Open AccessNeurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice
Author(s) -
Wilke Carlo,
Haas Eva,
Reetz Kathrin,
Faber Jennifer,
GarciaMoreno Hector,
Santana Magda M,
Warrenburg Bart,
Hengel Holger,
Lima Manuela,
Filla Alessandro,
Durr Alexandra,
Melegh Bela,
Masciullo Marcella,
Infante Jon,
Giunti Paola,
Neumann Manuela,
Vries Jeroen,
Pereira de Almeida Luis,
Rakowicz Maria,
Jacobi Heike,
Schüle Rebecca,
Kaeser Stephan A,
Kuhle Jens,
Klockgether Thomas,
Schöls Ludger,
Barro Christian,
HübenerSchmid Jeannette,
Synofzik Matthis
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201911803
Subject(s) - spinocerebellar ataxia , machado–joseph disease , ataxia , neurofilament , medicine , neurodegeneration , pathology , disease , biology , neuroscience , endocrinology , immunohistochemistry
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.