Detecting Microglial Density With Quantitative Multi-Compartment Diffusion MRI.

Sue Y Yi,Brian R Barnett,John-Paul J Yu,Paul A Rowley,Diego Hernando,Maribel Torres-Velázquez,Samuel A Hurley,Yuxin Zhang

doi:10.3389/fnins.2019.00081

Abstract

Neuroinflammation plays a central role in the neuropathogenesis of a wide-spectrum of neurologic and psychiatric disease, but current neuroimaging methods to detect and characterize neuroinflammation are limited. We explored the sensitivity of quantitative multi-compartment diffusion MRI, and specifically neurite orientation dispersion and density imaging (NODDI), to detect changes in microglial density in the brain. Monte Carlo simulations of water diffusion using a NODDI acquisition scheme were performed to measure changes in a virtual MRI signal following modeled cellular changes within the extra-neurite space. 12-week-old C57BL/6J male mice (n = 48; 24 control, 24 treated with colony stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622) were sacrificed at 0, 1, 3, and 7 days following withdrawal of CSF1R inhibition and were imaged ex-vivo to obtain measures of the orientation dispersion index (ODI). Following imaging, all brains were immunostained with Iba-1, NeuN, and GFAP for quantitative fluorescence microscopy. Cell populations were calculated with the ImageJ particle analyzer tool; correlation between microglial density and mean ODI values were calculated with Kendall's tau. Monte Carlo simulations demonstrate the sensitivity and positive correlation of ODI to increased occupancy in the extra-neurite space. Commensurate with our simulation data, ex-vivo NODDI imaging demonstrates an increase in ODI as microglia repopulate the brain following the withdrawal of CSF1R inhibition. Quantitative immunofluorescence of microglial density reveals that microglial density is positively correlated with ODI and greater hindered diffusion in the extra-neurite space (τ = 0.386, p < 0.05). Our results demonstrate that clinically feasible multi-compartment diffusion weighted imaging techniques such as NODDI are sensitive to microglial density and the cellular changes associated with microglial activation and highlights its potential to improve clinical diagnostic accuracy, patient risk stratification, and therapeutic monitoring of neuroinflammation in neurologic and psychiatric disease.

Highlights

Neuroinflammation plays a critical role in the neuropathogenesis of disorders of the central nervous system (CNS) from ischemic stroke and traumatic brain injury (Iadecola and Anrather, 2011; Woodcock and Morganti-Kossmann, 2013) to Alzheimer’s disease, schizophrenia, and major depression (Lull and Block, 2010; Mondelli et al, 2017)
In Monte Carlo simulations with only the axon bundle present, our simulations return a non-zero value of orientation dispersion index (ODI), supporting the hypothesis that any structure localizing to the extra-neurite space is able to contribute to alterations in water diffusivity within the extra-neurite compartment and to calculated values of ODI
The development of diffusion weighted imaging (DWI) and subsequent introduction of diffusion tensor imaging (DTI) have demonstrated water molecules diffuse differently in tissues depending on their type, integrity, and architecture (Soares et al, 2013) making diffusion imaging a promising tool for studying the microstructure of the brain

Summary

Introduction

Neuroinflammation plays a critical role in the neuropathogenesis of disorders of the central nervous system (CNS) from ischemic stroke and traumatic brain injury (Iadecola and Anrather, 2011; Woodcock and Morganti-Kossmann, 2013) to Alzheimer’s disease, schizophrenia, and major depression (Lull and Block, 2010; Mondelli et al, 2017). As microglia comprise 5–15% of all glial cells (Alliot et al, 1999; Ginhoux et al, 2010) and in response to inflammatory stimuli, undergo substantial changes in both morphology and density (Hinwood et al, 2012; Yang et al, 2013), these changes would be expected to significantly alter the degree of hindered diffusion in the extra-neurite compartment. These changes offer a potential opportunity to assess microglial activation and microglialmediated neuroinflammation by probing water diffusion using DWI (Figure 1)

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