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Cerebral microinfarcts: the invisible lesions
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Smith, EE, Schneider, JA, Wardlaw, JM & Greenberg, SM 2012, 'Cerebral microinfarcts: the invisible
lesions', Lancet Neurology, vol. 11, no. 3, pp. 272-282. https://doi.org/10.1016/S1474-4422(11)70307-6
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10.1016/S1474-4422(11)70307-6
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Cerebral Microinfarcts: The Invisible Lesions
Eric E. Smith, MD
1
, Julie A. Schneider, MD
2
, Joanna M. Wardlaw, MD
3,4
, and Steven M.
Greenberg, MD
5
1
Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary,
AB, Canada
2
Departments of Pathology and Neurological Sciences, Rush Alzheimer’s Disease Centre, Rush
University Medical Center, Chicago, IL, USA
3
Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE), University of Edinburgh, UK
4
Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration
5
Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
SUMMARY
The association between small but still visible lacunar infarcts and cognitive decline has been
established by multiple population-based radiological and pathological studies. Microscopic
examination of brain sections reveals even smaller but substantially more numerous
microinfarcts
,
the focus of the current review. These lesions often result from small vessel pathologies such as
arteriolosclerosis or cerebral amyloid angiopathy. They typically go undetected in clinical-
radiological correlation studies that rely on conventional structural MRI, though the largest acute
microinfarcts may be detectable by diffusion-weighted imaging. Given their high numbers and
widespread distribution, microinfarcts may directly disrupt important cognitive networks and thus
account for some of the neurologic dysfunction seen in association with lesions visible on
conventional MRI such as lacunar infarcts and white matter hyperintensities. Standardized
neuropathological assessment criteria and development of non-invasive means of detection during
life would be major steps towards understanding the causes and consequences of the otherwise
macroscopically invisible microinfarct.
© 2012 Elsevier Ltd. All rights reserved.
Corresponding author: Dr. Steven M. Greenberg, Department of Neurology, Massachusetts General Hospital, Kistler Stroke Research
Center, 175 Cambridge Street, Boston, MA, 02114, sgreenberg@partners.org.
CONFLICT OF INTEREST STATEMENT
Dr. Smith reports no conflicts of interest. Dr. Schneider reports serving as a consultant to AVID Radiopharmaceuticals, and serving on
advisory boards to Eli Lilly and Company and GE Healthcare. Dr. Wardlaw reports no conflicts of interest. Dr. Greenberg reports no
conflicts of interest.
AUTHOR CONTRIBUTIONS
Dr. Smith performed the literature search, reviewed relevant articles, carried out meta-analysis, wrote the first draft of sections of the
manuscript, and made revisions to the manuscript content. Dr. Schneider reviewed relevant articles from the literature search,
identified additional relevant articles, wrote the first draft of sections of the manuscript, and made revisions to the manuscript content.
Dr. Wardlaw reviewed relevant articles from the literature search, identified additional relevant articles, wrote the first draft of
sections of the manuscript, and made revisions to the manuscript content. Dr. Greenberg conceived the project, reviewed relevant
articles from the literature search, identified additional relevant articles, and made revisions to the manuscript content.
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NIH Public Access
Author Manuscript
Lancet Neurol
. Author manuscript; available in PMC 2013 March 01.
Published in final edited form as:
Lancet Neurol
. 2012 March ; 11(3): 272–282. doi:10.1016/S1474-4422(11)70307-6.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
INTRODUCTION
Many neuropathology and neuroimaging studies have shown that asymptomatic
cerebrovascular disease is extremely common.. Further, this so-called “silent” pathology
accounts for a surprisingly high portion of dementia.
1
Lacunes and white matter lesions
(WMLs) in particular have emerged as clear-cut risk factors for dementia in multiple
population-based clinical-radiological studies.
2, 3
While the association between these visible manifestations of cerebral small vessel disease
is strong and consistent, the mechanism remains challenging to explain. Are one or two
lacunes, for example, truly sufficient to impair cognition as suggested epidemiologically?
An important alternative explanation is that those few readily detectable lesions are instead
markers for substantially more numerous and widespread infarcts that are not visible to the
naked eye. Tiny
microinfarcts
are indeed a well described neuropathologic finding. These
lesions are characterized by bona fide tissue infarction, but on a scale that renders them
unapparent on gross pathologic examination or conventional structural MR imaging. This
review synthesizes current knowledge of the detection, appearance, prevalence, distribution,
and functional impact of microinfarcts along with recommended areas for future
investigation. Although microinfarcts represent just one in a spectrum of small vessel-
associated forms of brain injury (a list that also includes white matter T2-hyperintense
lesions and cerebral microbleeds), current data suggest that they may comprise the single
most widespread form of brain infarction and thus a major component of the causal pathway
between cerebral small disease and cognitive dysfunction.
SEARCH STRATEGY AND SELECTION CRITERIA
The PubMed database was searched with the Ovid search engine on December 2 2011 using
the terms “microinfarct(s)” and “microscopic infarct(s)” as keywords and MeSH headings,
and limited to articles including “brain”, “cerebral” or “central nervous system” as keywords
or MeSH headings. The search yielded 535 articles. A single author (EES) screened the
abstracts and eliminated 438 articles as not relevant; all study authors reviewed the
remaining 97 articles. Another 27 relevant articles were identified by consultation with
experts and hand searching of the reference lists of the retrieved articles.
STATISTICAL ANALYSIS
To derive the univariate pooled odds ratio for the relationship between microinfarcts and
dementia, we abstracted information on the prevalence of microinfarcts in persons with and
without dementia from the studies selected for review (see “Search Strategy and Selection
Criteria”). To reduce the risk of bias we only pooled data from community-based studies of
all-cause mortality that prospective selected participants during life, without including
hospital or clinic-based studies, for example. Univariate odds ratios were graphically
displayed as a forest plot and a pooled odds ratio was calculated using the DerSimonian and
Laird random effects model.
4
Heterogeneity in the odds ratios across studies was quantified
by the I-squared measure
5
and tested using the chi-square test. Statistical analyses were done
using Stata version 9.2 (StataCorp, Texas, USA).
NEUROPATHOLOGY OF MICROINFARCTS
Cerebral microinfarcts are typically defined as sharply delimited microscopic regions of
cellular death or tissue necrosis, sometimes with cavitation (that is, a central fluid-filled
cavity). The term “microscopic” denotes that these lesions are not visible by gross
inspection of the brain but seen by light microscopy (Figure 1).
6–9
The term “infarct” is
most commonly used for ischemia-related tissue loss, and indeed the pathologic appearance
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of microinfarcts is consistent with that of known ischemic infarctions. The precise
pathophysiologic cause or causes of microinfarcts are not entirely defined, however. To be
consistent with prior literature, we will nonetheless continue to refer to these lesions as
“microinfarcts.”
There are surprisingly few guidelines for the identification of microinfarcts, and many
studies provide little information on inclusion or exclusion criteria. The National Institute of
Neurologic Disorders and Stroke – Canadian Stroke Network Vascular Cognitive
Impairment (NINDS-CSN VCI) Harmonization Standards
6
uses the standard approach
defining microinfarcts as lesions “not visible to the naked eye but detected on histologic
examination” and further suggest that microinfarcts be differentiated from “incomplete
ischemic injury” or subinfarctive lesions, which appear as foci of cell loss or tissue
rarefaction with reactive changes but without frank tissue loss. However, this differentiation
can be difficult in practice. For example, a tissue section at the periphery of a genuine
microinfarct may demonstrate only subinfarctive changes, as cavitated infarcts can be
surrounded by gliosis some distance from their nidus.
10
For this reason, some studies are
inclusive of these incompletely infarcted lesions and define microinfarcts to include foci of
tissue pallor or astrocytosis,
8, 11, 12
whereas others require evidence of frank tissue necrosis
or encephalomalacia.
7, 13, 14
Some studies further exclude infarcts that are over 2 mm
14
or 4
mm
12
in diameter; presumably to exclude lesions that should be grossly visible. Another
source of variability in microinfarct detection is staining method. Although most studies
suggest that microinfarcts are readily identified on routine hematoxylin and eosin (H&E)
stain,
7, 11
immunohistochemical staining for markers of tissue injury such as reactive
astrocytes
15
or activated microglia
16
may make microinfarcts more recognizable and easier
to count.
7
However, the sensitivity and specificity of different staining methods for
microinfarcts has not been rigorously studied.
When identified in early stages of their evolution, microinfarcts show the predicted acute
ischemic appearance of red neurons (if cortical) and loss of tinctorial staining quality,
sometimes with vacuolization from cytotoxic edema. In subacute stages (starting at 3 to 5
days post-infarct), the lesions demonstrate an influx of macrophages that often clearly
demarcate the central region of the infarct from surrounding tissue. At approximately 10
days this is followed by a surrounding gemistocytic astrocytosis and fading of the dying
neurons. Chronic lesions typically show cavitation with few remaining central macrophages
and a surrounding fibrillary gliosis. However, chronic microinfarcts can also appear as a
linear “scar” with acellularity and fibrillary gliosis but little or no cavitation, causing
invagination of the pial surface and puckering of the surrounding tissue when in the cortex,
or if numerous, creating a cortical appearance of “granular atrophy”.
17
It is important to note
that like other foci of tissue necrosis, microinfarcts can have distant tissue effects such as
Wallerian, retrograde, or transynaptic degeneration.
7
The combination of local peri-infarct
gliosis
10
and distant degeneration may thus make the pathologic impact of microinfarcts
more widespread than simply the tissue volume occupied by the microinfarcts themselves.
Typical microinfarct size appears to be quite small. In a study of microscopic lesions
containing tissue necrosis, mean diameter of the lesions was approximately 0.2 mm.
18
In
another community-based clinical-pathologic study of aging the average size was much
larger, 1mm, with a range of 0.2 to 2.9 mm.
19
The small average size highlights the
challenges in designing imaging methods for detecting microinfarcts (see later
Neuroimaging of Cerebral Microinfarcts).
Microinfarcts are very common in the aging brain. Estimates of the frequency of one or
more detectable microinfarcts range from 16% to 46% in unselected elderly persons dying
of all causes (Table 1). Microinfarcts were detected in 33% of cognitively normal elderly
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dying of all causes in a combined analysis of 4 studies.
20
The heterogeneity in observed
prevalence likely arises in part from differences in cohort characteristics such as age and
coexisting medical conditions. An additional source of variation is the sampling strategy.
Because microinfarcts are very small lesions within a large brain that is typically only
sparsely sampled for microscopic pathology, their prevalence is likely to be affected by both
the volume and location of examined tissue. Sampling strategy is not necessarily the
overriding determinant of microinfarct prevalence, however; for example, a frequency of
19.3% was reported with 38 regions sampled
11
whereas another study found a frequency of
30% with only 9 regions sampled.
21
Microinfarct burden is often expressed as the number of microinfarcts per number of blocks
from specific regions
16
or by semiquantitative estimates across all sampled tissue blocks
(e.g. none, one, more than one or more than two).
8, 14, 22
The numbers of microinfarcts
detected in these studies are likely vast underestimates of the total brain burden, however, as
even systematic tissue sampling methods examine only a tiny fraction of the overall brain
volume. Calculations based on the sampling protocol used in reference 21 indicate that
observation of 1 or 2 microinfarcts in sampled tissue suggests the likely presence of
hundreds of microinfarcts across the total brain volume (Schneider and Greenberg,
unpublished data). Although direct measurement of total brain microinfarct burden has not
been performed (and may indeed be impractical), these calculations suggest that true number
is almost certainly orders of magnitude greater than the total burden of grossly visible
lacunar infarcts (typically 1 to 15 per brain).
23
Determining the distribution of microinfarcts across the brain, like their prevalence and
overall burden, is likely influenced by sampling strategy, which varies among studies. A
reasonable approach to standardized sampling is the Consortium to Establish a Registry for
Alzheimer’s Disease (CERAD) protocol for brain sampling with additional sectioning of the
anterior (centrum semiovale) and posterior white matter
24
as suggested by the NINDS –
CSN VCI Harmonization Standards.
6
Other important areas for sampling may include the
border zones of major arterial territories
18, 25, 26
as well as brain regions commonly involved
by lacunar infarction, the basal ganglia, thalamus, pons and cerebellum.
Microinfarct location can be classified as cortical or subcortical, a distinction that may be
useful for identifying associations with specific diseases.. Some studies of AD, for example,
report cortical microinfarcts predominantly in brain arterial border zone areas
18, 25, 26
or in
motor cortex in the setting of AD with motor impairment.
27
Cortical microinfarcts have also
been associated with cerebral amyloid angiopathy (CAA),
16, 26, 28–32
though the relationship
may be complicated by CAA-related perivascular hemosiderin deposition and astroglial
scarring that can be difficult to distinguish from incomplete microinfarction. Subcortical
microinfarcts, particularly in the putamen, have been described in hypertension
33
and
hypertensive encephalopathy
34
, and are probably associated with arteriolosclerosis, whereas
periventricular microinfarcts have been described in normal pressure hydrocephalus.
35
MICROINFARCTS AND SMALL VESSEL BRAIN DISEASE
In using the term “microinfarcts” for these lesions, the underlying supposition is that these
lesions are indeed the results of ischemic injury. Several lines of evidence support this
inference. As noted above, microinfarcts appear to share the histopathologic structure and
progression of macroscopic infarcts. Another suggestive feature is their association with
other markers of cerebrovascular disease such as ischemic macroscopic infarcts,
leukoencephalopathy, and intracerebral hemorrhages.
7, 21, 36–38
Most notable are the
observed associations of microinfarcts with advanced small vessel diseases,
14
including both
common age-related pathologies such as arteriolosclerosis and CAA
16, 26, 28–32
and
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