Objective: As new therapies for SCA3 are on the horizon, there is an urgent need to identify and validate sensitive biological markers that reflect the individual disease profile. Of particular interest are markers that are already sensitive in the pre-ataxia stage. As SCA3 is associated with widespread cerebral and spinal cord structural alterations [1][2][3], MRI-based brain and spinal cord morphometric measures are promising candidates for such markers.

Background: The European Spinocerebellar Type 3/Machado-Joseph Disease Initiative (ESMI) set up a trial ready cohort. In addition to a detailed clinical assessment MRI was pro- and retrospectively collected. In this analysis we included all available T1 MRI for a cross-sectional volumetric analysis in a large cohort of non-ataxic and ataxic mutation carriers and healthy controls.

Method: We collected T1 MRI of 326 subjects. We included 40 non-ataxic, 177 ataxic mutation carriers and 31 healthy controls in this interim analysis. To obtain individual morphometric profiles, we applied an optimized, automated analysis pipeline (Learning Embeddings for Atlas Propagation), that allows to segment the brain into 167 substructures for volumetric measurement [4]. In addition, the cervical spinal cord was manually segmented in a semiautomated way, and the cross-sectional area at the C2/C3 level was determined.

Results: Compared to controls, volumes of the medulla oblongata, pons, midbrain and pallidum were reduced in non-ataxic mutation carriers. In addition the 4th ventricle was enlarged. Ataxic mutation carriers had reduced volumes of cerebellar lobules, midbrain and pons, compared to non-ataxic mutation carriers. The left-right and anterior-posterior diameter of the spinal cord at the C2/C3 level was reduced in ataxic mutation carriers.

Conclusion: Use of an automated segmentation tool allowed to obtain individual brain morphometric profiles of SCA3 mutation carriers. Our data suggest that neurodegeneration of the pallidum, brainstem and cerebellar pathways reflected by enlargement of 4th ventricle starts before manifestation of ataxia, while cerebellar and spinal cord degeneration goes in parallel with the development of ataxia. We identified pallidum, brainstem and 4th ventricle volumes as sensitive markers of the pre-ataxia stage. They may thus serve as outcome markers in future preventive trials. Preliminary results were presented at the SCA global conference, March 2019.

References: 1 – Reetz K, et al. Brain 2013; 136:905–17. 2 – Rezende TJR, et al. Ann Neurol. 2018; 2018 Sep;84(3):401-408. 3 – Lukas C, et al. J Neurol. 2008 Aug;255(8): 1244-9. 4 – Wolz R, et al. Neuroimage 2010 Jan 15; 49(2): 1316–1325.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/brain-and-spinal-cord-structural-alterations-in-non-ataxic-and-ataxic-sca3-mutation-carriers/