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.

1. Introduction

Dementia is a leading cause of death and disability. The 2021 Global Status Report on dementia by the World Health Organization estimates that 55.2 million people were living with dementia worldwide in 2019, and this number is projected to increase to 78 and 139 million people by 2030 and 2050, respectively¹. The 2020 Lancet Commission on Dementia Prevention, Intervention, and Care emphasized that up to 40% of dementia cases can potentially be prevented or delayed by managing the associated risk factors^{1, 2}. Vascular risk factors, including hypertension, play an important role in the pathophysiology of dementia since up to 50% of patients diagnosed with Alzheimer’s disease (AD) have a mixed pathology at autopsy including cerebrovascular lesions^{3, 4}. Furthermore, it is now well established that midlife hypertension increases the risk for late-life dementia⁵, independently of genetic risk for dementia⁶. Thus, identifying the mechanisms underlying the relationship between hypertension and dementia remains a priority. Although studies have suggested promising risk reduction with adequate blood pressure (BP) control^{7, 8}, the effects are mixed and inconclusive^{9, 10}, and the question of whether certain antihypertensive classes provide greater cognitive benefits remains controversial^{11, 12}. New discoveries and particularly novel therapeutic targets are urgently needed to protect cognitive function in hypertensive patients. Furthermore, the early identification of patients at risk could be a valuable preventive strategy to stop, or at least delay, their evolution toward dementia. Advances in neuroimaging methods have enabled the characterization of subtle neuroradiological markers of hypertension-induced brain damage before macroscopic imaging signs become evident¹³.

In the present review we examine the effects of hypertension on the brain, potential mechanisms involved in the development of cognitive dysfunction, and their translational impact. Furthermore, we will discuss neuroimaging biomarkers that may serve as early predictors of hypertensive brain damage and cognitive impairment, and will underline outstanding questions that remain to be addressed in the field.

2. Hypertension and the cerebral vasculature

The cerebral vasculature is major target of damage induced by hypertension (Figure 1). In this section, we will examine the impact of hypertension on the structure and function of cerebral blood vessels, and on the resulting neurovascular pathology underlying cognitive impairment.

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.

a. Effects on cerebrovascular structure

In animal models, as in humans, hypertension has been linked to structural vascular wall alterations^{14, 15}. Hypertension is associated with or preceded by arterial stiffening^{16, 17}, caused by various factors including collagen deposition and elastin fragmentation¹⁸. This can increase pulse pressure and mechanical stress being transferred through the cerebrovascular tree resulting in adaptive changes aimed at protecting the downstream microcirculation¹⁴. A combination of mechanical, cellular, and molecular factors induce remodeling of the vascular smooth muscle cells (VSMC)¹⁹. A rearrangement of VSMC organization without changes to the cross-sectional area that results in a reduction in luminal diameter when the vessel is maximally dilated is termed eutrophic remodeling¹⁸, while an increase in VSMC cell volume or proliferation that leads to vascular wall thickening and reduction in luminal diameter is termed hypertrophic remodeling²⁰. In various animal models of hypertension, remodeling is typically present in pial and parenchymal arterioles, while stiffening is often observed in larger arteries¹⁸. In humans, remodeling has been reported in cerebral small vessels²¹, and arterial stiffness has been associated with cerebral small vessel disease (SVD), cognitive decline, and dementia²². The mechanisms of remodeling have not been fully elucidated, but include a combination of mechanical, cellular, and molecular factors, such as growth-promoting and pro-inflammatory actions of angiotensin II (AngII), a peptide involved in hypertension¹⁹, as well as increased reactive oxygen species (ROS)²³ and other factors²⁰.

Hypertension promotes the development and build-up of atherosclerotic plaques in carotid, vertebral, and intracranial cerebral arteries^{14, 18}. Endothelial dysfunction, discussed below, contributes to the development of atherosclerosis²⁴, due to a combination of shear stress and turbulent flow²⁵, increased free radicals, and reduced nitric oxide (NO) signaling²⁶ that accelerate inflammation and immune cell accumulation²⁷. Extracranial atherosclerosis increases the risk of cognitive decline²⁸, while intracranial atherosclerosis has been associated with AD²⁹. A recent proteomic study in autopsy samples of individuals with AD or mild cognitive impairment with intracranial atherosclerosis identified reduced synaptic regulation and plasticity as well as aberrant myelination as potential signaling mechanisms contributing to cognitive decline³⁰. Importantly, these contributions were found to be independent of amyloid plaques and neurofibrillary tangles, as well as other brain pathologies, thus unveiling a novel link between atherosclerosis and cognitive impairment in AD.

Hypertension also damages the microvasculature. Microvascular rarefaction, referring to a reduction in vascular density including both capillaries and arterioles, is present in both humans and animal models of hypertension^{18, 21}, and considering the relative paucity of vessels in the white matter (WM), it may contribute to WM lesions. Vascular rarefaction may result from increased pressure being transmitted to the microvascular bed³¹, but the mechanisms remain to be elucidated. Typical hypertensive microvascular lesions include deposition of a glass-like material in the vessel wall (lipohyalinosis) and microvascular necrosis (fibrinoid necrosis)³², observed predominantly in WM arterioles. Indeed, hypertension is an important culprit in SVD³³, a disorder that affects subcortical and periventricular WM arterioles, capillaries, and venules and is recognized as a major cause of cognitive impaiment³². Pathological features of SVD, detectable by magnetic resonance imaging (MRI), include white matter hyperintensities (WMHs), lacunes (small WM lesion of less than 15 mm), microhemorrhages and microinfarcts³⁴, and venous collagenosis³⁵. Particularly, cerebral microhemorrhages are associated hypertension^{36, 37} and worse cognitive function³⁸, and WMH-progression appears to be related to the duration of hypertension and effectiveness of BP control^{39, 40}. Another feature of SVD includes enlargement of the space surrounding intracerebral arteries and veins (perivascular spaces, PVS). This finding has raised the possibility that SVD may also affect the removal of potentially toxic proteins and metabolites from the brain, a process that uses the PVS as a conduit. Still extensively debated, several clearance mechanisms have been proposed to utilize the PVS^{41, 42}. A perivascular pathway is based on retrograde interstitial fluid (ISF) flow out of the brain parenchyma via arterial PVS, or within the wall of cerebral arteries (intramural peri-arterial drainage, IPAD)⁴³. Although still controversial⁴⁴, a “glymphatic” pathway is based on cerebrospinal fluid (CSF) flow into the brain via arterial PVS, entering the parenchyma through aquaporin-4 channels on astrocytic end-feet and exiting the parenchyma through the same channels via venular and then venous PVS⁴⁵. While there is evidence that the CSF-ISF flow may be impaired in hypertensive rats^{46, 47} and in a small cohort of patients with hypertension⁴⁸, the role of these clearance pathways on SVD pathobiology and on the deleterious cognitive effects of hypertension remains to be defined.

b. Effects on cerebrovascular function

Due to a lack of significant energy storage, the brain is highly dependent on a continuous blood supply to maintain adequate nutrient delivery and waste clearance. The mechanisms involved in cerebral blood flow (CBF) regulation have been thoroughly reviewed previously^{20, 49–51}; thus, we will focus on the effects of high BP on these key regulatory mechanisms.

Cerebrovascular autoregulation is a protective mechanism to ensure adequate brain perfusion despite BP fluctuations by maintaining CBF relatively constant within a certain range, typically ± 20 mmHg of baseline BP⁵¹. Static autoregulation is tested by producing stepwise increases or decreases in BP and measuring CBF once steady-state is reached⁵¹. In animal models, hypertension shifts the static autoregulatory pressure-flow curve to the right⁵¹, significantly increasing the risk for brain ischemia if pressure drops below the lower limit²⁰. The mechanisms underlying hypertension-induced changes in autoregulation in animal models involve a combination of structural alterations to the cerebral vasculature (stiffening and remodeling, discussed above) and changes in VSMC reactivity to increases in transmural pressure (myogenic tone)⁵¹. However, the shift appears to be reversible by antihypertensive drugs of various classes^{52, 53}, suggesting that lowering mechanical stress on the vasculature is key to protect cerebral autoregulation. In humans, there is limited data on the upper and lower limits of autoregulation due to the risks of vascular brain injury from excessive raising or lowering BP. In contrast to studies in animals, most studies in patients have reported no rightward shift of the static autoregulatory curve with hypertension⁵¹. Only one small study of 32 patients reported a rightward shift of the lower limit of cerebral autoregulation⁵⁴. Importantly, CBF is maintained constant or even increased with antihypertensive treatment^{51, 55}, including in older adults⁵⁶, challenging the long-standing theory that lowering BP would lead to cerebral hypoperfusion in hypertensive patients.

The concept of dynamic autoregulation refers to the efficiency and latency of the CBF response to rapid BP changes and is assessed by transcranial doppler flowmetry in large cerebral arteries. Although dynamic autoregulation seems to be preserved in patients with hypertension^{57, 58}, it may become impaired in untreated or malignant hypertension^{59, 60}, as also suggested by a study in which CBF, assessed by arterial spin labelling (ASL)-MRI, was monitored during changes in perfusion pressure induced by the head-down tilt test⁶¹. However, since impaired autoregulation appears to be associated with severity of WM injury in hypertensive patients⁶², future investigation should address the relationship between the timing of autoregulation dysfunction and the development of vascular pathology.

Endothelial cells (EC) participate in vasomotor tone regulation in the brain as in other organs⁵⁰. Hypertension impairs the ability of the endothelium to regulate CBF²⁰, and is associated with a reduction in NO bioavailability and consequent compromise of NO-mediated vasodilation^{14, 18}. These effects are mediated by impaired eNOS function and reduced NO production⁴ as well as increased vascular oxidative stress that further limits NO bioavailability⁶³. While direct evaluation of cerebral endothelial function is not easily achieved in humans, an NO synthesis inhibitor failed to reduce retinal arteriolar blood flow in hypertensive patients, suggesting deficient NO signaling and endothelial dysfunction⁶⁴. Interestingly, impaired endothelium-dependent vasodilation in systemic arteries correlates with WMHs⁶⁵ and microhemorrhages⁶⁶, raising the possibility that endothelial dysfunction is also present in cerebral microvessels. This hypothesis is supported by studies in post-mortem arterioles from SVD patients showing an impaired endothelium-dependent vasodilator response to acetylcholine⁶⁷.

EC are also the site of the blood-brain barrier (BBB), which determines the bidirectional exchange of molecules between blood and brain⁶⁸. Hypertension is associated with BBB disruption in several^69–74, but not all⁷⁵, animal models. In humans, BBB breakdown has been proposed as a core mechanism of SVD⁷⁶, and is an early biomarker of cognitive decline⁷⁷. Although BBB disruption has been reported in patients with hypertension^{78, 79}, it is often difficult to evaluate the effect of hypertension in the presence of other comorbidities. The mechanisms of BBB disruption in animal models appear to be independent of BP elevation^{69, 74}, and instead mediated by AngII^{70, 71, 80} and ROS⁷², even in models not based on direct AngII administration, such as the Dahl salt-sensitive rat⁷¹, spontaneously hypertensive rat (SHR)⁸⁰, and transverse aortic coarctation⁷². In AngII “slow pressor” hypertension, activation of the AngII type 1 receptor (AT1R) in cerebral EC by circulating AngII is necessary to initiate the disruption⁶⁹. Thus, it is not surprising that the BBB is not disrupted in deoxycorticosterone acetate (DOCA)-salt hypertension⁷⁵, a model of salt-sensitive hypertension in which circulating AngII is suppressed⁸¹. However, given that less than 15% of patients have elevated circulating AngII activity⁸², the role of endothelial AT1R activation in BBB breakdown in hypertensive patients remain to be determined.

Neurovascular coupling refers to the local CBF increase in response to neural activity, and is mediated by complex mechanisms involving both vascular and brain cells⁴⁹. With increasing energetic demands during neural activity, the increase in CBF ensures adequate delivery of glucose and oxygen, while also clearing potentially toxic byproducts of metabolic activity⁴⁹. Neurovascular coupling is attenuated in various mouse models of hypertension⁴, and similarly, patients with untreated hypertension have reduced regional CBF responses during various cognitive tasks^{83, 84}. In animal model of AngII hypertension, the mechanisms of neurovascular coupling impairment are independent of the rise in BP, given that the impairment cannot be induced by BP elevation with phenylephrine⁸⁵, and topical application of losartan rescues neurovascular coupling without lowering BP and is also effective in a genetic model of chronic hypertension (BPH mice)⁸⁶. The molecular mechanisms of neurovascular dysfunction include AngII signaling via the AT1R in perivascular macrophages (PVM)⁸⁵, as discussed in the section “Immune dysregulation and cognitive impairment in hypertension”. Although AngII augments astrocytic calcium signaling^{87, 88}, the role of astrocyte calcium-dependent signaling in mediating neurovascular coupling remains controversial⁸⁹. A recent study suggested that impairment of endothelial Kir2.1 channels, implicated in EC hyperpolarization and vasodilation in response to neural activity⁴⁹, mediates the neurovascular coupling deficits in BPH mice and not AT1R⁹⁰. However, this involvement was found under conditions of hyperaldosteronism resulting from long-term treatment with losartan and leading to Kir2.1 channel dysfunction, which is consistent with the observation that mineralocorticoid receptor blockade prevents cerebrovascular dysfunction and cognitive impairment in hypertensive mice⁹¹. Although elevated aldosterone levels have been associated with impaired cerebrovascular and cognitive function in elderly patients⁹², considering the beneficial effects of angiotensin receptor blockers (ARBs) on cognitive function^{93, 94}, ARB-induced hyperaldosteronism (aldosterone breakthrough) is unlikely to be the sole driver of hypertension-induced cognitive impairment in patients. The discrepancy between the involvement of AT1R and mineralocorticoid receptors emphasize the need to investigate their interaction and relative contribution to neurovascular and cognitive dysfunction.

c. Is the neurovascular dysfunction induced by hypertension sufficient to lead to cognitive impairment?

Although it is established that high BP targets both the large and small cerebral vasculature, contributing to different types of structural and functional alterations, whether these are enough to induce cognitive impairment cannot be concluded. Impairment of hemodynamic CBF regulation and BBB damage undermine the homeostasis of the brain microenvironment, but their progression and mechanistic association with cognitive decline remains to be established. Relevant to cognitive health, it is important to highlight that aging exacerbates the microvascular damage induced by hypertension and the profound impact of brain aging on cognitive outcomes cannot be underestimated^{95, 96}. Evidence of altered WM cerebrovascular reactivity preceding the development of WMHs⁹⁷ highlights the importance of CBF regulation in the pathogenesis of hypertensive brain injury. Although antihypertensive therapy may rescue CBF^{56, 98}, cognition is not always improved^{9, 10, 12}, suggesting that other factors may play a role. Inflammation and oxidative stress have been highlighted as crucial factors in the pathogenesis of cerebrovascular alterations induced by hypertension, but the underlying cellular and molecular mechanisms have not yet been fully elucidated. Consequently, studies investigating the molecular impact of hypertension at the single-cell level in both animal⁹⁹ and human brain vasculature¹⁰⁰ would be highly valuable.

3. Hypertension, immune dysregulation and cognitive impairment

Cytokines, both in the circulation and in the brain, may affect cerebrovascular and cognitive function. Although IL-6 alone does not induce endothelial dysfunction¹⁰¹, IL6-deficient mice are protected from the endothelial dysfunction induced by AngII hypertension in the carotids¹⁰¹, while the anti-inflammatory cytokine IL-10 can preserve endothelial function¹⁰². Circulating IL-17, elevated in both humans and animal models of hypertension and high dietary salt, may play an important role in BP elevation¹⁰³, cerebrovascular dysfunction¹⁰⁴, and cognitive impairment¹⁰⁵. IL-17 deficient mice have a blunted hypertensive response to AngII¹⁰⁶, and anti-IL-17 antibodies lower BP in various models of hypertension^{107, 108}. However, the BP lowering effects of anti-IL17 antibodies are not always consistent¹⁰⁹, and IL-17 deficient mice are not protected from hypertension induced by DOCA + AngII¹¹⁰. IL-17 can influence the vasculature, as shown by the finding that chronic infusion of IL-17 induces endothelial dysfunction in aortic rings¹¹¹, and IL-17 deficient mice are protected from AngII-induced aortic stiffening¹¹². Interestingly, IL-17 can induce cerebral endothelial dysfunction and lead to cognitive impairment independently of hypertension, supporting a direct effect on the cerebral vasculature¹⁰⁴. The contribution of IL-17 to cognitive impairment remains an important topic of investigation¹⁰⁵, and particularly its role in hypertension-induced brain injury and cognitive decline remains to be established.

a. Brain resident immune cells

Animal studies suggest that brain resident immune cells also contribute to the cerebrovascular and cognitive effects of hypertension. Hypertensive stimuli promptly activate microglial cells^113–115 which may contribute not only to BP regulation¹¹⁵, but also to neuroinflammation and cerebrovascular dysfunction^{113, 114}. In patients, a positron emission tomography (PET) imaging indicator of microglial activation was associated with hypertensive SVD¹¹⁶. Although the contribution of microglia to hypertension-induced cognitive impairment has not been determined, a different brain resident myeloid cell, the PVM, has been implicated in its development. PVM reside in the perivascular space closely apposed to cerebral arterioles and venules and have been linked to various brain diseases¹¹⁷. PVM are a major source of ROS, mediate both cerebrovascular and cognitive dysfunction in animal models of hypertension⁸⁵ and contribute to the BBB disruption⁶⁹. Although cerebral endothelial AT1R are sufficient to initiate the disruption (discussed above), their presence on PVM is necessary for the full expression of the BBB dysfunction⁶⁹ and cognitive impairment⁸⁵. Furthermore, pharmacological depletion of both microglia and PVM with a colony stimulating factor 1 receptor inhibitor protected hypertensive mice against cognitive impairment¹¹³.

b. How to target the immune system in hypertension?

Given the important role of immune dysregulation in the pathobiology of hypertension, the idea of targeting the immune system to lower BP is actively being investigated¹¹⁸. Whether immunotherapies would prove beneficial on hypertension-induced brain injury and cognitive impairment has received far less attention and remains an area of great translational importance. For example, targeting inflammatory mediators and ROS in brain myeloid cells, particularly PVM, could be a potential therapeutic approach. However, the use of immunomodulatory drug in large populations is still controversial due to the increased risk of secondary infections among the immunosuppressed¹¹⁸. Therefore, it is important to identify and select permissible targets among the patients at greatest risk of developing cognitive impairment.

4. Hypertension and neurodegeneration

In addition to the cerebrovascular alterations induced by hypertension, studies have focused on the contribution of hypertension to neurodegenerative pathology, specifically deposition of the amyloid-β (Aβ) peptide, the main component of amyloid plaques and a key pathological signature of AD. In rodent models of brain amyloid accumulation, AngII-induced hypertension enhances Aβ deposition^119–121, increases microhemorrhage burden¹²², and accelerates cognitive decline^{123, 124}. In wild-type mice, hypertension has also been associated with Aβ deposition both in the brain parenchyma^{114, 125, 126} and surrounding cerebral vessels¹²⁷. The underlying mechanisms have not been fully elucidated, but AngII has been suggested to increase both β-¹¹⁹ and γ- secretase¹²⁸ activity, enzymes responsible for cleaving Aβ from the amyloid precursor protein. Interestingly, AT1R deficiency decreases Aβ generation and plaque formation¹²⁸, and ARBs ameliorate amyloid pathology in both mouse models^{129, 130} and humans⁹³.

Cerebral amyloid accumulation in sporadic AD is mainly caused by impaired Aβ clearance from the brain¹³¹. In addition to perivascular, paravascular, and intramural clearance pathways^{41, 132, 133}, endothelial Aβ clearance may also occur through receptor-mediated transport across the BBB¹³⁴. One such receptor is the Receptor for Advanced Glycation End products (RAGE)¹³⁵. Like in AD¹³⁵, hypertension may activate RAGE to induce brain Aβ accumulation and cognitive impairment in animal models¹²⁶. RAGE has also been suggested to mediate Aβ deposition by modulating β- and γ-secretase activity¹³⁶ and, when engaged by Aβ, to disrupt the BBB¹³⁷. However, it remains unclear if these Aβ clearance pathways play a role in the cognitive impairment associated with hypertension in humans. Interestingly, plasma extracellular RAGE binding protein (EN-RAGE) levels have also been associated with increased risk of cognitive decline in a subset of participants from the Rotterdam Study¹³⁸, but the link with hypertension remains to be determined.

a. Does hypertension increase Alzheimer pathology?

Besides provoking ischemic-hypoxic damage in susceptible WM regions, hypertension may contribute to the development of typical signs of AD-like neuropathology, including amyloid plaques and/or tau neurofibrillary tangles. Early studies found an association between midlife elevated BP and the presence of neuritic plaques and neurofibrillary tangles at autopsy¹³⁹. Recent studies with amyloid PET show that while amyloid deposition itself is not associated with hypertension¹⁴⁰, its presence among hypertensive patients is closely associated with memory impairment¹⁴¹. Elevated levels of CSF phosphorylated tau, a biomarker of AD pathology, is associated with hypertension¹⁴², increased pulse pressure¹⁴³, and elevated BP variability¹⁴⁴. Aortic stiffness and elevated pulse pressure in older adults are also associated with higher tau burden, but not amyloid burden¹⁴⁵. Furthermore, hypertension is associated with worse cognitive function in AD patients¹⁴⁶. These findings raise the question of a synergistic relationship between cerebrovascular damage and AD pathology in mediating the cognitive impairment in hypertension. Although animal studies suggest this may be the case, evidence from patients is inconclusive. For example, a recent analysis of hypertensive patients enrolled in the SPRINT trial found no evidence for altered circulating biomarkers for AD, including Aβ and tau¹⁴⁷. Thus, the question remains whether blood and/or CSF biomarkers will prove useful for early identification of hypertensive patients at risk of developing cognitive impairment.

5. Neuroimaging assessment of hypertensive brain damage

Considering the overwhelming impact of chronic hypertension on the brain and its vasculature, it is fundamental to identify early biomarkers of disease progression. Advanced brain imaging techniques, discussed below, can provide valuable tools applicable to both humans and animal models. MRI is the predominant imaging modality utilized to estimate the various manifestations of brain damage associated with hypertension. Hence, standards for MRI acquisition, interpretation, and reporting have been defined using consistent terminology characterizing the various manifestations and stages of hypertensive brain damage¹⁴⁸. In humans, hypertension-induced brain injury is typically characterized by progression of WMHs¹⁴⁹, microstructural^{150, 151} and functional alterations¹⁵², that correlate with worsening of cognitive function¹⁵³ (Figure 2).

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).

It is a well-established notion that WMH represents a macroscopic hallmark of advanced hypertensive brain damage¹⁴, thus neuroimaging techniques have been developed in the search for early markers of injury to identify subtle vascular changes in normal-appearing brain tissue on conventional scans. For example, the brain microstructural tissue integrity of hypertensive patients has been examined through diffusion tensor imaging (DTI), which exploits the principle of water diffusion in WM and allows estimating the direction and magnitude of diffusion by providing quantitative metrics of WM microstructural integrity^{154, 155}. This technique makes it possible to define specific patterns of alterations that anticipate macroscopic damage and correlate with cognitive dysfunction^{150, 156}. Another technique, dynamic contrast-enhanced (DCE)-MRI, has been extensively used in patients with SVD to detect subtle regional changes in BBB integrity¹⁵⁷.

Resting-state functional MRI (rs-fMRI), a sensitive tool to detect changes in brain activity using the blood oxygenation level dependent (BOLD) contrast, has proven effective in evidencing alterations in the functional connectivity among specific regions associated with subtle cognitive impairment in hypertension¹⁵². Another technique, ASL-MRI, enables noninvasive regional CBF quantification¹⁵⁸, and has detected focal or global reductions in resting CBF in hypertensive patients^{159, 160}, consistent with previous reports using other methods, such as phase-contrast MRI⁹⁸, single photon emission computed tomography¹⁶¹, and PET¹⁶². ASL-MRI may also identify early markers potentially predictive of hypertensive brain injury, such as higher retrograde venous blood flow in the internal jugular veins of hypertensive patients¹⁶³. The possibility to assess the same imaging paradigms in experimental models further corroborate the translational relevance of searching for composite biomarkers that account for cardiovascular phenotypes, brain alterations, and behavioral profiles relevant in humans.

a. Will current biomarkers identify individuals at risk of cognitive impairment early?

Early identification of signs prodromal of late-life dementia could greatly improve the management of cognitive health in hypertensive patients. Advancements in neuroradiological and analytical tools for brain imaging, in combination with the expansion of blood and CSF biomarkers, will be fundamental to provide new directions for clinicians and instruct on how to identify and manage patients at risk. The MarkVCID Consortium aims to identify and validate useful biomarkers for SVD and vascular contributions to cognitive impairment and dementia. In addition to blood and CSF biomarkers¹⁶⁴, they also employ neuroimaging techniques including various MRI protocols and optical coherence tomography angiography (OCTA)¹⁶⁵, a technique that visualizes retinal capillaries as a marker of cerebral capillaries. These will be powerful next steps, in addition to the ongoing Alzheimer’s Disease Neuroimaging Initiative, which has already identified cerebrovascular dysfunction as an early biomarker of AD¹⁶⁶, and described the association between CSF phosphorylated tau and hypertension¹⁴² and increased pulse pressure¹⁴³. Subgroup analyses from both these datasets may aid in the identification of hypertension-specific biomarkers.

6. Conclusions

Data reviewed here show that, despite significant advances in antihypertensive therapy, hypertension still represents one of most insidious conditions that challenge brain health. The profound effects of chronically elevated BP on the cerebral vasculature and parenchyma substantially contribute to the increased risk of dementia observed in hypertensive patients¹⁶⁷. As discussed above, several questions remain about the development and progression of hypertension-induced cognitive impairment, the underlying mechanisms, and potential treatment strategies.

One of the most important remaining questions is whether adequate BP management provides relevant risk reduction? From a clinical perspective, intense efforts have been devoted to assessing the optimum BP threshold for therapy initiation, duration, drug class, and intensity of treatment. If BP management does improve cognitive outcomes, are certain antihypertensive drug classes superior to others? The AngII hypothesis suggests that greater neuroprotection is provided by antihypertensives that increase AT2 and AT4 activity (such as ARBs) versus those that decrease it (such as angiotensin converting enzyme inhibitors [ACEi]). A recent report found reduced risk for dementia with AngII-stimulating drugs compared to AngII-inhibiting drugs among community-dwelling individuals¹⁶⁸, a finding corroborated by new secondary analysis of a cohort of SPRINT trial participants¹⁶⁹. Additionally, ARB but not ACEi use is associated with lower amyloid and tau^{170, 171}, and reduced dementia risk¹⁷². The BBB permeability of antihypertensive drugs remains a topic of exploration, with a recent report suggesting potential superiority of BBB-permeable ARBs¹⁷³. Another important question is whether intensive vs standard BP control will provide greater protection? This problem is being addressed by various secondary analyses of SPRINT^{9, 39} and PRESERVE¹⁵⁵ trial data.

Because we cannot successfully identify patients at risk to subsequently treat and prevent hypertension-induced brain injury, extensive investigation on the molecular mechanisms underlying the cerebrovascular and neuropathological damage induced by hypertension is still needed. Considering no definitive conclusion on how to maximize benefits and reduce risks, novel therapeutic strategies are urgently needed to manage the risk of hypertension-induced brain injury and cognitive decline. These may include strategies targeting CBF regulation, the immune system, and/or clearance pathways in the brain, which can be combined with already existing antihypertensive therapy. A personalized precision medicine approach is likely to hold the key to prevent hypertension-induced cognitive decline, utilizing a combined assessment of early markers of disease, inflammatory status, vascular and metabolic comorbidities, and demographic and genetic factors.