Objective: The aim was to identify the sequence of brain regions becoming atrophic in the early phase of spinocerebellar ataxia type 3 (SCA3).

Background: SCA3 is the most common autosomal dominantly inherited ataxia worldwide. Up to now no effective treatment is available, but a first safety trials of a targeted therapy with antisense oligonucleotides (ASO) has started. While clinical scales lack sensitivity before disease onset, imaging biomarker have particular importance. A thorough understanding of the sequence of brain region atrophy will facilitate the stratification of SCA3 mutation carriers for early interventions.

Method: T1w MRI of 300 SCA3 mutation carriers as well as of 317 healthy controls from previous or ongoing observational studies at 19 European, Chinese and US sites were included.

Event based modeling (EBM) was used to derive a sequence of brain regions that become sequentially abnormal based on their volume reduced in comparison to healthy controls. Individual volumes were standardized and probabilistic cut-offs were derived using Gaussian mixture modelling.

Results: We observed one distinct sequence of brain atrophy in SCA3 starting in the most caudal parts of the brainstem: Medulla oblongata, pons, cerebellar white matter, flocculonodular lobe, midbrain in a straight forward sequence followed by pallidum, thalamus and inferior posterior as well as anterior lobe in still ordered but less sharply separated sequence [figure 1]. Almost all preataxic SCA3 mutation carriers cluster in the first 1/3 of EBM identified stages of mild atrophy [figure2].

Conclusion: Brain neurodegeneration in SCA3 starts before the clinical onset in the brainstem and cerebellar white matter. The order of atrophy is unique and distinct. Knowledge of this consecutive sequence might support the stratification of SCA3 mutation carriers for early interventions.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/unique-consecutive-order-of-brain-atrophy-in-spinocerebellar-ataxia-type-3-sca3/