Research Article: Stepwise occlusion of the carotid arteries of the rat: MRI assessment of the effect of donepezil and hypoperfusion-induced brain atrophy and white matter microstructural changes

Date Published: May 31, 2018

Publisher: Public Library of Science

Author(s): Gabriella Nyitrai, Tamás Spisák, Zsófia Spisák, Dávid Gajári, Pálma Diószegi, Tamás Zsigmond Kincses, András Czurkó, Mária A. Deli.


Bilateral common carotid artery occlusion (BCCAo) in the rat is a widely used animal model of vascular dementia and a valuable tool for preclinical pharmacological drug testing, although the varying degrees of acute focal ischemic lesions it induces could interfere with its translational value. Recently, a modification to the BCCAo model, the stepwise occlusion of the two carotid arteries, has been introduced. To acquire objective translatable measures, we used longitudinal multimodal magnetic resonance imaging (MRI) to assess the effects of semi-chronic (8 days) donepezil treatment in this model, with half of the Wistar rats receiving the treatment one week after the stepwise BCCAo. With an ultrahigh field MRI, we measured high-resolution anatomy, diffusion tensor imaging, cerebral blood flow measurements and functional MRI in response to whisker stimulation, to evaluate both the structural and functional effects of the donepezil treatment and stepwise BCCAo up to 5 weeks post-occlusion. While no large ischemic lesions were detected, atrophy in the striatum and in the neocortex, along with widespread white matter microstructural changes, were found. Donepezil ameliorated the transient drop in the somatosensory BOLD response in distant cortical areas, as detected 2 weeks after the occlusion but the drug had no effect on the long term structural changes. Our results demonstrate a measurable functional MRI effect of the donepezil treatment and the importance of diffusion MRI and voxel based morphometry (VBM) analysis in the translational evaluation of the rat BCCAo model.

Partial Text

An increasing amount of evidence has supported the notion that chronic cerebral hypoperfusion is deeply involved in several forms of cognitive impairments, including Alzheimer’s disease (AD) [1–5]. The reduction of blood flow and the concomitant pathological processes considerably impair the cerebral white matter and lead to gray matter atrophy revealed by neuroimaging [2, 6–8]. Consistently, these abnormalities have been shown to be related to cognitive impairment [1, 2, 9] and are also involved in the pathology of AD [10].

In this multimodal MRI study, we longitudinally monitored the effects of chronic hypoperfusion in the rat stepwise BCCAo model. The chronic hypoperfusion induced significant white matter microstructural alterations and gray matter atrophy revealed by TBSS analysis of DTI data and VBM analysis of high-resolution anatomical images. In this model, we found a decreased BOLD response to whisker stimulation at 2 weeks after the occlusions in various cortical, striatal and thalamic brain areas, which were restored by the 5th week. The semi-chronic administration of donepezil reversed the decline in the BOLD fMRI response in the ventral hippocampal areas measured immediately after the last dose of donepezil administration at 2 weeks after the occlusion, but did not modify the structural alterations of the grey and white matter.




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