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

Abstract

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.

Multimodal Magnetic Resonance Imaging and Therapeutic Intervention With Yi-nao-jie-yu Decoction in a Rat Model of Post-stroke Depression

“…Therefore, we further examined changes in brain tissue microstructure and metabolite concentrations in PSD rats. To be able to quantify the integrity of brain tissues, we employed the relatively new DTI technique, which mainly assesses microstructural changes in brain tissue by measuring the motility of water molecules ( 28 , 29 ). In recent years, DTI has been increasingly used to study neuropsychiatric disorders, and FA and ADC are the most common measures of DTI.…”

Genetic ablation ofSOD1G37Rselectively from corticofugal projection neurons protects corticospinal neurons from degeneration without affecting ALS onset and progression

“…Post mortem analyses of the motor cortex of ALS patients confirms the loss of CSN, or Betz cells (Charcot, 1874;Nihei and Kowall, 1993). Similarly numerous rodent models of the disease recapitulate CSN degeneration such as the C9-BAC mice (Liu et al, 2016), the hPFN1 G118V mice (Fil et al, 2016), the TDP43 A315V mice (Herdewyn et al, 2014;Wegorzewska et al, 2009), and the TDP43 G298S mice (Müller et al, 2019) and the SOD1 G93A rats (Thomsen et al, 2014), and SOD1 mouse models also display progressive loss of CSN that starts pre-symptomatically (Marques et al, 2019;Ozdinler et al, 2011;Yasvoina et al, 2013;Zang and Cheema, 2002). In the Sod1 G86R mouse model of the disease, we further demonstrated that CSN start degenerating long before first signs of MN degeneration can be observed and that CSN and MN degeneration are somatotopically related.…”

Diffusion Tensor Imaging-Based Studies at the Group-Level Applied to Animal Models of Neurodegenerative Diseases

“…DTI of ALS brains of SOD1-mice at 9.4 T and 16.7 T, respectively, have shown a presymptomatic decrease in axonal organization by FA and neurite content by Intracellular Volume Fraction across the spinal cord, corpus callosum, hippocampus, and cortex; the combination of DTI, neurite orientation dispersion, and density imaging (NODDI), and diffusion kurtosis imaging (DKI) (Marrale et al, 2016 ) models have proved to provide an assessment of the early microstructural changes in the ALS brain (Gatto et al, 2018b , c , 2019 ). Longitudinal DTI in the TDP-43 G 298 S ALS mouse model at the cohort level revealed cortical and callosal microstructure alterations (Müller et al, 2019 ); in this study, longitudinal DTI scans at 11.7 T of baseline and follow-up scans with an interval of several months were investigated by voxelwise comparison as well as by tractwise analysis, while histological investigations complemented the in-vivo results.…”

“…A hypothesis-guided approach is performed when using ROIs that are placed in defined anatomical regions and comparing the average DTI metrics values, that is, rotational invariant parameters of the diffusion tensor, within the respective ROI for the cohorts (e.g., Harsan et al, 2010 ; Müller et al, 2019 ) for quantitative comparisons of in-between ROIs or to show differences between various white matter regions. ROI analysis could be extensively performed by placing an arbitrary number of ROIs (e.g., Irie et al, 2018 ) with variable extension.…”

“…There is a growing number of large-scale connectomes for preclinical models obtained with DTI ex vivo (Nouls et al, 2018 ; Allan Johnson et al, 2019 ) and increasingly in vivo (Gimenez et al, 2017 ; Haber et al, 2017 ; Müller et al, 2019 ). At the same time, single-neuron resolution connectomes are being obtained for the whole mouse brain (Ho et al, 2014 ) or for individual structures (e.g., Commisso et al, 2018 ) using viral tracing tools and optical imaging.…”