TY  - JOUR
AU  - Wilke, Carlo
AU  - Haas, Eva
AU  - Reetz, Kathrin
AU  - Faber, Jennifer
AU  - Garcia‐Moreno, Hector
AU  - Santana, Magda M
AU  - Warrenburg, Bart
AU  - Hengel, Holger
AU  - Lima, Manuela
AU  - Filla, Alessandro
AU  - Durr, Alexandra
AU  - Melegh, Bela
AU  - Masciullo, Marcella
AU  - Infante, Jon
AU  - Giunti, Paola
AU  - Neumann, Manuela
AU  - Vries, Jeroen
AU  - Pereira de Almeida, Luis
AU  - Rakowicz, Maria
AU  - Jacobi, Heike
AU  - Schüle, Rebecca
AU  - Kaeser, Stephan A
AU  - Kuhle, Jens
AU  - Klockgether, Thomas
AU  - Schöls, Ludger
AU  - Barro, Christian
AU  - Hübener‐Schmid, Jeannette
AU  - Synofzik, Matthis
AU  - Deuschle, Christian
AU  - Stransky, Elke
AU  - Brockmann, Kathrin
AU  - Schulz, Jörg B
AU  - Baliko, Laszlo
AU  - Gaalen, Judith
AU  - Raposo, Mafalda
AU  - Jeromin, Andreas
TI  - Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice
JO  - EMBO molecular medicine
VL  - 12
IS  - 7
SN  - 1757-4684
CY  - Heidelberg
PB  - EMBO Press
M1  - DZNE-2020-01275
SP  - e11803
PY  - 2020
AB  - 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.
KW  - Animals
KW  - Biomarkers: blood
KW  - Cross-Sectional Studies
KW  - Female
KW  - Humans
KW  - Intermediate Filaments: chemistry
KW  - Machado-Joseph Disease: blood
KW  - Male
KW  - Mice
KW  - Prodromal Symptoms
KW  - Severity of Illness Index
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC7338806
C6  - pmid:32510847
DO  - DOI:10.15252/emmm.201911803
UR  - https://pub.dzne.de/record/153278
ER  -