Hypertension

REVIEW

Cerebral Small Vessel Disease, Hypertension, and

Vascular Contributions to Cognitive Impairment
and Dementia
Atticus H. Hainsworth , Hugh S. Markus , Julie A. Schneider

ABSTRACT: Hypertension-associated cerebral small vessel disease is a common finding in older people. Strongly associated
with age and hypertension, small vessel disease is found at autopsy in over 50% of people aged ≥65 years, with a spectrum
of clinical manifestations. It is the main cause of lacunar stroke and a major source of vascular contributions to cognitive
impairment and dementia. The brain areas affected are subcortical and periventricular white matter and deep gray nuclei.
Neuropathological sequelae are diffuse white matter lesions (seen as white matter hyperintensities on T2-weighted magnetic
resonance imaging), small ischemic foci (lacunes or microinfarcts), and less commonly, subcortical microhemorrhages. The
most common form of cerebral small vessel disease is concentric, fibrotic thickening of small penetrating arteries (up to
300 microns outer diameter) termed arteriolosclerosis. Less common forms are small artery atheroma and lipohyalinosis
(the lesions described by C. Miller Fisher adjacent to lacunes). Other microvascular lesions that are not reviewed here
include cerebral amyloid angiopathy and venous collagenosis. Here, we review the epidemiology, neuropathology, clinical
management, genetics, preclinical models, and pathogenesis of hypertensive small vessel disease. Knowledge gaps
include initiating factors, molecular pathogenesis, relationships between arterial pathology and tissue damage, possible
reversibility, pharmacological targets, and molecular biomarkers. Progress is anticipated from multicell transcriptomic and
proteomic profiling, novel experimental models and further target-finding and interventional clinical studies. (Hypertension.
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2024;81:75–86. DOI: 10.1161/HYPERTENSIONAHA.123.19943.) •

Key Words: arteries ◼ blood pressure ◼ dementia ◼ genetics ◼ neuropathology ◼ stroke ◼ white matter

C
erebral small vessel disease (SVD) is the term used although over 50 genetic loci associated with the risk of
to describe a brain microvascular disease or syn- sporadic SVD have emerged from genome-wide asso-
drome that is common in older people and, depend- ciation studies in recent years.13–15 Heritable, monogenic
ing on the definition, occurs in ≈50% of people aged over forms of SVD include cerebral autosomal dominant arte-
65 years.1–4 SVD is considered to be the primary cause riopathy with subcortical infarcts and leukoencephalopa-
of lacunar strokes.5–8 It is also a major factor in vascu- thy (CADASIL; due to mutations in NOTCH3), CARASIL
lar contributions to cognitive impairment and dementia (HTRA1), and collagen-IV (COL4A1/COL4A2).14 Rela-
(VCID).8–11 tive to the prevalent, sporadic SVD, these are rare, less
In clinical practice, SVD is diagnosed on the basis of strongly associated with hypertension and detected clini-
hallmark radiological features seen on magnetic reso- cally in younger people, usually with more severe disease.
nance imaging (MRI, eg, Figure 1)8,12: (1) subcortical This review covers the sporadic forms of SVD that are
small, focal infarcts, (2) diffuse white matter lesions, seen associated with hypertension. In practice, this means 3
as white matter hyperintensities (WMH) on T2-weighted well-defined neuropathological lesions in cerebral small
images, (3) less commonly, microhemorrhages in subcor- arteries: arteriolosclerosis, lipohyalinosis, and microath-
tical areas. Most (>95%) SVD is nonheritable, or sporadic, eroma (eg, Figure 2). Other forms of brain microvascular

This article is part of the Dementia Review Series.

Correspondence to: Atticus H. Hainsworth, Molecular and Clinical Sciences Research Institute, St George’s University of London, Cranmer Terr, London SW17 0RE,
United Kingdom. Email ahainsworth@sgul.ac.uk
For Sources of Funding and Disclosures, see page 83.
© 2023 The Authors. Hypertension is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the
terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
Hypertension is available at www.ahajournals.org/journal/hyp

Hypertension. 2024;81:75–86. DOI: 10.1161/HYPERTENSIONAHA.123.19943 January 2024   75

 Hainsworth et al Hypertensive Small Vessel Disease

Nonstandard Abbreviations and Acronyms

AD Alzheimer disease
Review

BBB blood-brain barrier

CAA cerebral amyloid angiopathy
CADASIL 
cerebral autosomal dominant arteri-
opathy with subcortical infarcts and
leukoencephalopathy
MRI magnetic resonance imaging
ROSMAP Religious Orders Study and Rush
Memory and Aging Project
SVD small vessel disease
VCID  vascular contributions to cognitive
impairment and dementia
WMH white matter hyperintensities

disease have been reviewed elsewhere.8,16,17 Here, we

will summarize the epidemiology, neuropathology, clini-
cal management, genetics, and preclinical models of
sporadic hypertensive SVD, ending with an overview of
theories about pathogenesis.

NOMENCLATURE
The nomenclature of SVD is confusing, often inexact
and varies across subspecialties. SVD is used to refer
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to a myriad of small vessel abnormalities with or without

Figure 1. Magnetic resonance imaging (MRI) evidence of
downstream tissue injuries.4,8,18 In diagnostic neuropa-
small vessel disease (SVD).
thology, SVD often refers to arteriolosclerosis and asso- A, Fluid-attenuated inversion recovery (FLAIR) MRI scans of an older
ciated tissue lesions. In clinical practice, usage is usually patient with minimal white matter hyperintensities. B, FLAIR MRI
limited to the tissue injury aspect, which can be visualized scans from equivalent areas of another older patient with extensive
radiologically and is presumed due to brain microvascu- white matter hyperintensities and a cavitated lacune (arrow). C,
Susceptibility-weighted images from 2 different patients with SVD,
lar disease (which can only be visualized under a micro-
showing multiple microbleeds (eg, marked with an arrow).
scope). More recently, enlarged perivascular spaces
and microbleeds are sometimes included in the rubric.
For the purposes of this review, the term SVD refers to with certainty. The Religious Orders Study and Rush
hypertension-associated sporadic forms of brain micro- Memory and Aging Project (ROSMAP) are large clinico-
vascular disease unless stated otherwise. pathologic studies of older people enrolled without known
dementia, with annual clinical assessments and agree-
ment to brain donation at death (Table 1). In the ROSMAP
METHODS studies, with over 1700 donated brains, the severity of
This review is based on the authors’ knowledge, with exper- arteriolosclerosis is determined at the level of the ante-
tise related to SVD in cellular and in vivo neuroscience (A.H.H.), rior basal ganglia. With an average age of death at about
clinical management, imaging and genetics (H.S.M.), neuropa- 90 years, SVD is highly prevalent, with about one-third of
thology, and epidemiology (J.A.S.). References are derived from the cohort showing moderate-to-severe arteriolosclero-
the authors’ archives and PubMed searches. sis.3,11,29 Prevalence of hypertension in ROSMAP is 67%
to 69% with some variation as the cohort grows.3 ROS-
MAP participants are predominantly White (90%–95%).
EPIDEMIOLOGY OF SVD AND VCID
ROSMAP Cohorts SVD Epidemiology
Because SVD nomenclature varies across disciplines and In the ROSMAP cohort, arteriolosclerosis is most sig-
the underlying vessel pathologies are only visualized on nificantly associated with elevated blood pressure and
brain tissue, the prevalence of SVD is difficult to estimate age.30 Arteriolosclerosis is more common in women, but

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 Hainsworth et al Hypertensive Small Vessel Disease

While definitions of SVD pathology vary, similar patterns

of prevalence have been seen in other large cohorts1,27
(Table 1).

Review
VCID Epidemiology
Blood pressure is an established risk factor for dementia,
with risk accruing in midlife not just in old age. Hyperten-
sion contributes to cognitive impairment through path-
ways independent of symptomatic stroke. This extensive
topic is well covered in recent reviews.34,35
Arteriolosclerosis is consistently related to dementia
in older people. Although strongly associated with hyper-
tension, arteriolosclerosis is not exclusively seen in hyper-
tension and is also seen in aging and diabetes.36 One of
the pathways by which arteriolosclerosis may contribute
to dementia is via small microinfarcts in the aging brain.37
In a pathway analysis of the neuropathological features
that mediate the association of age with dementia in
the ROSMAP cohort, about 30% of the association was
related to vascular pathways.38
Most studies have shown that the contribution of SVD
to cognitive impairment is additive, rather than synergis-
tic, with that of AD pathology (amyloid and tangles).26,39
Figure 2. Small arterial vessels in human brain: examples of
Even after accounting for infarcts, arteriolosclerosis
hypertensive small vessel disease.
A, A normal, healthy penetrating artery with thin wall and multiple has an added contribution to dementia and to multiple
myocyte nuclei (eg, marked with arrow). B, Arteriolosclerosis, domains of cognitive impairment.40
with approximately concentric wall thickening, with acellular
hyaline material (asterisk). C, Lipohyalinosis, with asymmetrical
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wall thickening around the lumen (*) and mural lipid-containing

macrophages (arrow). D, Fibrinoid necrosis in a larger penetrating
NEUROPATHOLOGY OF SVD
vessel. The wall is asymmetrically thickened with eosinophilic Vessel Pathology
fibrinoid material (*). E, Microatheroma in a penetrating vessel.
Asymmetrical thickening and cholesterol clefts are seen as open The 3 main forms of hypertensive SVD are compared in
slits (arrow) in the intimal layer. Internal lamina is visible (arrowhead) Table 2 (see examples in Figure 2). In the landmark serial
delimiting the intima. F, For comparison, large vessel atheroma in a sectioning studies of Fisher5,45–47, 2 vascular lesions were
leptomeningeal artery, with internal lamina clearly visible (arrowhead). identified upstream from lacunes: lipohyalinosis and ath-
Hematoxylin and eosin staining. Scale bars: A and B, 20 microns,
C through E, 50 microns, F, 1000 microns. C and D were kindly
eroma in small penetrating arteries (microatheroma).
supplied by Professor Colin Smith, University of Edinburgh. These 2 are now rarely seen in diagnostic neuropathol-
ogy or in brain autopsy series. This may be due to the
widespread use of blood pressure medications,36 or the
this is difficult to dissociate from longevity in women.31
fact that we do not deliberately sample them. Still com-
Severity of arteriolosclerosis has been noted to be more
mon is a third lesion, seen in the smallest penetrating
severe in African Americans.32 Microvascular disease is
arteries (up to 0.3 mm outer diameter), termed arteriolar
common in people with Alzheimer disease (AD) pathol-
sclerosis or arteriolosclerosis (small artery stiffening).6,7,36
ogy, and the association with AD and other neurodegen-
It appears likely that Fisher and some earlier neuropa-
erative pathologies may be complex. Arteriolosclerosis
thologists, who did not have access to MRI, immunohisto-
is related to Alzheimer type dementia but this may be
chemistry, or genetic data, considered arteriolosclerosis a
partly through the associated and added tissue injury in
part of normal brain aging.41,47,49 More recent brain series
the parenchyma.33
have associated arteriolosclerosis with hypertension,36,43
Many people with arteriolosclerosis also have large
WMH load,44,50 incidence of lacunar stroke,43 VCID and
vessel atherosclerosis, which is also common in older peo-
dementia.9–11
ple. About 30% of older people have moderate-to-severe
large vessel atherosclerosis.11 Similar to arteriolosclerosis, Lipohyalinosis
both age and blood pressure are strong risk factors for ath- Lipohyalinosis was identified by Fisher5,46 as the causal
erosclerosis, and downstream consequences can include lesion upstream from 40 of 50 lacunes, in brains from
various tissue injuries, including white matter changes and 4 people with severe hypertension. Lipohyalinosis
infarct (the latter often larger than in arteriolosclerosis). describes small arteries whose walls exhibited loss

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 Hainsworth et al Hypertensive Small Vessel Disease

Table 1. Prevalence of SVD and Associations With VCID in Large Autopsy Series (N=500 or More Brains)

Study acronym No. of brains, n (location) Prevalence of SVD Associations with VCID
ROSMAP 1767 (the United States) Arteriolosclerosis present in 33.5% of cases11; Arteriolosclerosis OR of AD dementia: 1.20. For each
Review

microinfarct in 29.4%11 (compare large vessel categorical increase in severity (absent, mild,
atherosclerosis in 33.1%,11 gross infarcts in 28% of moderate, severe19 ; compare AD pathology OR:
cases19) 4.40); microinfarct RR for dementia: 1.8 for dementia
(compare AD pathology RR: 4.0)20
Hisayama 1266 (Japan) Small infarcts found in 27.9% of cases21; fibrinoid 135/389 (35%) of dementia cases were vascular
necrosis: present in 17% of cases in 1971; 6% of dementia (unclear how defined)22
cases in 198121
BB-BABS 1089 (Brazil) Hyaline arteriolosclerosis present in 10.7% of people Hyaline arteriolosclerosis OR for cognitive impairment:
aged <80 years, 20.9% of those aged ≥80 years23 2.36 (in people aged <80 years), 1.86 (age ≥80
years)23
ACTS 863 (the United States) Cerebral microinfarcts present in 15.1% of cases24 Microinfarct RR for dementia: 4.80 (compare tau
pathology [Braak stage V–VI], RR: 5.89)25
HAAS 852 (males only; Hawaii, Lacunes and microinfarcts present in 18.0% of Microinfarct OR: 2.58 for cognitive impairment27
the United States) cases26
MRC-CFAS 510 (United Kingdom) Lacune(s), SVD and deep white matter lesions SVD RR for dementia: 2.69 at age 75 years (compare
present in 37% of cases28 hippocampal tangles RR: 8.61)1
ACTS indicates Adult Changes in Thought Study; AD, Alzheimer disease; BB-BABS, Brain Biobank of the Brazilian Aging Brain Study; HAAS, Honolulu Asia Aging
Study; MRC-CFAS, Medical Research Council Cognitive Function and Ageing Study; OR, odds ratio; ROSMAP, Religious Orders Study and Rush Memory and Aging
Project; RR, risk ratio; SVD, small vessel disease; and VCID, vascular contributions to cognitive impairment and dementia.

of myocytes, fibrosis, and fatty macrophages with lipid been suggested to transition into end-stage fibrosis or
deposits5 (Figure 2C). The lesion is eccentric, extend- arteriolosclerosis.
ing along a short segment of the vessel wall (hence the
term segmental disorganization).5,47 The wall contains an Microatheroma
eosinophilic deposit termed fibrinoid.5,51 Fibrinoid necro- Microatheroma refers to atherosclerosis in larger small
sis in the vessel wall (Figure 2D) is a feature of lipohyali- arteries (approximate range, 0.3–0.8 mm outer diameter)
nosis, found most commonly in uncontrolled or malignant analogous to that frequently detected in large arteries
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hypertension. Fibrinoid necrosis may be a transitory sta- (such as the carotids or middle cerebral artery) of older
tus for the vessel. The weakening of the wall may result people with hypertension. It features local, eccentric
in a Charcot-Bouchard aneurysm, with or without hemor- lipid deposits in the vessel wall, with myocyte loss and
rhage. Although originally thought to be specific to hyper- fatty macrophages (foam cells) in the wall5,6 (Figure 2E).
tension,5 lipohyalinosis is also (uncommonly) seen in the Fibrinoid necrosis is not a feature. Microatheroma in the
brains of people without hypertension.36 Lipohyalinosis is parent vessel at the origin of the perforating artery, or
considered a more acute or severe form of SVD that has in the proximal larger perforator arteries themselves,

Table 2. Comparing Different Neuropathological Forms of Hypertensive SVD

Type of Anatomic Prevalence associated

SVD Vessel type location with hypertension? Pathological features
Arteriolo- Small penetrating arteries, Subcortical, deep Common in older Symmetrical, concentric arterial fibrosis. Myocyte loss, with
sclerosis arterioles (OD: 20–300 WM, periventricular people3,10,41,42; associated endothelia spared. Often hyalinosis in the vessel wall. No mural
microns) WM, deep gray with HTN: yes.10,36,43; associ- lipid6,36,41,44
nuclei ated with lacunar lesions36,43;
associated with VCID9–11
Lipohyali- Small penetrating arteries, Subcortical, deep Rare; associated with HTN: Local, asymmetrical loss of structure in artery wall (segmental
nosis arterioles (OD: 80–300 WM, periventricular yes5; associated with arterial disorganization).5 Mural lipid and eosinophilic
microns) WM, deep gray lacunar lesions5,45,46 material (fibrinoid). Fibrinoid necrosis is a feature.5,6,46,47 A severe
nuclei lesion, now rarely seen. May progress to vessel wall fibrosis as
described in arteriolosclerosis.
Micro Small distributor and Cortical and Prevalence is uncertain; Nonconcentric; loss of myocytes, asymmetrical thinning of
atheroma larger penetrating arteries subcortical associated with HTN: yes; arteriole wall. Dissecting. Myocyte degeneration, macrophage
(OD: 300–800 microns) associated with lacunar infiltration. Abundant mural lipid5,6,46
lesions.5,45,46,48
CAA Lepto-meningeal and pen- Cortical gray mat- Common in older people; Deposition of insoluble amyloid, primarily Aβ40, less Aβ42. Not
etrating arteries. In some ter. Not in associated with HTN: no always concentric. Fibrinoid necrosis an occasional feature.17
cases, also capillaries subcortical WM
CAA is included for comparison. CAA indicates cerebral amyloid angiopathy; HTN, hypertension; SVD, small vessel disease; VCID, vascular contributions to cognitive
impairment and dementia; and WM, white matter.

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 Hainsworth et al Hypertensive Small Vessel Disease

has been associated with lacunar stroke.5,6,46 It is usu- not). Overall, we consider it likely that arteriolosclerosis is
ally associated with larger lacunar stroke, often isolated, a cause of symptomatic SVD, indeed a common cause.
and without prominent WMH.48 Microatheroma has Immunohistochemical studies indicate that the mural
been associated with an atherogenic risk factor profile, fibrosis in arteriolosclerosis is due to deposition of the

Review
in contrast with the predominant role of hypertension in fibrillar collagen types I and III, not the nonfibrillar base-
arteriolosclerosis. ment membrane type IV.44 The basement membrane
Although microatheroma is now a rare finding in diag- components collagen-IVα1/IVα2 are genetically asso-
nostic neuropathology (at least in higher–income countries), ciated with sporadic SVD, their expression is restricted
we cannot assume it is absent. Intracranial atherosclerotic to the subendothelial region, often in multilaminar lay-
stenosis was detected in 45% of a large, older cohort in a ers, and also to an adventitial layer encasing the ves-
recent magnetic resonance angiography imaging study.52 sel44 (Figure 3F). The endothelia of afflicted vessels are
Microatheroma favors arterial branch points, for example, strongly positive for thrombomodulin (Figure 3B) indicat-
at the perpendicular origin of MCA-derived perforators, a ing a highly anticoagulant lumen and ICAM1 (Intercellular
location rarely sampled in a histopathology block. It seems Adhesion Molecule-1) negative.61 This is the antithesis of
reasonable to assume, as Fisher did, that an individual with an activated endothelium and speaks against local vas-
severe large vessel atheroma (Figure 2F) has a high likeli- cular inflammation as a feature of arteriolosclerosis.61
hood of microatheroma. A dedicated histological study to Most neuropathology studies62–64 have found no associa-
assess microatheroma as a risk factor for human stroke, tion of SVD with local blood-brain barrier (BBB) dysfunc-
SVD, and VCID would be valuable. tion. This conflicts with some imaging findings65–68 and
A belief persists that microatheroma is more common in does not exclude a role for BBB changes in early phases
some racial groups, specifically African Americans (see a of the disease process.
classic study by Caplan et al53, and early references therein). In comparison, cerebral amyloid angiopathy (CAA) is
While there is heterogeneous evidence around this concept, not related to hypertension or other traditional vascular
non-white brain archives will allow it to be tested.54 risk factors (Table 2). CAA is associated with age, AD
pathology, and the APOE e4 allele, a well-known risk
Arteriolosclerosis factor for AD. CAA, which frequently accompanies AD-
Arteriolosclerosis is a fibrous, hyaline thickening of small related amyloid plaques, is restricted primarily to cortical
penetrating arteries in subcortical areas (subcortical gray matter, sparing subcortical white matter69 (whereas
and periventricular white matter and deep gray nuclei). lipohyalinosis and arteriolosclerosis are subcortical).
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Hypertension and old age are strong risk factors, with Similarly, CAA is related to microinfarcts and microbleeds
poor glucose control, elevated plasma homocysteine, and in the neocortex (rather than in white matter). CAA is
tobacco smoking also implicated. Links to hyperlipidemia reviewed elsewhere.8,17
are less well evidenced.
In arteriolosclerosis, there is a lack of lipid deposition
in the walls of SVD-positive vessels (in contrast to lipo- Parenchymal Pathology
hyalinosis and microatheroma6,7). Afflicted vessels are up While the pathological features that result from SVD are
to 300 microns outer diameter, characterized by concen- still debated, the following are generally agreed. First,
tric acellular layers of fibrous material6,7 (Figure 2B; Fig- small (<15 mm greatest diameter) ischemic foci or lacu-
ure 3). The endothelial layer remains intact and appears nes (from the Latin lacuna, meaning a hole or pond). Old
paradoxically healthy55 alongside depletion of myocytes lacunes can be seen as a cavity, slit, or scar, fluid-filled
in the vessel wall6,7,56 (Figure 3B and 3C). The degree of in vivo (Figure 1B) encased by a layer of fibrous reac-
wall thickening manifests to varying degrees along the tive astrocytes with scattered remaining macrophages,
length of a vessel.17,57 Luminal narrowing is not a uni- variable microgliosis, and sparse if any lymphocytes (Fig-
versal feature,58 though striking examples are sometimes ure 4D). Second, focal or diffuse white matter changes,
seen (Figure 3D and 3E).57 with pallor and reduced tissue density, suggestive of
No serial sectioning study has been performed to test edema (during acute stages) and some degree of demy-
directly whether arteriolosclerosis is linked to lacune for- elination in chronic, severe lesions (Figure 4A through
mation (or other manifestations of SVD, such as diffuse 4C).18,70,71 These are presumed to correspond to WMH
white matter damage). Based on vessel wall thickening seen on MRI scans50 (Figure 1B). A parenchymal fea-
and fibrosis, some dysfunction in CBF autoregulation is ture that is topologically linked with small penetrating
likely, making downstream hypoperfusion damage bio- arteries is hyperphosphorylated neurofilament-H within
logically plausible.6,59 The severity of arteriolosclerosis axonal bulbs (Figure 4E).72 Other features include sub-
is increased within WMH60 and correlates with number cortical iron deposits, some of which represent micro-
of lacunes.43 In 1997, Lammie et al36 demonstrated that hemorrhages (Figure 1C), but also possibly perivascular
arteriolosclerosis was common in 70 consecutive SVD extravasation, detected in MRI scans of some older peo-
cases (whereas lipohyalinosis and microatheroma were ple with sporadic SVD17 (Figure 4F). In hypertension,

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 Hainsworth et al Hypertensive Small Vessel Disease
Review

Figure 3. Histopathology of arteriolosclerosis.

Small penetrating arteries in subcortical white matter. A, Arteriolosclerosis, with hyaline, fibrotic wall thickening, and depleted, swollen
myocytes. HE stain. B, The endothelial cell layer is preserved, immunolabeled with thrombomodulin (brown, arrow). C, Depletion of myocytes,
immunolabeled with smooth muscle myosin (black, arrow). Light green counterstain. D and E, Collagenous fibrosis (green) in the vessel wall,
Masson trichrome stain. D shows a severely fibrotic vessel (arrow), close to another that exhibits no fibrosis (arrowhead), adjacent to the
cortical gray matter (marked with *). In E, the fibrotic vessel is enlarged. F, Collagen type IV α1/α2 immunolabeling shows duplication of the
intimal basal lamina (brown, arrow), maintained adventitial layer (arrowhead), and absence of type IV collagen in the hyaline fibrotic media.
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Scale bars: 50 (A), 20 (B), 50 (C), 500 (D), 100 (E), and 50 μm (F).

microhemorrhages are usually seen in subcortical gray indicated that this effect was most evident in the oldest-
or white matter. Recent reviews have discussed relation- old and was not driven by any specific drug class.77 In
ships between pathological aspects of different forms of other words, reduced systemic pressure was sufficient
SVD and the characteristic features seen on MRI.17,18,66 to produce cognitive benefit. The small but significant
reduction in WMH progression suggests that this effect
is accompanied by amelioration of SVD.78
CLINICAL MANAGEMENT OF SVD Despite its public health importance, there are few spe-
The most important clinical features of SVD are lacunar cific treatments for SVD.79,80 Most of the clinical trials look-
stroke and vascular cognitive impairment, encompassing ing at secondary prevention of stroke have not adequately
dementia.8,12 We now realize that SVD is also a major subtyped SVD to allow us to know how useful they are in
cause of intracerebral hemorrhage.8 SVD is associated SVD. The one exception is blood pressure, for which clini-
with subcortical microbleeds seen on T2* or susceptibility- cal trial data show that intensive treatment reduces the
weighted MRI scans73 and is a risk factor for subcortical risk of further stroke and probably also the risk of vascular
intracerebral hemorrhage.74 Other clinical presentations cognitive impairment81 and that this strategy appears to
include gait disturbance, apathy and other neurobehav- be safe in patients with severe SVD in whom autoregula-
ioral symptoms, and a non-Levodopa responsive Parkin- tion may be affected.82 Epidemiological evidence suggests
sonian syndrome. Particularly prominent features of the that there is a greater benefit from treating hypertension
cognitive impairment include executive dysfunction and in midlife than in later life, particularly for the prevention
impaired processing speed.75 of dementia.83 Antiplatelet agents are widely used in SVD
although there are limited data on which to base this deci-
sion. A multi-center phase-3 trial demonstrated that aspirin
BP Control, SVD, and VCID alone was preferable to dual antiplatelet therapy with aspi-
Intensive BP lowering as a strategy to reduce risk rin and clopidogrel in long-term secondary prevention.84
of cognitive impairment is supported by several clini- Two major factors underlie our lack of knowledge
cal studies.76,77 Data from over 9000 older Americans about treatments in SVD and VCID.79,80 The first has

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 Hainsworth et al Hypertensive Small Vessel Disease

Review
Figure 4. Parenchymal lesions associated with small vessel disease.
A, Ex vivo magnetic resonance imaging-directed tissue sampling of a frontal cortical block containing white matter hyperintensity (marked
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with *) from the Rush archive. B and C, The block from A, stained with hematoxylin-eosin (B) and Luxol fast blue (C), showing white matter
pallor (*). D, In another case, astrocytes immunolabeled with GFAP (glial fibrillary acidic protein) (brown) around the border of a microinfarct
(*). E, Axonal bulbs (arrow), immunopositive for hyperphosphorylated neurofilament-H (brown), centered around a small penetrating artery. F,
Microhemorrhage (marked with arrow) labeled with Perl’s stain, around a small artery. Scale bars: B and C, 5 mm. D, 500 microns. E, 100
microns. F, 20 microns.

been inadequate knowledge about the underlying caused by NOTCH3 mutations. The second most com-
pathophysiology and potential treatment targets. This mon is CADASIL2 caused by autosomal dominant
situation is improving with genetic studies and other HTRA1 mutations.90 HTRA1 is also the gene underly-
advances.14,79 The second is a lack of adequate subtyp- ing CARASIL (with autosomal recessive inheritance).
ing in clinical trials, to determine whether treatments are Major clinical features of both CADASIL and CADASIL2
efficacious in definite SVD. Recent phase II clinical tri- include migraine with aura, early-onset lacunar stroke,
als have tested existing medications for possible repur- encephalopathy, depression, and early-onset dementia.
posing in people with symptomatic SVD. These include MRI features are similar to those of sporadic SVD but
the PDE5 (phosphodiesterase-5) inhibitor tadalafil85 WMH are often severe at a younger age and frequently
and the combination of cilostazol with a NO donor.86 seen in the anterior temporal poles and the corpus cal-
Sets of criteria for the definition of SVD for clinical tri- losum, which are rarely affected in sporadic SVD. Micro-
als, and for finding targets for intervention, have been bleeds occur in both CADASIL and CADASIL2 but are
published.87,88 Recent guidelines have been developed particularly frequent in the COL4A1/2 monogenic forms
to provide a framework for optimal trial design in SVD, of SVD, which also frequently present with intracerebral
including choice of outcome measures.89 hemorrhage.91
Genetic risk is also important for sporadic SVD, but
here common variants or polymorphisms in multiple
Genetics of SVD genes are thought to each confer a small increase in
In discussing genetic factors in sporadic SVD, it is risk. To date, over 50 independent genetic loci have been
instructive to consider monogenic, familial forms of associated with SVD at the genome-wide significance
SVD. A number of different underlying genes have been level, including loci associated with lacunar stroke13 and
described but by far the most common is CADASIL, with covert, MRI-defined SVD.14,15 The genes identified

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 Hainsworth et al Hypertensive Small Vessel Disease

point to a major role of blood pressure–related pathways, of the whole disease process occurring in humans.94,95
and also mechanisms that seem independent of vascu- Larger species (primates, canines, ovines, swine) have
lar risk factors, particularly ECM (extracellular matrix) the advantages of a large gyrencephalic brain and
structure and function. Future use of high-throughput cerebral blood vessels that more resemble their human
Review

molecular approaches (epigenomics, transcriptomics, counterparts.44,94

proteomics, and metabolomics) will enable integration of
genetic associations with functional data to decipher the
biological roles of genetic risk loci in SVD.14 HYPOTHESES OF SVD PATHOGENESIS
Genetic studies in sporadic SVD are highlighting The mechanism by which SVD vascular pathology leads
novel disease processes and potential therapeutic path- to parenchymal changes remains incompletely defined.
ways. A key target appears to be the ECM and proteins Mechanisms may be heterogeneous and dependent on
of the matrisome,92 defined as the ensemble of 1000+ the risk factor profile (severity of hypertension, diabe-
genes encoding ECM-associated proteins. NOTCH3 and tes), the type of SVD, and its anatomic location.3 Various
HTRA1 mutations seem to cause ECM disruption by pathogenic pathways have been proposed.
converging pathways, while COL4A1/2 mutations result First, an early, simple hypothesis was that, by analogy
in disruption of the collagen-IV matrix essential for ECM with large vessel ischemic stroke, small artery embolic
integrity.92 Increasing evidence suggests monogenic and occlusion produced a correspondingly smaller, lacunar
sporadic SVD share disease mechanisms; common vari- lesion.100 This was not supported by the serial section-
ants in both HTRA1 and COL4A1/2 have been associ- ing of brain tissue performed by Fisher5 who found few
ated with both sporadic lacunar stroke and WMH.13,15 emboli, or by transcranial Doppler imaging in lacunar
The boundaries between sporadic and monogenic patients with stroke where embolic events were rare.101
SVD have been blurred by the finding that typical muta- As small arteries exhibiting SVD have abundant endo-
tions causing monogenic SVD seem to be much more thelial thrombomodulin, the potent physiological anti-
common in the general population than expected from thrombotic protein, local thrombosis leading to occlusion
the prevalence of clinical monogenic SVD.14 For example, appears unlikely.61
while the reported prevalence of CADASIL is about 4 in In a second hypothesis, local BBB dysfunction
10 000 in the United Kingdom, typical cysteine-changing causes SVD vessel pathology, as well as parenchymal
NOTCH3 mutations are seen in 1 in 800 individuals in a changes.36,102 The rationale is that multiple reactive, harm-
large population cohort (UK Biobank).93 A similar situa-
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ful plasma components are allowed access to the CNS,

tion was found for HTRA1 and COL4A1/2 mutations.93 triggering cell damage in the artery wall and diffuse myelin
The clinical significance of these mutations in the gen- and axonal damage in the white matter. Plasma extrava-
eral population remains to be determined but their pres- sation also represents an excess water load, with risk
ence is associated with an increased risk of stroke and of vasogenic edema. In support of this view, the WMH
VCID.93 Why some mutations result in typical monogenic attributed to SVD resembles fluid diffusion patterns. MRI
disease and others are much less penetrant is uncertain, data show enhanced brain accumulation of intravascular
although cardiovascular risk factors and mutation posi- contrast agents in people with SVD, relative to controls,65
tion influence their phenotype,93 and modifier genes have with accumulation especially evident within WMH.65,67,68 By
been hypothesized. contrast, neuropathology studies have not supported this
hypothesis, with extravascular plasma markers showing
little relation to SVD.62–64 The relation of histological mark-
PRECLINICAL MODELS IN SVD AND VCID ers of BBB dysfunction to AD pathology is more robust.103
Experimental animal models relevant to SVD and VCID In a third hypothesis, chronic underperfusion (oligemia)
have been reviewed by ourselves and others.94–96 Sponta- links small artery fibrosis to diffuse white matter damage
neous lesions occur in some rodent models, for example, and ultimately a focal lacunar lesion. In support of this
spontaneously hypertensive stroke-prone rats develop view, regulation of cerebral blood flow—rapidly and pre-
focal infarcts and hemorrhages.97 Spontaneously hyper- cisely autoregulated in healthy brain tissue—is disrupted
tensive stroke-prone rats do not display the vessel pathol- in lacunar stroke.104,105 This accords with neuropathologi-
ogy of SVD44,98 and chronic hypertension alone appears cal findings that histological markers of cell ischemia are
insufficient to generate SVD-like arterial changes in rats expressed within WMH.60 Insufficient arteriolar dilatation,
or monkeys.44,98 Molecular pathways link hypertension, leading to repeated episodes of underperfusion, might
endothelial dysfunction, and oligodendrocyte damage in be expected to cause cumulative damage in brain tis-
spontaneously hypertensive stroke-prone rats.99 sue, with lesional features including disruption of myelin
In our view, rodent models offer a platform to assess structure, some axonal loss, patchy BBB dysfunction,
some specific aspects of SVD pathophysiology (such as congregation of microglia and macrophages (to remove
blood vessel fibrosis, perivascular trafficking, white mat- debris), and heightened astrocyte activity (to clear edema
ter degeneration) but do not provide a unified model fluid). These features resemble those of an incomplete

82   January 2024 Hypertension. 2024;81:75–86. DOI: 10.1161/HYPERTENSIONAHA.123.19943

 Hainsworth et al Hypertensive Small Vessel Disease

lacune.106 As oligemia, edema, and BBB dysfunction significance in disease. At the level of gene expression,
are all interdependent, separating this from the previous there is a burgeoning collection of cell atlases derived
hypothesis is challenging, especially in a chronic, nonfa- from brain tissue samples.117 These reveal disease-related
tal disease.59 changes in the RNA profile of each cell type, includ-

Review
Fourth, a further suggested pathogenic process is ing vascular cells, within a brain biospecimen.117,119,120
inflammation, both systemic and within the CNS.4 Inflam- Coupled with advances in single-cell proteomics, these
matory cells are found in the white matter of some post- atlases are informing on cell subtypes (eg, subfamilies of
mortem brains from patients with SVD.60,64,107 Evidence oligodendroglia, microglia, and endothelial cells) and cell-
for CNS inflammation is also supported by positron cell interactions relevant to brain disease. For SVD, they
emission tomography imaging of patients with SVD, will reveal novel molecular agents as possible biomarkers
using radioligands such as 11C-PK11195 targeted and drug targets.79,80 Aided by novel chemistry and bet-
against the translocator protein, a mitochondrial sur- ter translational platforms, all accelerated by the power of
face protein upregulated in microglial activation. Both artificial intelligence, these are likely to provide real prog-
increased global 11C-PK11195 binding108 and focal ress in how we understand and treat SVD and VCID.
hot spots of increased binding, have been reported in
SVD.109 Systemic blood markers of inflammation have
also been reported to be elevated in SVD and to corre- ARTICLE INFORMATION
late with radiological disease severity, although whether Affiliations
such changes are casual or secondary to tissue damage Molecular and Clinical Sciences Research Institute, St George’s University of
London, United Kingdom (A.H.H.). Department of Neurology, St George’s Univer-
is uncertain.110,111 sity Hospitals NHS Foundation Trust, London, United Kingdom (A.H.H.). Stroke
Research Group, Department of Clinical Neurosciences, University of Cambridge,
United Kingdom (H.S.M.). Rush Alzheimer’s Disease Center, Departments of Pa-
Possible Molecular Mechanisms thology and Neurological Sciences, Rush University Medical Center, Chicago, IL
(J.A.S.).
In terms of molecular mechanisms, preclinical data from
various laboratories have suggested possible hypoth- Acknowledgments
The authors thank Fatemeh Geranmayeh, Gustavo Roman, and Colin Smith for
eses as to how hypertension influences neurovascu- comments on the article. A.H. Hainsworth thanks Leslie Bridges, Margaret Esiri,
lar function and VCID.112 Invoking neuroinflammation, and Alistair Lammie for many helpful discussions. The views expressed in this
endothelial dysfunction, and fibrosis, these mechanisms article are those of the individual authors.
include aberrant activity of the renin-angiotensin sys-
Downloaded from http://ahajournals.org by on March 29, 2024

Sources of Funding
tem, loss of BBB components, or defective NO, cytokine, Research in A.H. Hainsworth’s group is funded by the UK Medical Research
or endothelin signaling. Examples of particular interest Council (MR/R005567/1 and MR/T033371/1), British Heart Foundation
(PG/20/10397 and SP/F/22/150042), and UK Alzheimer’s Society and Al-
include IL-6 (interleukin-6),113 ET-1 (endothelin-1) (via zheimer’s Drug Discovery Foundation (20140901). H.S. Markus is supported by a
ETA receptors),114 and perivascular collagen produc- British Heart Foundation program grant (RG/F/22/110052). Infrastructural sup-
tion.44,115 The dramatis personae of the neurovascular port was provided by the Cambridge British Heart Foundation Centre of Research
Excellence (RE/18/1/34212) and Cambridge University Hospitals National In-
unit, including pericytes, myofibroblasts, and perivascu- stitute for Health and Care Research (NIHR) Biomedical Research center (BRC-
lar macrophages116 are all likely participants.117 1215-20014). J.A. Schneider has received funding from US National Institutes of
Health (R01AG017917, R01AG064233, R01AG061028, P30AG072975, and
P30AG010161).

SUMMARY AND FUTURE DIRECTIONS IN Disclosures

SVD AND VCID A.H. Hainsworth has received honoraria from Eli-Lilly and from National Institute
on Aging (NIA). He serves as a consultant for AriBio Co, Ltd. and chairs the De-
This is an exciting time in SVD research. The dementia mentiasPlatform UK Vascular Experimental Medicine group. J.A. Schneider has
received honoraria from Eli Lilly, Alnylam Pharmaceuticals, Inc, Apellis Pharma-
field in general has been energized by recent progress ceuticals, Inc, and Fondation Alzheimer. She has served as an expert witness for
in antibody therapy for AD, which will have spin-off ben- the US National Hockey League. The other author reports no conflicts.
efits for VCID research.118 Early-phase clinical trials in
SVD are also emerging.79,85,86 Though neutral, these offer
possible directions for further trials to deliver therapeutic REFERENCES
interventions in SVD and hence in VCID.80 We anticipate 1. Savva GM, Wharton SB, Ince PG, Forster G, Matthews FE, Brayne C; Medi-
cal Research Council Cognitive Function and Ageing Study. Age, neuro-
more, carefully designed clinical trials in SVD, utilizing pathology, and dementia. N Engl J Med. 2009;360:2302–2309. doi:
recently developed guidelines.87–89 10.1056/NEJMoa0806142
It is a truism that since the era of C. Miller Fisher this 2. MRC-CFAS. Pathological correlates of late-onset dementia in a mul-
ticentre, community-based population in England and Wales. Neuro-
field has lacked molecular targets. Modern biology and pathology group of the Medical Research Council Cognitive Function
big data streams are changing that. Genome-wide asso- and Ageing Study (MRC CFAS). Lancet. 2001;357:169–175. doi:
ciation study data have provided an impressive catalog 10.1016/s0140-6736(00)03589-3
3. Oveisgharan S, Kim N, Agrawal S, Yu L, Leurgans S, Kapasi A, Arfanakis K,
of candidate genes linked to sporadic SVD.14 All will Bennett DA, Schneider JA, Buchman AS. Brain and spinal cord arteriolo-
require conscientious laboratory studies to evaluate their sclerosis and its associations with cerebrovascular disease risk factors in

Hypertension. 2024;81:75–86. DOI: 10.1161/HYPERTENSIONAHA.123.19943 January 2024   83

 Hainsworth et al Hypertensive Small Vessel Disease

community-dwelling older adults. Acta Neuropathol. 2023;145:219–233. 24. Brenowitz WD, Keene CD, Hawes SE, Hubbard RA, Longstreth WT Jr,
doi: 10.1007/s00401-022-02527-z Woltjer RL, Crane PK, Larson EB, Kukull WA. Alzheimer’s disease neuro-
4. Gouw AA, Seewann A, van der Flier WM, Barkhof F, Rozemuller AM, pathologic change, Lewy body disease, and vascular brain injury in clinic-
Scheltens P, Geurts JJG. Heterogeneity of small vessel disease: a system- and community-based samples. Neurobiol Aging. 2017;53:83–92. doi:
atic review of MRI and histopathology correlations. J Neurol Neurosurg Psy- 10.1016/j.neurobiolaging.2017.01.017
Review

chiatry. 2011;82:126–135. doi: 10.1136/jnnp.2009.204685 25. Sonnen JA, Larson EB, Crane PK, Haneuse S, Li G, Schellenberg GD,
5. Fisher CM. The arterial lesions underlying lacunes. Acta Neuropathol. Craft S, Leverenz JB, Montine TJ. Pathological correlates of dementia in a
1968;12:1–15. doi: 10.1007/BF00685305 longitudinal, population-based sample of aging. Ann Neurol. 2007;62:406–
6. Lammie GA. Hypertensive cerebral small vessel disease and stroke. Brain 413. doi: 10.1002/ana.21208
Pathol. 2002;12:358–370. doi: 10.1111/j.1750-3639.2002.tb00450.x 26. Launer LJ, Petrovitch H, Ross GW, Markesbery W, White LR. AD brain
7. Lammie GA. Pathology of small vessel stroke. Br Med Bull. 2000;56:296– pathology: vascular origins? Results from the HAAS autopsy study. Neurobiol
306. doi: 10.1258/0007142001903229333 Aging. 2008;29:1587–1590. doi: 10.1016/j.neurobiolaging.2007.03.008
8. Cannistraro RJ, Badi M, Eidelman BH, Dickson DW, Middlebrooks EH, Meschia JF. 27. White LR, Edland SD, Hemmy LS, Montine KS, Zarow C,
CNS small vessel disease: a clinical review. Neurology. 2019;92:1146–1156. Sonnen JA, Uyehara-Lock JH, Gelber RP, Ross GW, Petrovitch H, et al.
doi: 10.1212/WNL.0000000000007654 Neuropathologic comorbidity and cognitive impairment in the Nun and
9. Esiri MM, Wilcock GK, Morris JH. Neuropathological assessment of the Honolulu-Asia aging studies. Neurology. 2016;86:1000–1008. doi:
lesions of significance in vascular dementia. J Neurol Neurosurg Psychiatry. 10.1212/WNL.0000000000002480
1997;63:749–753. doi: 10.1136/jnnp.63.6.749 28. Matthews FE, Brayne C, Lowe J, McKeith I, Wharton SB, Ince P. Epide-
10. Ighodaro ET, Abner EL, Fardo DW, Lin AL, Katsumata Y, Schmitt FA, miological pathology of dementia: attributable-risks at death in the medi-
Kryscio RJ, Jicha GA, Neltner JH, Monsell SE, et al; Alzheimer's Disease cal research council cognitive function and ageing study. PLoS Med.
Neuroimaging Initiative (ADNI). Risk factors and global cognitive status 2009;6:e1000180. doi: 10.1371/journal.pmed.1000180
related to brain arteriolosclerosis in elderly individuals. J Cereb Blood Flow 29. Kapasi A, DeCarli C, Schneider JA. Impact of multiple pathologies on the
Metab. 2017;37:201–216. doi: 10.1177/0271678X15621574 threshold for clinically overt dementia. Acta Neuropathol. 2017;134:171–
11. Lamar M, Leurgans S, Kapasi A, Barnes LL, Boyle PA, 186. doi: 10.1007/s00401-017-1717-7
Bennett DA, Arfanakis K, Schneider JA. Complex profiles of cere- 30. Arvanitakis Z, Capuano AW, Lamar M, Shah RC, Barnes LL, Bennett DA,
brovascular disease pathologies in the aging brain and their rela- Schneider JA. Late-life blood pressure association with cerebrovascular
tionship with cognitive decline. Stroke. 2022;53:218–227. doi: and Alzheimer disease pathology. Neurology. 2018;91:e517–e525. doi:
10.1161/STROKEAHA.121.034814 10.1212/WNL.0000000000005951
12. Rosenberg GA, Wallin A, Wardlaw JM, Markus HS, Montaner J, Wolfson L, 31. Barnes LL, Lamar M, Schneider JA. Sex differences in mixed neuropatholo-
Iadecola C, Zlokovic BV, Joutel A, Dichgans M, et al. Consensus statement gies in community-dwelling older adults. Brain Res. 2019;1719:11–16. doi:
for diagnosis of subcortical small vessel disease. J Cereb Blood Flow Metab. 10.1016/j.brainres.2019.05.028
2015;36:6–25. doi: 10.1038/jcbfm.2015.172 32. Barnes LL, Leurgans S, Aggarwal NT, Shah RC, Arvanitakis Z, James BD,
13. Traylor M, Persyn E, Tomppo L, Klasson S, Abedi V, Bakker MK, Torres N, Buchman AS, Bennett DA, Schneider JA. Mixed pathology is more likely
Li L, Bell S, Rutten-Jacobs L, et al; Helsinki Stroke, Study Dutch Parel- in Black than White decedents with Alzheimer dementia. Neurology.
snoer Institute-Cerebrovascular Accident (CVA) Study Group. Genetic 2015;85:528–534. doi: 10.1212/WNL.0000000000001834
basis of lacunar stroke: a pooled analysis of individual patient data and 33. Kapasi A, Leurgans SE, Arvanitakis Z, Barnes LL, Bennett DA,
genome-wide association studies. Lancet Neurol. 2021;20:351–361. doi: Schneider JA. Abeta (amyloid beta) and tau tangle pathology modifies the
10.1016/S1474-4422(21)00031-4 association between small vessel disease and cortical microinfarcts. Stroke.
Downloaded from http://ahajournals.org by on March 29, 2024

14. Bordes C, Sargurupremraj M, Mishra A, Debette S. Genetics of common 2021;52:1012–1021. doi: 10.1161/STROKEAHA.120.031073
cerebral small vessel disease. Nat Rev Neurol. 2022;18:84–101. doi: 34. Levine DA, Springer MV, Brodtmann A. Blood pressure and vas-
10.1038/s41582-021-00592-8 cular cognitive impairment. Stroke. 2022;53:1104–1113. doi:
15. Persyn E, Hanscombe KB, Howson JMM, Lewis CM, Traylor M, 10.1161/STROKEAHA.121.036140
Markus HS. Genome-wide association study of MRI markers of cerebral 35. Palta P, Albert MS, Gottesman RF. Heart health meets cognitive health: evi-
small vessel disease in 42,310 participants. Nat Commun. 2020;11:2175. dence on the role of blood pressure. Lancet Neurol. 2021;20:854–867. doi:
doi: 10.1038/s41467-020-15932-3 10.1016/S1474-4422(21)00248-9
16. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical 36. Lammie GA, Brannan F, Slattery J, Warlow C. Nonhypertensive cerebral
characteristics to therapeutic challenges. Lancet Neurol. 2010;9:689–701. small-vessel disease an autopsy study. Stroke. 1997;28:2222–2229. doi:
doi: 10.1016/S1474-4422(10)70104-6 10.1161/01.str.28.11.2222
17. van Veluw SJ, Arfanakis K, Schneider JA. Neuropathology of vascular brain 37. Huang J, Biessels GJ, de Leeuw FE, Ii Y, Skoog I, Mok V, Chen C, Hilal S.
health: insights from ex vivo magnetic resonance imaging-histopathology Cerebral microinfarcts revisited: detection, causes, and clinical relevance. Int
studies in cerebral small vessel disease. Stroke. 2022;53:404–415. doi: J Stroke. 2023. doi: 10.1177/17474930231187979
10.1161/STROKEAHA.121.032608 38. Power MC, Mormino E, Soldan A, James BD, Yu L, Armstrong NM,
18. Humphreys CA, Smith C, Wardlaw JM. Correlations in post-mortem Bangen KJ, Delano-Wood L, Lamar M, Lim YY, et al. Combined neuro-
imaging-histopathology studies of sporadic human cerebral small vessel pathological pathways account for age-related risk of dementia. Ann Neurol.
disease: a systematic review. Neuropathol Appl Neurobiol. 2021;47:910– 2018;84:10–22. doi: 10.1002/ana.25246
930. doi: 10.1111/nan.12737 39. Vemuri P, Lesnick TG, Przybelski SA, Knopman DS, Preboske GM,
19. Arvanitakis Z, Capuano AW, Leurgans SE, Bennett DA, Schneider JA. Kantarci K, Raman MR, Machulda MM, Mielke MM, Lowe VJ, et al. Vascular
Relation of cerebral vessel disease to Alzheimer’s disease dementia and and amyloid pathologies are independent predictors of cognitive decline in
cognitive function in elderly people: a cross-sectional study. Lancet Neurol. normal elderly. Brain. 2015;138:761–771. doi: 10.1093/brain/awu393
2016;15:934–943. doi: 10.1016/s1474-4422(16)30029-1 40. Boyle PA, Yu L, Wilson RS, Leurgans SE, Schneider JA, Bennett DA.
20. Arvanitakis Z, Leurgans SE, Barnes LL, Bennett DA, Schneider JA. Micro- Person-specific contribution of neuropathologies to cognitive loss in old
infarct pathology, dementia, and cognitive systems. Stroke. 2011;42:722– age. Ann Neurol. 2018;83:74–83. doi: 10.1002/ana.25123
727. doi: 10.1161/STROKEAHA.110.595082 41. Baker AB, Iannone A. Cerebrovascular disease. II. The smaller intracerebral
21. Masuda J, Tanaka K, Omae T, Ueda K, Sadoshima S. Cerebrovascu- arteries. Neurology. 1959;9:391–396. doi: 10.1212/wnl.9.6.391
lar diseases and their underlying vascular lesions in Hisayama, Japan: a 42. Furuta A, Ishii N, Nishihara Y, Horie A. Medullary arteries in aging and
pathological study of autopsy cases. Stroke. 1983;14:934–940. doi: dementia. Stroke. 1991;22:442–446. doi: 10.1161/01.str.22.4.442
10.1161/01.str.14.6.934 43. Dozono K, Ishii N, Nishihara Y, Horie A. An autopsy study of the incidence
22. Honda H, Sasaki K, Hamasaki H, Shijo M, Koyama S, Ohara T, Ninomiya T, of lacunes in relation to age, hypertension, and arteriosclerosis. Stroke.
Kiyohara Y, Suzuki SO, Iwaki T. Trends in autopsy-verified dementia preva- 1991;22:993–996. doi: 10.1161/01.str.22.8.993
lence over 29 years of the Hisayama study. Neuropathology. 2016;36:383– 44. Kumar AA, Yeo N, Whittaker M, Attra P, Barrick TR, Bridges LR, Dickson DW,
387. doi: 10.1111/neup.12298 Esiri MM, Farris CW, Graham D, et al. Vascular collagen type-IV in hyperten-
23. Suemoto CK, Leite REP, Ferretti-Rebustini REL, Rodriguez RD, Nitrini R, sion and cerebral small vessel disease. Stroke. 2022;53:3696–3705. doi:
Pasqualucci CA, Jacob-Filho W, Grinberg LT. Neuropathological lesions 10.1161/STROKEAHA.122.037761
in the very old: results from a large Brazilian autopsy study. Brain Pathol. 45. Fisher CM. Lacunes: small, deep cerebral infarcts. Neurology. 1965;15:774–
2019;29:771–781. doi: 10.1111/bpa.12719 784. doi: 10.1212/wnl.15.8.774

84   January 2024 Hypertension. 2024;81:75–86. DOI: 10.1161/HYPERTENSIONAHA.123.19943

 Hainsworth et al Hypertensive Small Vessel Disease

46. Fisher CM. Lacunar strokes and infarcts: a review. Neurology. 1982;32:871– 68. Wong S, Jacobus JFA, Zhang E, Hoff E, Staals J,
876. doi: 10.1212/wnl.32.8.871 van Oostenbrugge R, Backes WH. Blood-brain barrier impairment and
47. Fisher CM. Cerebral miliary aneurysms in hypertension. Am J Pathol. hypoperfusion are linked in cerebral small vessel disease. Neurology.
1972;66:313–330. 2019;92:e1669. doi: 10.1212/WNL.0000000000007263
48. Boiten J, Lodder J, Kessels F. Two clinically distinct lacunar infarct entities? 69. Alakbarzade V, French JM, Howlett DR, Attems J, Francis PT,

Review
A hypothesis. Stroke. 1993;24:652–656. doi: 10.1161/01.str.24.5.652 Stratton S, Clark CN, Pereira AC, Hainsworth AH. Cerebral amyloid angi-
49. Baker AB. Structure of the small cerebral arteries in hypertension. Am J opathy distribution in older people: a cautionary note. Alzheimers Dement
Pathol. 1941;17:39–46.1. (NY). 2021;7:e12145. doi: 10.1002/trc2.12145
50. Arfanakis K, Evia AM, Leurgans SE, Cardoso LFC, Kulkarni A, Alqam N, 70. Fazekas F, Kleinert R, Offenbacher H, Schmidt R, Kleinert G, Payer F,
Lopes LF, Vieira D, Bennett DA, Schneider JA. Neuropathologic correlates Radner H, Lechner H. Pathologic correlates of incidental MRI white mat-
of white matter hyperintensities in a community-based cohort of older ter signal hyperintensities. Neurology. 1993;43:1683–1689. doi:
adults. J Alzheimers Dis. 2020;73:333–345. doi: 10.3233/JAD-190687 10.1212/wnl.43.9.1683
51. Feigin I, Popoff N. Neuropathological changes late in cerebral edema: 71. Smallwood A, Oulhaj A, Joachim C, Christie S, Sloan C, Smith AD,
the relationship to trauma, hypertensive disease and Binswanger’s Esiri M. Cerebral subcortical small vessel disease and its relation to cogni-
encephalopathy. J Neuropathol Exp Neurol. 1963;22:500–511. doi: tion in elderly subjects: a pathological study in the Oxford Project to Inves-
10.1097/00005072-196307000-00011 tigate Memory and Ageing (OPTIMA) cohort. Neuropathol Appl Neurobiol.
52. Gutierrez J, Khasiyev F, Liu M, DeRosa JT, Tom SE, Rundek T, Cheung K, 2012;38:337–343. doi: 10.1111/j.1365-2990.2011.01221.x
Wright CB, Sacco RL, Elkind MSV. Determinants and outcomes of asymptom- 72. Anad A, Barker MK, Katanga JA, Arfanakis K, Bridges LR, Esiri MM,
atic intracranial atherosclerotic stenosis. J Am Coll Cardiol. 2021;78:562– Isaacs JD, Prpar Mihevc S, Pereira AC, Schneider JA, et al. Vasculocentric
571. doi: 10.1016/j.jacc.2021.05.041 axonal NfH in small vessel disease. J Neuropathol Exp Neurol. 2022;81:182–
53. Caplan LR, Gorelick PB, Hier DB. Race, sex and occlusive cerebrovascular 192. doi: 10.1093/jnen/nlab134
disease: a review. Stroke. 1986;17:648–655. doi: 10.1161/01.str.17.4.648 73. Duering M, Biessels GJ, Brodtmann A, Chen C, Cordonnier C, de Leeuw FE,
54. Barnes LL, Shah RC, Aggarwal NT, Bennett DA, Schneider JA. The minority Debette S, Frayne R, Jouvent E, Rost NS, et al. Neuroimaging standards
aging research study: ongoing efforts to obtain brain donation in African for research into small vessel disease-advances since 2013. Lancet Neurol.
Americans without dementia. Curr Alzheimer Res. 2012;9:734–745. doi: 2023;22:602–618. doi: 10.1016/S1474-4422(23)00131-X
10.2174/156720512801322627 74. Wilson D, Charidimou A, Ambler G, Fox ZV, Gregoire S, Rayson P,
55. Hainsworth AH, Oommen AT, Bridges LR. Endothelial cells and human Imaizumi T, Fluri F, Naka H, Horstmann S, et al. Recurrent stroke
cerebral small vessel disease. Brain Pathol. 2015;25:44–50. doi: risk and cerebral microbleed burden in ischemic stroke and
10.1111/bpa.12224 TIA: a meta-analysis. Neurology. 2016;87:1501–1510. doi:
56. Norton EJ, Bridges LR, Kenyon LC, Esiri MM, Bennett DC, Hainsworth AH. 10.1212/WNL.0000000000003183
Cell senescence and cerebral small vessel disease in the brains of people 75. Ohlmeier L, Nannoni S, Pallucca C, Brown RB, Loubiere L,
aged 80 years and older. J Neuropathol Exp Neurol. 2019;78:1066–1072. Markus HS; DNA Lacunar 2 Investigators. Prevalence of, and risk factors
doi: 10.1093/jnen/nlz088 for, cognitive impairment in lacunar stroke. Int J Stroke. 2023;18:62–69. doi:
57. Tanoi Y, Okeda R, Budka H. Binswanger’s encephalopathy: serial sections 10.1177/17474930211064965
and morphometry of the cerebral arteries. Acta Neuropathol. 2000;100:347– 76. Peters R, Xu Y, Fitzgerald O, Aung HL, Beckett N, Bulpitt C, Chalmers J,
355. doi: 10.1007/s004010000203 Forette F, Gong J, Harris K, et al; Dementia Risk Reduction (DIRECT) Col-
58. Miao Q, Paloneva T, Tuisku S, Roine S, Poyhonen M, Viitanen M, Kalimo H. laboration. Blood pressure lowering and prevention of dementia: an indi-
Arterioles of the lenticular nucleus in CADASIL. Stroke. 2006;37:2242– vidual patient data meta-analysis. Eur Heart J. 2022;43:4980–4990. doi:
Downloaded from http://ahajournals.org by on March 29, 2024

2247. doi: 10.1161/01.STR.0000236838.84150.c2 10.1093/eurheartj/ehac584

59. Hainsworth AH. White matter lesions in cerebral small vessel disease: 77. Elahi FM, Alladi S, Black SE, Claassen J, DeCarli C, Hughes TM, Moonen J,
underperfusion or leaky vessels? Neurology. 2019;92:687–688. doi: Pajewski NM, Price BR, Satizabal C, et al. Clinical trials in vascular cognitive
10.1212/WNL.0000000000007258 impairment following SPRINT-MIND: an international perspective. Cell Rep
60. Fernando MS, Simpson JE, Matthews F, Brayne C, Lewis CE, Barber R, Med. 2023;4:101089. doi: 10.1016/j.xcrm.2023.101089
Kalaria RN, Forster G, Esteves F, Wharton SB, et al; MRC Cognitive Func- 78. Nasrallah IM, Pajewski NM, Auchus AP, Chelune G, Cheung AK,
tion and Ageing Neuropathology Study Group. White matter lesions in Cleveland ML, Coker LH, Crowe MG, Cushman WC, Cutler JA, et al; SPRINT
an unselected cohort of the elderly: molecular pathology suggests ori- MIND Investigators for the SPRINT Research Group. Association of inten-
gin from chronic hypoperfusion injury. Stroke. 2006;37:1391–1398. doi: sive vs standard blood pressure control with cerebral white matter lesions.
10.1161/01.STR.0000221308.94473.14 JAMA. 2019;322:524–534. doi: 10.1001/jama.2019.10551
61. Giwa MO, Williams J, Elderfield K, Jiwa NS, Bridges LR, Kalaria RN, 79. Smith EE, Markus HS. New treatment approaches to modify the
Markus HS, Esiri MM, Hainsworth AH. Neuropathologic evidence of endo- course of cerebral small vessel diseases. Stroke. 2019;51:38–46. doi:
thelial changes in cerebral small vessel disease. Neurology. 2012;78:167– 10.1161/strokeaha.119.024150
174. doi: 10.1212/WNL.0b013e3182407968 80. Hainsworth AH, Elahi FM, Corriveau RA. An introduction to therapeu-
62. Young VG, Halliday GM, Kril JJ. Neuropathologic correlates of tic approaches to vascular cognitive impairment. Cereb Circ Cogn Behav.
white matter hyperintensities. Neurology. 2008;71:804–811. doi: 2021;2:100033. doi: 10.1016/j.cccb.2021.100033
10.1212/01.wnl.0000319691.50117.54 81. Williamson JD, Pajewski NM, Auchus AP, Bryan RN, Chelune G, Cheung AK,
63. Bridges LR, Andoh J, Lawrence AJ, Khoong CHL, Poon WW, Esiri MM, Cleveland ML, Coker LH, Crowe MG, Cushman WC, et al; SPRINT MIND
Markus HS, Hainsworth AH. Blood-brain barrier dysfunction and cerebral small Investigators for the SPRINT Research Group. Effect of intensive vs stan-
vessel disease (arteriolosclerosis) in brains of older people. J Neuropathol Exp dard blood pressure control on probable dementia: a randomized clinical
Neurol. 2014;73:1026–1033. doi: 10.1097/NEN.0000000000000124 trial. JAMA. 2019;321:553–561. doi: 10.1001/jama.2018.21442
64. Hainsworth AH, Minett T, Andoh J, Forster G, Bhide I, Barrick TR, 82. Croall ID, Tozer DJ, Moynihan B, Khan U, O’Brien JT, Morris RG,
Elderfield K, Jeevahan J, Markus HS, Bridges LR. Neuropathology of white Cambridge VC, Barrick TR, Blamire AM, Ford GA, et al; PRESERVE
matter lesions, blood-brain barrier dysfunction, and dementia. Stroke. Study Team. Effect of standard vs intensive blood pressure con-
2017;48:2799–2804. doi: 10.1161/STROKEAHA.117.018101 trol on cerebral blood flow in small vessel disease: the PRESERVE
65. Topakian R, Barrick TR, Howe FA, Markus HS. Blood-brain barrier perme- randomized clinical trial. JAMA Neurol. 2018;75:720–727. doi:
ability is increased in normal-appearing white matter in patients with lacunar 10.1001/jamaneurol.2017.5153
stroke and leucoaraiosis. J Neurol Neurosurg Psychiatry. 2010;81:192–197. 83. Abell JG, Kivimaki M, Dugravot A, Tabak AG, Fayosse A, Shipley M,
doi: 10.1136/jnnp.2009.172072 Sabia S, Singh-Manoux A. Association between systolic blood pressure and
66. Wardlaw JM, Smith C, Dichgans M. Small vessel disease: mecha- dementia in the Whitehall II cohort study: role of age, duration, and thresh-
nisms and clinical implications. Lancet Neurol. 2019;18:684–696. doi: old used to define hypertension. Eur Heart J. 2018;39:3119–3125. doi:
10.1016/S1474-4422(19)30079-1 10.1093/eurheartj/ehy288
67. Taheri S, Gasparovic C, Huisa BN, Adair JC, Edmonds E, Prestopnik J, 84. Benavente OR, Hart RG, McClure LA, Szychowski JM, Coffey CS,
Grossetete M, Shah NJ, Wills J, Qualls C, et al. Blood-brain barrier permea- Pearce LA; SPS3 Investigators. Effects of clopidogrel added to aspirin in
bility abnormalities in vascular cognitive impairment. Stroke. 2011;42:2158– patients with recent lacunar stroke. N Engl J Med. 2012;367:817–825. doi:
2163. doi: 10.1161/STROKEAHA.110.611731 10.1056/NEJMoa1204133

Hypertension. 2024;81:75–86. DOI: 10.1161/HYPERTENSIONAHA.123.19943 January 2024   85

 Hainsworth et al Hypertensive Small Vessel Disease

85. Pauls MMH, Binnie LR, Benjamin P, Betteridge S, Clarke B, Dhillon MK, 104. Shi Y, Thrippleton MJ, Makin SD, Marshall I, Geerlings MI, de Craen AJM,
Ghatala R, Hainsworth FAH, Howe FA, Khan U, et al. The PASTIS trial: test- van Buchem MA, Wardlaw JM. Cerebral blood flow in small vessel dis-
ing tadalafil for possible use in vascular cognitive impairment. Alzheimers ease: a systematic review and meta-analysis. J Cereb Blood Flow Metab.
Dement. 2022;18:2393–2402. doi: 10.1002/alz.12559 2016;36:1653–1667. doi: 10.1177/0271678X16662891
86. Wardlaw JM, Woodhouse LJ, Mhlanga II, Oatey K, Heye AK, Bamford J, 105. Immink RV, van Montfrans GA, Stam J, Karemaker JM, Diamant M,
Review

Cvoro V, Doubal FN, England T, Hassan A, et al. Isosorbide mononitrate van Lieshout JJ. Dynamic cerebral autoregulation in acute lacunar and
and cilostazol treatment in patients with symptomatic cerebral small vessel middle cerebral artery territory ischemic stroke. Stroke. 2005;36:2595–
disease: the lacunar intervention trial-2 (LACI-2) randomized clinical trial. 2600. doi: 10.1161/01.STR.0000189624.06836.03
JAMA Neurol. 2023;80:682–692. doi: 10.1001/jamaneurol.2023.1526 106. Lammie GA, Brannan F, Wardlaw JM. Incomplete lacunar infarction
87. Sachdev PS, Lipnicki DM, Crawford JD, Brodaty H. The vascular behavioral (type Ib lacunes). Acta Neuropathol. (Berl). 1998;96:163–171. doi:
and cognitive disorders criteria for vascular cognitive disorders: a validation 10.1007/s004010050877
study. Eur J Neurol. 2019;26:1161–1167. doi: 10.1111/ene.13960 107. Simpson JE, Ince PG, Higham CE, Gelsthorpe CH, Fernando MS,
88. Skrobot OA, Black SE, Chen C, DeCarli C, Erkinjuntti T, Ford GA, Matthews F, Forster G, O'Brien JT, Barber R, Kalaria RN, et al; MRC
Kalaria RN, O'Brien J, Pantoni L, Pasquier F, et al; VICCCS Group. Progress Cognitive Function and Ageing Neuropathology Study Group. Microglial
toward standardized diagnosis of vascular cognitive impairment: guidelines activation in white matter lesions and nonlesional white matter of
from the vascular impairment of cognition classification consensus study. ageing brains. Neuropathol Appl Neurobiol. 2007;33:670–683. doi:
Alzheimers Dement. 2018;14:280–292. doi: 10.1016/j.jalz.2017.09.007 10.1111/j.1365-2990.2007.00890.x
89. Markus HS, van Der Flier WM, Smith EE, Bath P, Biessels GJ, Briceno E, 108. Low A, Mak E, Malpetti M, Passamonti L, Nicastro N, Stefaniak JD,
Brodtman A, Chabriat H, Chen C, de Leeuw FE, et al. Framework for clini- Savulich G, Chouliaras L, Su LRowe JB, et al. In vivo neuroinflamma-
cal trials in cerebral small vessel disease (FINESSE): a review. JAMA tion and cerebral small vessel disease in mild cognitive impairment and
Neurol. 2022;79:1187–1198. doi: 10.1001/jamaneurol.2022.2262 Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2020;92:45–52. doi:
90. Debette S, Markus HS. Stroke genetics: discovery, insight into mecha- 10.1136/jnnp-2020-323894
nisms, and clinical perspectives. Circ Res. 2022;130:1095–1111. doi: 109. Walsh J, Tozer DJ, Sari H, Hong YT, Drazyk A, Williams G, Shah NJ,
10.1161/CIRCRESAHA.122.319950 O'Brien JT, Aigbirhio FI, Rosenberg G, et al. Microglial activation and
91. Mancuso M, Arnold M, Bersano A, Burlina A, Chabriat H, Debette S, blood-brain barrier permeability in cerebral small vessel disease. Brain.
Enzinger C, Federico A, Filla A, Finsterer J, et al. Monogenic cerebral small- 2021;144:1361–1371. doi: 10.1093/brain/awab003
vessel diseases: diagnosis and therapy consensus recommendations of 110. Hassan A, Hunt BJ, O’Sullivan M, Parmar K, Bamford JM, Briley D,
the European academy of neurology. Eur J Neurol. 2020;27:909–927. doi: Brown MM, Thomas DJ, Markus HS. Markers of endothelial dysfunction in
10.1111/ene.14183 lacunar infarction and ischaemic leukoaraiosis. Brain. 2003;126:424–432.
92. Joutel A, Haddad I, Ratelade J, Nelson MT. Perturbations of the cere- doi: 10.1093/brain/awg040
brovascular matrisome: a convergent mechanism in small vessel dis- 111. Low A, Mak E, Rowe JB, Markus HS, O’Brien JT. Inflammation and
ease of the brain? J Cereb Blood Flow Metab. 2016;36:143–157. doi: cerebral small vessel disease: a systematic review. Ageing Res Rev.
10.1038/jcbfm.2015.62 2019;53:100916. doi: 10.1016/j.arr.2019.100916
93. Cho BPH, Harshfield EL, Al-Thani M, Tozer DJ, Bell S, Markus HS. 112. Santisteban MM, Iadecola C, Carnevale D. Hypertension, neurovascular
Association of vascular risk factors and genetic factors with penetrance of dysfunction, and cognitive impairment. Hypertension. 2023;80:22–34. doi:
variants causing monogenic stroke. JAMA Neurol. 2022;79:1303–1311. 10.1161/HYPERTENSIONAHA.122.18085
doi: 10.1001/jamaneurol.2022.3832 113. Schuett H, Luchtefeld M, Grothusen C, Grote K, Schieffer B. How much
94. Hainsworth AH, Allan SM, Boltze J, Cunningham C, Farris C, Head E, is too much? Interleukin-6 and its signalling in atherosclerosis. Thromb
Downloaded from http://ahajournals.org by on March 29, 2024

Ihara M, Isaacs JD, Kalaria RN, Lesnik Oberstein SAMJ, et al. Translational Haemost. 2009;102:215–222. doi: 10.1160/TH09-05-0297
models for vascular cognitive impairment: a review including larger species. 114. Berry C, Sidik N, Pereira AC, Ford TJ, Touyz RM, Kaski JC, Hainsworth AH.
BMC Med. 2017;15:16. doi: 10.1186/s12916-017-0793-9 Small-vessel disease in the heart and brain: current knowledge, unmet ther-
95. Hainsworth AH, Markus HS. Do in vivo experimental models reflect human apeutic need, and future directions. J Am Heart Assoc. 2019;8:e011104.
cerebral small vessel disease? A systematic review. J Cereb Blood Flow doi: 10.1161/JAHA.118.011104
Metab. 2008;28:1877–1891. doi: 10.1038/jcbfm.2008.91 115. Inagaki T, Fujiwara K, Shinohara Y, Azuma M, Yamazaki R,
96. Bailey EL, McCulloch J, Sudlow C, Wardlaw JM. Potential animal models Mashima K, Sakamoto A, Yashiro T, Ohno N. Perivascular macrophages
of lacunar stroke: a systematic review. Stroke. 2009;40:e451–e458. doi: produce type I collagen around cerebral small vessels under prolonged
10.1161/STROKEAHA.108.528430 hypertension in rats. Histochem Cell Biol. 2021;155:503–512. doi:
97. Bailey EL, Smith C, Sudlow CL, Wardlaw JM. Is the spontaneously hy- 10.1007/s00418-020-01948-9
pertensive stroke prone rat a pertinent model of sub cortical isch- 116. Faraco G, Sugiyama Y, Lane D, Garcia-Bonilla L, Chang H, Santisteban MM,
emic stroke? A systematic review. Int. J. Stroke. 2011;6:434–444. doi: Racchumi G, Murphy M, Van Rooijen N, Anrather J, et al. Perivascular
10.1111/j.1747-4949.2011.00659.x macrophages mediate the neurovascular and cognitive dysfunction as-
98. Brittain JF, McCabe C, Khatun H, Kaushal N, Bridges LR, Holmes WM, sociated with hypertension. J Clin Invest. 2016;126:4674–4689. doi:
Barrick TR, Graham D, Dominiczak AF, Mhairi Macrae I, et al. An MRI- 10.1172/JCI86950
histological study of white matter in stroke-free SHRSP. J Cereb Blood 117. Iadecola C, Smith EE, Anrather J, Gu C, Mishra A, Misra S, Perez-Pinzon MA,
Flow Metab. 2013;33:760–763. doi: 10.1038/jcbfm.2013.14 Shih AY, Sorond FA, van Veluw SJ, et al; American Heart Association
99. Rajani RM, Quick S, Ruigrok SR, Graham D, Harris SE, Verhaaren BFJ, Stroke Council Council on Arteriosclerosis Thrombosis and Vascular
Fornage M, Seshadri S, Atanur SS, Dominiczak AF, et al. Reversal of Biology Council on Cardiovascular Radiology and Intervention Council
endothelial dysfunction reduces white matter vulnerability in cerebral on Hypertension Council on Lifestyle and Cardiometabolic Health.
small vessel disease in rats. Sci Transl Med. 2018;10:eaam9507. doi: The neurovasculome: key roles in brain health and cognitive impair-
10.1126/scitranslmed.aam9507 ment: a scientific statement from the American Heart Association/
100. Ay H, Oliveira-Filho J, Buonanno FS, Ezzeddine M, Schaefer PW, Rordorf G, American Stroke Association. Stroke. 2023;54:e251–e271. doi:
Schwamm LH, Gonzalez RG, Koroshetz WJ. Diffusion-weighted imaging 10.1161/STR.0000000000000431
identifies a subset of lacunar infarction associated with embolic source. 118. Wallin A, Alladi S, Black SE, Chen C, Greenberg SM, Gustafson D, Isaacs JD,
Stroke. 1999;30:2644–2650. doi: 10.1161/01.str.30.12.2644 Jokinen H, Kalaria R, Mok V, et al. What does aducanumab treatment of
101. Kaposzta Z, Young E, Bath PM, Markus HS. Clinical application of as- Alzheimer’s disease mean for research on vascular cognitive disorders?
ymptomatic embolic signal detection in acute stroke: a prospective study. Cereb Circ Cogn Behav. 2022;3:100044. doi: 10.1016/j.cccb.2022.100044
Stroke. 1999;30:1814–1818. doi: 10.1161/01.str.30.9.1814 119. Yang AC, Vest RT, Kern F, Lee DP, Agam M, Maat CA, Losada PM,
102. Wardlaw JM, Sandercock PA, Dennis MS, Starr J. Is breakdown of the blood- Chen MB, Schaum N, Khoury N, et al. A human brain vascular atlas reveals
brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia? diverse mediators of Alzheimer’s risk. Nature. 2022;603:885–892. doi:
Stroke. 2003;34:806–812. doi: 10.1161/01.STR.0000058480.77236.B3 10.1038/s41586-021-04369-3
103. Sengillo JD, Winkler EA, Walker CT, Sullivan JS, Johnson M, 120. Winkler EA, Kim CN, Ross JM, Garcia JH, Gil E, Oh I, Chen LQ, Wu D,
Zlokovic BV. Deficiency in mural vascular cells coincides with blood-brain Catapano JS, Raygor K, et al. A single-cell atlas of the normal and mal-
barrier disruption in Alzheimer’s disease. Brain Pathol. 2013;23:303–310. formed human brain vasculature. Science. 2022;375:eabi7377. doi:
doi: 10.1111/bpa.12004 10.1126/science.abi7377

86   January 2024 Hypertension. 2024;81:75–86. DOI: 10.1161/HYPERTENSIONAHA.123.19943