Morphometric Brain Changes in a Merino Sheep (Ovis aries) CLN6 Neuronal Ceroid Lipofuscinosis Model

The neuronal ceroid lipofuscinoses are the most common group of human paediatric genetic neurodegenerative disorders and have also been reported in multiple animal species. This study explores sheep with the CLN6 disease subtype, which occurs in humans either as a late-infantile or as an adult-onset disease. This study characterised morphometric changes that occur in the brains of 15-month-old Merino sheep with CLN6 disease compared to healthy, adult Merino control brains using ultra-high field magnetic resonance imaging (MRI). The formalin-fixed brains of seven affected and three wild-type control sheep were scanned in a 9.4 T Bruker MRI scanner with a T1-weighted gradient echo. Bioimaging technology 'Amira-Avizo' was used to segment each region of interest to create a 3D reconstruction of each ovine brain. Volumetric and statistical analysis of each region of interest found that the thalamus, corpus callosum, occipital cortex, hippocampal region and striatum of affected sheep all experienced a significant loss of volume; 80%, 77%, 73%, 50%, 46% respectively, compared to the control brains. The left side of the affected brain showed a significant reduction of 44%, while the volume of the lateral ventricle non-significantly increased by 43%. However, the cerebellum and arbour vitae of affected sheep lost 15% and 8% of their volume, respectively, which was not significant. These findings are overall consistent with previous gross pathology, histopathology and traditional in vivo MRI findings of ovine CLN6 disease models, but suggest that postmortem ultra-high field MRI of formalin-fixed brains can be a complementary approach to in vivo studies. Volumetric analysis of affected brain regions, including the corpus callosum, thalamus, occipital cortex, striatum, and hippocampal region, can provide valuable biomarkers for assessing the effectiveness of therapeutic interventions in NCL.