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Intracranial atherosclerosis
and inflammation: Lessons
from the East and the West
Juan F Arenillas

Website:
http://www.braincirculation.org
DOI:
10.4103/2394-8108.162531

Abstract:
Intracranial atherosclerosis (ICAS) is a major cause of ischemic stroke worldwide. Patients affected by this disease
have a high risk of suffering further ischemic strokes and other major vascular events despite the best medical
therapy available. However, identification of factors that characterize a high-risk ICAS patient is a clinical problem
that is yet to be solved. Inflammation is known to play a crucial role in all the stages of atherosclerosis affecting
extracranial arterial beds but its role in ICAS is not firmly established. Circulating inflammatory biomarkers may
represent a valuable tool to assess the importance of systemic and local (intraplaque) inflammation in ICAS
pathogenesis. In this article, we have reviewed studies with inflammatory biomarkers performed in symptomatic
and asymptomatic ICAS patients published in the recent literature. Their findings strongly support the hypothesis
that inflammation determines the risk of progression and complication of symptomatic ICAS.
Key words:
Atherosclerosis, biomarkers, inflammation, intracranial, intracranial stenosis

Intracranial Atherosclerosis and

Translational Research

Department of
Neurology, Hospital
ClnicoUniversitario,
University of Valladolid,
Valladolid, Spain
Address for
correspondence:
Dr. Juan F Arenillas,
Department of Neurology,
Hospital Clnico
Universitario, University
of Valladolid, Ramn y
Cajal 3, Valladolid - 47003,
Spain.
E-mail: jfarenillas@
saludcastillayleon.es
Submission: 08-05-2015
Accepted: 15-06-2015

he ultimate aim of translational research is to

provide applicable solutions to relevant clinical
problems by means of a continuous crosstalk
between clinical studies and basic research, as
shown in Figure 1.[1] Intracranial atherosclerosis
(ICAS) is characterized by the development,
progression, and complication of atherosclerotic
plaques affecting the intracranial large arteries.
ICAS represents the most common cause of
ischemic stroke among patients of Asian ancestry.
[2,3]
Moreover, ICAS is more prevalent among
Hispanics and Africans whereas in Caucasians,
ICAS may account for 8-10% of all ischemic strokes.
[4]
Thus, taking the distribution of the worlds
population into account, ICAS may represent the
most common cause of stroke globally.[5]
According to these observations, ICAS represents
a major health problem worldwide. However,
there are important clinical problems affecting
ICAS patients that are yet to be solved and these
present as potential targets for translational
research. First, symptomatic ICAS is still
burdened with a high risk of recurrent stroke
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2015 Brain Circulation | Published by Wolters Kluwer Health Medknow

despite the best medical therapy although the

aggressive medical treatment with or without
stenting in high-risk patients with intracranial
artery stenosis (SAMMPRIS) medical treatment
paradigm was able to reduce the annual
recurrence rate by almost 50% as compared
to the rate reported in the Warfarin-Aspirin
Symptomatic Intracranial Disease (WASID)
study less than one decade earlier.[6,7] Second,
symptomatic ICAS patients are burdened with
a high global vascular risk and frequently have
concomitant coronary heart and peripheral
arterial diseases.[8,9] Therefore, the identification
of factors that characterize high-risk ICAS
patients is highly necessary. Third, the real
importance of ICAS may be underestimated,
especially in Caucasians. Traditionally, ICAS
diagnosis has been done based on the detection
of intracranial stenosis, but as high-resolution
magnetic resonance imaging (HRMRI) arterywall studies have shown, arterial remodeling
is present in the intracranial arteries and
accordingly, nonstenotic ICAS may become
a common yet underrecognized problem.[10]
Fourth, the relationship between ICAS, vascular
cognitive impairment, and Alzheimers disease
is unclear and intriguing.[11]In this article, we
have focused on the characterization of highrisk ICAS and more concretely, we attempted
to review the evidence regarding the role of
How to cite this article: Arenillas JF. Intracranial
at eros lerosis an inflammation: essons rom t e
East and the West. Brain Circ 2015;1:47-52.
47

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Arenillas: Inflammation in ICAS

inflammation in determining the risks of progression and

complication of ICAS.

Inflammation in Atherosclerosis:
Local and Systemic Views
Atherosclerosis is a chronic inflammatory process of lipidrich lesion growth in the vascular wall that can cause
myocardial infarction and stroke among other clinical
consequences.[12]An increased mechanistic understanding
of the pathogenesis of atherosclerosis in other vascular
beds has shown that inflammation plays a crucial role in all
stages of atherothrombosis, from early atherosclerotic lesion
formation to its progression and destabilization leading to
clinical events. The dynamics of atherosclerosis over time
can be seen as a struggle between the processes of vascular
injury and repair where persistent inflammation leads to a
predominance of aggressive mechanisms and a derangement
of vascular reparative capacity. From a clinicians perspective,
inflammation requires to be assessed in vivo and in real-time
in order to be incorporated in the diagnosis and treatment of
atherosclerotic patients. Extensive research is being carried
out to develop imaging and molecular methods that will be
able to detect and measure vascular inflammation such as
positron emission tomography-magnetic resonance imaging
(PET-MRI), HRMRI with inflammation-targeted contrasts,
molecular imaging, and biomarkers.
The relationship between inflammation and atherosclerosis
might have to be considered from both a local and a
systemic perspective.[12] Locally, inflammatory infiltration
within the atherosclerotic lesion renders the plaque more
vulnerable, i.e., prone to rupture and suffer thrombotic
complications. Systemically, persisting chronic inflammation
is characterized by excessive circulating inflammatory cells
and proinflammatory cytokines. Circulating monocytes
can be recruited inside the evolving atherosclerotic lesion

Figure 1: Translational research in ICAS

Stages of translational research in ICAS: 1) Identification of the most relevant
clinical problems that remain to be solved through clinical observation 2)
Development of clinical and basic research models oriented to solve the clinical
problem (patient-oriented) 3) Cyclic crosstalk between clinical and basic research
by which the findings obtained at each level influence methodology and result in
interpretation at the other level 4) Clinical trial design and development based on
the results of basic research and clinical pilot studies
48

via adhesion molecules expressed on the dysfunctional

endothelium and can then enter the plaque, thereby kindling
inflammation inside it. Moreover, circulating inflammatory
cytokines originating from different sources may exert their
effects on the endothelium, rendering it more proinflammatory
and prothrombotic. In this context, inflammatory blood
biomarkers may represent a valuable tool to assess in vivo
and in real-time the interplay between systemic and local
inflammations. Vascular risk factors such as hypertension
and hypercholesterolemia can induce the expression of
circulating inflammatory mediators that lead to altered
wall function and promotion of atherosclerosis progression.
While the overexpression of some inflammatory mediators
such as interleukin-6 (IL-6) and C-reactive protein (CRP)
may inform us about the existence of an ongoing chronic
systemic inflammation;[13] other inflammatory molecules such
as lipoprotein-associated phospholipase A2 (Lp-PLA2) are
released into the blood stream from the inflammatory cells
that reside inside the atherosclerotic lesion, thus reflecting the
plaques intrinsic inflammatory activity.[14]

Inflammation and Icas: Unresolved Questions

While the deleterious role of persisting inflammation in
atherosclerosis is clear in all extracranial arterial beds, the lack
of access to pathological specimens from symptomatic ICAS
patients makes it difficult to ascertain how inflammation is
involved in ICAS pathogenesis. Figure 2 illustrates the main
groups of prognostic factors that may influence the outcome of
symptomatic ICAS according to the recent literature. Regarding
the factors associated with the intracranial atherosclerotic
plaque itself, more attention is increasingly being paid to
plaque activity. In this context, what we know from other
arterial territories is that not only are plaque morphology and
the degree of stenosis relevant but that plaque activity may also

Figure 2: Symptomatic ICAS prognostic factor schema

The main prognostic factors in symptomatic ICAS that we know, thanks to the
research done during the last few decades, could be summarized following this
schema. These groups of factors interact among themselves in each ICAS patient
and determine the risk of disease progression and clinical recurrence. Inflammation
may have a dual role in ICAS since the inflammatory response is controlled
systemically and at the same time, local inflammatory infiltration inside the
atheromatous plaque may determine plaque activity. In fact, inflammation typically
exemplifies the intimate interplay between systemic and local factors that may be
as crucial for ICAS as it is for atherosclerosis affecting other arterial beds
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Arenillas: Inflammation in ICAS

play a crucial role in determining the atherosclerotic lesions

risk. Moreover, due to the process of arterial remodeling, large
atherosclerotic plaques may grow outwardly without causing
overt stenosis. The main question that remains to be clarified
here is whether the inflammatory state of the plaque is the main
contributor to the risk of giving rise to acute clinical events in
ICAS as it happens in other arterial beds.
Why would atherosclerosis have a differential behavior in
intracranial arteries? Why do some investigators believe
that it is not possible to directly extrapolate what we have
learnt from other arterial territories and just apply it to
ICAS? First, some classic reports based on necropsy series
stated that atheromatous plaques found in intracranial
arteries were frequently stable and did not often show
the morphological features traditionally associated with
vulnerable plaques.[15,16] This vision has dominated the field
until recent works demonstrated that symptomatic intracranial
atherosclerotic plaques can exhibit the hallmarks of unstable
plaques such as intraplaque vasculature, intraplaque
hemorrhage, or plaque rupture.[17-19] And second, intracranial
arteries have differential anatomic features and are exposed
to particular hemodynamic factors. They are muscular-type
arteries that contain only a few medial elastic fibers, a thick and
dense internal elastic lamina, and a few adventitial vasa vasorum,
and they lack an external elastic lamina.[20] Moreover, the
compliance of the aorta and the carotid arteries maintains a
low pulse pressure in the intracranial arteries, retarding the
development of ICAS until the extracranial arteries stiffness
increases with age and exposure to vascular risk factors. In
addition, intracranial arteries were reported with an enhanced
antioxidant capacity.[21] These unique features are claimed to
justify the special characteristics of intracranial atherosclerotic
lesions found in the recent necropsy series such as fibrosis,
small lipid pools, and a low grade of inflammatory infiltration
by macrophages and T cells.[20] However, this necropsy study
was performed in asymptomatic patients and this theoretical
plaque stability is a contrast with to the aggressive clinical
behavior of this disease once it becomes symptomatic as
has been mentioned earlier in this manuscript. Other recent
studies found increased inflammatory infiltration in the
middle cerebral artery symptomatic versus asymptomatic
atherosclerotic lesions.[18] Therefore, further research is needed
to clarify this issue.
New imaging methods such as HRMRI may help us understand
the real importance of inflammation in ICAS and whether
it varies between individuals and also across the different
intracranial arteries. The first study aiming to correlate HRMRI
findings with plaque histology showed little inflammation
inside the basilar artery plaque, although the plaque was
not deemed to be symptomatic. [22]Interestingly, HRMRI
postcontrast enhancement of intracranial atherosclerotic
plaques is more frequent in symptomatic plaques than in
asymptomatic plaques but whether this phenomenon reflects
the degree of inflammatory infiltration inside the plaque is yet
to be elucidated.[23]

Inflammatory Biomarkers in ICAS

Together with wall-imaging techniques, biomarker
studies represent another valuable method to assess
Brain Circulation - Vol 1, Issue 1, January 2015

the participation of inflammation in ICAS in vivo. Table

1 summarizes some of the most relevant studies with
inflammatory blood biomarkers in ICAS, which have been
published during the past 15 years.[24-37] These studies can
be categorized in three groups. The first group comprises
cross-sectional studies conducted on stroke patients where
biomarker concentration is compared across different stroke
subtypes, including ICAS.[24,26,27,31] Among them, the study
conducted in Caucasian patients showed that the ICAS
group had the highest level of adhesion molecules, which
first suggested the existence of an endothelial inflammatory
activation in this condition. [24] However, the other three
studies conducted on Asian patients found significantly
lower concentrations of CRP and matrix metalloproteinase 2
(MMP-2) in the ICAS group as compared to the extracranial
atherosclerosis group.
The strongest evidence in favor of the involvement of
inflammation in ICAS pathogenesis comes from the second
group of longitudinal studies, which evaluated the capacity
of several inflammatory biomarkers to predict ICAS
progression[29,32,33] and the risk of recurrent stroke and other
vascular events in symptomatic ICAS patients. [25,28,30,34]
Baseline CRP[29] and IL-6[32] level in Caucasian and Asian
symptomatic ICAS patients, respectively, predicted ICAS
progression in long-term follow-up studies. Regarding
the risk of clinical recurrence, biomarkers of systemic
inflammation, such as CRP and leukocyte count, were also
found to be predictors of further ischemic strokes and other
major vascular events in symptomatic ICAS patients.[25,28,34]
Taken together, these findings suggest that persisting
systemic inflammation may promote the progression and
complication of atherosclerosis in the intracranial arteries
also, as it does extracranially. Besides these markers of
systemic inflammation, other molecules that are more
informative about the local inflammatory activity within
the atherosclerotic plaque, such as adhesion molecules and
Lp-PLA2, have also been evaluated in these longitudinal
studies. [30,34] In this context, the most relevant findings
were derived from the Biomarkers of Ischemic Outcomes
in Symptomatic Intracranial Stenosis (BIOSIS) study, a
biomarker study affiliated with the SAMMPRIS clinical
trial the results of which were presented partially at the
2014 International Stroke Conference.[34] Interestingly, LpPLA2 level at the study entry predicted specifically further
ischemic strokes within the symptomatic intracranial
stenosis territory as well as any major ischemic event during
follow-up. This observation strongly supports the hypothesis
that local inflammation inside the intracranial atherosclerotic
plaque may determine its risk of complication, giving rise
to further clinical events.
Finally, the third group of investigations comprises populationbased studies aiming to identify factors associated with
asymptomatic ICAS in apparently healthy individuals.[35-37]
According to those investigating, the relevance of systemic
inflammation in the development of asymptomatic ICAS
remains controversial. In two of the investigations, the CRP
level was found to be lower in asymptomatic ICAS than in
extracranial atherosclerosis;[35,36] the largest study identified
CRP as an independent predictor of asymptomatic ICAS and
intracranial atheromatous burden.
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Arenillas: Inflammation in ICAS

Table 1: Inflammatory biomarker studies in ICAS

Reference
Fassbender et al. 1999[24]

Study design
Single-center, case-control, crosssectional study

N
20 ICAS, 89 ECAS, 64 SVD,
67 controls

Arenillas et al. 2003[25]

Single-center, longitudinal,
observational

71 consecutive symptomatic
ICAS

Bang et al. 2005[26]

Single-center, cross-sectional

Bang et al. 2005[27]

Single-center, cross-sectional

AIS patients: 112 ECAS vs

160 ICAS
439 AIS patients

Obviagele et al. 2007[28]

Multicentric, randomized clinical

trial (WASID)

WASID sample symptomatic

ICAS patients

Arenillas et al. 2008[29]

Single-center, longitudinal,
observational
Single-center, longitudinal,
observational

75 consecutive symptomatic
ICAS
75 consecutive symptomatic
ICAS

Jeon et al. 2012[31]

Single-center, cross-sectional

Shimizu et al. 2013[32]

Single-center, longitudinal,
observational, MRA
Single-center, longitudinal,
observational
Multicentric, randomized clinical
trial (SAMMPRIS)
BIOSIS study

Chronic ischemic stroke.

80 ICAS, 29 ECAS, 68 SVD
48 AIS biomarkers <48 h
onset
179 symptomatic ICAS (BAD)

Massot et al. 2011[30]

Men et al. 2013[33]

Frankel et al. 2014[34]

Takahashi et al. 2008[35]

Lpez-Cancio 2012[36]

Wang et al. 2014[37]

Population-based, cross-sectional,
asymptomatic
Population-based, cross-sectional,
asymptomatic
B-AsIA study
Population-based, cross-sectional,
asymptomatic
Asymptomatic Polyvascular
Abnormalities Community study

SAMMPRIS medical treatment

arm.227 symptomatic ICAS

138 asymptomatic ICAS, 267

ECAS, 435 controls
933 apparently healthy
individuals
5,440 apparently healthy
individuals

Main findings
ICAS group showed the highest level
of circulating adhesion molecules,
E-selectin, and ICAM-1
High CRP as a predictor of further
ICAS-related ischemic events and other
vascular events
CRP level significantly lower in ICAS vs
ECAS
Metabolic syndrome predicts ICAS vs
other subtypes. CRP lower in ICAS
Elevated WBC count at entry predicted
increased risk of stroke and vascular
death
CRP and PAI-1 as predictors of ICAS
progression
Lp-PLA2 activity as a predictor of further
vascular events
Same series: CRP, E-selectin, and PAI-1
as predictors of new ischemic stroke
(unpublished)
Low plasma MMP-2 associated with
ICAS subtype
Baseline IL-6 level predicted
MRA-assessed ICAS progression
Hcy associated with progression and
CRP with poor outcome
Lp-PLA2 predictor of ICAS-related
ischemic stroke, any ischemic stroke,
and stroke andvascular death
E-selectin and CRP predictors of any
ischemic stroke and stroke and vascular
death
CRP level associated with asymptomatic
ECAS, not ICAS
ADMA associated with isolated ICAS.
Resistin-associated with combined
ICAS+ECAS
CRP independent predictor of
asymptomatic ICAS and intracranial
atherosclerotic burden

ICAS = Intracranial atherosclerosis, ECAS = Extracranial atherosclerosis, SVD = Small vessel disease, ICAM-1 = Intercellular adhesion molecule 1,
CRP = C-reactive protein, AIS = Acute ischemic stroke, WBC = White blood cell, PAI-1 = Plasminogen activator inhibitor 1, LpPLA2 = Lipoprotein-associated
phospholipase A2, MMP-2 = Matrix metalloproteinase 2, BAD = Branch atheromatous disease, ADMA = Asymmetric dimethylarginine

Regarding their potential clinical applicability, inflammatory

biomarkers in ICAS could be very useful for:
1. Risk stratification in ICAS patients by helping to identify
those patients at a higher risk of future ischemic stroke or
major vascular events, thus aiding in preventive strategies
design;
2. The evaluation and monitoring of the intensity of plaques
inflammatory activity over time and its response to different
therapies; and
3. The identification of new therapeutic targets and drugs
against ICAS progression and complication.
In order to develop this promising potential and be able
to incorporate inflammatory biomarkers into the clinical
routine, some of the highest priorities for future research
would be:
50

1. New biomarker discovery using molecular pathways

arrays and omics technology,
2. Advanced statistics to identify biomarkers whose predictive
capacity has an added value over the prediction provided
by well-established risk factors in ICAS,
3. Multimodal studies combining modern imaging methods
and biomarker technology, and
4. Basic research with biomarkers in animal models of ICAS.

Conclusion
A growing body of evidence provided by biomarker studies
strongly supports the hypothesis that inflammation is
involved in the progression and complication of symptomatic
ICAS. Thus, inflammatory biomarkers may have an increasing
clinical applicability in the identification of high-risk ICAS
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Arenillas: Inflammation in ICAS

patients and in monitoring the response to preventive

therapies. Moreover, some of the biomarkers themselves
could become therapeutic targets for new anti-inflammatory
strategies. Finally, multimodal studies combining modern
imaging methods and novel biomarker technology might be
needed to clarify the role of inflammation in ICAS and its
therapeutic potential.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.

16.

17.

18.

19.

20.

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