Brain microbleeds: more evidence, but still a clinical dilemma

Charlotte Cordonnier
Univ Lille Nord de France, CHU Lille, EA 1046. Pole de
neurologie, Lille, France
Correspondence to Charlotte Cordonnier, MD, PhD,
Univ Lille Nord de France, CHU Lille, EA 1046. Pole de
neurologie, F-59000 Lille, France
Tel: +33 320 446814; fax: +33 320 446028;
e-mail: charlotte.cordonnier@chru-lille.fr
Current Opinion in Neurology 2011, 24:6974

Purpose of review
Brain microbleeds (BMBs) are a radiological construct that is meant to represent a
specific underlying microscopic pathology: perivascular collections of hemosiderin
deposits. BMBs may represent two different types of underlying vasculopathies:
hypertensive vasculopathy and cerebral amyloid angiopathy. This brief review highlights
some recent works discussing their nature, and both their diagnostic and prognostic
values.
Recent findings
The improvement of detection techniques has modified our perception of BMBs
prevalence, which can reach 35% among healthy people compared with 5% when
conventional techniques are used. Our knowledge on BMBs is evolving very quickly.
The careful study of their anatomical distribution sheds light on their histological
significance: deep BMBs may represent hypertensive vasculopathies and lobar ones
cerebral amyloid angiopathy.
Summary
Despite an explosion of publications on BMBs, their diagnostic and prognostic values
have only received indirect support and remain to be explored. To date, BMBs should
not contraindicate antithrombotic treatment in settings wherein benefits have clearly
been demonstrated in clinical trials and meta-analyses. One intriguing field is
Alzheimers disease, in which BMBs may be a missing link between two important
theories on the neuropathogenesis of Alzheimers disease: the amyloid cascade
hypothesis and the vascular hypothesis.
Keywords
cerebral amyloid angiopathy, dementia, microbleeds, small-vessel disease, stroke
Curr Opin Neurol 24:6974
2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
1350-7540

Introduction
The increasing use of hem-sensitive gradient echo
(GRE-T2) sequences in MRI of the brain during the
research and clinical investigation of neurological disorders especially stroke has led to the frequent
detection of small, homogeneous, round foci of low signal
intensity called brain microbleeds (BMBs). They have
been considered as rare and silent lesions, but the development of specific magnetic resonance sequences raised
the interest in this radiological construct that is meant to
represent a specific underlying microscopic pathology:
perivascular collections of hemosiderin deposits. Many
studies in different settings demonstrated that BMBs are
not at all rare. Using conventional magnetic resonance
sequences, the prevalence of BMBs is about 5% in
healthy people, but increase with age, 34% in ischemic
and 60% in hemorrhagic strokes [1]. The prevalence is
less in first-ever compared with recurrent strokes,
suggesting that BMBs are a marker for the evolution or
severity of the underlying cerebrovascular disease. In
Alzheimers disease, one patient out of five has BMBs
and this finding might shed some light on the complex
1350-7540 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

pathophysiology of Alzheimers disease. BMBs also raise

many clinical dilemmas as their diagnostic and prognostic
values remain unclear (Fig. 1).
Despite the appearance of several comprehensive
reviews of BMB [15], recent advances warrant a new
assessment of our current state of knowledge. This
review focuses on BMB detection, temporal changes,
interpretation and controversial data for the use of BMBs
as diagnostic or prognostic markers. Finally, we review
data on the intriguing field of BMBs in Alzheimers
disease.

Basis for review and identification of

references
References for this article were identified through searches
of the MEDLINE database with search terms microbleed(s), microh(a)emorrhage(s), petechial h(a)emorrhage(s) between January 2009 and August 2010. The
references from identified articles and the authors own
files were also searched for relevant publications. Only
articles published in English or with available translations
DOI:10.1097/WCO.0b013e328341f8c0

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70 Cerebrovascular disease

of relevant data were reviewed. The final reference list was

chosen on the basis of relevance to the topics covered in
this article.

Detection of brain microbleeds: improvement

of techniques modify the estimated
prevalence
Visual interpretation of BMBs may be difficult and may
explain variations in reported prevalence. Indeed, BMBs
are often less than 5 mm and have many potential mimics.
Validated visual scales such as Brain Observer MicroBleed Scale (BOMBS) [6] or Microbleed Anatomical
Rating Scale (MARS) [7] will help to improve intraobserver and interobserver reliability. Technical issues
are also responsible for the heterogeneity of the literature
data. Sequence parameters that particularly affect sensitivity to susceptibility in T2-weighted MRI are flip
angle and echo time [8]. High spatial resolution offers
the possibility of minimizing the partial volume averaging that might interfere with BMB detection. Using
a three-dimensional Fourier transform technique in T2weighted MRI allows acquisition of very thin image
slices. Application of three-dimensional T2-weighted
MRI at high spatial resolution was shown to depict more
BMBs when compared with conventional two-dimensional GRE at lower resolution: with this technique
the prevalence of BMBs in healthy people increased to
35.5% [9]. Use of image postprocessing techniques such
as susceptibility-weighted imaging may further enhance
the contrast between brain tissue and hemosiderin deposits and its application to BMB imaging also appears

Key points
 BMBs diagnostic and prognostic values have only
received indirect support and remain to be
explored.
 BMBs should not contraindicate antithrombotic
treatment in settings wherein benefits have clearly
been demonstrated in clinical trials and metaanalyses.
 One intriguing field is Alzheimers disease, in which
BMBs may be a missing link between two important theories on the neuropathogenesis of Alzheimers disease: the amyloid cascade hypothesis and
the vascular hypothesis.
promising, yielding substantially higher contrast index
for individual BMB relative to conventional T2weighted MRI [10,11]. Magnet strength also improves
detection rate [10]. Moreover, the use in research of
7-Tesla machines enabling visualization of BMBs and
information about their relation with arteries and veins
will contribute to improve our understanding of BMBs
development [12]. Unfortunately, to date, no consensus
has been reached to recommend a specific imaging protocol and heterogeneity in methods used in the literature
may remain for some time.

Is there a continuum between brain

microbleeds and macrobleeds?
It seems that the volume of small and big hemorrhages
has a bimodal distribution [5]. The cut-point that best

Figure 1 Brain microbleeds

Brain MRI (axial slice, gradient echo T2 sequence) showing (a) one brain microbleed in deep location (black arrow) and (b) two brain microbleeds in
cortico-subcortical location (white arrows).

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Brain microbleeds Cordonnier 71

divides the microbleed and macrobleed peaks is a

diameter of 5.1 mm, similar to the 510 mm maximum
conventionally used to define BMBs. This suggests that
microbleeds and macrobleeds may represent two distinct
entities, perhaps with different pathophysiology. Unfortunately, these measurements were only performed in
patients with probable cerebral amyloid angiopathy
(CAA) and, therefore, cannot be generalized [for example
to deep intracerebral hemorrhages (ICHs) due to smallvessel disease].

Temporal changes of brain microbleeds

Until recently, few data were available regarding the
temporal changes of BMBs [13] and published data on
BMBs mainly came from cross-sectional designs. As
clinicians were concerned with their potential prognostic
values, some authors carefully studied their temporal
changes.
In a small cohort of 21 surviving patients with ischemic
stroke or transient ischemic attack, half of surviving
patients with BMBs at baseline developed new BMBs
over a 5.6-year period compared with only 8% of matched
microbleed-free patients. The presence of BMBs at baseline predicted new BMB development. Data from a
memory clinic were also available and in a naturalistic
cohort of 254 memory clinic patients who underwent
repeated MRI over an average period of 2 years, one
or more new BMBs were observed in 12% of patients
[14]. Here again, presence and number of baseline
BMBs were strong predictors of incident BMBs. If new
BMBs appearance over time is a marker of poor prognosis,
we might hypothesize that their evaluation on sequential
MRI will help to tailor and monitor our treatments.

certain diagnosis is based on histological examination of

brain tissue. The diagnosis is, therefore, mainly made at
postmortem. Neuroradiological markers such as BMBs
would be very helpful, but to date, despite their wide use
by clinicians, BMBs have not been validated in pathological studies as part of the diagnostic criteria for probable CAA. In the first article validating the Boston criteria
published in 2001 [17], BMBs were not systematically
evaluated as 24 of 39 patients were investigated either
with computed tomography (n 17) or MRI without
GRE-T2 sequences (n 7). Moreover, the patients
included in this study had all suffered from a large
ICH, precluding generalizability of the results to other
populations. Focusing on patients with a genetic Dutch
form of CAA, van Rooden et al. [18] evaluated the
diagnostic value of lobar BMBs when included in the
Boston criteria. The integration of BMBs in the criteria
slightly improved without reaching statistical significance from 59% [95% confidence interval (CI) 4175]
to 67% (95% CI 4881). Because all patients were
affected by the disease, no data on specificity or predictive values can be extracted. Apart from that, generalizability of these results coming from a rare genetic form
of disease remains arguable. Whether a lobar distribution
of BMBs can be used to make the diagnosis in the
absence of macrobleed remains to be determined, but
this idea has received indirect support from the correlation between isolated lobar BMBs and the apolipoprotein E (APOE) e4 allele noted in the population-based
Rotterdam Scan Study [19]. Given the relationship
between APOE e4 and CAA, these results raise the
interesting possibility that isolated lobar BMBs might
reflect the presence of advanced CAA.

Brain microbleeds and antithrombotic

treatments
Brain microbleeds: a radiological construct
that is meant to represent a specific
underlying microscopic pathology
Published reports of the pathology of BMBs are scarce
[15]. Data suggest that they are associated with two
different underlying vasculopathies: hypertensive vasculopathy and CAA. Even if this may be an oversimplistic
approach, BMBs located in deep regions of the brain such
as basal ganglia may reflect hypertensive vasculopathy
and those located in lobar regions may reflect CAA. A
recent postmortem MRI study performed in demented
patients brings some valuable histological data to support
this approach [16].

Brain microbleeds as a diagnostic marker for

cerebral amyloid angiopathy?
The major problem with sporadic CAA is the absence of
reliable, noninvasive diagnostic tests. Currently, the only

In a population-based sample of 1062 people, 60 years

and older and free of dementia, but some with vascular
risk factors or previous history of stroke, BMBs were more
prevalent among users of antiplatelet drugs (adjusted
odds ratio 1.71, 95% CI 1.22.4) [20]. These data
should be carefully interpreted. Indeed, some general
newspapers (for example in UK or France) alerted the
general population on the potential risk of antiplatelet
drugs. Data from such a cross-sectional study do not,
however, show that these patients with BMBs are at
increased risk of bleeding when treated with antiplatelet
drugs. The presence of BMBs on MRI does not tell us
when these bleeds actually occurred. Vascular disease or
risk factors may act as a confounder here: BMBs may be
due to the ongoing vascular disease and not to the
treatment of this disease.
Lovelock et al. [21] recently brought the first systematic
evidence of an association between warfarin-associated

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72 Cerebrovascular disease

ICH and BMBs. In a pooled analysis of 3817 patients with

ischemic stroke or transient ischemic attack and 1460
patients with ICH, the authors found an excess of BMBs
in warfarin-associated ICH that was not found in warfarin-associated ischemic stroke or transient ischemic
attack. Although there were relatively few data on
warfarin users, these preliminary results indicate that
warfarin may be hazardous in patients with BMBs.
Similar but weaker associations between BMB frequency
and antiplatelet-associated ICH were also seen, but these
results have to be interpreted with caution because there
was significant heterogeneity between cohorts in analyses
involving antiplatelet-associated ICH. The limited available prospective data also support the hypothesis that the
presence of BMBs increases the risk of future ICH as a
complication of antithrombotic drug use. More data are
required on ICH in non-Asian cohorts. The risk of
antithrombotic-associated ICH appears to be highest in
Asian patients, and so the apparent risk of antithrombotic-associated ICH in the presence of BMBs may also
differ between ethnic groups. These data suggest that
more prospective data on the safety of antithrombotic
drugs in such patients are urgently required.

stroke; second, the risk of future ICH (despite secondary

prevention) in a population of ischemic strokes is very
low even in the presence of BMBs. The same finding was
found in a small prospective study of 21 patients during
a mean follow-up for 5.6 years: among eight patients
with BMBs, only one ICH occurred versus no ICH in
13 patients without BMBs [28].
Among patients suffering from an ICH, no recent studies
were published and some data suggest, especially in lobar
ICH, that lobar BMBs might predict future risk of symptomatic ICH [13]. However, this question remains to be
further studied in large prospective cohorts.

Brain microbleeds and Alzheimers disease

In Alzheimers disease, BMBs are of special interest as
they may have a crucial role in the pathophysiology of the
disease. They may be a missing link between two important theories on the neuropathogenesis of Alzheimers
disease: the amyloid cascade hypothesis and the vascular
hypothesis.
Evidence for a link with cerebral amyloid angiopathy

Therefore, to date, in patients with BMBs, antithrombotic treatment should not be contraindicated in the setting
of a clear overall benefit established from randomized
trials and meta-analyses. For antiplatelet drugs in the
setting of primary prevention, no data are available to
date and it is possible that in patients with multiple
BMBs, the benefit/risk ratio is less favourable than it
is overall.

Brain microbleeds as a prognostic marker for

recurrent strokes?
The design of studies aiming at answering such an
important clinical question is fundamental, but very often
a poor design has altered the quality of the results.
Previous data suggested that stroke patients with BMBs
were more likely to suffer from a recurrent stroke during
follow-up.
Studies showing an increased risk of ICH in patients with
BMBs after an ischemic stroke were mainly performed in
Asian populations [2225]. One study performed in
Canada suggested that the risk of recurrence mainly
concerned ischemic events [26]. Thijs et al. [27] found
that among 487 patients followed-up for a median of
2.2 years, two patients developed ICH, 32 recurrent
ischemic strokes and three an undetermined stroke.
Lobar BMBs (alone or in association with deep BMBs)
were associated with recurrent strokes. This study highlighted two things: first, BMBs are a marker of the
severity of the underlying vascular disease, but only lobar
BMBs were associated with an increased risk of recurrent

In Alzheimers disease, only eight brains have been

reported to date [16]. The majority of the BMBs
appeared in a cortico-subcortical location and amyloidb deposition was present in the vessel walls adjacent to
the bleeds suggesting that cortico-subcortical BMBs are a
consequence of underlying CAA. Other data support the
link with CAA: in a study comparing Alzheimers disease
patients with many BMBs to Alzheimers disease patients
without any BMB, patients with many BMBs were more
likely to be homozygous for APOE e4 and to have more
severely reduced levels of cerebrospinal fluid amyloid-b
142 than Alzheimers disease patients without any
BMBs [29]. Notably, the BMBs in this study almost
invariably had a cortico-subcortical location.
Prognostic markers in Alzheimers disease?

A study on the predictive value of BMBs in patients with

mild cognitive impairment showed that the observation
of at least one BMB on MRI yielded more than two-fold
increased, though nonsignificant, risk of developing nonAlzheimers dementia [30]. Another study showed that
occurrence of BMBs on susceptibility-weighted MRI in
patients with mild cognitive impairment predicted subsequent cognitive decline [31]. Only one study investigated the association of BMBs with subsequent mortality
[32]. BMBs on presenting MRI were associated with
more than two-fold increased risk of mortality which
could not be explained by other expressions of smallvessel disease on MRI (i.e. white matter hyperintensities), or vascular comorbidity. There was a clear dose
effect relationship, with a higher number of BMBs being
related with an increased risk, whereas one or a few

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Brain microbleeds Cordonnier 73

BMBs did not have much impact. It is tempting to

assume that the increased risk of mortality is due to
increased occurrence of hemorrhage, but at present this
remains speculative.

Conclusion
Despite an explosion of publications on BMBs, their
diagnostic and prognostic values have only received
indirect support and remain to be explored. Improvement
of imaging techniques will help to better understand how
BMB appears and how they evolve. Unfortunately, MRI
will not be sufficient to discuss the histological substrate
of those intriguing lesions and we desperately need
histological data in this field. To date, BMBs should
not contraindicate antithrombotic treatment in settings
in which benefits have clearly been demonstrated.

References and recommended reading

Papers of particular interest, published within the annual period of review, have
been highlighted as:

of special interest
 of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (p. 92).

14 Goos JD, Henneman WJ, Sluimer JD, et al. Incidence of cerebral microbleeds:
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naturalistic evolution of BMBs in a memory clinic setting with detailed data on
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authors designed an MRI protocol dedicated to improve the detection of BMBs.
Then they had a look at the association between antithrombotic treatment at the
time of MRI and the presence (and anatomical distribution) of BMBs. With its large
sample size (1062 patients) and population-based design, their results are robust.
Unfortunately, it is a cross-sectional study precluding conclusions on BMBs
prognostic value.

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causing difficulty in distinguishing BMBs from mimics.

8


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27 Thijs V, Lemmens R, Schoofs C, et al. Microbleeds and the risk of recurrent


stroke. Stroke 2010; 41:20052009.
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74 Cerebrovascular disease
29 Goos JD, Kester MI, Barkhof F, et al. Patients with Alzheimer disease with
 multiple microbleeds: relation with cerebrospinal fluid biomarkers and cognition. Stroke 2009; 40:34553460.
Previous studies were not able to show any relationship between BMBs occurrence and cognitive performance. In previous studies, most patients had only one
or a few BMBs. Therefore, the authors designed a proof-of-principle casecontrol
study and selected the 5% of patients with Alzheimers disease with the most
severe BMBs burden and compared these with patients with Alzheimers disease
without any BMBs. They showed a relationship between multiple BMBs and more
pronounced impairment in a number of cognitive domains.
30 Staekenborg SS, Koedam EL, Henneman WJ, et al. Progression of mild
cognitive impairment to dementia: contribution of cerebrovascular disease
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31 Kirsch W, McAuley G, Holshouser B, et al. Serial susceptibility weighted MRI

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32 Henneman WJ, Sluimer JD, Cordonnier C, et al. MRI biomarkers of vascular


damage and atrophy predicting mortality in a memory clinic population. Stroke
2009; 40:492498.
This is the first study assessing the predictive value of BMBs with respect to
mortality in a population other than a stroke population. The authors included 1138
consecutive patients including 357 patients with Alzheimers disease. Unfortunately, the study was not designed to collect data about cause of death of all
deceased patients.

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