Characterizing the Neuroimaging and Histopathological Correlates of Cerebral Small Vessel Disease in Spontaneously Hypertensive Stroke-Prone Rats.

Yousef Hannawi,Eder Caceres,Jay L Zweier,Cameron L Rink,Jan M Schwab,Kimerly A Powell,Mohamed G Ewees,Anna Bratasz

doi:10.3389/fneur.2021.740298

Yousef Hannawi, Eder Caceres + Show 6 more

Open Access

https://doi.org/10.3389/fneur.2021.740298

Copy DOI

Abstract

Introduction: Spontaneously hypertensive stroke-prone rats (SHRSP) are used to model clinically relevant aspects of human cerebral small vessel disease (CSVD). To decipher and understand the underlying disease dynamics, assessment of the temporal progression of CSVD histopathological and neuroimaging correlates is essential.Materials and Methods: Eighty age-matched male SHRSP and control Wistar Kyoto rats (WKY) were randomly divided into four groups that were aged until 7, 16, 24 and 32 weeks. Sensorimotor testing was performed weekly. Brain MRI was acquired at each study time point followed by histological analyses of the brain.Results: Compared to WKY controls, the SHRSP showed significantly higher prevalence of small subcortical hyperintensities on T2w imaging that progressed in size and frequency with aging. Volumetric analysis revealed smaller intracranial and white matter volumes on brain MRI in SHRSP compared to age-matched WKY. Diffusion tensor imaging (DTI) showed significantly higher mean diffusivity in the corpus callosum and external capsule in WKY compared to SHRSP. The SHRSP displayed signs of motor restlessness compared to WKY represented by hyperactivity in sensorimotor testing at the beginning of the experiment which decreased with age. Distinct pathological hallmarks of CSVD, such as enlarged perivascular spaces, microbleeds/red blood cell extravasation, hemosiderin deposits, and lipohyalinosis/vascular wall thickening progressively accumulated with age in SHRSP.Conclusions: Four stages of CSVD severity in SHRSP are described at the study time points. In addition, we find that quantitative analyses of brain MRI enable identification of in vivo markers of CSVD that can serve as endpoints for interventional testing in therapeutic studies.

Highlights

Hypertensive stroke-prone rats (SHRSP) are used to model clinically relevant aspects of human cerebral small vessel disease (CSVD)
Our results suggest that Spontaneously hypertensive stroke-prone rats (SHRSP), an animal model of marked hypertension, is a relevant model for human CSVD with the development of consistent CSVD lesions with age and associated changes in brain MRI volumetric measures
We aimed in this study to define the neuroimaging and histopathological features of CSVD and their progression at several time points of SHRSP life by utilizing quantitative neuroimaging in association with histopathological analyses

Summary

Introduction

Hypertensive stroke-prone rats (SHRSP) are used to model clinically relevant aspects of human cerebral small vessel disease (CSVD). CSVD refers to the pathological processes that affect the brain small vessels in association with aging and hypertension among other cardiovascular risk factors [1, 3]. These various pathological processes result in different manifestations on the brain MRI and histology involving dilatation of the perivascular spaces, demyelination, lacunes, and microbleed formation [1, 3]. Several experimental models have been attempted to simulate certain pathological aspects of the disease These existing experimental models include hypertensive animals, such as the spontaneously hypertensive rats (SHR) and the spontaneously hypertensive stroke-prone rats (SHRSP) with or without salt loading [4, 6]. Across the studies in the literature, aging SHRSP have been most frequently used as a model for human CSVD [4, 8,9,10,11,12]

Objectives

Methods

Results

Conclusion