Combined Diffusion Tensor Imaging and Quantitative Susceptibility Mapping Discern Discrete Facets of White Matter Pathology Post-injury in the Rodent Brain

Abstract

Early loss of white matter microstructure integrity is a significant cause of long-term neurological disorders following traumatic brain injury (TBI). White matter abnormalities typically involve axonal loss and demyelination. In-vivo imaging tools to detect and differentiate such microstructural changes are not well-explored. This work utilizes the conjoint potential offered by advanced magnetic resonance imaging techniques, including quantitative susceptibility mapping (QSM) and diffusion tensor imaging (DTI), to discern the underlying white matter pathology at specific time points (5 h, 1, 3, 7, 14, and 30 days) post-injury in the controlled cortical impact mouse model. A total of 42 animals were randomized into six TBI groups (n = 6 per group) and one sham group (n = 6). Histopathology was performed to validate in-vivo findings by performing myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) immunostaining for the assessment of changes to myelin and astrocytes. After 5 h of injury radial diffusivity (RD) was increased in white matter without a significant change in axial diffusivity (AxD) and susceptibility values. After 1 day post-injury RD was decreased. AxD and susceptibility changes were seen after 3 days post-injury. Susceptibility increases in white matter were observed in both ipsilateral and contralateral regions and persisted for 30 days. In histology, an increase in GFAP immunoreactivity was observed after 3 days post-injury and remained high for 30 days in both ipsilateral and contralateral white matter regions. A loss in MBP signal was noted after 3 days post-injury that continued up to 30 days. In conclusion, these results demonstrate the complementary ability of DTI and QSM in discerning the micro-pathological processes triggered following TBI. While DTI revealed acute and focal white matter changes, QSM mirrored the temporal demyelination in the white matter tracts and diffuse regions at the chronic state.

A single closed head injury in mice induces chronic, progressive white matter atrophy and increased phospho-tau expressing oligodendrocytes

“…This gray matter atrophy was unchanged at 180 DPI (Figure 2C). This is similar to the gray matter atrophy reported in the murine controlled cortical impact (CCI) TBI model that produces rapid gray matter atrophy that continued to increase between 14 and 30 DPI and persists at 180 DPI (Mohamed et al, 2021;Soni et al, 2020).…”

“…In preclinical models, progressive atrophy and neural loss peristed for one year followng fluid percussion injury (Smith et al, 1997). Some rodent TBI models show only transient changes in DTI that return to sham levels after 30 DPI (Soni et al, 2020); others have shown chronic degeneration particularly of white matter (Armstrong et al, 2016; Mac Donald et al, 2007; Mohamed et al, 2021; Soni et al, 2020). In the controlled cortical impact (CCI) model of TBI, increased gray matter atrophy ocurred close to the impact site (Mohamed et al, 2021).…”

Diffusion Tensor Imaging Detects Acute Pathology-Specific Changes in the P301L Tauopathy Mouse Model Following Traumatic Brain Injury

“…In the gray matter, the cn-dentate gyrus, CA1 region (the ipsilateral hippocampus was washed away during brain processing for histology), ipsilateral and contralateral amygdala, cortex, and thalamus were explored. Regions-of-interest were drawn manually on the study-specific template using the Australian mouse brain mapping consortium template ( Watson et al, 2017 ) and the Allen adult mouse brain atlas 3 as a reference ( Soni et al, 2020 ). Diffusion and anisotropy values were extracted from the regions-of-interest and correlated with the measures from immunohistochemistry, namely, phosphorylated tau, microglia, and astrocytes.…”

Post mortem mapping of connectional anatomy for the validation of diffusion MRI

“…Though glia morphologies are exquisitely characterized by histology, the relationship between glia and diffusion parameters remains relatively unexplored. Recently, increased density of activated microglia, a marker of inflammation, has been related to reduced FA in traumatic brain injury (Soni et al, 2020) and, intriguingly, the NODDI dispersion parameter (Yi et al, 2019), which Yi et al argue is a marker for greater hindered diffusion in the extra-cellular space.…”