Diffusion tensor and volumetric magnetic resonance measures as biomarkers of brain damage in a small animal model of HIV.

Margaret R Lentz,William C Reid,Dianne E Lee,Kristin L Peterson,Joelle Sarlls,Martin J Lizak,Dragan Maric,Dima A Hammoud,Wael G Ibrahim,Hao Huang

doi:10.1371/journal.pone.0105752

Abstract

BackgroundThere are currently no widely accepted neuro-HIV small animal models. We wanted to validate the HIV-1 Transgenic rat (Tg) as an appropriate neuro-HIV model and then establish in vivo imaging biomarkers of neuropathology, within this model, using MR structural and diffusion tensor imaging (DTI).MethodsYoung and middle-aged Tg and control rats were imaged using MRI. A subset of middle-aged animals underwent longitudinal repeat imaging six months later. Total brain volume (TBV), ventricular volume (VV) and parenchymal volume (PV = TBV–VV) were measured. Fractional anisotropy (FA) and mean diffusivity (MD) values of the corpus callosum (CC) were calculated from DTI data.ResultsTBV and PV were smaller in Tg compared to control rats in young and middle-aged cohorts (p<0.0001). VV increased significantly (p = 0.005) over time in the longitudinal Tg cohort. There were lower FA (p<0.002) and higher MD (p<0.003) values in the CC of middle-aged Tg rats compared to age-matched controls. Longitudinally, MD significantly decreased over time in Tg rats (p<0.03) while it did not change significantly in the control cohort over the same period of time (p>0.05).ConclusionsWe detected brain volume loss in the Tg rat, probably due to astrocytic dysfunction/loss, loss of structural/axonal matrix and striatal neuronal loss as suggested by immunofluorescence. Increased MD and decreased FA in the CC probably reflect microstructural differences between the Tg and Control rats which could include increased extracellular space between white matter tracts, demyelination and axonal degeneration, among other pathologies. We believe that the Tg rat is an adequate model of neuropathology in HIV and that volumetric MR and DTI measures can be potentially used as biomarkers of disease progression.

Highlights

Even in the era of anti-retroviral therapy (ART), 30–50% of HIV-positive (HIV+) subjects on a successful treatment regimen will develop some degree of cognitive impairment [1,2]
Cross-Sectional Volumetric Imaging We found that both young and middle-aged Transgenic rat (Tg) animals had significantly lower Total brain volume (TBV) (ANOVA, p,0.0001) and PV (ANOVA, p,0.0001) compared to their corresponding age-matched controls (Figure. 2A)
Cross-sectional diffusion tensor imaging (DTI) imaging results Statistically significant lower fractional anisotropy (FA) values were seen in the corpus callosum (CC) of both young and middle-aged Tg cohorts in comparison to their corresponding age-matched control groups (p = 0.03 and p,0.002 respectively) (Figure. 3A)

Summary

Introduction

Even in the era of anti-retroviral therapy (ART), 30–50% of HIV-positive (HIV+) subjects on a successful treatment regimen will develop some degree of cognitive impairment [1,2]. On the other hand, water diffusion is comparatively non-uniform and more directional due to the presence of various physiological obstacles such as macromolecules, cell membranes, and fiber tracts This is referred to as anisotropic motion. FA is calculated from the eigenvalues of the ellipsoid to provide a normalized value to the tensor’s degree of anisotropy (0 is completely isotropic, like free water, and 1 is completely anisotropic) [8,9,10,11,15,16] Another DTI measure is diffusivity which includes Axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD), all calculated from the eigenvalues (l) of the tensor ellipsoid. We wanted to validate the HIV-1 Transgenic rat (Tg) as an appropriate neuro-HIV model and establish in vivo imaging biomarkers of neuropathology, within this model, using MR structural and diffusion tensor imaging (DTI)

Methods

Results

Discussion

Conclusion