Mapping Clinical Progression to Brain Atrophy in CLN2 Patients Under Cerliponase Alfa Treatment: A Prospective...

Neuronal ceroid lipofuscinosis type 2 (CLN2) disease, a lysosomal storage disorder, causes early childhood psychomotor regression, vision loss, seizures, and rapid progressive gray matter loss. However, the link between neurodegenerative processes induced by lysosomal pathophysiology and the clinical phenotype remains unclear. This study investigated the longitudinal association of gray matter atrophy on MRI with in-depth clinical phenotyping in 27 patients receiving intraventricular enzyme therapy (n_timepoints = 170; biannual clinical assessments and MRIs). Longitudinal changes in cortical thickness and subcortical volumes were modeled via linear mixed effects regression. We used linear regression to correlate 24-week (Δ24) changes in clinical assessments with global cortical thickness and applied multivariate data-driven statistics to model how specific brain regions are associated with clinical domains. Our analysis revealed a significant reduction in the mean cortical thickness over time (β = -0.002, p = 0.021), corresponding to an annual loss of 4.2%, compared to natural history controls with 12.5%, respectively. Regional analysis revealed a widespread pattern of cortical and subcortical gray matter atrophy. Global cortical thickness reductions over 24 weeks (Δ24) were significantly associated with changes in the Hamburg motor and language scale Δ24, Weill Cornell scale Δ24, and Movement Disorder Inventory Δ24. Multivariate statistics identified a significant latent dimension relating regional morphometric abnormalities to worse clinical outcomes, accounting for 82% of the shared variance. Leveraging connectome data, we demonstrated that atrophy was linked to brain network architecture. Given their strong associations with clinical outcomes, MRI-based brain morphometric measures are promising CLN2 disease biomarkers to aid diagnosis, monitor disease progression, and guide therapy.