Longitudinal diffusion tensor magnetic resonance imaging analysis at the cohort level reveals disturbed cortical and callosal microstructure with spared corticospinal tract in the TDP-43(G298S) ALS mouse model

BACKGROUND: In vivo diffusion tensor imaging (DTI) of the mouse brain was used to identify TDP-43 associated alterations in a mouse model for amyotrophic lateral sclerosis (ALS). METHODS: Ten mice with TDP-43(G298S) overexpression under control of the Thy1.2 promoter and 10 wild type (wt) underwent longitudinal DTI scans at 11.7 T, including one baseline and one follow-up scan with an interval of about 5 months. Whole brain-based spatial statistics (WBSS) of DTI-based parameter maps was used to identify longitudinal alterations of TDP-43(G298S) mice compared to wt at the cohort level. Results were supplemented by tractwise fractional anisotropy statistics (TFAS) and histological evaluation of motor cortex for signs of neuronal loss. RESULTS: Alterations at the cohort level in TDP-43(G298S) mice were observed cross-sectionally and longitudinally in motor areas M1/M2 and in transcallosal fibers but not in the corticospinal tract. Neuronal loss in layer V of motor cortex was detected in TDP-43(G298S) at the later (but not at the earlier) timepoint compared to wt. CONCLUSION: DTI mapping of TDP-43(G298S) mice demonstrated progression in motor areas M1/M2. WBSS and TFAS are useful techniques to localize TDP-43(G298S) associated alterations over time in this ALS mouse model, as a biological marker.