Abstract
Our aims were to assess the spatiotemporal development of brain pathology in a mouse model of chronic hypoperfusion using magnetic resonance imaging (MRI), and to test whether the renin-angiotensin system (RAS) can offer therapeutic benefit. For the first time, different patterns of cerebral blood flow alterations were observed in hypoperfused mice that ranged from an immediate and dramatic to a delayed decrease in cerebral perfusion. Diffusion tensor imaging revealed increases in several quantitative parameters in different brain regions that are indicative of white-matter degeneration; this began around 3 weeks after induction of hypoperfusion. While this model may be more variable than previously reported, neuroimaging tools represent a promising way to identify surrogate markers of pathology. Vascular remodelling was observed in hypoperfused mice, particularly in the anterior part of the Circle of Willis. While the angiotensin II receptor type 2 agonist, Compound 21 (C21), did not influence this response, it did promote expansion of the basilar artery in microcoil animals. Furthermore, C21-treated animals exhibited increased brain lymphocyte infiltration, and importantly, C21 had opposing effects on spatial reference memory in hypoperfused and sham mice. These results suggest that the RAS may have a role in vascular cognitive impairment.
Highlights
Vascular cognitive impairment (VCI) refers to a group of cognitive disorders that are presumed to share a vascular origin; together they represent the second leading cause of dementia after Alzheimer’s disease
Large increases in T2 are associated with vasogenic edema and pathology, but T2 was relatively stable over time in all three measured volumes of interest (VOIs): corpus callosum, internal capsule, and striatum (Figure 2A)
We showed that the Angiotensin II type 2 receptors (AT2Rs) agonist Compound 21 (C21) differentially influenced spatial reference memory in hypoperfused and sham mice
Summary
Vascular cognitive impairment (VCI) refers to a group of cognitive disorders that are presumed to share a vascular origin; together they represent the second leading cause of dementia after Alzheimer’s disease. The exact pathophysiology of VCI is not understood, but the incidence and known risk factors (hypertension, atherosclerosis, advanced age, and obesity) are on the rise. Despite identification of VCI as a top research priority for the 10 years by the Stroke Progress Review Group at the National A few reports have described similar findings, as well as spatial working memory impairments after 1 to 2 months of hypoperfusion.[4,5] Another group reported hippocampal degeneration when survival times were extended to 8 months,[6] and, by bilaterally varying the degree of stenosis, one group observed microinfarcts within the most severely deprived cortex.[7]
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