Stage-dependent biomarker changes in spinocerebellar ataxia type 3

Abstract

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3) is the most common autosomal dominant ataxia. In view of the development of targeted therapies for SCA3, precise knowledge of stage-dependent fluid and MRI biomarker changes is needed. We analyzed cross-sectional data of 292 SCA3 mutation carriers including 57 pre-ataxic individuals, and 108 healthy controls from the European Spinocerebellar ataxia type 3/Machado-Joseph Disease Initiative (ESMI) cohort. Blood concentrations of mutant ATXN3 and neurofilament light (NfL) were determined, and volumes of pons, cerebellar white matter (CWM) and cerebellar grey matter (CGM) were measured on MRI. Mutant ATXN3 concentrations were high before and after ataxia onset, while NfL continuously increased and deviated from normal 11.9 years before onset. Pons and CWM volumes decreased, but the deviation from normal was only 2.0 years (pons) and 0.3 years (CWM) before ataxia onset. We propose a staging model of SCA3 that includes an initial asymptomatic carrier stage followed by the biomarker stage defined by absence of ataxia, but a significant rise of NfL. The biomarker stage leads into the ataxia stage, defined by manifest ataxia. The present analysis provides a robust framework for further studies aiming at elaboration and differentiation of the staging model of SCA3.

Blood levels of neurofilament light are associated with disease progression in a mouse model of spinocerebellar ataxia type 3

“…Our findings in aged homozygous Q84/Q84 mice reveal synonymous trends, with significantly increased blood NfL levels at late-stage disease. Although these mice showed no correlation between age and serum NfL, this result is consistent with studies on patients with SCA3 demonstrating decreased magnitude of blood NfL increases over time ( Li et al, 2019 ; Peng et al, 2022 ; Wilke et al, 2020b ; Faber et al, 2023 preprint). This suggests a plateau effect, i.e.…”

“…Studies in patients with SCA3 have demonstrated trends for NfL increases between the pre-ataxic stage and symptomatic ataxia onset ( Wilke et al, 2020b ; Li et al, 2019 ; Peng et al, 2022 ; Faber et al, 2023 preprint), and stably increased NfL levels during the symptomatic ataxic phase. These trends are reflective of increased neuronal turnover during the pre-ataxic phase and stably increased neuronal turnover during the symptomatic ataxic phase ( Wilke et al, 2020b ).…”

“…In particular, NfL has been evidenced to hold notable value as a biomarker for SCA3. Patients with SCA3 exhibit significantly higher serum, plasma and CSF NfL levels than those of unaffected controls ( Wilke et al, 2018 , 2020b ; Li et al, 2019 ; Peng et al, 2022 ; Garcia-Moreno et al, 2022 ; Coarelli et al, 2021 ; Prudencio et al, 2020 ; Faber et al, 2023 preprint). Remarkably, SCA3 carriers in pre-ataxic stages also show increased NfL in biofluids prior to age of onset of clinical ataxia presentation ( Wilke et al, 2020b ; Li et al, 2019 ).…”

“…Remarkably, SCA3 carriers in pre-ataxic stages also show increased NfL in biofluids prior to age of onset of clinical ataxia presentation ( Wilke et al, 2020b ; Li et al, 2019 ). Specifically, pre-ataxic patients demonstrate significantly higher serum NfL than that of unaffected controls more than 10 years prior to ataxia onset ( Faber et al, 2023 preprint). Furthermore, biofluid NfL levels in patients with SCA3 have been found to correlate with various measures of disease progression and severity, including age ( Wilke et al, 2020b ; Li et al, 2019 ; Coarelli et al, 2021 ), CAG repeat size ( Wilke et al, 2020b ; Coarelli et al, 2021 ), Scale for Assessment and Rating of Ataxia (SARA) and International Cooperating Ataxia Rating Scale (ICARS) scores ( Wilke et al, 2020b ; Li et al, 2019 ; Peng et al, 2022 ; Garcia-Moreno et al, 2022 ; Coarelli et al, 2021 ), and volume of affected brain regions ( Li et al, 2019 ; Peng et al, 2022 ; Coarelli et al, 2021 ).…”

CAG repeat mosaicism is gene specific in spinocerebellar ataxias

“…SCA7 ataxic individuals have a higher level of expansion compared to premanifest individuals. Until now, the accumulation of the disease protein has been used as a biomarker in Huntington disease or SCA3; 29 , 30 the EI described here in SCA7 could be used to distinguish affected individuals for trial enrollment purposes. A study in a larger group would strengthen these data.…”