Hypertension

REVIEW

Hypertension, Neurovascular Dysfunction, and

Cognitive Impairment
Monica M. Santisteban , Costantino Iadecola , Daniela Carnevale

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.

Key Words: Alzheimer disease ◼ blood-brain barrier ◼ cognition ◼ dementia ◼ risk factors
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D
ementia 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 mil-
lion people by 2030 and 2050, respectively.1 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 pathophysiol-
ogy of dementia since up to 50% of patients diagnosed
with Alzheimer disease (AD) have a mixed pathology at
autopsy including cerebrovascular lesions.3,4 Further-
more, it is now well established that midlife hypertension
increases the risk for late-life dementia,5 independently of
genetic risk for dementia.6 Thus, identifying the mecha-
nisms 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 incon-
clusive,9,10 and the question of whether certain antihyper-
tensive classes provide greater cognitive benefits remain
controversial.11,12 New discoveries and particularly novel
therapeutic targets are urgently needed to protect cog-
nitive 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 evolu-
tion toward dementia. Advances in neuroimaging methods
have enabled the characterization of subtle neuroradio-
logical markers of hypertension-induced brain damage
before macroscopic imaging signs become evident.13
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 neu-
roimaging 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.

Correspondence to: Daniela Carnevale, IRCCS Neuromed - Technology Park Località Camerelle 86077 - Pozzilli(IS), Italy, Email daniela.carnevale@uniroma1.it or
Monica M. Santisteban, Feil Family Brain and Mind Research Institute 407 E 61st ST New York, NY 10065, Email mms2012@med.cornell.edu
For Sources of Funding and Disclosures, see page 29.
© 2022 American Heart Association, Inc.
Hypertension is available at www.ahajournals.org/journal/hyp

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 Santisteban et al Hypertension and Dementia

typically present in pial and parenchymal arterioles whereas

Nonstandard Abbreviations and Acronyms stiffening is often observed in larger arteries.18 In humans,
remodeling has been reported in cerebral small vessels,21
Aβ amyloid-β and arterial stiffness has been associated with cerebral

Review
ACE angiotensin-converting enzyme small vessel disease (SVD), cognitive decline, and demen-
AD Alzheimer disease tia.22 The mechanisms of remodeling have not been fully
AngII angiotensin II elucidated, but include a combination of mechanical, cel-
ARB angiotensin receptor blocker lular, and molecular factors, such as growth-promoting and
AT1R AngII type 1 receptor
proinflammatory actions of AngII (angiotensin II), a peptide
involved in hypertension,19 as well as increased reactive
BBB blood-brain barrier
oxygen species23 and other factors.20
BP blood pressure
Hypertension promotes the development and buildup
CBF cerebral blood flow of atherosclerotic plaques in carotid, vertebral, and intra-
EN-RAGE extracellular RAGE binding protein cranial cerebral arteries.14,18 Endothelial dysfunction,
MRI magnetic resonance imaging discussed below, contributes to the development of ath-
OCTA optical coherence tomography erosclerosis,24 due to a combination of shear stress and
angiography turbulent flow,25 increased free radicals, and reduced NO
PVM perivascular macrophages signaling26 that accelerate inflammation and immune cell
PVS perivascular spaces accumulation.27 Extracranial atherosclerosis increases
RAGE receptor for advanced glycation end the risk of cognitive decline,28 whereas intracranial ath-
products erosclerosis has been associated with AD.29 A recent
SVD small vessel disease proteomic study in autopsy samples of individuals with
WM white matter AD or mild cognitive impairment with intracranial ath-
WMHs WM hyperintensities erosclerosis identified reduced synaptic regulation and
plasticity as well as aberrant myelination as potential
signaling mechanisms contributing to cognitive decline.30
Importantly, these contributions were found to be inde-
HYPERTENSION AND THE CEREBRAL pendent of amyloid plaques and neurofibrillary tangles, as
VASCULATURE well as other brain pathologies, thus unveiling a novel link
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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 struc-
ture and function of cerebral blood vessels, and on the
resulting neurovascular pathology underlying cognitive
impairment.
Effects on Cerebrovascular Structure
In animal models, as in humans, hypertension has been
linked to structural vascular wall alterations.14,15 Hyperten-
sion is associated with or preceded by arterial stiffening,16,17
caused by various factors including collagen deposition
and elastin fragmentation.18 This can increase pulse pres-
sure and mechanical stress being transferred through the
cerebrovascular tree resulting in adaptive changes aimed
at protecting the downstream microcirculation.14 A combi-
nation of mechanical, cellular, and molecular factors induce
remodeling of the vascular smooth muscle cells.19 A rear-
rangement of vascular smooth muscle cell organization
without changes to the cross-sectional area that results in
a reduction in luminal diameter when the vessel is maxi-
mally dilated is termed eutrophic remodeling,18 whereas an
increase in vascular smooth muscle cell volume or prolif-
eration that leads to vascular wall thickening and reduction
in luminal diameter is termed hypertrophic remodeling.20
In various animal models of hypertension, remodeling is
between atherosclerosis and cognitive impairment in AD.
Hypertension also damages the microvasculature.
Microvascular rarefaction, referring to a reduction in vas-
cular density including both capillaries and arterioles, is
present in both human and animal models of hyperten-
sion,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 bed,31 but the
mechanisms remain to be elucidated. Typical hypertensive
microvascular lesions include deposition of a glass-like
material in the vessel wall (lipohyalinosis) and microvascu-
lar necrosis (fibrinoid necrosis),32 observed predominantly
in WM arterioles. Indeed, hypertension is an important
culprit in SVD,33 a disorder that affects subcortical and
periventricular WM arterioles, capillaries, and venules and
is recognized as a major cause of cognitive impairment.32
Pathological features of SVD, detectable by magnetic
resonance imaging (MRI), include WM hyperintensities
(WMHs), lacunes (small WM lesion of <15 mm), microhe-
morrhages and microinfarcts,34 and venous collagenosis.35
Particularly, cerebral microhemorrhages are associated
hypertension36,37 and worse cognitive function,38 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 sur-
rounding intracerebral arteries and veins (perivascular

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 Santisteban et al Hypertension and Dementia
Review

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
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impairment. Details described in the text. Ang II indicates angiotensin II; Astro, astrocyte; AT1R, Ang II type 1 receptor; BBB, blood-brain
barrier; CBF, cerebral blood flow; CCA, common carotid artery; HTN, hypertension; MAP, mean arterial pressure; Nox2, NADPH oxidase 2; NT,
normotension; PVM, perivascular macrophages; and ROS, reactive oxygen species.

spaces, PVS). This finding has raised the possibility that
SVD may also affect the removal of potentially toxic pro-
teins 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 flow out of the brain parenchyma via arte-
rial PVS, or within the wall of cerebral arteries (intramu-
ral peri-arterial drainage).43 Although still controversial,44
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 PVS.45 Although
there is evidence that the CSF–interstitial fluid flow may
be impaired in hypertensive rats46,47 and in a small cohort
of patients with hypertension,48 the role of these clearance
pathways on SVD pathobiology and on the deleterious
cognitive effects of hypertension remains to be defined.
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 clear-
ance. The mechanisms involved in cerebral blood flow
(CBF) regulation have been thoroughly reviewed previ-
ously20,49-51; thus, we will focus on the effects of high BP
on these key regulatory mechanisms.
Cerebrovascular autoregulation is a protective mech-
anism to ensure adequate brain perfusion despite BP
fluctuations by maintaining CBF relatively constant within
a certain range, typically ±20 mm Hg of baseline BP.51
Static autoregulation is tested by producing stepwise
increases or decreases in BP and measuring CBF once
steady-state is reached.51 In animal models, hyperten-
sion shifts the static autoregulatory pressure-flow curve
to the right,51 significantly increasing the risk for brain
ischemia if pressure drops below the lower limit.20 The
mechanisms underlying hypertension-induced changes
in autoregulation in animal models involve a combination
of structural alterations to the cerebral vasculature (stiff-
ening and remodeling, discussed above) and changes
in vascular smooth muscle cell 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 mechani-
cal stress on the vasculature is key to protect cerebral

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 Santisteban et al
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 lower-
ing BP. In contrast to studies in animals, most studies
in patients have reported no rightward shift of the static
autoregulatory curve with hypertension.51 Only one small
study of 32 patients reported a rightward shift of the
lower limit of cerebral autoregulation.54 Importantly, CBF
is maintained constant or even increased with antihyper-
tensive treatment,51,55 including in older adults,56 chal-
lenging 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 labeling–
MRI, was monitored during changes in perfusion pres-
sure induced by the head-down tilt test.61 However, since
impaired autoregulation appears to be associated with
severity of WM injury in hypertensive patients,62 future
investigations should address the relationship between
the timing of autoregulation dysfunction and the devel-
opment of vascular pathology.
Endothelial cells participate in vasomotor tone regu-
lation in the brain as in other organs.50 Hypertension
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impairs the ability of the endothelium to regulate CBF20
and is associated with a reduction in NO bioavailability
and consequent compromise of NO-mediated vasodila-
tion.14,18 These effects are mediated by impaired eNOS
(endothelial NO synthase) function and reduced NO pro-
duction,4 as well as increased vascular oxidative stress
that further limits NO bioavailability.63 Although direct
evaluation of cerebral endothelial function is not eas-
ily achieved in humans, an NO synthesis inhibitor failed
to reduce retinal arteriolar blood flow in hypertensive
patients, suggesting deficient NO signaling and endo-
thelial dysfunction.64 Interestingly, impaired endothelium-
dependent vasodilation in systemic arteries correlates
with WMHs65 and microhemorrhages,66 raising the
possibility that endothelial dysfunction is also present
in cerebral microvessels. This hypothesis is supported
by studies in postmortem arterioles from SVD patients
showing an impaired endothelium-dependent vasodilator
response to acetylcholine.67
Endothelial cells are also the site of the blood-
brain barrier (BBB), which determines the bidirectional
exchange of molecules between blood and brain.68
Hypertension is associated with BBB disruption in sev-
eral,69-74 but not all,75 animal models. In humans, BBB
breakdown has been proposed as a core mechanism of
SVD,76 and is an early biomarker of cognitive decline.77
Although BBB disruption has been reported in patients
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Hypertension and Dementia
with hypertension,78,79 it is often difficult to evaluate the
effect of hypertension in the presence of other comor-
bidities. The mechanisms of BBB disruption in animal
models appear to be independent of BP elevation,69,74
Review
and instead mediated by AngII70,71,80 and reactive oxy-
gen species,72 even in models not based on direct
AngII administration, such as the Dahl salt-sensitive
rat,71 spontaneously hypertensive rat,80 and transverse
aortic coarctation.72 In AngII slow pressor hyperten-
sion, activation of the AT1R (AngII type 1 receptor) in
cerebral endothelial cells by circulating AngII is neces-
sary to initiate the disruption.69 Thus, it is not surprising
that the BBB is not disrupted in deoxycorticosterone
acetate salt hypertension,75 a model of salt-sensitive
hypertension in which circulating AngII is suppressed.81
However, given that <15% of patients have elevated
circulating AngII activity,82 the role of endothelial AT1R
activation in BBB breakdown in hypertensive patients
remains 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 cells. 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 activity.49
Neurovascular coupling is attenuated in various mouse
models of hypertension,4 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 neu-
rovascular coupling impairment are independent of the
rise in BP, given that the impairment cannot be induced
by BP elevation with phenylephrine,85 and topical appli-
cation of losartan rescues neurovascular coupling with-
out lowering BP and is also effective in a genetic model
of chronic hypertension (Blood Pressure High [BPH]
mouse).86 The molecular mechanisms of neurovascular
dysfunction include AngII signaling via the AT1R in peri-
vascular macrophages (PVM),85 as discussed in the sec-
tion Immune dysregulation and cognitive impairment in
hypertension. Although AngII augments astrocytic cal-
cium signaling,87,88 the role of astrocyte calcium-depen-
dent signaling in mediating neurovascular coupling
remains controversial.89 A recent study suggested that
impairment of endothelial Kir2.1 channels, implicated
in endothelial cell hyperpolarization and vasodilation in
response to neural activity,49 mediates the neurovascu-
lar coupling deficits in BPH mice and not AT1R.90 How-
ever, 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 mineralo-
corticoid receptor blockade prevents cerebrovascular
dysfunction and cognitive impairment in hypertensive
mice.91 Although elevated aldosterone levels have been
January 2023   25
 Santisteban et al
associated with impaired cerebrovascular and cognitive
function in elderly patients,92 considering the beneficial
effects of angiotensin receptor blockers (ARBs) on
cognitive function,93,94 ARB-induced hyperaldosteron-
Review
ism (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 emphasizes the
need to investigate their interaction and relative contri-
bution to neurovascular and cognitive dysfunction.
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 impair-
ment cannot be concluded. Impairment of hemodynamic
CBF regulation and BBB damage undermine the homeo-
stasis of the brain microenvironment, but their progres-
sion and mechanistic association with cognitive decline
remain 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
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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 vascu-
lature100 would be highly valuable.
HYPERTENSION, IMMUNE
DYSREGULATION, AND COGNITIVE
IMPAIRMENT
Cytokines, both in the circulation and in the brain, may
affect cerebrovascular and cognitive function. Although
IL (interleukin)-6 alone does not induce endothelial
dysfunction,101 IL-6–deficient mice are protected from
the endothelial dysfunction induced by AngII hyperten-
sion in the carotids,101 whereas the anti-inflammatory
cytokine IL-10 can preserve endothelial function.102
Circulating IL-17, elevated in both human and animal
models of hypertension and high dietary salt, may play
26   January 2023 Hypertension. 2023;80:22–34. DOI: 10.1161/HYPERTENSIONAHA.122.18085
Hypertension and Dementia
an important role in BP elevation,103 cerebrovascular
dysfunction,104 and cognitive impairment.105 IL-17–defi-
cient mice have a blunted hypertensive response to
AngII,106 and anti–IL-17 antibodies lower BP in various
models of hypertension.107,108 However, the BP-lowering
effects of anti–IL-17 antibodies are not always con-
sistent,109 and IL-17–deficient mice are not protected
from hypertension induced by deoxycorticosterone
acetate+AngII.110 IL-17 can influence the vasculature,
as shown by the finding that chronic infusion of IL-17
induces endothelial dysfunction in aortic rings,111 and
IL-17–deficient mice are protected from AngII-induced
aortic stiffening.112 Interestingly, IL-17 can induce
cerebral endothelial dysfunction and lead to cognitive
impairment independently of hypertension, supporting
a direct effect on the cerebral vasculature.104 The con-
tribution 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.
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 cells113-115 which may contribute not
only to BP regulation115 but also to neuroinflammation
and cerebrovascular dysfunction.113,114 In patients, a posi-
tron emission tomography imaging indicator of microg-
lial activation was associated with hypertensive SVD.116
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 perivas-
cular space closely apposed to cerebral arterioles and
venules and has been linked to various brain diseases.117
PVM are a major source of reactive oxygen species,
mediate both cerebrovascular and cognitive dysfunc-
tion in animal models of hypertension85 and contribute
to the BBB disruption.69 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
impairment.85 Furthermore, pharmacological depletion of
both microglia and PVM with a colony-stimulating factor
1 receptor inhibitor protected hypertensive mice against
cognitive impairment.113
How to Target the Immune System in
Hypertension?
Given the important role of immune dysregulation in
the pathobiology of hypertension, the idea of target-
ing the immune system to lower BP is actively being
investigated.118 Whether immunotherapies would prove
 Santisteban et al
beneficial on hypertension-induced brain injury and cog-
nitive impairment has received far less attention and
remains an area of great translational importance. For
example, targeting inflammatory mediators and reactive
oxygen species 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 immunosuppressed.118 Therefore,
it is important to identify and select permissible targets
among the patients at greatest risk of developing cogni-
tive impairment.
HYPERTENSION AND
NEURODEGENERATION
In addition to the cerebrovascular alterations induced by
hypertension, studies have focused on the contribution
of hypertension to neurodegenerative pathology, spe-
cifically deposition of the Aβ (amyloid-β) peptide, the
main component of amyloid plaques and a key patho-
logical signature of AD. In rodent models of brain amy-
loid accumulation, AngII-induced hypertension enhances
Aβ deposition,119-121 increases microhemorrhage bur-
den,122 and accelerates cognitive decline.123,124 In wild-
type mice, hypertension has also been associated with
Aβ deposition both in the brain parenchyma114,125,126 and
surrounding cerebral vessels127. The underlying mecha-
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nisms 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 formation,128 and
ARBs ameliorate amyloid pathology in both mouse mod-
els129,130 and humans.93
Cerebral amyloid accumulation in sporadic AD is
mainly caused by impaired Aβ clearance from the
brain.131 In addition to perivascular, paravascular, and
intramural clearance pathways,41,132,133 endothelial
Aβ clearance may also occur through receptor-medi-
ated transport across the BBB.134 One such receptor
is the receptor for advanced glycation end products
(RAGE).135 Like in AD,135 hypertension may activate
RAGE to induce brain Aβ accumulation and cognitive
impairment in animal models.126 RAGE has also been
suggested to mediate Aβ deposition by modulating β-
and γ-secretase activity136 and, when engaged by Aβ, to
disrupt the BBB.137 However, it remains unclear if these
Aβ clearance pathways play a role in the cognitive
impairment associated with hypertension in humans.
Interestingly, plasma EN-RAGE (extracellular RAGE
binding protein) levels have also been associated with
increased risk of cognitive decline in a subset of par-
ticipants from the Rotterdam Study,138 but the link with
hypertension remains to be determined.
Hypertension. 2023;80:22–34. DOI: 10.1161/HYPERTENSIONAHA.122.18085
Hypertension and Dementia
Does Hypertension Increase Alzheimer
Pathology?
Besides provoking ischemic-hypoxic damage in suscep-
Review
tible WM regions, hypertension may contribute to the
development of typical signs of AD-like neuropathology,
including amyloid plaques or tau neurofibrillary tangles.
Early studies found an association between midlife
elevated BP and the presence of neuritic plaques and
neurofibrillary tangles at autopsy.139 Recent studies with
amyloid positron emission tomography show that while
amyloid deposition itself is not associated with hyper-
tension,140 its presence among hypertensive patients is
closely associated with memory impairment.141 Elevated
levels of CSF phosphorylated tau, a biomarker of AD
pathology, is associated with hypertension,142 increased
pulse pressure,143 and elevated BP variability.144 Aortic
stiffness and elevated pulse pressure in older adults are
also associated with higher tau burden, but not amyloid
burden.145 Furthermore, hypertension is associated with
worse cognitive function in AD patients.146 These findings
raise the question of a synergistic relationship between
cerebrovascular damage and AD pathology in mediating
the cognitive impairment in hypertension. Although ani-
mal 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 tau.147 Thus, the question remains
whether blood or CSF biomarkers will prove useful for
early identification of hypertensive patients at risk of
developing cognitive impairment.
NEUROIMAGING ASSESSMENT OF
HYPERTENSIVE BRAIN DAMAGE
Considering the overwhelming impact of chronic hyper-
tension on the brain and its vasculature, it is fundamen-
tal to identify early biomarkers of disease progression.
Advanced brain imaging techniques, discussed below,
can provide valuable tools applicable to both human 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 characteriz-
ing the various manifestations and stages of hyperten-
sive brain damage.148 In humans, hypertension-induced
brain injury is typically characterized by progression of
WMHs,149 microstructural,150,151 and functional altera-
tions152 that correlate with worsening of cognitive func-
tion (Figure 2).153
It is a well-established notion that WMH represents
a macroscopic hallmark of advanced hypertensive brain
damage14; thus neuroimaging techniques have been
January 2023   27
 Santisteban et al
Review
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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, which exploits the principle of water diffusion
in WM and allows estimating the direction and mag-
nitude 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 cog-
nitive dysfunction.150,156 Another technique, dynamic
contrast-enhanced–MRI, has been extensively used in
patients with SVD to detect subtle regional changes in
BBB integrity.157
28   January 2023 Hypertension. 2023;80:22–34. DOI: 10.1161/HYPERTENSIONAHA.122.18085
Hypertension and Dementia
Figure 2. Hypothetical sequence of
events initiated by hypertension and
corresponding imaging correlates.
Hypertension promotes microvascular
injury, including damage to vascular
and immune cells. These effects lead
to impaired vasodilation, blood-brain
barrier dysfunction, arterial stiffening,
and neuroinflammation. This progressive
damage is visible on magnetic resonance
imaging (MRI) scans with different levels
of analysis. Microstructural damage of
white matter (WM) and functional altered
connectivity of the brain is detectable on
30-direction diffusion tensor imaging (DTI)
imaging sequences and tractography
and resting-state–functional MRI
functional networks reconstruction in
a representative hypertensive patient
without signs of WM matter damage
evidenced at macrostructural MRI. WM
hyperintensities in a representative patient
with sustained untreated hypertension.
WM damage is barely visible as
hypodense spots on T1 weighted image
(T1) imaging (left) and noticeable as
hyperintense spots on T2-weighted-Fluid-
Attenuated Inversion Recovery (T2-FLAIR)
(right).
Resting-state functional MRI, a sensitive tool to detect
changes in brain activity using the blood oxygenation level–
dependent contrast, has proven effective in evidencing
alterations in the functional connectivity among specific
regions associated with subtle cognitive impairment in
hypertension.152 Another technique, arterial spin labeling–
MRI, enables noninvasive regional CBF quantification,158
and has detected focal or global reductions in resting
CBF in hypertensive patients,159,160 consistent with previ-
ous reports using other methods, such as phase-contrast
MRI,98 single photon emission computed tomography,161
and positron emission tomography.162 Arterial spin labeling–
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
 Santisteban et al
patients.163 The possibility to assess the same imaging
paradigms in experimental models further corroborates the
translational relevance of searching for composite biomark-
ers that account for cardiovascular phenotypes, brain altera-
tions, and behavioral profiles relevant in humans.
Will Current Biomarkers Identify Individuals at
Risk of Cognitive Impairment Early?
Early identification of signs prodromal of late-life demen-
tia could greatly improve the management of cognitive
health in hypertensive patients. Advancements in neu-
roradiological and analytical tools for brain imaging,
in combination with the expansion of blood and CSF
biomarkers, will be fundamental to provide new direc-
tions for clinicians and instruct on how to identify and
manage patients at risk. The Biomarkers for Vascular
Contributions to Cognitive Impairment and Dementia
(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 biomarkers,164 they also employ neuroimaging
techniques including various MRI protocols and optical
coherence tomography angiography (OCTA),165 a tech-
nique that visualizes retinal capillaries as a marker of
cerebral capillaries. These will be powerful next steps,
in addition to the ongoing Alzheimer’s Disease Neuro-
imaging Initiative, which has already identified cerebro-
vascular dysfunction as an early biomarker of AD166 and
Downloaded from http://ahajournals.org by ramosmaryesther@gmail.com on October 13, 2023
described the association between CSF phosphorylated
tau and hypertension142 and increased pulse pressure.143
Subgroup analyses from both these datasets may aid in
the identification of hypertension-specific biomarkers.
CONCLUSIONS
Data reviewed here show that, despite significant
advances in antihypertensive therapy, hypertension still
represents one of most insidious conditions that chal-
lenge brain health. The profound effects of chronically
elevated BP on the cerebral vasculature and parenchyma
substantially contribute to the increased risk of demen-
tia observed in hypertensive patients.167 As discussed
above, several questions remain about the develop-
ment 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 thresh-
old for therapy initiation, duration, drug class, and intensity
of treatment. If BP management does improve cognitive
outcomes, are certain antihypertensive drug classes supe-
rior to others? The AngII hypothesis suggests that greater
Hypertension. 2023;80:22–34. DOI: 10.1161/HYPERTENSIONAHA.122.18085
Hypertension and Dementia
neuroprotection is provided by antihypertensives that
increase AT2 and AT4 activity (such as ARBs) versus those
that decrease it (such as ACE [angiotensin-converting
enzyme] inhibitors). A recent report found reduced risk for
Review
dementia with AngII-stimulating drugs compared to AngII-
inhibiting drugs among community-dwelling individuals,168 a
finding corroborated by new secondary analysis of a cohort
of Systolic Blood Pressure Intervention Trial (SPRINT) trial
participants.169 Additionally, ARB but not ACE inhibitor use
is associated with lower amyloid and tau,170,171 and reduced
dementia risk.172 The BBB permeability of antihyperten-
sive drugs remains a topic of exploration, with a recent
report suggesting potential superiority of BBB-permeable
ARBs.173 Another important question is whether intensive
versus standard BP control will provide greater protec-
tion? This problem is being addressed by various second-
ary analyses of SPRINT9,39 and PRESERVE (Randomized
Trial of Intensive Versus Standard Blood Pressure Control
in Small Vessel Disease)155 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 ther-
apeutic 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, or clearance pathways
in the brain, which can be combined with already exist-
ing antihypertensive therapy. A personalized precision
medicine approach is likely to hold the key to prevent
hypertension-induced cognitive decline, utilizing a com-
bined assessment of early markers of disease, inflam-
matory status, vascular and metabolic comorbidities, and
demographic and genetic factors.
ARTICLE INFORMATION
Affiliations
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York,
NY (M.M.S., C.I.). Department of Molecular Medicine, “Sapienza” University of
Rome, Italy (D.C.). Research Unit of Neuro and Cardiovascular Pathophysiology,
IRCCS Neuromed, Pozzilli, Italy (D.C.).
Acknowledgments
Figures were created with BioRender.com. The support from the Leon Levy Fel-
lowship in Neuroscience (M.M. Santisteban) and the Feil Family Foundation is
gratefully acknowledged.
Sources of Funding
M.M. Santisteban is a recipient of National Institute of Health (NIH) grant
NS123507 (National Institute of Neurological Disorders and Stroke [NINDS]/
National Institute on Aging [NIA]). D. Carnevale is recipient of funding from the
Italian Ministry of Health “Ricerca Corrente”.
Disclosures
C. Iadecola serves on the strategic advisory board of Broadview Ventures. The
other authors report no conflicts.
January 2023   29
 Santisteban et al
REFERENCES
1. World Health Organization. Global status report on the public health response
to dementia. World Health Organization; 2021.
2. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S,
Review
Brayne C, Burns A, Cohen-Mansfield J, Cooper C, et al. Dementia preven-
tion, intervention, and care: 2020 report of the lancet commission. Lancet.
2020;396:413–446. doi: 10.1016/S0140-6736(20)30367-6
3. Azarpazhooh MR, Avan A, Cipriano LE, Munoz DG, Sposato LA,
Hachinski V. Concomitant vascular and neurodegenerative pathologies
double the risk of dementia. Alzheimers Dement. 2018;14:148–156. doi:
10.1016/j.jalz.2017.07.755
4. Santisteban MM, Iadecola C. Hypertension, dietary salt and cogni-
tive impairment. J Cereb Blood Flow Metab. 2018;38:2112–2128. doi:
10.1177/0271678X18803374
5. McGrath ER, Beiser AS, DeCarli C, Plourde KL, Vasan RS, Greenberg SM,
Seshadri S. Blood pressure from mid- to late life and risk of incident dementia.
Neurology. 2017;89:2447–2454. doi: 10.1212/WNL.0000000000004741
6. Littlejohns TJ, Collister JA, Liu X, Clifton L, Tapela NM, Hunter DJ. Hyperten-
sion, a dementia polygenic risk score, apoe genotype, and incident demen-
tia. Alzheimers Dement. 2022. doi:10.1002/alz.12680
7. Williamson JD, Pajewski NM, Auchus AP, Bryan RN, Chelune G,
Cheung AK, et al. Effect of intensive vs standard blood pressure control on
probable dementia: a randomized clinical trial. Jama. 2019;321:553–561.
doi: 10.1001/jama.2018.21442
8. Hughes D, Judge C, Murphy R, Loughlin E, Costello M, Whiteley W, Bosch
J, O’Donnell MJ, Canavan M. Association of blood pressure lowering with
incident dementia or cognitive impairment: a systematic review and meta-
analysis. JAMA. 2020;323:1934–1944. doi: 10.1001/jama.2020.4249
9. Rapp SR, Gaussoin SA, Sachs BC, Chelune G, Supiano MA, Lerner AJ,
Wadley VG, Wilson VM, Fine LJ, Whittle JC, et al; SPRINT Research Group.
Effects of intensive versus standard blood pressure control on domain-spe-
cific cognitive function: a substudy of the SPRINT randomised controlled trial.
Lancet Neurol. 2020;19:899–907. doi: 10.1016/S1474-4422(20)30319-7
10. Du XL, Simpson LM, Osani MC, Yama JM, Davis BR. Risk of developing
alzheimer’s disease and related dementias in allhat trial participants receiv-
ing diuretic, ace-inhibitor, or calcium-channel blocker with 18 years of fol-
low-up. J Alzheimers Dis Parkinsonism. 2022;12:541.
Downloaded from http://ahajournals.org by ramosmaryesther@gmail.com on October 13, 2023
11. Peters R, Yasar S, Anderson CS, Andrews S, Antikainen R, Arima H,
Beckett N, Beer JC, Bertens AS, Booth A, et al. Investigation of antihyper-
tensive class, dementia, and cognitive decline: a meta-analysis. Neurology.
2020;94:e267–e281. doi: 10.1212/WNL.0000000000008732
12. Ding J, Davis-Plourde KL, Sedaghat S, Tully PJ, Wang W, Phillips C,
Pase MP, Himali JJ, Gwen Windham B, Griswold M, et al. Antihyperten-
sive medications and risk for incident dementia and Alzheimer’s disease: a
meta-analysis of individual participant data from prospective cohort studies.
Lancet Neurol. 2020;19:61–70. doi: 10.1016/S1474-4422(19)30393-X
13. de Roos A, van der Grond J, Mitchell G, Westenberg J. Magnetic reso-
nance imaging of cardiovascular function and the brain: is dementia a
cardiovascular-driven disease? Circulation. 2017;135:2178–2195. doi:
10.1161/CIRCULATIONAHA.116.021978
14. Iadecola C, Gottesman RF. Neurovascular and cognitive dysfunc-
tion in hypertension. Circ Res. 2019;124:1025–1044. doi: 10.1161/
CIRCRESAHA.118.313260
15. Webb AJS, Werring DJ. New insights into cerebrovascular pathophysi-
ology and hypertension. Stroke. 2022;53:1054–1064. doi: 10.1161/
STROKEAHA.121.035850
16. Kaess BM, Rong J, Larson MG, Hamburg NM, Vita JA, Levy D,
Benjamin EJ, Vasan RS, Mitchell GF. Aortic stiffness, blood pressure pro-
gression, and incident hypertension. JAMA. 2012;308:875–881. doi:
10.1001/2012.jama.10503
17. Humphrey JD, Harrison DG, Figueroa CA, Lacolley P, Laurent S. Cen-
tral artery stiffness in hypertension and aging: a problem with cause
and consequence. Circ Res. 2016;118:379–381. doi: 10.1161/
CIRCRESAHA.115.307722
18. Hu X, De Silva TM, Chen J, Faraci FM. Cerebral vascular disease and neu-
rovascular injury in ischemic stroke. Circ Res. 2017;120:449–471. doi:
10.1161/CIRCRESAHA.116.308427
19. Schiffrin EL. Mechanisms of remodelling of small arteries, antihyperten-
sive therapy and the immune system in hypertension. Clin Invest Med.
2015;38:E394–E402. doi: 10.25011/cim.v38i6.26202
20. Pires PW, Dams Ramos CM, Matin N, Dorrance AM. The effects of
hypertension on the cerebral circulation. Am J Physiol Heart Circ Physiol.
2013;304:H1598–H1614. doi: 10.1152/ajpheart.00490.2012
30   January 2023 Hypertension. 2023;80:22–34. DOI: 10.1161/HYPERTENSIONAHA.122.18085
Hypertension and Dementia
21. Rizzoni D, De Ciuceis C, Porteri E, Paiardi S, Boari GE, Mortini P, Cornali C,
Cenzato M, Rodella LF, Borsani E, et al. Altered structure of small cerebral
arteries in patients with essential hypertension. J Hypertens. 2009;27:838–
845. doi: 10.1097/HJH.0b013e32832401ea
22. van Sloten TT, Protogerou AD, Henry RM, Schram MT, Launer LJ,
Stehouwer CD. Association between arterial stiffness, cerebral small
vessel disease and cognitive impairment: a systematic review and meta-
analysis. Neurosci Biobehav Rev. 2015;53:121–130. doi: 10.1016/j.
neubiorev.2015.03.011
23. Chan SL, Baumbach GL. Deficiency of Nox2 prevents angiotensin II-
induced inward remodeling in cerebral arterioles. Front Physiol. 2013;4:133.
doi: 10.3389/fphys.2013.00133
24. Xu S, Ilyas I, Little PJ, Li H, Kamato D, Zheng X, Luo S, Li Z, Liu P,
Han J, et al. Endothelial dysfunction in atherosclerotic cardiovascular dis-
eases and beyond: from mechanism to pharmacotherapies. Pharmacol Rev.
2021;73:924–967. doi: 10.1124/pharmrev.120.000096
25. Tabas I, García-Cardeña G, Owens GK. Recent insights into the cel-
lular biology of atherosclerosis. J Cell Biol. 2015;209:13–22. doi:
10.1083/jcb.201412052
26. Li H, Horke S, Förstermann U. Vascular oxidative stress, nitric oxide and
atherosclerosis. Atherosclerosis. 2014;237:208–219. doi: 10.1016/j.
atherosclerosis.2014.09.001
27. Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat
Immunol. 2011;12:204–212. doi: 10.1038/ni.2001
28. Gardener H, Caunca MR, Dong C, Cheung YK, Elkind MSV, Sacco RL,
Rundek T, Wright CB. Ultrasound markers of carotid atherosclerosis and
cognition: the northern manhattan study. Stroke. 2017;48:1855–1861. doi:
10.1161/STROKEAHA.117.016921
29. Arvanitakis Z, Capuano AW, Leurgans SE, Bennett DA, Schneider JA.
Relation of cerebral vessel disease to Alzheimer’s disease dementia and
cognitive function in elderly people: a cross-sectional study. Lancet Neurol.
2016;15:934–943. doi: 10.1016/S1474-4422(16)30029-1
30. Wingo AP, Fan W, Duong DM, Gerasimov ES, Dammer EB, Liu Y,
Harerimana NV, White B, Thambisetty M, Troncoso JC, et al. Shared proteomic
effects of cerebral atherosclerosis and Alzheimer’s disease on the human
brain. Nat Neurosci. 2020;23:696–700. doi: 10.1038/s41593-020-0635-5
31. Ungvari Z, Toth P, Tarantini S, Prodan CI, Sorond F, Merkely B,
Csiszar A. Hypertension-induced cognitive impairment: from pathophysi-
ology to public health. Nat Rev Nephrol. 2021;17:639–654. doi:
10.1038/s41581-021-00430-6
32. Wardlaw JM, Smith C, Dichgans M. Small vessel disease: mecha-
nisms and clinical implications. Lancet Neurol. 2019;18:684–696. doi:
10.1016/S1474-4422(19)30079-1
33. Lammie GA. Hypertensive cerebral small vessel disease and stroke. Brain
Pathol. 2002;12:358–370. doi: 10.1111/j.1750-3639.2002.tb00450.x
34. Ter Telgte A, van Leijsen EMC, Wiegertjes K, Klijn CJM, Tuladhar AM,
de Leeuw FE. Cerebral small vessel disease: from a focal to a global perspec-
tive. Nat Rev Neurol. 2018;14:387–398. doi: 10.1038/s41582-018-0014-y
35. Keith J, Gao FQ, Noor R, Kiss A, Balasubramaniam G, Au K, Rogaeva E,
Masellis M, Black SE. Collagenosis of the deep medullary veins: an under-
recognized pathologic correlate of white matter hyperintensities and peri-
ventricular infarction? J Neuropathol Exp Neurol. 2017;76:299–312. doi:
10.1093/jnen/nlx009
36. Romero JR, Preis SR, Beiser A, DeCarli C, Viswanathan A, Martinez-Ramirez S,
Kase CS, Wolf PA, Seshadri S. Risk factors, stroke prevention treatments, and
prevalence of cerebral microbleeds in the Framingham Heart Study. Stroke.
2014;45:1492–1494. doi: 10.1161/STROKEAHA.114.004130
37. Ungvari Z, Tarantini S, Kirkpatrick AC, Csiszar A, Prodan CI. Cere-
bral microhemorrhages: mechanisms, consequences, and preven-
tion. Am J Physiol Heart Circ Physiol. 2017;312:H1128–H1143. doi:
10.1152/ajpheart.00780.2016
38. Poels MM, Ikram MA, van der Lugt A, Hofman A, Niessen WJ, Krestin GP,
Breteler MM, Vernooij MW. Cerebral microbleeds are associated with worse
cognitive function: the Rotterdam Scan Study. Neurology. 2012;78:326–
333. doi: 10.1212/WNL.0b013e3182452928
39. Reboussin DM, Pajewski NM, Williamson JD. Analysis of long-term ben-
efits of intensive blood pressure control-reply. JAMA. 2019;322:170. doi:
10.1001/jama.2019.5860
40. Verhaaren BF, Vernooij MW, de Boer R, Hofman A, Niessen WJ,
van der Lugt A, Ikram MA. High blood pressure and cerebral white matter
lesion progression in the general population. Hypertension. 2013;61:1354–
1359. doi: 10.1161/HYPERTENSIONAHA.111.00430
41. Carare RO, Aldea R, Agarwal N, Bacskai BJ, Bechman I, Boche D, Bu G,
Bulters D, Clemens A, Counts SE, et al. Clearance of interstitial fluid (ISF) and
 Santisteban et al
CSF (CLIC) group-part of Vascular Professional Interest Area (PIA): Cerebro-
vascular disease and the failure of elimination of Amyloid-β from the brain and
retina with age and Alzheimer’s disease-Opportunities for Therapy. Alzheimers
Dement (Amst). 2020;12:e12053. doi: 10.1002/dad2.12053
42. Wardlaw JM, Benveniste H, Nedergaard M, Zlokovic BV, Mestre H, Lee H,
Doubal FN, Brown R, Ramirez J, MacIntosh BJ, et al; colleagues from the
Fondation Leducq Transatlantic Network of Excellence on the Role of
the Perivascular Space in Cerebral Small Vessel Disease. Perivascular
spaces in the brain: anatomy, physiology and pathology. Nat Rev Neurol.
2020;16:137–153. doi: 10.1038/s41582-020-0312-z
43. Nimmo J, Johnston DA, Dodart JC, MacGregor-Sharp MT, Weller RO,
Nicoll JAR, Verma A, Carare RO. Peri-arterial pathways for clearance
of α-Synuclein and tau from the brain: Implications for the pathogen-
esis of dementias and for immunotherapy. Alzheimers Dement (Amst).
2020;12:e12070. doi: 10.1002/dad2.12070
44. Mestre H, Mori Y, Nedergaard M. The brain’s glymphatic system: cur-
rent controversies. Trends Neurosci. 2020;43:458–466. doi: 10.1016/j.
tins.2020.04.003
45. Hablitz LM, Nedergaard M. The glymphatic system: a novel component
of fundamental neurobiology. J Neurosci. 2021;41:7698–7711. doi:
10.1523/JNEUROSCI.0619-21.2021
46. Koundal S, Elkin R, Nadeem S, Xue Y, Constantinou S, Sanggaard S, Liu X,
Monte B, Xu F, Van Nostrand W, et al. Optimal mass transport with lagrangian
workflow reveals advective and diffusion driven solute transport in the glym-
phatic system. Sci Rep. 2020;10:1990. doi: 10.1038/s41598-020-59045-9
47. Mortensen KN, Sanggaard S, Mestre H, Lee H, Kostrikov S, Xavier ALR,
Gjedde A, Benveniste H, Nedergaard M. Impaired glymphatic transport in
spontaneously hypertensive rats. J Neurosci. 2019;39:6365–6377. doi:
10.1523/JNEUROSCI.1974-18.2019
48. Zhang Y, Zhang R, Ye Y, Wang S, Jiaerken Y, Hong H, Li K, Zeng Q, Luo X,
Xu X, et al. The influence of demographics and vascular risk factors on
glymphatic function measured by diffusion along perivascular space. Front
Aging Neurosci. 2021;13:693787. doi: 10.3389/fnagi.2021.693787
49. Schaeffer S, Iadecola C. Revisiting the neurovascular unit. Nat Neurosci.
2021;24:1198–1209. doi: 10.1038/s41593-021-00904-7
50. Ashby JW, Mack JJ. Endothelial Control of Cerebral Blood Flow. Am J
Pathol. 2021;191:1906–1916. doi: 10.1016/j.ajpath.2021.02.023
51. Claassen JAHR, Thijssen DHJ, Panerai RB, Faraci FM. Regulation of cerebral
Downloaded from http://ahajournals.org by ramosmaryesther@gmail.com on October 13, 2023
blood flow in humans: physiology and clinical implications of autoregulation.
Physiol Rev. 2021;101:1487–1559. doi: 10.1152/physrev.00022.2020
52. Vorstrup S, Barry DI, Jarden JO, Svendsen UG, Braendstrup O, Graham DI,
Strandgaard S. Chronic antihypertensive treatment in the rat reverses hyper-
tension-induced changes in cerebral blood flow autoregulation. Stroke.
1984;15:312–318. doi: 10.1161/01.str.15.2.312
53. Dupuis F, Atkinson J, Limiñana P, Chillon JM. Captopril improves cerebro-
vascular structure and function in old hypertensive rats. Br J Pharmacol.
2005;144:349–356. doi: 10.1038/sj.bjp.0706001
54. Strandgaard S. Autoregulation of cerebral blood flow in hypertensive
patients. The modifying influence of prolonged antihypertensive treat-
ment on the tolerance to acute, drug-induced hypotension. Circulation.
1976;53:720–727. doi: 10.1161/01.cir.53.4.720
55. Dolui S, Detre JA, Gaussoin SA, Herrick JS, Wang DJJ, Tamura MK,
Cho ME, Haley WE, Launer LJ, Punzi HA, et al. Association of intensive
vs standard blood pressure control with cerebral blood flow: second-
ary analysis of the sprint mind randomized clinical trial. JAMA Neurol.
2022;79:380–389. doi: 10.1001/jamaneurol.2022.0074
56. van Rijssel AE, Stins BC, Beishon LC, Sanders ML, Quinn TJ, Claassen JAHR,
de Heus RAA. Effect of antihypertensive treatment on cerebral blood
flow in older adults: a systematic review and meta-analysis. Hypertension.
2022;79:1067–1078. doi: 10.1161/HYPERTENSIONAHA.121.18255
57. Traon AP, Costes-Salon MC, Galinier M, Fourcade J, Larrue V. Dynamics of
cerebral blood flow autoregulation in hypertensive patients. J Neurol Sci.
2002;195:139–144. doi: 10.1016/s0022-510x(02)00010-2
58. Eames PJ, Blake MJ, Panerai RB, Potter JF. Cerebral autoregulation
indices are unimpaired by hypertension in middle aged and older peo-
ple. Am J Hypertens. 2003;16(9 Pt 1):746–753. doi: 10.1016/s0895-
7061(03)00947-6
59. Müller M, Österreich M, Lakatos L, Hessling AV. Cerebral macro- and
microcirculatory blood flow dynamics in successfully treated chronic
hypertensive patients with and without white mater lesions. Sci Rep.
2020;10:9213. doi: 10.1038/s41598-020-66317-x
60. Immink RV, van den Born BJ, van Montfrans GA, Koopmans RP, Karemaker
JM, van Lieshout JJ. Impaired cerebral autoregulation in patients with malig-
nant hypertension. Circulation. 2004;110:2241–2245. doi: 10.1161/01.
CIR.0000144472.08647.40
Hypertension. 2023;80:22–34. DOI: 10.1161/HYPERTENSIONAHA.122.18085
Hypertension and Dementia
61. Seiller I, Pavilla A, Ognard J, Ozier-Lafontaine N, Colombani S, Cepeda
Ibarra Y, Mejdoubi M. Arterial hypertension and cerebral hemodynamics:
impact of head-down tilt on cerebral blood flow (arterial spin-labeling-MRI)
in healthy and hypertensive patients. J Hypertens. 2021;39:979–986. doi:
10.1097/HJH.0000000000002709
Review
62. Matsushita K, Kuriyama Y, Nagatsuka K, Nakamura M, Sawada T,
Omae T. Periventricular white matter lucency and cerebral blood flow auto-
regulation in hypertensive patients. Hypertension. 1994;23:565–568. doi:
10.1161/01.hyp.23.5.565
63. Paravicini TM, Sobey CG. Cerebral vascular effects of reactive oxygen spe-
cies: recent evidence for a role of NADPH-oxidase. Clin Exp Pharmacol
Physiol. 2003;30:855–859. doi: 10.1046/j.1440-1681.2003.03920.x
64. Delles C, Michelson G, Harazny J, Oehmer S, Hilgers KF, Schmieder RE.
Impaired endothelial function of the retinal vasculature in hypertensive patients.
Stroke. 2004;35:1289–1293. doi: 10.1161/01.STR.0000126597.11534.3b
65. Hoth KF, Tate DF, Poppas A, Forman DE, Gunstad J, Moser DJ, Paul RH,
Jefferson AL, Haley AP, Cohen RA. Endothelial function and white mat-
ter hyperintensities in older adults with cardiovascular disease. Stroke.
2007;38:308–312. doi: 10.1161/01.STR.0000254517.04275.3f
66. Nezu T, Hosomi N, Aoki S, Kubo S, Araki M, Mukai T, Takahashi T,
Maruyama H, Higashi Y, Matsumoto M. Endothelial dysfunction is asso-
ciated with the severity of cerebral small vessel disease. Hypertens Res.
2015;38:291–297. doi: 10.1038/hr.2015.4
67. Bagi Z, Brandner DD, Le P, McNeal DW, Gong X, Dou H, Fulton DJ, Beller A,
Ngyuen T, Larson EB, et al. Vasodilator dysfunction and oligodendrocyte
dysmaturation in aging white matter. Ann Neurol. 2018;83:142–152. doi:
10.1002/ana.25129
68. Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV. Blood-brain
barrier: from physiology to disease and back. Physiol Rev. 2019;99:21–78.
doi: 10.1152/physrev.00050.2017
69. Santisteban MM, Ahn SJ, Lane D, Faraco G, Garcia-Bonilla L, Racchumi G,
Poon C, Schaeffer S, Segarra SG, Körbelin J, et al. Endothelium-macrophage
crosstalk mediates blood-brain barrier dysfunction in hypertension. Hyperten-
sion. 2020;76:795–807. doi: 10.1161/HYPERTENSIONAHA.120.15581
70. Vital SA, Terao S, Nagai M, Granger DN. Mechanisms underlying the cerebral
microvascular responses to angiotensin II-induced hypertension. Microcircula-
tion. 2010;17:641–649. doi: 10.1111/j.1549-8719.2010.00060.x
71. Pelisch N, Hosomi N, Ueno M, Nakano D, Hitomi H, Mogi M,
Shimada K, Kobori H, Horiuchi M, Sakamoto H, et al. Blockade of AT1
receptors protects the blood-brain barrier and improves cognition in Dahl
salt-sensitive hypertensive rats. Am J Hypertens. 2011;24:362–368. doi:
10.1038/ajh.2010.241
72. Poulet R, Gentile MT, Vecchione C, Distaso M, Aretini A, Fratta L, Russo G,
Echart C, Maffei A, De Simoni MG, et al. Acute hypertension induces oxida-
tive stress in brain tissues. J Cereb Blood Flow Metab. 2006;26:253–262.
doi: 10.1038/sj.jcbfm.9600188
73. Fan Y, Lan L, Zheng L, Ji X, Lin J, Zeng J, Huang R, Sun J. Spontaneous
white matter lesion in brain of stroke-prone renovascular hypertensive rats:
a study from MRI, pathology and behavior. Metab Brain Dis. 2015;30:1479–
1486. doi: 10.1007/s11011-015-9722-9
74. Biancardi VC, Son SJ, Ahmadi S, Filosa JA, Stern JE. Circulating angioten-
sin II gains access to the hypothalamus and brain stem during hypertension
via breakdown of the blood-brain barrier. Hypertension. 2014;63:572–579.
doi: 10.1161/HYPERTENSIONAHA.113.01743
75. Rodrigues SF, Granger DN. Cerebral microvascular inflammation in
DOCA salt-induced hypertension: role of angiotensin II and mitochon-
drial superoxide. J Cereb Blood Flow Metab. 2012;32:368–375. doi:
10.1038/jcbfm.2011.139
76. Wardlaw JM, Makin SJ, Valdés Hernández MC, Armitage PA, Heye AK,
Chappell FM. Blood-brain barrier failure as a core mechanism in cerebral
small vessel disease and dementia: Evidence from a cohort study. Alzheim-
ers Dement. 2017;13:634–643. doi: 10.1016/j.jalz.2016.09.006
77. Nation DA, Sweeney MD, Montagne A, Sagare AP, D’Orazio LM, Pachicano M,
Sepehrband F, Nelson AR, Buennagel DP, Harrington MG, et al. Blood-brain
barrier breakdown is an early biomarker of human cognitive dysfunction. Nat
Med. 2019;25:270–276. doi: 10.1038/s41591-018-0297-y
78. Dankbaar JW, Hom J, Schneider T, Cheng SC, Lau BC, van der
Schaaf I, Virmani S, Pohlman S, Wintermark M. Age- and anatomy-related
values of blood-brain barrier permeability measured by perfusion-CT in
non-stroke patients. J Neuroradiol. 2009;36:219–227. doi: 10.1016/j.
neurad.2009.01.001
79. Muñoz Maniega S, Chappell FM, Valdés Hernández MC, Armitage PA,
Makin SD, Heye AK, Thrippleton MJ, Sakka E, Shuler K, Dennis MS,
et al. Integrity of normal-appearing white matter: Influence of age,
visible lesion burden and hypertension in patients with small-vessel
January 2023   31
 Santisteban et al
disease. J Cereb Blood Flow Metab. 2017;37:644–656. doi:
10.1177/0271678X16635657
80. Mowry FE, Peaden SC, Stern JE, Biancardi VC. TLR4 and AT1R mediate
blood-brain barrier disruption, neuroinflammation, and autonomic dysfunc-
tion in spontaneously hypertensive rats. Pharmacol Res. 2021;174:105877.
Review
doi: 10.1016/j.phrs.2021.105877
81. Basting T, Lazartigues E. DOCA-Salt Hypertension: an Update. Curr Hyper-
tens Rep. 2017;19:32. doi: 10.1007/s11906-017-0731-4
82. Alderman MH, Cohen HW, Sealey JE, Laragh JH. Plasma renin activity lev-
els in hypertensive persons: their wide range and lack of suppression in
diabetic and in most elderly patients. Am J Hypertens. 2004;17:1–7. doi:
10.1016/j.amjhyper.2003.08.015
83. Jennings JR, Muldoon MF, Ryan C, Price JC, Greer P, Sutton-Tyrrell K,
van der Veen FM, Meltzer CC. Reduced cerebral blood flow response and
compensation among patients with untreated hypertension. Neurology.
2005;64:1358–1365. doi: 10.1212/01.WNL.0000158283.28251.3C
84. Jennings JR, Muldoon MF, Ryan CM, Mintun MA, Meltzer CC, Townsend
DW, Sutton-Tyrrell K, Shapiro AP, Manuck SB. Cerebral blood flow in
hypertensive patients: an initial report of reduced and compensatory blood
flow responses during performance of two cognitive tasks. Hypertension.
1998;31:1216–1222. doi: 10.1161/01.hyp.31.6.1216
85. Faraco G, Sugiyama Y, Lane D, Garcia-Bonilla L, Chang H, Santisteban
MM, Racchumi G, Murphy M, Van Rooijen N, Anrather J, et al. Perivas-
cular macrophages mediate the neurovascular and cognitive dysfunction
associated with hypertension. J Clin Invest. 2016;126:4674–4689. doi:
10.1172/JCI86950
86. Kazama K, Wang G, Frys K, Anrather J, Iadecola C. Angiotensin II attenu-
ates functional hyperemia in the mouse somatosensory cortex. Am J
Physiol Heart Circ Physiol. 2003;285:H1890–H1899. doi: 10.1152/
ajpheart.00464.2003
87. Diaz JR, Kim KJ, Brands MW, Filosa JA. Augmented astrocyte microdomain
Ca2+ dynamics and parenchymal arteriole tone in angiotensin II-infused
hypertensive mice. Glia. 2019;67:551–565. doi: 10.1002/glia.23564
88. Boily M, Li L, Vallerand D, Girouard H. Angiotensin II disrupts neurovascular
coupling by potentiating calcium increases in astrocytic endfeet. J Am Heart
Assoc. 2021;10:e020608. doi: 10.1161/JAHA.120.020608
89. Del Franco AP, Chiang PP, Newman EA. Dilation of cortical capillaries is
not related to astrocyte calcium signaling. Glia. 2022;70:508–521. doi:
Downloaded from http://ahajournals.org by ramosmaryesther@gmail.com on October 13, 2023
10.1002/glia.24119
90. Koide M, Harraz OF, Dabertrand F, Longden TA, Ferris HR, Wellman GC,
Hill-Eubanks DC, Greenstein AS, Nelson MT. Differential restoration of
functional hyperemia by antihypertensive drug classes in hypertension-
related cerebral small vessel disease. J Clin Invest. 2021;131:149029. doi:
10.1172/JCI149029
91. Diaz-Otero JM, Yen TC, Fisher C, Bota D, Jackson WF, Dorrance AM. Min-
eralocorticoid receptor antagonism improves parenchymal arteriole dilation
via a TRPV4-dependent mechanism and prevents cognitive dysfunction in
hypertension. Am J Physiol Heart Circ Physiol. 2018;315:H1304–H1315.
doi: 10.1152/ajpheart.00207.2018
92. Hajjar I, Hart M, Mack W, Lipsitz LA. Aldosterone, cognitive function, and
cerebral hemodynamics in hypertension and antihypertensive therapy. Am J
Hypertens. 2015;28:319–325. doi: 10.1093/ajh/hpu161
93. Hajjar I, Levey A. Association Between Angiotensin Receptor Blockers and
Longitudinal Decline in Tau in Mild Cognitive Impairment. JAMA Neurol.
2015;72:1069–1070. doi: 10.1001/jamaneurol.2015.1001
94. Nation DA, Ho J, Yew B; Alzheimer’s Disease Neuroimaging Initiative. Older
adults taking at1-receptor blockers exhibit reduced cerebral amyloid reten-
tion. J Alzheimers Dis. 2016;50:779–789. doi: 10.3233/JAD-150487
95. Toth P, Tucsek Z, Sosnowska D, Gautam T, Mitschelen M, Tarantini S,
Deak F, Koller A, Sonntag WE, Csiszar A, et al. Age-related autoregula-
tory dysfunction and cerebromicrovascular injury in mice with angiotensin
II-induced hypertension. J Cereb Blood Flow Metab. 2013;33:1732–1742.
doi: 10.1038/jcbfm.2013.143
96. Toth P, Tarantini S, Springo Z, Tucsek Z, Gautam T, Giles CB,
Wren JD, Koller A, Sonntag WE, Csiszar A, et al. Aging exacerbates
hypertension-induced cerebral microhemorrhages in mice: role of res-
veratrol treatment in vasoprotection. Aging Cell. 2015;14:400–408. doi:
10.1111/acel.12315
97. Sam K, Crawley AP, Conklin J, Poublanc J, Sobczyk O, Mandell DM,
Venkatraghavan L, Duffin J, Fisher JA, Black SE, et al. Development of white
matter hyperintensity is preceded by reduced cerebrovascular reactivity. Ann
Neurol. 2016;80:277–285. doi: 10.1002/ana.24712
98. Muller M, van der Graaf Y, Visseren FL, Mali WP, Geerlings MI; SMART
Study Group. Hypertension and longitudinal changes in cerebral blood
32   January 2023 Hypertension. 2023;80:22–34. DOI: 10.1161/HYPERTENSIONAHA.122.18085
Hypertension and Dementia
flow: the SMART-MR study. Ann Neurol. 2012;71:825–833. doi:
10.1002/ana.23554
99. Vanlandewijck M, He L, Mäe MA, Andrae J, Ando K, Del Gaudio F, Nahar K,
Lebouvier T, Laviña B, Gouveia L, et al. A molecular atlas of cell types
and zonation in the brain vasculature. Nature. 2018;554:475–480. doi:
10.1038/nature25739
100. Winkler EA, Kim CN, Ross JM, Garcia JH, Gil E, Oh I, et al. A single-cell
atlas of the normal and malformed human brain vasculature. Science.
2022;375:eabi7377. doi: 10.1126/science.abi7377
101. Schrader LI, Kinzenbaw DA, Johnson AW, Faraci FM, Didion SP. IL-6 de-
ficiency protects against angiotensin II induced endothelial dysfunction
and hypertrophy. Arterioscler Thromb Vasc Biol. 2007;27:2576–2581. doi:
10.1161/ATVBAHA.107.153080
102. Didion SP, Kinzenbaw DA, Schrader LI, Chu Y, Faraci FM. Endogenous inter-
leukin-10 inhibits angiotensin II-induced vascular dysfunction. Hypertension.
2009;54:619–624. doi: 10.1161/HYPERTENSIONAHA.109.137158
103. Higaki A, Mahmoud AUM, Paradis P, Schiffrin EL. Role of interleukin-23/
interleukin-17 axis in T-cell-mediated actions in hypertension. Cardiovasc
Res. 2021;117:1274–1283. doi: 10.1093/cvr/cvaa257
104. Faraco G, Brea D, Garcia-Bonilla L, Wang G, Racchumi G, Chang H,
Buendia I, Santisteban MM, Segarra SG, Koizumi K, et al. Dietary salt
promotes neurovascular and cognitive dysfunction through a gut-initi-
ated TH17 response. Nat Neurosci. 2018;21:240–249. doi: 10.1038/
s41593-017-0059-z
105. Cipollini V, Anrather J, Orzi F, Iadecola C. Th17 and cognitive impair-
ment: possible mechanisms of action. Front Neuroanat. 2019;13:95. doi:
10.3389/fnana.2019.00095
106. Madhur MS, Lob HE, McCann LA, Iwakura Y, Blinder Y, Guzik TJ,
Harrison DG. Interleukin 17 promotes angiotensin II-induced hypertension
and vascular dysfunction. Hypertension. 2010;55:500–507. doi: 10.1161/
HYPERTENSIONAHA.109.145094
107. Saleh MA, Norlander AE, Madhur MS. Inhibition of interleukin 17-a but not
interleukin-17f signaling lowers blood pressure and reduces end-organ
inflammation in angiotensin ii-induced hypertension. JACC Basic Transl Sci.
2016;1:606–616. doi: 10.1016/j.jacbts.2016.07.009
108. Amador CA, Barrientos V, Peña J, Herrada AA, González M, Valdés S,
Carrasco L, Alzamora R, Figueroa F, Kalergis AM, et al. Spironolactone de-
creases DOCA-salt-induced organ damage by blocking the activation of T
helper 17 and the downregulation of regulatory T lymphocytes. Hypertension.
2014;63:797–803. doi: 10.1161/HYPERTENSIONAHA.113.02883
109. Markó L, Kvakan H, Park JK, Qadri F, Spallek B, Binger KJ, Bowman
EP, Kleinewietfeld M, Fokuhl V, Dechend R, et al. Interferon-γ signal-
ing inhibition ameliorates angiotensin II-induced cardiac damage.
Hypertension. 2012;60:1430–1436. doi: 10.1161/HYPERTENSIONAHA.
112.199265
110. Krebs CF, Lange S, Niemann G, Rosendahl A, Lehners A, Meyer-
Schwesinger C, Stahl RA, Benndorf RA, Velden J, Paust HJ, et al. Deficiency
of the interleukin 17/23 axis accelerates renal injury in mice with deoxy-
corticosterone acetate+angiotensin ii-induced hypertension. Hypertension.
2014;63:565–571. doi: 10.1161/HYPERTENSIONAHA.113.02620
111. Nguyen H, Chiasson VL, Chatterjee P, Kopriva SE, Young KJ,
Mitchell BM. Interleukin-17 causes Rho-kinase-mediated endothelial
dysfunction and hypertension. Cardiovasc Res. 2013;97:696–704. doi:
10.1093/cvr/cvs422
112. Wu J, Thabet SR, Kirabo A, Trott DW, Saleh MA, Xiao L,
Madhur MS, Chen W, Harrison DG. Inflammation and mechanical stretch
promote aortic stiffening in hypertension through activation of p38
mitogen-activated protein kinase. Circ Res. 2014;114:616–625. doi:
10.1161/CIRCRESAHA.114.302157
113. Kerkhofs D, van Hagen BT, Milanova IV, Schell KJ, van Essen H, Wijnands E,
Goossens P, Blankesteijn WM, Unger T, Prickaerts J, et al. Pharmacological
depletion of microglia and perivascular macrophages prevents Vascular
Cognitive Impairment in Ang II-induced hypertension. Theranostics.
2020;10:9512–9527. doi: 10.7150/thno.44394
114. Carnevale D, Mascio G, Ajmone-Cat MA, D’Andrea I, Cifelli G,
Madonna M, Cocozza G, Frati A, Carullo P, Carnevale L, et al. Role
of neuroinflammation in hypertension-induced brain amyloid pathol-
ogy. Neurobiol Aging. 2012;33:205.e19–205.e29. doi: 10.1016/j.
neurobiolaging.2010.08.013
115. Shen XZ, Li Y, Li L, Shah KH, Bernstein KE, Lyden P, Shi P. Microglia
participate in neurogenic regulation of hypertension. Hypertension.
2015;66:309–316. doi: 10.1161/HYPERTENSIONAHA.115.05333
116. Low A, Mak E, Malpetti M, Passamonti L, Nicastro N, Stefaniak JD, et
al. In vivo neuroinflammation and cerebral small vessel disease in mild
 Santisteban et al
cognitive impairment and alzheimer’s disease. J Neurol Neurosurg Psychiatry.
2020;92:45–52. doi: 10.1136/jnnp-2020-323894
117. Kierdorf K, Masuda T, Jordão MJC, Prinz M. Macrophages at CNS inter-
faces: ontogeny and function in health and disease. Nat Rev Neurosci.
2019;20:547–562. doi: 10.1038/s41583-019-0201-x
118. Murray EC, Nosalski R, MacRitchie N, Tomaszewski M, Maffia P,
Harrison DG, Guzik TJ. Therapeutic targeting of inflammation in hyperten-
sion: from novel mechanisms to translational perspective. Cardiovasc Res.
2021;117:2589–2609. doi: 10.1093/cvr/cvab330
119. Faraco G, Park L, Zhou P, Luo W, Paul SM, Anrather J, Iadecola C.
Hypertension enhances Aβ-induced neurovascular dysfunction, promotes
β-secretase activity, and leads to amyloidogenic processing of APP. J
Cereb Blood Flow Metab. 2016;36:241–252. doi: 10.1038/jcbfm.2015.79
120. Díaz-Ruiz C, Wang J, Ksiezak-Reding H, Ho L, Qian X, Humala N, Thomas S,
Martínez-Martín P, Pasinetti GM. Role of hypertension in aggravating abeta
neuropathology of ad type and tau-mediated motor impairment. Cardiovasc
Psychiatry Neurol. 2009;2009:107286. doi: 10.1155/2009/107286
121. Cao C, Hasegawa Y, Hayashi K, Takemoto Y, Kim-Mitsuyama S. Chronic
angiotensin 1-7 infusion prevents angiotensin-ii-induced cognitive dys-
function and skeletal muscle injury in a mouse model of alzheimer’s dis-
ease. J Alzheimers Dis. 2019;69:297–309. doi: 10.3233/JAD-181000
122. Nyúl-Tóth Á, Tarantini S, Kiss T, Toth P, Galvan V, Tarantini A,
Yabluchanskiy A, Csiszar A, Ungvari Z. Increases in hypertension-induced
cerebral microhemorrhages exacerbate gait dysfunction in a mouse
model of Alzheimer’s disease. Geroscience. 2020;42:1685–1698. doi:
10.1007/s11357-020-00256-3
123. Cifuentes D, Poittevin M, Dere E, Broquères-You D, Bonnin P,
Benessiano J, Pocard M, Mariani J, Kubis N, Merkulova-Rainon T, et al.
Hypertension accelerates the progression of Alzheimer-like pathology
in a mouse model of the disease. Hypertension. 2015;65:218–224. doi:
10.1161/HYPERTENSIONAHA.114.04139
124. Kruyer A, Soplop N, Strickland S, Norris EH. Chronic hyperten-
sion leads to neurodegeneration in the tgswdi mouse model of al-
zheimer’s disease. Hypertension. 2015;66:175–182. doi: 10.1161/
HYPERTENSIONAHA.115.05524
125. Bueche CZ, Hawkes C, Garz C, Vielhaber S, Attems J, Knight RT,
Reymann K, Heinze HJ, Carare RO, Schreiber S. Hypertension drives
parenchymal β-amyloid accumulation in the brain parenchyma. Ann Clin
Downloaded from http://ahajournals.org by ramosmaryesther@gmail.com on October 13, 2023
Transl Neurol. 2014;1:124–129. doi: 10.1002/acn3.27
126. Carnevale D, Mascio G, D’Andrea I, Fardella V, Bell RD,
Branchi I, Pallante F, Zlokovic B, Yan SS, Lembo G. Hypertension in-
duces brain β-amyloid accumulation, cognitive impairment, and memory
deterioration through activation of receptor for advanced glycation end
products in brain vasculature. Hypertension. 2012;60:188–197. doi:
10.1161/HYPERTENSIONAHA.112.195511
127. Gentile MT, Poulet R, Di Pardo A, Cifelli G, Maffei A, Vecchione C,
Passarelli F, Landolfi A, Carullo P, Lembo G. Beta-amyloid deposition in
brain is enhanced in mouse models of arterial hypertension. Neurobiol
Aging. 2009;30:222–228. doi: 10.1016/j.neurobiolaging.2007.06.005
128. Liu J, Liu S, Matsumoto Y, Murakami S, Sugakawa Y, Kami A,
Tanabe C, Maeda T, Michikawa M, Komano H, et al. Angiotensin type
1a receptor deficiency decreases amyloid β-protein generation and
ameliorates brain amyloid pathology. Sci Rep. 2015;5:12059. doi:
10.1038/srep12059
129. Wang J, Ho L, Chen L, Zhao Z, Zhao W, Qian X, Humala N, Seror I,
Bartholomew S, Rosendorff C, et al. Valsartan lowers brain beta-amyloid
protein levels and improves spatial learning in a mouse model of Alzheimer
disease. J Clin Invest. 2007;117:3393–3402. doi: 10.1172/JCI31547
130. Kurata T, Lukic V, Kozuki M, Wada D, Miyazaki K, Morimoto N,
Ohta Y, Deguchi K, Ikeda Y, Kamiya T, et al. Telmisartan reduces progres-
sive accumulation of cellular amyloid beta and phosphorylated tau with
inflammatory responses in aged spontaneously hypertensive stroke
resistant rat. J Stroke Cerebrovasc Dis. 2014;23:2580–2590. doi:
10.1016/j.jstrokecerebrovasdis.2014.05.023
131. Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris
JC, Yarasheski KE, Bateman RJ. Decreased clearance of CNS beta-
amyloid in Alzheimer’s disease. Science. 2010;330:1774. doi: 10.1126/
science.1197623
132. van Veluw SJ, Hou SS, Calvo-Rodriguez M, Arbel-Ornath M, Snyder AC,
Frosch MP, Greenberg SM, Bacskai BJ. Vasomotion as a driving force for
paravascular clearance in the awake mouse brain. Neuron. 2020;105:549–
561.e5. doi: 10.1016/j.neuron.2019.10.033
133. Rajna Z, Mattila H, Huotari N, Tuovinen T, Krüger J, Holst SC,
Korhonen V, Remes AM, Seppänen T, Hennig J, et al. Cardiovascular
Hypertension. 2023;80:22–34. DOI: 10.1161/HYPERTENSIONAHA.122.18085
Hypertension and Dementia
brain impulses in Alzheimer’s disease. Brain. 2021;144:2214–2226. doi:
10.1093/brain/awab144
134. Deane R, Wu Z, Zlokovic BV. RAGE (yin) versus LRP (yang) balance regu-
lates alzheimer amyloid beta-peptide clearance through transport across
the blood-brain barrier. Stroke. 2004;35(11 Suppl 1):2628–2631. doi:
Review
10.1161/01.STR.0000143452.85382.d1
135. Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E,
Welch D, Manness L, Lin C, Yu J, et al. RAGE mediates amyloid-beta pep-
tide transport across the blood-brain barrier and accumulation in brain. Nat
Med. 2003;9:907–913. doi: 10.1038/nm890
136. Fang F, Yu Q, Arancio O, Chen D, Gore SS, Yan SS, Yan SF. RAGE mediates
Aβ accumulation in a mouse model of Alzheimer’s disease via modulation
of β- and γ-secretase activity. Hum Mol Genet. 2018;27:1002–1014. doi:
10.1093/hmg/ddy017
137. Kook SY, Hong HS, Moon M, Ha CM, Chang S, Mook-Jung I. Aβ1₋42-
RAGE interaction disrupts tight junctions of the blood-brain bar-
rier via Ca²⁺-calcineurin signaling. J Neurosci. 2012;32:8845–8854. doi:
10.1523/JNEUROSCI.6102-11.2012
138. Chen J, Mooldijk SS, Licher S, Waqas K, Ikram MK, Uitterlinden AG,
Zillikens MC, Ikram MA. Assessment of advanced glycation end products and
receptors and the risk of dementia. JAMA Netw Open. 2021;4:e2033012.
doi: 10.1001/jamanetworkopen.2020.33012
139. Petrovitch H, White LR, Izmirilian G, Ross GW, Havlik RJ, Markesbery W,
Nelson J, Davis DG, Hardman J, Foley DJ, et al. Midlife blood pressure
and neuritic plaques, neurofibrillary tangles, and brain weight at death:
the HAAS. Honolulu-Asia aging Study. Neurobiol Aging. 2000;21:57–62.
doi: 10.1016/s0197-4580(00)00106-8
140. Lane CA, Barnes J, Nicholas JM, Sudre CH, Cash DM, Parker TD,
Malone IB, Lu K, James SN, Keshavan A, et al. Associations between
blood pressure across adulthood and late-life brain structure and pathol-
ogy in the neuroscience substudy of the 1946 British birth cohort (Insight
46): an epidemiological study. Lancet Neurol. 2019;18:942–952. doi:
10.1016/S1474-4422(19)30228-5
141. Smith EE, Muzikansky A, McCreary CR, Batool S, Viswanathan A,
Dickerson BC, Johnson K, Greenberg SM, Blacker D. Impaired memory is
more closely associated with brain beta-amyloid than leukoaraiosis in hyper-
tensive patients with cognitive symptoms. PLoS One. 2018;13:e0191345.
doi: 10.1371/journal.pone.0191345
142. Guo T, Landau SM, Jagust WJ; Alzheimer’s Disease Neuroimaging
Initiative. Age, vascular disease, and Alzheimer’s disease pathologies in
amyloid negative elderly adults. Alzheimers Res Ther. 2021;13:174. doi:
10.1186/s13195-021-00913-5
143. Nation DA, Edmonds EC, Bangen KJ, Delano-Wood L, Scanlon BK,
Han SD, Edland SD, Salmon DP, Galasko DR, Bondi MW; Alzheimer’s
Disease Neuroimaging Initiative Investigators. Pulse pressure in relation
to tau-mediated neurodegeneration, cerebral amyloidosis, and progres-
sion to dementia in very old adults. JAMA Neurol. 2015;72:546–553. doi:
10.1001/jamaneurol.2014.4477
144. Sible IJ, Nation DA; Alzheimer’s Disease Neuroimaging Initiative. Visit-to-
Visit Blood Pressure Variability and CSF Alzheimer Disease Biomarkers
in Cognitively Unimpaired and Mildly Impaired Older Adults. Neurology.
2022;98:e2446–e2453. doi: 10.1212/WNL.0000000000200302
145. Cooper LL, O’Donnell A, Beiser AS, Thibault EG, Sanchez JS,
Benjamin EJ, Hamburg NM, Vasan RS, Larson MG, Johnson KA, et
al. Association of aortic stiffness and pressure pulsatility with global
amyloid-β and regional tau burden among framingham heart study
participants without dementia. JAMA Neurol. 2022;79:710–719. doi:
10.1001/jamaneurol.2022.1261
146. Moonga I, Niccolini F, Wilson H, Pagano G, Politis M; Alzheimer’s Disease
Neuroimaging Initiative. Hypertension is associated with worse cognitive
function and hippocampal hypometabolism in Alzheimer’s disease. Eur J
Neurol. 2017;24:1173–1182. doi: 10.1111/ene.13374
147. Pajewski NM, Elahi FM, Tamura MK, Hinman JD, Nasrallah IM, Ix JH,
Miller LM, Launer LJ, Wright CB, Supiano MA, et al. Plasma amyloid beta,
neurofilament light chain, and total tau in the Systolic Blood Pressure
Intervention Trial (SPRINT). Alzheimers Dement. 2022;18:1472–1483. doi:
10.1002/alz.12496
148. Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small
vessel disease: insights from neuroimaging. Lancet Neurol. 2013;12:483–
497. doi: 10.1016/S1474-4422(13)70060-7
149. Nam KW, Kwon HM, Jeong HY, Park JH, Kwon H, Jeong SM. Cerebral small
vessel disease and stage 1 hypertension defined by the 2017 American
College of Cardiology/American Heart Association Guidelines. Hypertension.
2019;73:1210–1216. doi: 10.1161/HYPERTENSIONAHA.119.12830
January 2023   33
 Santisteban et al
150. Carnevale L, D’Angelosante V, Landolfi A, Grillea G, Selvetella G, Storto M,
Lembo G, Carnevale D. Brain MRI fiber-tracking reveals white matter alter-
ations in hypertensive patients without damage at conventional neuroim-
aging. Cardiovasc Res. 2018;114:1536–1546. doi: 10.1093/cvr/cvy104
151. Maillard P, Seshadri S, Beiser A, Himali JJ, Au R, Fletcher E,
Review
Carmichael O, Wolf PA, DeCarli C. Effects of systolic blood pressure on
white-matter integrity in young adults in the Framingham Heart Study:
a cross-sectional study. Lancet Neurol. 2012;11:1039–1047. doi:
10.1016/S1474-4422(12)70241-7
152. Carnevale L, Maffei A, Landolfi A, Grillea G, Carnevale D, Lembo G. Brain
functional magnetic resonance imaging highlights altered connections
and functional networks in patients with hypertension. Hypertension.
2020;76:1480–1490. doi: 10.1161/HYPERTENSIONAHA.120.15296
153. Jiménez-Balado J, Riba-Llena I, Abril O, Garde E, Penalba A, Ostos E,
Maisterra O, Montaner J, Noviembre M, Mundet X, et al. Cognitive
impact of cerebral small vessel disease changes in patients with
hypertension. Hypertension. 2019;73:342–349. doi: 10.1161/
HYPERTENSIONAHA.118.12090
154. Gons RA, de Laat KF, van Norden AG, van Oudheusden LJ, van Uden IW,
Norris DG, Zwiers MP, de Leeuw FE. Hypertension and cerebral diffusion
tensor imaging in small vessel disease. Stroke. 2010;41:2801–2806. doi:
10.1161/STROKEAHA.110.597237
155. Markus HS, Egle M, Croall ID, Sari H, Khan U, Hassan A,
Harkness K, MacKinnon A, O’Brien JT, Morris RG, et al; PRESERVE Study
Team. PRESERVE: randomized trial of intensive versus standard blood
pressure control in small vessel disease. Stroke. 2021;52:2484–2493.
doi: 10.1161/STROKEAHA.120.032054
156. Shen J, Tozer DJ, Markus HS, Tay J. Network efficiency mediates the re-
lationship between vascular burden and cognitive impairment: a diffusion
tensor imaging study in uk biobank. Stroke. 2020;51:1682–1689. doi:
10.1161/STROKEAHA.119.028587
157. Chagnot A, Barnes SR, Montagne A. Magnetic resonance imaging of
blood-brain barrier permeability in dementia. Neuroscience. 2021;474:14–
29. doi: 10.1016/j.neuroscience.2021.08.003
158. van Dalen JW, Mutsaerts HJ, Petr J, Caan MW, van Charante EPM,
MacIntosh BJ, van Gool WA, Nederveen AJ, Richard E. Longitudinal
relation between blood pressure, antihypertensive use and cerebral
blood flow, using arterial spin labelling MRI. J Cereb Blood Flow Metab.
Downloaded from http://ahajournals.org by ramosmaryesther@gmail.com on October 13, 2023
2021;41:1756–1766. doi: 10.1177/0271678X20966975
159. Dai W, Lopez OL, Carmichael OT, Becker JT, Kuller LH, Gach HM. Abnormal
regional cerebral blood flow in cognitively normal elderly subjects with hyper-
tension. Stroke. 2008;39:349–354. doi: 10.1161/STROKEAHA.107.495457
160. Deverdun J, Akbaraly TN, Charroud C, Abdennour M, Brickman AM,
Chemouny S, Steffener J, Portet F, Bonafe A, Stern Y, et al. Mean arterial
pressure change associated with cerebral blood flow in healthy older adults.
Neurobiol Aging. 2016;46:49–57. doi: 10.1016/j.neurobiolaging.2016.05.012
161. Waldstein SR, Lefkowitz DM, Siegel EL, Rosenberger WF, Spencer RJ,
Tankard CF, Manukyan Z, Gerber EJ, Katzel L. Reduced cerebral blood
flow in older men with higher levels of blood pressure. J Hypertens.
2010;28:993–998. doi: 10.1097/hjh.0b013e328335c34f
162. Beason-Held LL, Moghekar A, Zonderman AB, Kraut MA, Resnick SM.
Longitudinal changes in cerebral blood flow in the older hypertensive brain.
Stroke. 2007;38:1766–1773. doi: 10.1161/STROKEAHA.106.477109
34   January 2023 Hypertension. 2023;80:22–34. DOI: 10.1161/HYPERTENSIONAHA.122.18085
Hypertension and Dementia
163. Rodrigues JCL, Strelko G, Warnert EAH, Burchell AE, Neumann
S, Ratcliffe LEK, Harris AD, Chant B, Bowles R, Nightingale AK, et al.
Retrograde blood flow in the internal jugular veins of humans with hyper-
tension may have implications for cerebral arterial blood flow. Eur Radiol.
2020;30:3890–3899. doi: 10.1007/s00330-020-06752-6
164. Wilcock D, Jicha G, Blacker D, Albert MS, D’Orazio LM, Elahi FM,
Fornage M, Hinman JD, Knoefel J, Kramer J, et al; MarkVCID
Consortium. MarkVCID cerebral small vessel consortium: I. Enrollment,
clinical, fluid protocols. Alzheimers Dement. 2021;17:704–715. doi:
10.1002/alz.12215
165. Lu H, Kashani AH, Arfanakis K, Caprihan A, DeCarli C, Gold BT, Li Y,
Maillard P, Satizabal CL, Stables L, et al; MarkVCID Consortium. MarkVCID
cerebral small vessel consortium: II. Neuroimaging protocols. Alzheimers
Dement. 2021;17:716–725. doi: 10.1002/alz.12216
166. Iturria-Medina Y, Sotero RC, Toussaint PJ, Mateos-Pérez JM, Evans AC;
Alzheimer’s Disease Neuroimaging Initiative. Early role of vascu-
lar dysregulation on late-onset Alzheimer’s disease based on mul-
tifactorial data-driven analysis. Nat Commun. 2016;7:11934. doi:
10.1038/ncomms11934
167. Levine DA, Springer MV, Brodtmann A. Blood pressure and vascu-
lar cognitive impairment. Stroke. 2022;53:1104–1113. doi: 10.1161/
STROKEAHA.121.036140
168. van Dalen JW, Marcum ZA, Gray SL, Barthold D, Moll van Charante EP,
van Gool WA, Crane PK, Larson EB, Richard E. Association of an-
giotensin ii-stimulating antihypertensive use and dementia risk: post
hoc analysis of the PreDIVA trial. Neurology. 2021;96:e67–e80. doi:
10.1212/WNL.0000000000010996
169. Marcum ZA, Cohen JB, Zhang C, Derington CG, Greene TH, Ghazi L,
Herrick JS, King JB, Cheung AK, Bryan N, et al; Systolic Blood Pressure
Intervention Trial (SPRINT) Research Group. Association of antihyper-
tensives that stimulate vs inhibit types 2 and 4 angiotensin ii receptors
with cognitive impairment. JAMA Netw Open. 2022;5:e2145319. doi:
10.1001/jamanetworkopen.2021.45319
170. Ouk M, Wu CY, Rabin JS, Edwards JD, Ramirez J, Masellis M,
Swartz RH, Herrmann N, Lanctôt KL, Black SE, et al; Alzheimer’s Disease
Neuroimaging Initiative. Associations between brain amyloid accumu-
lation and the use of angiotensin-converting enzyme inhibitors versus
angiotensin receptor blockers. Neurobiol Aging. 2021;100:22–31. doi:
10.1016/j.neurobiolaging.2020.12.011
171. Glodzik L, Rusinek H, Kamer A, Pirraglia E, Tsui W, Mosconi L, Li Y,
McHugh P, Murray J, Williams S, et al. Effects of vascular risk fac-
tors, statins, and antihypertensive drugs on PiB deposition in cogni-
tively normal subjects. Alzheimers Dement (Amst). 2016;2:95–104. doi:
10.1016/j.dadm.2016.02.007
172. Scotti L, Bassi L, Soranna D, Verde F, Silani V, Torsello A, Parati G,
Zambon A. Association between renin-angiotensin-aldosterone sys-
tem inhibitors and risk of dementia: A meta-analysis. Pharmacol Res.
2021;166:105515. doi: 10.1016/j.phrs.2021.105515
173. Ho JK, Moriarty F, Manly JJ, Larson EB, Evans DA, Rajan KB, Hudak
EM, Hassan L, Liu E, Sato N, et al. Blood-brain barrier crossing re-
nin-angiotensin drugs and cognition in the elderly: a meta-analysis.
Hypertension. 2021;78:629–643. doi: 10.1161/HYPERTENSIONAHA.
121.17049