Distinguishing microgliosis and tau deposition in the mouse brain using paramagnetic and diamagnetic susceptibility source separation

Tauopathies, including Alzheimer's disease (AD), are neurodegenerative disorders characterized by hyperphosphorylated tau protein aggregates in the brain. In addition to protein aggregates, microglia-mediated inflammation and iron dyshomeostasis are other pathological features observed in AD and other tauopathies. It is known that these alterations at the subcellular level occur much before the onset of macroscopic tissue atrophy or cognitive deficits. The ability to detect these microstructural changes with MRI therefore has substantive importance for improved characterization of disease pathogenesis. In this study, we demonstrate that quantitative susceptibility mapping (QSM) with paramagnetic and diamagnetic susceptibility source separation has the potential to distinguish neuropathological alterations in a transgenic mouse model of tauopathy. 3D multi-echo gradient echo data were acquired from fixed brains of PS19 (Tau) transgenic mice and age-matched wild-type (WT) mice (n = 5 each) at 11.7 T. The multi-echo data were fit to a 3-pool complex signal model to derive maps of paramagnetic component susceptibility (PCS) and diamagnetic component susceptibility (DCS). Group-averaged signal fraction and composite susceptibility maps showed significant region-specific differences between the WT and Tau mouse brains. Significant bilateral increases in PCS and |DCS| were observed in specific hippocampal and cortical sub-regions of the Tau mice relative to WT controls. Comparison with immunohistological staining for microglia (Iba1) and phosphorylated-tau (AT8) further indicated that the PCS and DCS differences corresponded to regional microgliosis and tau deposition in the PS19 mouse brains, respectively. The results demonstrate that quantitative susceptibility source separation may provide sensitive imaging markers to detect distinct pathological alterations in tauopathies.