Regional Brain and Spinal Cord Volume Loss in Spinocerebellar Ataxia Type 3

Jennifer Faber, Tamara Schaprian, Koyak Berkan, Kathrin Reetz, Marcondes Cavalcante França Jr, Thiago Junqueira Ribeiro de Rezende, Jiang Hong, Weihua Liao, Bart van de Warrenburg, Judith van Gaalen, Alexandra Durr, Fanny Mochel, Paola Giunti, Hector Garcia-Moreno, Ludger Schoels, Holger Hengel, Matthis Synofzik, Benjamin Bender, Gulin Oz, James Joers, Jereon J de Vries, Jun-Suk Kang, Dagmar Timmann-Braun, Heike Jacobi, Jon Infante, Richard Joules, Sandro Romanzetti, Jorn Diedrichsen, Matthias Schmid, Robin Wolz, Thomas Klockgether, Jennifer Faber, Tamara Schaprian, Koyak Berkan, Kathrin Reetz, Marcondes Cavalcante França Jr, Thiago Junqueira Ribeiro de Rezende, Jiang Hong, Weihua Liao, Bart van de Warrenburg, Judith van Gaalen, Alexandra Durr, Fanny Mochel, Paola Giunti, Hector Garcia-Moreno, Ludger Schoels, Holger Hengel, Matthis Synofzik, Benjamin Bender, Gulin Oz, James Joers, Jereon J de Vries, Jun-Suk Kang, Dagmar Timmann-Braun, Heike Jacobi, Jon Infante, Richard Joules, Sandro Romanzetti, Jorn Diedrichsen, Matthias Schmid, Robin Wolz, Thomas Klockgether

Abstract

Background: Given that new therapeutic options for spinocerebellar ataxias are on the horizon, there is a need for markers that reflect disease-related alterations, in particular, in the preataxic stage, in which clinical scales are lacking sensitivity.

Objective: The objective of this study was to quantify regional brain volumes and upper cervical spinal cord areas in spinocerebellar ataxia type 3 in vivo across the entire time course of the disease.

Methods: We applied a brain segmentation approach that included a lobular subsegmentation of the cerebellum to magnetic resonance images of 210 ataxic and 48 preataxic spinocerebellar ataxia type 3 mutation carriers and 63 healthy controls. In addition, cervical cord cross-sectional areas were determined at 2 levels.

Results: The metrics of cervical spinal cord segments C3 and C2, medulla oblongata, pons, and pallidum, and the cerebellar anterior lobe were reduced in preataxic mutation carriers compared with controls. Those of cervical spinal cord segments C2 and C3, medulla oblongata, pons, midbrain, cerebellar lobules crus II and X, cerebellar white matter, and pallidum were reduced in ataxic compared with nonataxic carriers. Of all metrics studied, pontine volume showed the steepest decline across the disease course. It covaried with ataxia severity, CAG repeat length, and age. The multivariate model derived from this analysis explained 46.33% of the variance of pontine volume.

Conclusion: Regional brain and spinal cord tissue loss in spinocerebellar ataxia type 3 starts before ataxia onset. Pontine volume appears to be the most promising imaging biomarker candidate for interventional trials that aim at slowing the progression of spinocerebellar ataxia type 3. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Trial registration: ClinicalTrials.gov NCT01470729.

Keywords: MRI; biomarker; spinocerebellar ataxia; volumetry.

© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Figures

FIG. 1.
FIG. 1.
Regional volume loss along the time course of the disease. Each metric, being mean cross-sectional area of cervical spinal cord levels C2 and C3 and volumes of medulla oblongata, pons, midbrain, cerebellar white matter, anterior lobe of the cerebellum, cerebellar lobules crus II and X. and pallidum of SCA3 mutation carriers, was z-transformed in relation to healthy controls of the same age. The x axis represents the estimated disease duration in years. The estimated 95% confidence interval is given in dark gray. For a better orientation, the following reference lines and ranges are given: the vertical dashed line marks the estimated clinical onset; the horizontal dashed line marks the average of the healthy control group, represented by a z score of 0; the medium- and light-gray areas represent the range ± 1 and respective ±2 standard deviations of the healthy control group distribution.

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