Animal Models: Vascular Models of Cognitive Dysfunction

Introduction

Convincing evidence supports a link between vascular disease, cognitive impairment and dementia, including Alzheimer disease (AD) . A compromised cerebral vasculature with structural alterations, impaired dilatory capacity, and failure to maintain brain perfusion and adjust flow in response to increased neuronal activity may result in cerebral dysfunctions that translate into cognitive failure. In human, a vasculopathology is a key factor in vascular cognitive impairment (VCI) and vascular dementia (VaD), the second most common form of dementia after AD, notwithstanding the fact that VaD and AD often coexist . VaD can be caused by diverse pathological conditions that become manifest with aging and impede on the cerebral vasculature. Therefore, the multifaceted origin of VaD is difficult to faithfully recapitulate in animal models. We will review selected animal models in which a chronic cerebral hypoperfusion appears as the main culprit of the cognitive decline, admitting that there is no perfect model. We will attempt to identify some commonality between the models that may help better understand the human disease and identify possible target pathways that may lead to new treatment options.

Cognitive Dysfunction of Vascular Origin in Human

In humans, cognitive impairment or dementia resulting from vascular dysfunctions can be due to causes as diverse as cardiovascular diseases, metabolic diseases, and genetic or sporadic small-vessel diseases (SVDs), age being generally an underlying key factor . For the most part, patients with VCI and VaD, as well as patients with AD with vascular pathology, are characterized by discrete infarcts, chronic vasculopathy, and diffuse lesions in deep gray nuclei and white matter (WM). The vascular pathology is not identical depending on the disease etiology, but its main landmarks are a lack of integrity of the blood vessel (thickened walls; fibrosis; pericyte, endothelial, or smooth muscle cell degeneration), deficits in baseline perfusion and cerebral blood flow (CBF) evoked by increased neuronal activity (functional hyperemia or neurovascular coupling), reduced vascular compliance, cerebral autoregulation and endothelial function, and a compromised blood–brain barrier (BBB). In addition, abnormalities in neuronal circuits, glial cells, and WM (such as WM hyperintensities or leukoaraiosis seen on imaging modalities) are likely to be implicated in the cascade of events that leads to deterioration of cognitive function. Accordingly, it has been hypothesized that chronic brain hypoperfusion is a key event in triggering cognitive failure. It is important that animal models recapitulate as many aspects of the human disease as possible, and particularly the chronic cerebral hypoperfusion, to get insight into the underlying pathogenic cascade and help advance treatment options. The animal models selected in this short review all meet this prerequisite ( Table 66.1 ).

Animal Models: Advantages and Limitations