Journal Article

DZNE-2020-01275

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice

Wilke, C. (First author)DZNE* ; Haas, E. ; Reetz, K. ; Faber, J. ; Garcia‐Moreno, H. ; Santana, M. M. ; Warrenburg, B. ; Hengel, H.DZNE* ; Lima, M. ; Filla, A. ; Durr, A. ; Melegh, B. ; Masciullo, M. ; Infante, J. ; Giunti, P. ; Neumann, M.DZNE* ; Vries, J. ; Pereira de Almeida, L. ; Rakowicz, M. ; Jacobi, H. ; Schüle, R.DZNE* ; Kaeser, S. A.DZNE* ; Kuhle, J. ; Klockgether, T. ; Schöls, L.DZNE* ; Barro, C. ; Hübener‐Schmid, J. ; Synofzik, M.DZNE* ; Deuschle, C. ; Stransky, E. ; Brockmann, K. ; Schulz, J. B. ; Baliko, L. ; Gaalen, J. ; Raposo, M. ; Jeromin, A.

2020
EMBO Press Heidelberg

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Please use a persistent id in citations: doi:10.15252/emmm.201911803

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.

Keyword(s): Animals (MeSH) ; Biomarkers: blood (MeSH) ; Cross-Sectional Studies (MeSH) ; Female (MeSH) ; Humans (MeSH) ; Intermediate Filaments: chemistry (MeSH) ; Machado-Joseph Disease: blood (MeSH) ; Male (MeSH) ; Mice (MeSH) ; Prodromal Symptoms (MeSH) ; Severity of Illness Index (MeSH)

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Contributing Institute(s):

1. Core ICRU (Core ICRU)
2. Patient Studies Bonn (Patient Studies Bonn)
3. Parkinson Genetics (AG Gasser)
4. Molecular Neuropathology of Neurodegenerative Diseases (AG Neumann)
5. Functional Neurogeriatrics (AG Maetzler)
6. Cell Biology of Neurological Diseases (AG Jucker)
7. Clinical Alzheimer’s Disease Research (AG Jessen)
8. Clinical Neurogenetics (AG Schöls)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)
2. 345 - Population Studies and Genetics (POF3-345) (POF3-345)
3. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)

Experiment(s):

1. European Spinocerebellar Ataxia Type 3/Machado-Joseph Disease Initiative

Appears in the scientific report 2020

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