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

Abstract

Traumatic brain injury (TBI) has been linked with tauopathy. However, imaging methods that can non-invasively detect tau-protein abnormalities following TBI need further investigation. This study aimed to investigate the potential of diffusion tensor imaging (DTI) to detect tauopathy following TBI in P301L mutant-tau-transgenic-pR5-mice. A total of 24 9-month-old pR5 mice were randomly assigned to sham and TBI groups. Controlled cortical injuries/craniotomies were performed for TBI/sham groups followed by DTI data acquisition on days 1 and 7 post-injury. DTI data were analyzed by using voxelwise analysis and track-based spatial statistics for gray matter and white matter. Further, immunohistochemistry was performed for total-tau and phosphorylated-tau, astrocytes, and microglia. To detect the association of DTI with these pathological markers, a correlation analysis was performed between DTI and histology findings. At day 1 post-TBI, DTI revealed a widespread reduction in fractional anisotropy (FA) and axial diffusivity (AxD) in the TBI group compared to shams. On day 7, further reduction in FA, AxD, and mean diffusivity and increased radial diffusivity were observed. FA was significantly increased in the amygdala and cortex. Correlation results showed that in the ipsilateral hemisphere FA reduction was associated with increased phosphorylated-tau and glial-immunoreactivity, whereas in the contralateral regions, the FA increase was associated with increased immunostaining for astrocytes. This study is the first to exploit DTI to investigate the effect of TBI in tau-transgenic mice. We show that alterations in the DTI signal were associated with glial activity following TBI and would most likely reflect changes that co-occur with/without phosphorylated-tau. In addition, FA may be a promising measure to identify discrete pathological processes such as increased astroglia activation, tau-hyperphosphorylation or both in the brain following TBI.

White Matter Alterations in Military Service Members With Remote Mild Traumatic Brain Injury

“…In these conditions, the interpretation of higher fractional anisotropy values as solely indicative of increased white matter integrity may not hold true. Some studies indicated that astrocytes undergoing structural remodeling postinjury, thereby driving glial scarring, lead to anisotropic tissue microstructure causing an increase in fractional anisotropy . Notably, a 2011 study performing a histological analysis showed that glial fibrillary acidic protein (GFAP), which is a marker for gliosis, was significantly positively correlated with fractional anisotropy and axial diffusivity.…”

AR12 increases BAG3 expression which is essential for Tau and APP degradation via LC3-associated phagocytosis and macroautophagy

“…Deletion of Rubicon in the macrophages abolished the degradation of all tested proteins and the increase in eIF2α S51 phosphorylation (Supplementary Figure 1). We next determined in HCN2 neuronal cells and in BV2 microglia the abilities of AR12 and neratinib to reduce the expression of mutant forms of APP and Tau [26][27][28][29]. AR12 and the drug combination reduced the expression of Tau 301L which trended to be less than the reduction of wild type Tau (Figure 5).…”

Post-COVID-19 human memory impairment: A PRISMA-based systematic review of evidence from brain imaging studies

“…From the perspective of neuroinflammatory-related changes in brain white matter, which are often reflected through DTI (Ji et al, 2017;Soni et al, 2021;Ouellette, 2022), all the three DTI studies included in this review suggested the abnormal changes in white matter in COVID-19 patients with memory symptoms (Lu et al, 2020;Silva et al, 2021;Huang C. et al, 2022;Huang S. et al, 2022), indicating the involvement of neuroinflammatory factors in these symptoms. Fernández-Castañeda et al found that even mild COVID-19 infections could result in significant brain inflammation followed by brain cell dysregulation (e.g., loss of oligodendrocytes in white matter), and this would be expected to predict cognitive problems (Fernández-Castañeda et al, 2022a).…”