Trajectories of Pontine Volume in Patients with Multiple System Atrophy

Objectives: To investigate trajectories of regional brain volume changes in multiple system atrophy (MSA) and their potential utility as surrogate markers of disease progression in the cerebellar subtype (MSA-C). Background: Reliable biomarkers for tracking disease progression in MSA are urgently needed. Although several studies have explored neuroimaging markers, imaging measures that are reliable and reproducible at the individual-level are lacking. Methods: Longitudinal three-dimensional (3D)-T1 images from multiple cohorts of 21 subjects with probable MSA-C, 19 with probable MSA-parkinsonian subtype (MSA-P), 113 with Parkinson's disease, and 227 healthy controls were processed using the FreeSurfer longitudinal pipeline. Extracted volumes were assessed for individual longitudinal trajectories, intra-individual variability, and pontine regional volume decline. Results: Pontine volumes showed lower intra-individual variability in measurements compared with other infratentorial brain regions. All probable MSA-C patients exhibited a decline in pontine volume, ranging from −3.6% to −16.8% per year (mean: −9.1%), falling more than two standard deviations below the mean of healthy controls. In MSA-C, the temporal dynamics of pontine volumes exhibited nonlinear changes, characterized by progressive atrophy in the earlier period of the disease, followed by a pre-plateau phase associated with advanced disability in the later period. Predictive modeling suggests that pontine atrophy may begin before symptom onset of MSA-C. Conclusions: Pontine volume is a sensitive marker of disease progression, exhibiting a nonlinear decline with low intra-individual variability in measurements and greater volume loss in the earlier stages, reaching a pre-plateau phase in the later stages with advanced disability.