open access: Nature Reviews: Key Advances in Medicine

of stroke-related death compared with those
with no lesions. The location of the lesions
also affected the risk of poor clinical outcomes:
compared with individuals without
any lesions, patients with nonlobar microbleeds
had a twofold increase in the risk of
cardiovascular death, and indivi duals with
probable CAA type (lobar) microbleeds had
a sevenfold increase in the risk of strokerelated
death. These findings support the
hypothesis that microbleeds have separate
etiologies depending on their location in
the brain, 1 and may provide an indication
for the use of anticoagulant treatment in
patients with these lesions—in particular,
those with lobar microbleeds.
The importance of detecting microbleeds
before and during clinical trials was underlined
in an extensive review on amyloidrelated
imaging abnormali ties (ARIA) by
Sperling et al. for the Alzheimer’s Association
Research Roundtable Work group. 6
These imaging abnormalities, seen on MRI,
are thought to represent a spectrum of ‘leaky
vessels’ that occur following anti- amyloid
immunization therapy. The working hypothesis
was that vasogenic edema (now called
ARIA-E) caused leakage only of proteinaceous
fluids from the vessels, whereas
microbleeding—under the new umbrella
term ARIA-H (for hemorrhage)—caused
more-extensive leakiness of the vessels
that allowed blood cells to cross the blood–
brain barrier. For patients in clinical trials,
the presence of microbleeds at baseline
may be a risk factor for developing ARIA,
Key advances
■ Lobar microbleeds in patients with
dementia were found to be associated
with high amyloid burden 3
■ Microbleeds were shown to have
different etiologies and associated risk
of mortality on the basis of their location
in the brain 5
■ New terminology for amyloid‑related
imaging abnormalties (ARIA) and a
new cut‑off point for microbleeds in
participants of amyloid‑modifying clinical
trials were introduced 6
■ Susceptibility‑weighted imaging showed
enhanced sensitivity for detecting
microbleeds compared with gradient‑
echo imaging, and may help in future
for identifying associations between
microbleeds and clinical outcomes 7
■ Studies that compared imaging with
histopathology of microbleeds suggest
that further refinement of imaging
techniques is required to accurately
detect these lesions 8
as the number of lobar lesions is assumed
to correlate with the presence and severity
of CAA.
Given the uncertainty regarding the risk
of ARIA and concerns about CAA severity,
Sperling et al. recommended a cut-off value
for the exclusion of participants in trials of
amyloid-modifying therapies for AD at four
microbleeds. 6 This new guideline allows for
variability in imaging measurements and
reflects the uncertainty regarding the clinical
relevance of small numbers of microbleeds.
The authors further stated that occurrence of
new asymptomatic microbleeds in patients
during trials should not auto matically disqualify
them from receiving further treatment;
however, owing to a lack of data,
no exact cut-off for dis qualification could
be given. As the authors stressed, counting
of microbleeds is not an exact science,
and the uncertainty is further complicated
by the varying sensitivities of different MRI
techniques for detecting these lesions.
Reporting in Stroke in May 2011, Goos
et al. 7 compared conventional gradient-echo
imag ing with SWI to detect microbleeds in
140 patients from a memory clinic, and
also to determine whether microbleeds
were associated with patient and clinical
characteristics. As expected, use of the
more-advanced SWI technique enabled
identi fication of patients with microbleeds
with a greater sensitivity than could be
achieved with gradient-echo imaging (40%
versus 23%). SWI also detected a higher
num ber of microbleeds per patient than
did gradient-echo imaging. However, the
corre lation between lesion numbers, clinical
out comes and other radiological outcomes
was limited. The clinical relevance of microbleeds
will probably depend more on their
location and size, than on the total number
of lesions per se. The authors concluded,
therefore, that although new imaging techniques
can show a higher number of lesions,
conventional imaging methods can already
detect the majority of clinically relevant
lesions. New imaging methods might help
in identifying any associations between
lesions and clinical and radiological outcomes;
however, these new techniques are
in urgent need of validation.
De Reuck et al. 8 made an interesting
attempt to validate MRI findings with
patho logy, as reported in Cerebrovascular
Disorders. The researchers investigated
20 post mortem brains from patients with
AD with different cerebrovascular lesions.
Images of 45 large sections of the cerebral
hemi spheres, brainstem and cere bellum
NEUROLOGY
Figure 1 | Brain microbleeds on MRI.
Numerous lobar microbleeds with sparing of
the basal ganglia and thalamus, suggestive
of severe cerebral amyloid angiopathy in a
71‑year‑old patient with dementia with
Lewy bodies. Image obtained using
susceptibility‑weighted imaging at 3T.
obtained using 7.0T T2*-weighted MRI
were paired with images showing histological
detection of hematomas and microbleeds.
In the cortico- subcortical regions,
the sensitivity, specificity, and positive and
negative predictive values of T2* imaging
to detect microbleeds were excellent.
How ever, analysis of MRI alone resulted
in an over estimation of microbleeds in
the stria tum due to the presence of iron
de posits that were, in fact, not related to
real hemor rhages. Furthermore, 31% of T2*
hypo signals in the deep white matter were
shown to be vessels filled with post mortem
thrombi. Judging from these findings,
more studies are needed before we can fully
understand the correlations between MRI
and pathology in patients with AD.
From this selection of studies published
in 2011, we can conclude that lobar microbleeds
are a marker for underlying amyloid
patho logy, are associated with strokerelated
mortality, and should be adequately
investi gated in patients participating in
anti- amyloid clinical trials. Optimizaton
of imaging methods to detect microbleeds
will be of the utmost importance,
and emerging techni ques will need to be
evaluated and calibrated using clinical and
pathological correlates.
VU University Medical Center, Alzheimer Center,
Department of Neurology, De Boelelaan, 1118
1081 HZ Amsterdam, The Netherlands
(P. Scheltens, J. D. C. Goos).
Correspondence to: P. Scheltens
p.scheltens@vumc.nl
KEY ADVANCES IN MEDICINE JANUARY 2012 | S61