Objective: This study aims to identify data-driven turning points in MRI biomarkers of SCA3 to characterize region-specific disease transitions and inform early intervention strategies.

Background: SCA3 is a rare neurodegenerative disorder causing progressive motor impairment. While brainstem and cerebellar atrophy are well-documented, their precise timing and sequence remain unclear. Defining these transitions is essential for identifying early intervention windows and improving clinical trial design.

Method: This study analyzed 423 MRI scans from 183 ESMI participants (55 healthy controls (HC), 32 preSCA3, 96 SCA3). MRI data were acquired using a standardized 3T protocol, and T1-weighted scans were processed with FastSurfer and CerebNet. Disease duration was defined as time to onset for preSCA3 and years since gait disturbances for SCA3.

To assess structural decline, atrophy slopes were computed between visits for each subject using normalized volumetric data. To model disease progression, the first derivative of a sigmoid was fitted to these slopes, capturing slow, rapid, and plateau phases of neurodegeneration while accounting for inter-individual variability. Turning points were identified using the 95% cumulative threshold of the primitive (integral) of the fitted sigmoid-derivative. Kaplan-Meier survival analysis was performed to estimate the probability of an individual’s atrophy rate exceeding 2 standard deviations from the HC group.

Results: Distinct turning points across brainstem and cerebellar structures revealed region-specific neurodegeneration. The medulla transitioned earliest, followed by the pons and midbrain, with survival probabilities of 0.97–0.99. In the cerebellum, white matter declined earlier than gray matter, suggesting differential progression (see Figure 1 for an example). Kaplan-Meier analysis confirmed ongoing degeneration in the symptomatic phase. Turning points and and survival-based transitions can be seen in Table 1.

Conclusion: Medullary atrophy occurs first, followed by pons degeneration closer to symptom onset and midbrain atrophy progressing into the symptomatic phase. In the cerebellum, white matter declines earlier than gray matter. These findings offer a data-driven framework for identifying key disease transitions and may help refine early intervention strategies.

Turning points and survival transitions in SCA3

Example of methodological approach in white matter

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MDS Abstracts - https://www.mdsabstracts.org/abstract/turning-points-in-disease-progression-detecting-mri-biomarker-transitions-in-sca3-using-longitudinal-data/