Natural history of MRI brain volumes in patients with neuronal ceroid lipofuscinosis 3: a sensitive imaging biomarker.

PURPOSE: Grey matter (GM) atrophy due to neuronal loss is a striking feature of patients with CLN3 disease. A precise and quantitative description of disease progression is needed in order to establish an evaluation tool for current and future experimental treatments. In order to develop a quantitative marker to measure brain volume outcome, we analysed the longitudinal volumetric development of GM, white matter (WM) and lateral ventricles and correlated those with the clinical course. METHODS: One hundred twenty-two MRI scans of 35 patients (21 females; 14 males; age 15.3 ± 4.8 years) with genetically confirmed CLN3 disease were performed. A three-dimensional T1-weighted sequence was acquired with whole brain coverage. Volumetric segmentation of the brain was performed with the FreeSurfer image analysis suite. The clinical severity was assessed by the Hamburg jNCL score, a disease-specific scoring system. RESULTS: The volumes of supratentorial cortical GM and supratentorial WM, cerebellar GM, basal ganglia/thalamus and hippocampus significantly (r = - 0.86 to - 0.69, p < 0.0001) decreased with age, while the lateral ventricle volume increased (r = 0.68, p < 0.0001). Supratentorial WM volume correlated poorer with age (r = - 0.56, p = 0.0001). Supratentorial cortical GM volume showed the steepest (4.6% (± 0.2%)) and most uniform decrease with strongest correlation with age (r = - 0.86, p < 0.0001). In addition, a strong correlation with disease specific clinical scoring existed for the supratentorial cortical GM volume (r = 0.85, p = < 0.0001). CONCLUSION: Supratentorial cortical GM volume is a sensitive parameter for assessment of disease progression even in early and late disease stages and represents a potential reliable outcome measure for evaluation of experimental therapies.

Volumetric Description of Brain Atrophy in Neuronal Ceroid Lipofuscinosis 2: Supratentorial Gray Matter Shows Uniform Disease Progression.

BACKGROUND AND PURPOSE: Experimental therapies for ceroid lipofuscinosis, neuronal, 2 (CLN2), a genetic disorder of childhood associated with progressive brain atrophy, are currently being developed. Because quantitative descriptions of the natural course of brain volume loss are needed to evaluate novel therapies, we performed MR imaging volumetry of patients with CLN2 to identify a suitable MR imaging marker of disease progression. MATERIALS AND METHODS: Thirteen patients (8 females, 5 males) were recruited from a prospective natural disease cohort of patients with neuronal ceroid lipofuscinosis. Repeated MR imaging volumetric analysis (29 datasets) was performed by using the FreeSurfer Software Suite. Follow-up time ranged from 8 months to 5.3 years. MR imaging-segmented brain volumes were correlated to patient age and clinical scores. RESULTS: Segmented brain volumes correlated significantly with patient age (lateral ventricles, r = 0.606, P = .001; supratentorial cortical GM, r = -0.913, P < .001; supratentorial WM, r = -0.865, P < .001; basal ganglia/thalamus, r = -0.832, P < .001; cerebellar GM, r = -0.659, P < .001; cerebellar WM, r = -0.830, P < .001) and clinical scores (lateral ventricles, r = -0.692, P < .001; supratentorial cortical GM, r = 0.862, P < .001; supratentorial WM, r = 0.735, P < .001; basal ganglia/thalamus, r = 0.758, P < .001; cerebellar GM, r = 0.609, P = .001; cerebellar WM, r = 0.638, P < .001). Notably, supratentorial cortical GM showed a uniform decline across the patient cohort. During late stages of the disease when the clinical score was zero, segmented brain volumes still correlated with patient age; this finding suggests that MR imaging volumetry allows quantitative assessment of disease progression at stages when it cannot be detected by clinical assessment alone. CONCLUSIONS: Automated MR imaging volumetry, as a nonsubjective and highly sensitive tool, is feasible in CLN2 disease and provides a quantitative basis to evaluate novel experimental therapies.