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Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice

Abstract With molecular treatments coming into reach for spinocerebellar ataxia type 3 (SCA3), easily accessible, cross-species validated biomarkers for human and preclinical trials are warranted, particularly for the preataxic disease stage. We assessed serum levels of neurofilament light (NfL) and...

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Main Authors: Wilke, Carlo (Author) , Jacobi, Heike (Author)
Format: Article (Journal)
Language:English
Published: 8 June 2020
In: EMBO molecular medicine
Year: 2020, Volume: 12, Issue: 7
ISSN:1757-4684
DOI:10.15252/emmm.201911803
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.15252/emmm.201911803
Verlag, lizenzpflichtig, Volltext: https://www.embopress.org/doi/10.15252/emmm.201911803
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Author Notes:Carlo Wilke, Eva Haas, Kathrin Reetz, Jennifer Faber, Hector Garcia-Moreno, Magda M Santana, Bart van de Warrenburg, Holger Hengel, Manuela Lima, Alessandro Filla, Alexandra Durr, Bela Melegh, Marcella Masciullo, Jon Infante, Paola Giunti, Manuela Neumann, Jeroen de Vries, Luis Pereira de Almeida, Maria Rakowicz, Heike Jacobi, Rebecca Schüle, Stephan A Kaeser, Jens Kuhle, Thomas Klockgether, Ludger Schöls, SCA3 neurofilament study group, Christian Barro, Jeannette Hübener-Schmid, Matthis Synofzik
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Summary:Abstract With molecular treatments coming into reach for spinocerebellar ataxia type 3 (SCA3), easily accessible, cross-species validated biomarkers for human and preclinical trials are warranted, particularly for the preataxic disease stage. We assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in ataxic and preataxic subjects of two independent multicentric SCA3 cohorts and in a SCA3 knock-in mouse model. Ataxic SCA3 subjects showed increased levels of both NfL and pNfH. In preataxic subjects, NfL levels increased with proximity to the individual expected onset of ataxia, with significant NfL elevations already 7.5 years before onset. Cross-sectional NfL levels correlated with both disease severity and longitudinal disease progression. Blood NfL and pNfH increases in human SCA3 were each paralleled by similar changes in SCA3 knock-in mice, here also starting already at the presymptomatic stage, closely following ataxin-3 aggregation and preceding Purkinje cell loss in the brain. Blood neurofilaments, particularly NfL, might thus provide easily accessible, cross-species validated biomarkers in both ataxic and preataxic SCA3, associated with earliest neuropathological changes, and serve as progression, proximity-to-onset and, potentially, treatment-response markers in both human and preclinical SCA3 trials.
Item Description:Gesehen am 08.09.2020
Physical Description:Online Resource
ISSN:1757-4684
DOI:10.15252/emmm.201911803

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