcids. 2020;21:1006-1016.8. Wilke C, Mengel D, Schöls L, et al. Levels of neurofilament light at the preataxic andataxic stages of spinocerebellar ataxia type 1. Neurology. 2022;98(20):e1985-e1996.9. Yang L, Shao YR, Li XY, Ma Y, Dong Y, Wu ZY. Association of the level of neuro-filament light with disease severity in patients with spinocerebellar ataxia type 2.Neurology. 2021;97(24):e2404-e2413.822 Neurology | Volume 98, Number 20 | May 17, 2022 Neurology.org/NCopyright © 2022 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.DOI 10.1212/WNL.00000000002003602022;98;821-822 Published Online before print March 9, 2022Neurology Benedetta NacmiasHighlighting Key Questions of Application and Future ChallengesNeurofilaments as Decay Rate Biomarker in Spinocerebellar Ataxia Type 1:This information is current as of March 9, 2022ServicesUpdated Information & http://n.neurology.org/content/98/20/821.fullincluding high resolution figures, can be found at:References http://n.neurology.org/content/98/20/821.full#ref-list-1This article cites 8 articles, 2 of which you can access for free at: Subspecialty Collections http://n.neurology.org/cgi/collection/trinucleotide_repeat_diseasesTrinucleotide repeat diseases http://n.neurology.org/cgi/collection/spinocerebellar_ataxiaSpinocerebellar ataxiafollowing collection(s): This article, along with others on similar topics, appears in the  Permissions & Licensing http://www.neurology.org/about/about_the_journal#permissionsits entirety can be found online at:Information about reproducing this article in parts (figures,tables) or in  Reprints http://n.neurology.org/subscribers/advertiseInformation about ordering reprints can be found online:rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.1951, it is now a weekly with 48 issues per year. Copyright © 2022 American Academy of Neurology. All ® is the official journal of the American Academy of Neurology. Published continuously sinceNeurology 

Neurofilaments as Decay Rate Biomarker in Spinocerebellar Ataxia Type 1: Highlighting Key Questions of Application and Future Challenges

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Neurofilaments as Decay Rate Biomarker in Spinocerebellar Ataxia Type 1: Highlighting Key Questions of Application and Future Challenges

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