Longitudinal 8-year Brain Volumetric Analysis in 35 CLN3 Patients: Successful Development of a Sensitive Marker to Measure Clinical Outcome

Background/Purpose: A precise description of disease progression in NCL3 is urgently needed to establish an evaluation tool for future experimental treatments. This is especially challenging, as CLN3 disease may present with variable clinical disease progression. To develop a quantitative marker to measure brain volume outcome, we analyzed the longitudinal volumetric development of gray matter (GM), white matter (WM), and lateral ventricles and correlated those with the clinical course.

Methods: A total of 122 MRIs of 35 patients (14 males; 21 females; age 15.3 ± 4.8 years) with genetically confirmed CLN3 disease were performed on 1.5T scanners. A 3D T1-weighted MP-RAGE sequence was acquired. Volumetric segmentation of the brain was performed using Freesurfer Software suite. The clinical severity was assessed by the Hamburg juvenile NCL score, a disease-specific scoring system.

Results: The volumes of cortical GM, cerebellar GM and WM, basal ganglia + thalami, and hippocampus significantly (all p < 0.0001) decreased with age, while the lateral ventricle volume increased (p < 0.0001). Supratentorial WM volume correlated much poorer with age than the other observed regions (R = 0.21, p = 0.0094). Decrease of cortical gray matter volume showed the most uniform decrease with strongest correlation with age (R = 0.814, p < 0.0001). CLN3 patients lost on average 4.6% (± 0.2%) of cortical GM per year. In addition, a strong correlation with clinical scoring existed for the cortical GM (R = 0.823, p = <0.0001).

Conclusion: Cortical GM volume decline seems to be the most sensitive parameter for assessment of disease progression and represents a potential sensitive outcome measure for the evaluation of future therapies.