Levels of Neurofilament Light at the Preataxic and Ataxic Stages of Spinocerebellar Ataxia Type

被引:18
作者
Wilke, Carlo [1 ,3 ]
Mengel, David [1 ,3 ]
Schols, Ludger [2 ,3 ]
Hengel, Holger [2 ,3 ]
Rakowicz, Maria [4 ]
Klockgether, Thomas [5 ,6 ]
Durr, Alexandra [7 ]
Filla, Alessandro [8 ]
Melegh, Bela [9 ,10 ]
Schule, Rebecca [2 ,3 ]
Reetz, Kathrin [11 ,12 ]
Jacobi, Heike [6 ,13 ]
Synofzik, Matthis [1 ,3 ]
机构
[1] Univ Tubingen, Hertie Inst Clin Brain Res & Ctr Neurol, Div Translat Genom Neurodegenerat Dis, Tubingen, Germany
[2] Univ Tubingen, Hertie Inst Clin Brain Res & Ctr Neurol, Dept Neurodegenerat Dis, Tubingen, Germany
[3] German Ctr Neurodegenerat Dis DZNE, Tubingen, Germany
[4] Inst Psychiat & Neurol, Dept Neurol 1, Warsaw, Poland
[5] Univ Hosp Bonn, Dept Neurol, Bonn, Germany
[6] German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
[7] Sorbonne Univ, Paris Brain Inst, APHP, INSERM,CNRS, Paris, France
[8] Univ Naples Federico II, Dept Neurosci & Reprod & Odontostomatol Sci, Naples, Italy
[9] Univ Pecs, Sch Med, Dept Med Genet, Pecs, Hungary
[10] Univ Pecs, Sch Med, Szentagothai Res Ctr, Pecs, Hungary
[11] Rhein Westfal TH Aachen, Dept Neurol, Aachen, Germany
[12] Rhein Westfal TH Aachen, Forschungszentrum Julich, JARA BRAIN Inst Mol Neurosci & Neuroimaging, Aachen, Germany
[13] Univ Heidelberg Hosp, Dept Neurol, Heidelberg, Germany
基金
欧盟地平线“2020”;
关键词
CHAIN; INDIVIDUALS; PROGRESSION; BIOMARKERS; FEATURES; PROTEIN; DISEASE; ONSET; BLOOD; RISCA;
D O I
10.1212/WNL.0000000000200257
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Background and Objectives Neurofilament light (NfL) appears to be a promising fluid biomarker in repeat-expansion spinocerebellar ataxias (SCAs), with piloting studies in mixed SCA cohorts suggesting that NfL might be increased at the ataxic stage of SCA type 1 (SCA1). We here hypothesized that NfL is increased not only at the ataxic stage of SCA1, but also at its (likely most treatment-relevant) preataxic stage. Methods We assessed serum NfL (sNfL) and CSF NfL (cNfL) levels in both preataxic and ataxic SCA1, leveraging a multicentric cohort recruited at 6 European university centers, and clinical follow-up data, including actually observed (rather than only predicted) conversion to the ataxic stage. Levels of sNfL and cNfL were assessed by single-molecule array and ELISA technique, respectively. Results Forty individuals with SCA1 (23 preataxic, 17 ataxic) and 89 controls were enrolled, including 11 preataxic individuals converting to the ataxic stage. sNfL levels were increased at the preataxic (median 15.5 pg/mL [interquartile range 10.5-21.1 pg/mL]) and ataxic stage (31.6 pg/mL [26.2-37.7 pg/mL]) compared to controls (6.0 pg/mL [4.7-8.6 pg/mL]), yielding high age-corrected effect sizes (preataxic: r = 0.62, ataxic: r = 0.63). sNfL increases were paralleled by increases of cNfL at both the preataxic and ataxic stage. In preataxic individuals, sNfL levels increased with proximity to predicted ataxia onset, with significant sNfL elevations already 5 years before onset, and confirmed in preataxic individuals with actually observed ataxia onset. sNfL increases were detected already in preataxic individuals with SCA1 without volumetric atrophy of cerebellum or pons, suggesting that sNfL might be more sensitive to early preataxic neurodegeneration than the currently known most change-sensitive regions in volumetric MRI. Using longitudinal sNfL measurements, we estimated sample sizes for clinical trials with the reduction of sNfL as the endpoint. Discussion sNfL levels might provide easily accessible peripheral biomarkers in both preataxic and ataxic SCA1, allowing stratification of preataxic individuals regarding proximity to onset, early detection of neurodegeneration even before volumetric MRI alterations, and potentially capture of treatment response in clinical trials.
引用
收藏
页码:E1985 / E1996
页数:12
相关论文
共 31 条
[1]   Promising Results in 18-Month Analysis of Alzheimer Drug Candidate [J].
Abbasi, Jennifer .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2018, 320 (10) :965-965
[2]   Autosomal dominant cerebellar ataxias: Imaging biomarkers with high effect sizes [J].
Adanyeguh, Isaac M. ;
Perlbarg, Vincent ;
Henry, Pierre-Gilles ;
Rinaldi, Daisy ;
Petit, Elodie ;
Valabregue, Romain ;
Brice, Alexis ;
Durr, Alexandra ;
Mochel, Fanny .
NEUROIMAGE-CLINICAL, 2018, 19 :858-867
[3]   Correlation between CSF and blood neurofilament light chain protein: a systematic review and meta-analysis [J].
Alagaratnam, Jasmini ;
von Widekind, Sophia ;
De Francesco, Davide ;
Underwood, Jonathan ;
Edison, Paul ;
Winston, Alan ;
Zetterberg, Henrik ;
Fidler, Sarah .
BMJ NEUROLOGY OPEN, 2021, 3 (01)
[4]   Blood neurofilament light: a critical review of its application to neurologic disease [J].
Barro, Christian ;
Chitnis, Tanuja ;
Weiner, Howard L. .
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY, 2020, 7 (12) :2508-2523
[5]   Evaluation of mutant huntingtin and neurofilament proteins as potential markers in Huntington's disease [J].
Byrne, Lauren M. ;
Rodrigues, Filipe B. ;
Johnson, Eileanor B. ;
Wijeratne, Peter A. ;
De Vita, Enrico ;
Alexander, Daniel C. ;
Palermo, Giuseppe ;
Czech, Christian ;
Schobel, Scott ;
Scahill, Rachael I. ;
Heslegrave, Amanda ;
Zetterberg, Henrik ;
Wild, Edward J. .
SCIENCE TRANSLATIONAL MEDICINE, 2018, 10 (458)
[6]   Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysis [J].
Byrne, Lauren M. ;
Rodrigues, Filipe B. ;
Blennow, Kaj ;
Durr, Alexandra ;
Leavitt, Blair R. ;
Roos, Raymund A. C. ;
Scahill, Rachael I. ;
Tabrizi, Sarah J. ;
Zetterberg, Henrik ;
Langbehn, Douglas ;
Wild, Edward J. .
LANCET NEUROLOGY, 2017, 16 (08) :601-609
[7]   Plasma neurofilament light chain predicts cerebellar atrophy and clinical progression in spinocerebellar ataxia [J].
Coarelli, Giulia ;
Darios, Frederic ;
Petit, Emilien ;
Dorgham, Karim ;
Adanyeguh, Isaac ;
Petit, Elodie ;
Brice, Alexis ;
Mochel, Fanny ;
Durr, Alexandra .
NEUROBIOLOGY OF DISEASE, 2021, 153
[8]   Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6 [J].
du Montcel, Sophie Tezenas ;
Durr, Alexandra ;
Rakowicz, Maria ;
Nanetti, Lorenzo ;
Charles, Perrine ;
Sulek, Anna ;
Mariotti, Caterina ;
Rola, Rafal ;
Schols, Ludger ;
Bauer, Peter ;
Dufaure-Gare, Isabelle ;
Jacobi, Heike ;
Forlani, Sylvie ;
Schmitz-Huebsch, Tanja ;
Filla, Alessandro ;
Timmann, Dagmar ;
van de Warrenburg, Bart P. ;
Marelli, Cecila ;
Kang, Jun-Suk ;
Giunti, Paola ;
Cook, Arron ;
Baliko, Laszlo ;
Bela, Melegh ;
Boesch, Sylvia ;
Szymanski, Sandra ;
Berciano, Jose ;
Infante, Jon ;
Buerk, Katrin ;
Masciullo, Marcella ;
Di Fabio, Roberto ;
Depondt, Chantal ;
Ratka, Susanne ;
Stevanin, Giovanni ;
Klockgether, Thomas ;
Brice, Alexis ;
Golmard, Jean-Louis .
JOURNAL OF MEDICAL GENETICS, 2014, 51 (07) :479-486
[9]   Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy [J].
Finkel, R. S. ;
Mercuri, E. ;
Darras, B. T. ;
Connolly, A. M. ;
Kuntz, N. L. ;
Kirschner, J. ;
Chiriboga, C. A. ;
Saito, K. ;
Servais, L. ;
Tizzano, E. ;
Topaloglu, H. ;
Tulinius, M. ;
Montes, J. ;
Glanzman, A. M. ;
Bishop, K. ;
Zhong, Z. J. ;
Gheuens, S. ;
Bennett, C. F. ;
Schneider, E. ;
Farwell, W. ;
De Vivo, D. C. .
NEW ENGLAND JOURNAL OF MEDICINE, 2017, 377 (18) :1723-1732
[10]   Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles [J].
Friedrich, Jillian ;
Kordasiewicz, Holly B. ;
O'Callaghan, Brennon ;
Handler, Hillary P. ;
Wagener, Carmen ;
Duvick, Lisa ;
Swayze, Eric E. ;
Rainwater, Orion ;
Hofstra, Bente ;
Benneyworth, Michael ;
Nichols-Meade, Tessa ;
Yang, Praseuth ;
Chen, Zhao ;
Ortiz, Judit Perez ;
Clark, H. Brent ;
Oz, Gulin ;
Larson, Sarah ;
Zoghbi, Huda Y. ;
Henzler, Christine ;
Orr, Harry T. .
JCI INSIGHT, 2018, 3 (21)