Hypertension, Neurovascular Dysfunction, and Cognitive Impairment

Abstract

Hypertension affects a significant proportion of the adult and aging population and represents an important risk factor for vascular cognitive impairment and late-life dementia. Chronic high blood pressure continuously challenges the structural and functional integrity of the cerebral vasculature, leading to microvascular rarefaction and dysfunction, and neurovascular uncoupling that typically impairs cerebral blood supply. Hypertension disrupts blood-brain barrier integrity, promotes neuroinflammation, and may contribute to amyloid deposition and Alzheimer pathology. The mechanisms underlying these harmful effects are still a focus of investigation, but studies in animal models have provided significant molecular and cellular mechanistic insights. Remaining questions relate to whether adequate treatment of hypertension may prevent deterioration of cognitive function, the threshold for blood pressure treatment, and the most effective antihypertensive drugs. Recent advances in neurovascular biology, advanced brain imaging, and detection of subtle behavioral phenotypes have begun to provide insights into these critical issues. Importantly, a parallel analysis of these parameters in animal models and humans is feasible, making it possible to foster translational advancements. In this review, we provide a critical evaluation of the evidence available in experimental models and humans to examine the progress made and identify remaining gaps in knowledge.

Keywords: Alzheimer disease; blood-brain barrier; cognition; dementia; risk factors.

Figure 1.. Hypertension induced cerebrovascular alterations.

Hypertension has profound effects on the structure and function of cerebral blood vessels associated with increased risk for cognitive impairment. Details described in the text. Ang II: angiotensin II; Astro: astrocyte; AT1R: Ang II type 1 receptor; BBB: blood-brain barrier; CCA: common carotid artery; CBF: cerebral blood flow; HTN: hypertension; MAP: mean arterial pressure; NO: nitric oxide; Nox2: NADPH oxidase 2; NT: normotension; PVM: perivascular macrophages; ROS: reactive oxygen species.

Figure 2.. Radiological manifestations of progressive hypertension-induced brain damage.

Hypertension promotes microvascular injury, including damage to vascular and immune cells. These effects lead to impaired vasodilation, BBB dysfunction, arterial stiffening, neuroinflammation. This progressive damage is visible on MRI scans with different levels of analysis. Microstructural damage of WM and functional altered connectivity of the brain is detectable on 30 direction DTI imaging sequences and tractography and resting state-fMRI functional networks reconstruction in a representative hypertensive patient without signs of WM matter damage evidenced at macrostructural MRI. WMH in a representative patient with sustained untreated hypertension. WM damage is barely visible as hypodense spots on T1W imaging (left) and noticeable as hyperintense spots on T2-FLAIR (right).