Diffusion magnetic resonance imaging-derived free water detects neurodegenerative pattern induced by interferon-γ
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Imaging biomarkers for immune activation may be valuable for early-stage detection, therapeutic testing, and research on neurodegenerative conditions. In the present study, we determined whether diffusion magnetic resonance imaging-derived free water signal is a sensitive marker for neuroinflammatory effects of interferon-gamma (Ifn-γ). Neonatal wild-type mice were injected in the cerebral ventricles with recombinant adeno-associated viruses expressing the inflammatory cytokine Ifn-γ. Groups of mice expressing Ifn-γ and age-matched controls were imaged at 1, 5 and 8 months. Mice deficient in Ifngr1−/− and Stat1−/− were scanned at 5 months as controls for the signaling cascades activated by Ifn-γ. The results indicate that Ifn-γ affected fractional anisotropy (FA), mean diffusivity (MD), and free water (FW) in white matter structures, midline cortical areas, and medial thalamic areas. In these structures, FA and MD decreased progressively from 1 to 8 months of age, while FW increased significantly. The observed reductions in FA and MD and increased FW with elevated brain Ifn-γ was not observed in Ifngr1−/− or Stat1−/− mice. These results suggest that the observed microstructure changes involve the Ifn-gr1 and Stat1 signaling. Interestingly, increases in FW were observed in midbrain of Ifngr1−/− mice, which suggests alternative Ifn-γ signaling in midbrain. Although initial evidence is offered in relation to the sensitivity of the FW signal to neurodegenerative and/or inflammatory patterns specific to Ifn-γ, further research is needed to determine applicability and specificity across animal models of neuroinflammatory and degenerative disorders.
KeywordsInterferon gamma Diffusion MRI Free water White matter Aging Inflammation
This work was supported by the National Institutes of Health (P50AG047266, R01NS052318, R01NS075012, T32NS082168, P50NS091856, 1R01AG055798). The authors thank the Advanced Magnetic Resonance Imaging and Spectroscopy (AMRIS) facility and National High Magnetic Field Laboratory (NHMFL) for their continued support (National Science Foundation Cooperative Agreement No. DMR-1157490 and the State of Florida).
MF planned the experiments, imaged mice, analyzed data, and wrote the manuscript. PC planned the experiments, wrote the manuscript, injected neonatal mice, performed immunohistochemistry and analysis. CCD injected neonatal mice and performed immunohistochemistry. PDP planned experiments, imaged mice, contributed to manuscript writing and editing. EO made custom modifications to free water algorithm for mouse brain image analysis. LMCP carried out the free water correction processing on MATLAB, contributed to manuscript writing and editing. DEV made custom modifications to free water algorithm for mouse brain image analysis, provided overall support and contributed to manuscript writing and editing. TEG planned experiments, provided overall support and contributed to manuscript writing and editing.
This work was supported by the National Institutes of Health (P50AG047266, R01NS052318, R01NS075012, T32NS082168, P50NS091856, 1R01AG055798).
Compliance with ethical standards
Conflict of interest
Authors declare that they have no competing interests.
All procedures received prior approval from the Institutional Animal Care and Use Committee of the University of Florida and follow all applicable NIH guidelines.
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