Wilke C, Haas E, Reetz K, Faber J, Garcia-Moreno H, Santana MM, van de Warrenburg B, Hengel H, Lima M, Filla A, Durr A, Melegh B, Masciullo M, Infante J, Giunti P, Neumann M, de Vries J, Pereira de Almeida L, Rakowicz M, Jacobi H, Schüle R, Kaeser SA, Kuhle J, Klockgether T, Schöls L, Barro C, Hübener-Schmid J and Synofzik M.
EMBO Mol Med (2020)e11803
With molecular treatments coming into reach for spinocerebellar ataxia type 3 (SCA 3), 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 SCA 3 cohorts and in a SCA 3 knock‐in mouse model. Ataxic SCA 3 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 SCA 3 were each paralleled by similar changes in SCA 3 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 SCA 3, associated with earliest neuropathological changes, and serve as progression, proximity‐to‐onset and, potentially, treatment‐response markers in both human and preclinical SCA3 trials.