Diffusion Basis Spectrum and Diffusion Tensor Imaging Detect Hippocampal Inflammation and Dendritic Injury in a Virus-Induced Mouse Model of Epilepsy.

Jie Zhan,Tsen-Hsuan Lin,Zezhong Ye,Sheng-Kwei Song,Robert S. Fujinami,Michael Wallendorf,Chunyu Song,Peng Sun,Jane E. Libbey,Honghan Gong

doi:10.3389/fnins.2018.00077

Abstract

Hippocampal CA1 inflammation and dendritic loss are common in epilepsy. Quantitative detection of coexisting brain inflammation and injury could be beneficial in monitoring disease progression and assessing therapeutic efficacy. In this work, we used conventional diffusion tensor imaging (DTI, known to detect axonal injury and demyelination) and a novel diffusion basis spectrum imaging (DBSI, known to detect axonal injury, demyelination, and inflammation) to detect hippocampal CA1 lesions resulting from neuronal dendritic injury/loss and concomitant inflammation in Theiler's murine encephalomyelitis virus (TMEV)-induced seizure mice. Following the cross-sectional ex vivo diffusion magnetic resonance imaging measurements, immunohistochemistry was performed to validate DTI and DBSI findings. Both DTI and DBSI detected immunohistochemistry-confirmed dendritic injury in the hippocampal CA1 region. Additionally, DBSI-derived restricted isotropic diffusion tensor fraction correlated with 4',6-diamidine-2'-phenylindole dihydrochloride (DAPI)-positive nucleus counts, and DBSI-derived fiber fraction correlated with dendrite density assessed by microtubule-associated protein 2 staining. DTI-derived fractional anisotropy (FA) correlated with dendrite density and negatively correlated with DAPI-positive nucleus counts. Although both DTI and DBSI detected hippocampal injury/inflammation, DTI-FA was less specific than DBSI-derived pathological metrics for hippocampal CA1 dendritic injury and inflammation in TMEV-induced seizure mice.

Highlights

Acute seizures, which can be initiated by various infective agents such as parasites, bacteria and viruses, are followed by a latent period leading up to the development of late unprovoked epileptic seizures (Getts et al, 2008; Vezzani et al, 2016)
Color-coded diffusion metric maps of left and right hippocampal CA1 regions were overlaid on the diffusion-weighted Magnetic Resonance Imaging (MRI) (Figure 1)
At 6 days after infection, hippocampal CA1 DTIFA (Figure 1A) and Diffusion tensor imaging (DTI)-λ (Figure 1B) decreased in TMEVinfected mice compared to the sham control

Summary

Introduction

Acute seizures, which can be initiated by various infective agents such as parasites, bacteria and viruses, are followed by a latent period leading up to the development of late unprovoked epileptic seizures (Getts et al, 2008; Vezzani et al, 2016). A Theiler’s murine encephalomyelitis virus (TMEV)-induced seizure model has recently been developed in C57BL/6J mice to mimic infection-induced temporal lobe epilepsy (Libbey et al, 2008; Kirkman et al, 2010; Stewart et al, 2010a,b; Libbey and Fujinami, 2011). In this model, acute seizures occur between 3 and 10 days after infection, followed by a variable latent period after which spontaneous seizures develop. TMEV-infected mouse brains exhibit various signs of neuroinflammation during acute seizures, including activated microglia/macrophages, gliosis, perivascular cuffing, and increased mRNA expression of proinflammatory cytokines, supporting the key role that inflammation plays in the development of acute seizures in the TMEV-induced seizure model (Kirkman et al, 2010; Libbey et al, 2011; Cusick et al, 2013)

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Results

Conclusion