Basic Mechanisms of Brain Injury and Cognitive Decline in Hypertension

Abstract

Dementia affects almost 50 million adults worldwide, and remains a major cause of death and disability. Hypertension is a leading risk factor for dementia, including Alzheimer disease and Alzheimer disease-related dementias. Although this association is well-established, the mechanisms underlying hypertension-induced cognitive decline remain poorly understood. By exploring the mechanisms mediating the detrimental effects of hypertension on the brain, studies have aimed to provide therapeutic insights and strategies on how to protect the brain from the effects of blood pressure elevation. In this review, we focus on the basic mechanisms contributing to the cerebrovascular adaptions to elevated blood pressure and hypertension-induced microvascular injury. We also assess the cellular mechanisms of neurovascular unit dysfunction, focusing on the premise that cognitive impairment ensues when the dynamic metabolic demands of neurons are not met due to neurovascular uncoupling, and summarize cognitive deficits across various rodent models of hypertension as a resource for investigators. Despite significant advances in antihypertensive therapy, hypertension remains a critical risk factor for cognitive decline, and several questions remain about the development and progression of hypertension-induced cognitive impairment.

Keywords: cerebral small vessel disease; cognitive decline; dementia; hypertension; neurovascular unit.

Figure 1.. Cerebral small vessel disease manifestations in hypertension.

White matter lesions are visualized as white densities on FLAIR MRIs, and may result from ischemia and breakdown of the blood-brain barrier (BBB) leading to loss of oligodendrocytes, demyelination of neurons, and microglia activation. Lacunar infarcts are found on FLAIR MRIs and contain necrotic waste and have evidence of gliosis, myelin loss, and neuronal loss. Enlarged perivascular spaces are CSF filled spaces that can be seen on T2-weighted MRIs. Inflammation results in the enlargement of these spaces. Cerebral microbleeds, visualized as small circular depositions of blood in SWI MRIs. Studies suggest increased oxidative stress leads to weakening of the microvessels allowing them to rupture in response to the increased pressure. FLAIR, fluid attenuated inversion recovery; MRI, magnetic resonance imaging; BBB, blood brain barrier; CSF, cerebral spinal fluid; ROS, reactive oxygen species, SWI, susceptibility weighted imaging.

Figure 2.. Hypertension impairs the function of the neurovascular unit.

Hypertension affects all cell-types of the neurovascular unit via various mechanisms resulting in endothelial cell (EC) dysfunction, BBB disruption, and impaired neurovascular coupling (NVC). Endothelial dysfunction may result from reduced nitric oxide (NO) bioavailability, resulting from impaired eNOS function and increased ROS production by perivascular macrophages (PVM). Angiotensin II (AngII) type 1 receptor (AT1R) activation in both EC and PVM, and a potential interaction with toll-like receptor 4 (TLR4) in EC, contribute to disruption of the blood-brain barrier (BBB). Neurovascular coupling is impaired by PVM-derived ROS, aldosterone (Aldo)-induced damage of K_IR2.1 channels and endothelial hyperpolarization, as well as altered calcium signaling in astrocytic endfeet. Pericytes express Nox4 which is upregulated by AngII and may contribute to vascular inflammation. AngII, angiotensin II; K_IR2.1, inwardly rectifying potassium channel 2.1; Nox, NADPH oxidase; TRPV4, transient receptor potential vanilloid 4; Nox2, NADPH oxidase 2.