The Ins and Outs of the BCCAo Model for Chronic Hypoperfusion: A Multimodal and Longitudinal MRI Approach

Abstract

Cerebral hypoperfusion induced by bilateral common carotid artery occlusion (BCCAo) in rodents has been proposed as an experimental model of white matter damage and vascular dementia. However, the histopathological and behavioral alterations reported in this model are variable and a full characterization of the dynamic alterations is not available. Here we implemented a longitudinal multimodal magnetic resonance imaging (MRI) design, including time-of-flight angiography, high resolution T1-weighted images, T2 relaxometry mapping, diffusion tensor imaging, and cerebral blood flow measurements up to 12 weeks after BCCAo or sham-operation in Wistar rats. Changes in MRI were related to behavioral performance in executive function tasks and histopathological alterations in the same animals. MRI frequently (70%) showed various degrees of acute ischemic lesions, ranging from very small to large subcortical infarctions. Independently, delayed MRI changes were also apparent. The patterns of MRI alterations were related to either ischemic necrosis or gliosis. Progressive microstructural changes revealed by diffusion tensor imaging in white matter were confirmed by observation of myelinated fiber degeneration, including severe optic tract degeneration. The latter interfered with the visually cued learning paradigms used to test executive functions. Independently of brain damage, BCCAo induced progressive arteriogenesis in the vertebrobasilar tree, a process that was associated with blood flow recovery after 12 weeks. The structural alterations found in the basilar artery were compatible with compensatory adaptive changes driven by shear stress. In summary, BCCAo in rats induces specific signatures in multimodal MRI that are compatible with various types of histological lesion and with marked adaptive arteriogenesis.

Chronic Cerebral Hypoperfusion Induced Synaptic Proteome Changes in the rat Cerebral Cortex

“…Indeed, blood supply by the carotid arteries was blocked in all animals. Blood supply to the brain by other routes including the visibly thickened vertebro-basilar artery compatible with the progressive process of vascular remodelling (Soria et al, 2013). Our results indicate that these adaptations are accompanied by alteration of the synaptic protein content.…”

Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil–DNA glycosylase impair learning in a mouse model of vascular cognitive impairment

“…The present study is the first to show the effects of elevated levels of plasma homocysteine via dietary folic acid deficiency in a progressively degenerative neurovascular disease model in UNG-deficient mice. One of the findings that was most interesting from the present study was that the FADD with the corresponding hyperhomocysteinemia was able to increase arterial remodeling to an even greater extent than hypoperfusion, which is well known to induce this response phenomenon [53,54]. However, it is conceivable that elevated levels of plasma homocysteine can affect arterial remodeling, for example, homocysteine has been shown to increase smooth muscle cell proliferation by reducing levels of nitric oxide [55].Additionally, increased levels of homocysteine result in reduced levels of SAM, a global methyl donor, therefore altering the DNA methylation pattern, which could also affect vascular function [2].Interestingly, the remodeling we observed was not present in Ung−/− mice, even in combination with a FADD, suggesting that Ung is required for remodeling, and DNA repair must play a major role in this process.…”

Parvalbumin and Neuropeptide Y Neuronal Loss in the Hippocampal CA1 Subarea is Associated with Cognitive Deficits in a Rat Model of Chronic Cerebral Hypoperfusion

“…Chronic cerebral hypoperfusion (CCH) presents persistent reduction in cerebral blood flow (CBF) and mild cognitive impairment [1,2], and is associated with cognitive decline in aging, Alzheimer's disease (AD) and vascular dementia (VaD), so the pathological processes of CCH have been focused to explore the underlying mechanisms in these diseases [3][4][5]. Permanent bilateral common carotid artery occlusion (BCCAO), also called 2-VO, produces a chronic, global hypoperfusion state and is less severe than 4-VO (both common carotid arteries and both vertebral arteries occlusion) [2].…”

“…Permanent bilateral common carotid artery occlusion (BCCAO), also called 2-VO, produces a chronic, global hypoperfusion state and is less severe than 4-VO (both common carotid arteries and both vertebral arteries occlusion) [2]. BCCAO is so far a common paradigm of experimental models of VaD and AD [2,6,7], and can induce diffuse white matter lesions, hippocampal neuronal cell loss, micro-infarcts and micro-hemorrhages, as well as obvious cognitive impairments such as spatial learning and memory deficits [1,6]. Generally, hippocampus is responsible of spatial learning and memory processes, specifically, neuronal damage caused by BCCAO in the hippocampus is restricted to CA1 subarea [8,9], and some studies further discovered that performance of spatial learning shows a significant correlation with the numbers of neurons in the CA1 area [10,11].…”