Magnetic resonance‐based axonal microstructure measures are differentially modulated by interleukin‐6 in amyloid expressing TgCRND8 mice

Abstract

Non-invasive assessments of microstructure changes linked to axonal pathology in Alzheimer's disease (AD) may be critical to early interventions to slow progression. Axons and synapses accumulate a variety of proteins, including amyloid precursor protein (APP) and β-amyloid (Aβ), which in turn alter functional activity in cognitive brain areas connected along major white matter pathways. In the extracellular space, the presence of ‘dystrophic neurites’ surrounding Aβ plaques and the presence of active neuroimmune cells can contribute to alterations in extracellular free water, tissue anisotropy and diffusion rates, as well as the density and geometric arrangement of axonal processes. In the present study, we used high field diffusion magnetic resonance imaging (dMRI) to determine the effects of increased levels Aβ and the inflammatory signaling cytokine interleukin-6 (IL6) on a range of tissue microstructure measures in mice. Subsets of transgenic (Tg)CRND8 mice with early onset expression of human APP (APPswe KM670671NL/APPInd V717F) and wildtype controls were induced to express brain IL6 using previously published adenoassociated viral vector (AAV) methods (n=48; 50% females). Mice were scanned at 11 Tesla using a 2-shell (b=600/2000) 54-gradient direction dMRI sequence. Images were post-processed using: (1) a bi-tensor model of diffusion that allows the partitioning of free water contributions to the diffusion tensor and (2) the neurite orientation dispersion and density imaging (NODDI) model. To avoid partial volume contamination of tissue microstructure measures by cerebroventricular water (CSF), major white matter (WM) tracts and hippocampus were manually segmented in ITKSNAP using fractional anisotropy (FA) maps and T2 anatomical scans. Sampled WM tracts included the splenium and genu of the corpus callosum, anterior commissure, cerebral peduncles, and fimbria. The resulting data using the free water correction method depicted a complex set of axonal and hippocampal microstructural changes that suggested restricted diffusion rates, reduced directionality of diffusion, and extracellular free water in Tg mice harboring human APP mutations. IL6 appeared to partially counteract this effect. In addition, results from the NODDI model suggested that the density of neurites and the geometric arrangement are increased by Aβ. IL6 effects on neurite density and orientation dispersion seemed modest but trended toward effects similar to Aβ. Our data support the development and use of microstructure imaging techniques to characterize early in vivo changes in neurodegenerative diseases and with aging. Support or Funding Information This work was supported by the National Institutes of Health (R01NS052318, R01NS075012, T32NS082168, P50NS091856 and P50AG047266). The authors acknowledge support from the Advanced Magnetic Resonance Imaging and Spectroscopy (AMRIS) facility (National Science Foundation Cooperative Agreement No. DMR-1157490 and the State of Florida). Changes in white matter fractional anisotropy and free water in response to amyloidosis and interleukin-6 in mice scanned at 11 Tesla This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.