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.

Keywords: Spinocerebellar ataxia; biomarker; disease modeling.

Figure 1:. Scale for the Assessment and Rating of Ataxia (SARA) scores, fluid and MRI biomarker data in SCA3 mutation carriers in relation to time of ataxia onset.

Data were analyzed with additive Gaussian regression on a time scale defined by ataxia onset. The time of ataxia onset is indicated with a vertical dashed line in all graphs. The estimated 95% CIs are shown by the shaded areas around the curves. (A) SARA sum score. The SARA cut-off of 3 defining manifest ataxia is given as a dashed horizontal line. (B) Plasma concentrations of elongated ATXN3. Data are given in ng/ml. (C) Serum concentrations of neurofilament light (NfL), MRI volumes of the pons, cerebellar with matter (CWM) and grey matter (CGM). Data were z-transformed in relation to healthy controls of same age. Y-axis of volume values is inverted for better comparability of volume loss and NfL increase. Mean of healthy controls is given as a horizontal line, the 1 SD range by dashed, and the 2 SD range by dotted lines.

Figure 2:. Staging model of SCA3.

Proposed staging model of SCA3 based on the studied fluid and MRI biomarker data. The model 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, which is defined by manifest ataxia. Following previous suggestions, the ataxia stage is further subdivided into three substages defined by milestones of gait deterioration.

Figure 3. Scale for the Assessment and Rating of Ataxia (SARA) scores, fluid and MRI biomarker data in the carrier, biomarker and ataxia stage of SCA3.

Data were analyzed with one-way ANOVA followed by pairwise comparisons using Tukey’s test * p<0.01; **p<0.001. NfL - neurofilament light, CWM – cerebellar white matter, CGM – cerebellar grey matter, eTIV – estimated intracranial volume.