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.

Hypertension: Causes and Consequences of Circadian Rhythms in Blood Pressure

“…10,[13][14][15][16][17][18][19][20][21][22][23] In relation to the brain, hypertension is a risk factor for carotid artery and intracranial atherosclerosis, dysregulation of cerebral blood flow (CBF), and classic ischemic strokes. [24][25][26] Cerebral small vessel disease-a key cause of reduced CBF, microinfarcts, microbleeds, blood-brain barrier (BBB) dysfunction, and abnormalities of the perivascular space-is also driven by hypertension. 5,14,[25][26][27][28][29] Both large vessel disease and small vessel disease promote the vascular component of reduced brain health: loss of cognitive reserve, cognitive impairment, dementias, and neurodegeneration (Figure 1).…”

“…Hypertension, particularly during midlife, is a leading risk factor for cognitive decline and some forms of neurodegeneration. 5,7,24,26,203 The risk for hypertension-associated cognitive dysfunction may be even greater in Black and Hispanic individuals compared with White individuals. 204 Interestingly, attention to this relationship has revealed that the link between hypertension and cognition may begin earlier in life than previously appreciated, even in childhood.…”

“…24,250,256 In models of Ang II-dependent hypertension and SHRs, increased permeability of the BBB has been observed. 24,[256][257][258][259] This effect was increased in a model of aging. 260 Mechanisms that have been implicated in these changes include activation of endothelial AT1 (angiotensin type 1) receptors, oxidative stress, perivascular macrophages, reduced expression of claudin-5, and increased endothelial transcytosis.…”

“…260 Mechanisms that have been implicated in these changes include activation of endothelial AT1 (angiotensin type 1) receptors, oxidative stress, perivascular macrophages, reduced expression of claudin-5, and increased endothelial transcytosis. 24,[257][258][259] To what extent absolute levels of BP versus changes in diurnal dipping patterns influence the loss of BBB integrity during hypertension is unclear.…”

“…255 Hypertension is associated with impairment of the BBB. 24,250,256 In models of Ang II-dependent hypertension and SHRs, increased permeability of the BBB has been observed. 24,[256][257][258][259] This effect was increased in a model of aging.…”