Journal of Cerebral Blood Flow & Metabolism (2011) 31, 18361851

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Review Article

Heterogeneity in the penumbra

Gregory J del Zoppo1,2*, Frank R Sharp3,4, Wolf-Dieter Heiss5 and Gregory W Albers6
1

Department of Medicine (Division of Hematology), University of Washington School of Medicine, Seattle,

Washington, USA; 2Department of Neurology, University of Washington School of Medicine, Seattle,
Washington, USA; 3Department of Neurology, MIND Institute, University of California at Davis Medical
Center, Sacramento, California, USA; 4Department of Genetics, MIND Institute, University of California
at Davis Medical Center, Sacramento, California, USA; 5Max Planck Institute for Neurological Research,
Cologne, Germany; 6Department of Neurology and Neurological Sciences, Stanford University Medical
Center, Palo Alto, California, USA

Original experimental studies in nonhuman primate models of focal ischemia showed flow-related
changes in evoked potentials that suggested a circumferential zone of low regional cerebral blood
flow with normal K + homeostasis, around a core of permanent injury in the striatum or the cortex.
This became the basis for the definition of the ischemic penumbra. Imaging techniques of the time
suggested a homogeneous core of injury, while positing a surrounding penumbral region that
could be salvaged. However, both molecular studies and observations of vascular integrity indicate
a more complex and dynamic situation in the ischemic core that also changes with time. The
microvascular, cellular, and molecular events in the acute setting are compatible with heterogeneity
of the injury within the injury center, which at early time points can be described as multiple minicores associated with multiple mini-penumbras. These observations suggest the progression of
injury from many small foci to a homogeneous defect over time after the onset of ischemia. Recent
observations with updated imaging techniques and data processing support these dynamic
changes within the core and the penumbra in humans following focal ischemia.
Journal of Cerebral Blood Flow & Metabolism (2011) 31, 18361851; doi:10.1038/jcbfm.2011.93; published online 6 July 2011
Keywords: focal ischemia; imaging; ischemic penumbra; metabolic characteristics; microvessel characteristics;

molecular characteristics

Introduction
Occlusion of a brain-supplying artery for an extended period of ischemia leads to permanent injury if
return of flow is inadequate. Astrup et al (1977, 1981)
posited the development of a core of injury destined
for tissue destruction (infarction), surrounded by a
penumbra of metabolically metastable tissue that
has the potential for full recovery (Figure 1A)
(Branston et al, 1974, 1977). This general depiction
*
Correspondence: Dr GJ del Zoppo, MD, Department of Medicine (in
Hematology), Department of Neurology, University of Washington
School of Medicine, Box 359756 at Harborview Medical Center, 325
Ninth Avenue, Seattle, WA 98104, USA.
E-mail: grgdlzop@u.washington.edu
The work reported here has been supported in part by NIH grants
NS 053716, NS 038710, and NS 036945 to Dr del Zoppo, NIH
grants NS066845 and NS054652 to Dr Sharp, and NIH grants
NS39325 and NS044848 to Dr Albers, and funding by the WDH
Foundation to Dr Heiss.
Received 7 January 2011; revised 8 May 2011; accepted 9 May
2011; published online 6 July 2011

of the penumbra has greatly influenced the concept

of ischemic stroke following thrombotic and thromboembolic occlusion of brain-supplying arteries, and
our attempts to enhance tissue recovery clinically.
However, evolving data regarding cellular and
molecular responses to ischemia, the interrelationships of vascular and neuronal activation (the
neurovascular unit), experience with models of focal
ischemia, and progress in acute imaging techniques
in both animals and patients have suggested important refinements to the penumbra concept.
Although the original conceptualization of the
penumbra remains solid, newer data that take into
account the time course of injury development,
potential interactions of boundary zones to the core,
and the vascular territory at risk within the stricken
hemisphere may provide even greater relevance
to patient outcome than indicated by many acute
intervention clinical trials. Recent work is beginning
to address these issues and could point the way to
further constructive developments in brain injury
management.

Heterogeneity in the penumbra

GJ del Zoppo et al
1837

Figure 1 The penumbra. (A) Depiction of the penumbra based

on rCBF and electrophysiological studies on the nonhuman
primate (from Symon (1980), with permission). (B) Depiction of
the relationship among rCBF, electrical failure in the dependent
cerebral tissue, and ischemia (taken from a figure in the study by
Astrup et al (1977), with permission). rCBF, regional cerebral
blood flow.

Evolving Definitions of the Penumbra

Early approaches to modeling focal ischemia in
mammals sought to develop discrete regions of neuron
injury by manipulating the cerebral vascular supply.
As model development moved toward the more
clinically relevant occlusion of the middle cerebral
artery (MCA) in the nonhuman primate, descriptions of
neuron function and integrity were linked to regional
changes in regional cerebral blood flow (rCBF). By
necessity, the concept of the penumbra has depended
in a large part on the techniques used to visualize it.
From the notion of a circumferential region of
metabolic disturbance that has not reached the
threshold of permanent injury, the concept has
evolved to include (1) characteristic electrophysiological changes, (2) biochemical/molecular alterations, (3) responses of the microvasculature, (4)
metabolic changes defined by imaging methods,

and (5) observed differences between regions of

abnormal tissue perfusion and diffusion regions on
magnetic resonance imaging (MRI) studies.
In the original electrophysiological concept, the
ischemic penumbra was an area that became
electrically silent, but could recover function if the
rCBF was restored in time (Heiss, 1992; Hossmann,
1994). An operational definition states that the
penumbra is ischemic tissue which is functionally
impaired and is at risk for infarction, but has the
potential to be salvagedy. If not salvaged this tissue
is progressively recruited into the infarct core, which
will expand with time into the maximal volume
originally at risk (Baron, 1999). Imaging of the
penumbra, using positron emission tomography
(PET) has allowed measurement of rCBF, cerebral
metabolic rate for oxygen (CMRO2), rCMRglc (regional
cerebral metabolic rate of glucose), and oxygen
extraction fraction (OEF). Infarction usually corresponds to rCBF decreased below 12 mL/100 g per min
and rCMRO2 below 65 mm/100 g per min, whereas the
penumbra has been defined as rCBF decreased to
12 to 22 mL/100 mg per min, the rCMRO2 above
65 mm/100 g per min, and OEF increased to 50% to
90% (Heiss, 2000). The concept of a mismatch
between areas of blood perfusion and H2O diffusion
in the injured territory as revealed by high fieldstrength magnetic MRI has provided a possible way
to image the penumbra in humans.
Using animal models and methods with increased
resolution, alterations in protein synthesis occur
within and around the regions of injury. In regions
of decreased rCBF, molecular correlates of the
penumbra are: (1) decreased protein synthesis that
can recover, (2) preserved ATP, (3) synthesis of heatshock proteins (Hsps), and possibly (4) a successful
unfolded protein response (Sharp et al, 2000). If
these molecular criteria are met, the tissue has the
capacity to be salvaged if blood flow is restored.
Once considered to be inert conduits, the microvasculature has been shown to respond rapidly and
dynamically within the territory at risk, containing
the ischemic core and regions peripheral to the core.
Microvessel adhesion receptor and basal lamina
matrix expression can present as mini-cores and
mini-penumbras within the early evolving core of
neuron injury, after occlusion of a brain-supplying
artery, in a characteristic time-dependent manner
(Tagaya et al, 2001). Given that the microvasculature,
which in capillaries consists of the endothelium
basal lamina matrixastrocyte end-feet complex,
serves neurons (as part of a hypothetical neurovascular unit), changes in microvessels and neurons
must to be connected locally.
Each of these definitions describes the events/
conditions in regions of focal ischemic injury within
the territory at risk. Not considered by these
definitions is whether the processes that determine
the penumbra or core occur uniformly in adjacent
areas over time and whether the active conversion of
the penumbra to core occurs at the interface of the
Journal of Cerebral Blood Flow & Metabolism (2011) 31, 18361851

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GJ del Zoppo et al
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core. Recent data have suggested that the core of

ischemic injury develops heterogeneously, and with
time coalesces dynamically into a homogenous core.
These data are consistent with the original concepts
of the penumbra and core, but recognize the dynamic
complex heterogeneous processes involved. This
refinement has potential therapeutic implications.

The Ischemic Penumbra and the

Ischemic Core
The ischemic penumbra was initially defined by
physiologic experiments performed in large animals
subjected to focal cerebral ischemia as (1) a region
around a central core of low rCBF and physiologic
silence, (2) a boundary region with release of
intracellular K + , and (3) a region of metabolic
instability that could be recovered.
Symon et al (1980) described the penumbra as a
tissue of evolving injury around a homogeneous
central core destined for infarction. Symon et al
(1974) showed that 3 years after the rapid reduction
in rCBF in the MCA territory in the nonhuman
primate (Papio sp), a residual core of low rCBF
remained that was congruent with the acute CBF
reduction. Regions of CBF peripheral to the core
had returned to normal levels. Branston et al (1974),
using the same nonhuman primate model, related
the loss in evoked potential (EP) amplitude to
significant reductions in local CBF. Here, the rCBF
threshold for 50% reduction in EP amplitude was
B18 mL/100 g per min, when regional flow was
reduced by phlebotomy and induced hypotension.
The functional threshold for neurologic dysfunction progressed from mild paresis at 22 mL/100 g per
min to complete paralysis at 8 mL/100 g per min.
Hence, the presence of a boundary zone in which the
EP amplitude was sensitive to blood pressure/flow
could be defined. Reduction in EP amplitude
correlated with cellular K + release into the surrounding tissue. When measured with H2 clearance
electrodes, rCBF reduction could be observed at
which the EP amplitude remained at 50% normal
and K + extravasation occurred in the core, but not
in the peripheral zones (Symon et al, 1974; Branston
et al, 1977). Further studies have shown a differential
sensitivity of K + and Ca2 + extravasation when rCBF
ranged from 8 to 15 mL/100 g per min (Harris and
Symon, 1984); EP amplitude decreased when rCBF
dropped below 15 mL/100 g per min even when
K + extravasation was not observed (Branston et al,
1977). On the basis of model studies, flow rates of
12 mL/100 g per min lasting for 2 to 3 hours led to
large infarctions, but individual cells became necrotic after shorter intervals of time and at higher levels
of residual flow. The potential for irreversible
damage or recovery then seemed determined not
only by the level of residual flow but also by the
duration of flow disturbance for a given region.
Journal of Cerebral Blood Flow & Metabolism (2011) 31, 18361851

Figure 2 Response of tissue to the duration of rCBF reduction,

and development of the penumbra. Diagram of CBF thresholds
required for the preservation of function and morphology of brain
tissue. The activity of individual neurons is blocked when flow
decreases below a certain threshold (dashed line) and returns
when flow is increased again above this threshold. The upper
recordings are from a single neuron before, during, and after
reversible MCA occlusion. The fate of a single cell depends on
the duration for which CBF is impaired below a certain level. The
curved solid line demarcates conditions for structurally damaged
from a functionally impaired, but morphologically intact tissue,
the penumbra. The dashed line distinguishes tissue not at risk
from the functionally impaired tissue. MCA, middle cerebral
artery; rCBF, regional cerebral blood flow.

These observations form the basis for the familiar

temporal relationship among rCBF, electrical function,
and brain tissue integrity characterizing regions of
permanent injury and of reversible injury from
ischemia onset (Figure 1B) (Jones et al, 1981). This
synthesis implies that the core is homogeneous, and
expands as a wave front with time into a penumbra of
tissue that is at least initially not doomed to infarction.
The range of perfusion between those limitsa rCBF
level below which neuronal function is impaired and a
lower threshold below which irreversible membrane
failure and morphologic damage occurtypifies the
ischemic penumbra (Astrup et al, 1981).
Separately, experiments using multiple electrodes in
cats subjected to focal cerebral ischemia, which simultaneously assessed single-cell activity and local flow,
showed pockets of low flow and cortical neuron
vulnerability in closely adjacent cortical areas (Rosner
et al, 1986). The altered single-cell activity with grouped
or regular discharges at flow levels just above the
threshold correlated with the gradual appearance of
functional deficits (Figure 2). Spontaneous neuronal
activity and EPs were restored when blood flow was
reestablished (Heiss et al, 1976; Heiss and Rosner, 1983).

Metabolic Characteristics of the

Penumbra and Core
Energy demands of the central nervous system are
high and almost entirely provided by oxidative

Heterogeneity in the penumbra

GJ del Zoppo et al
1839

glucose metabolism. Increases in glucose consumption (and rCBF) evoked by functional activation are
most prominent in synapse-rich regions, i.e., which
contain axonal terminals, dendritic processes, and
astrocytic processes that envelope the synapses and
microvasculature. Energy requirements for functional activation are mostly caused by stimulation
of Na + K + -ATPase activity to restore the ionic
gradients across neuron cell membranes and membrane potentials that are altered by the spike activity
(Sokoloff, 1999).
From its conceptual foundation in experiments in
the nonhuman primate, further work on metabolic
aberrations in the at-risk tissue proceeded in
smaller animal models of focal cerebral ischemia.
Loss of bioluminescent ATP and tissue acidosis
occur in the ischemic core and penumbra (Astrup
et al, 1977; Hossman and Mies, 2007) (AJ Strong,
personal communication). The relationships among
ischemic perfusion, functional impairment, biochemical disturbances, tissue damage, and duration
of critical perfusion were shown in PET imaging
studies of cats following MCA occlusion (Heiss et al,
1994, 1997). The PET imaging studies have suggested
three phases of injury progression:
(1) At flows below the threshold of energy metabolism
(B20% to 30% of preocclusion values), acute
ischemic injury is usually established within
minutes after the onset of ischemia (Branston
et al, 1974, 1977; Astrup et al, 1977, 1981).
(2) During the subsequent subacute phase (flows
ranging from 25% to 50% of preocclusion values),
the core expands into the penumbra, defined as
areas of decreased CBF and O2 metabolism, but
increased OEF. In most models, the core has
consumed the entire penumbra within 4 to
6 hours, whereas in some animal models and in
some humans (Heiss et al, 1992), the extension of
the core into the penumbra can require > 24 hours.
This expansion is postulated to be attributed in
part to peri-infarct spreading depression, and other
factors related to the failure to restore CBF. Periinfarct spreading depressions are initiated at the
border of the infarct core and spread over the
ipsilateral hemisphere. During spreading depression, the metabolic rate of the tissue markedly
increases in response to the activated ion exchange
pumps (Somjen, 2001), but is not associated with
an increased rCBF in ischemic areas of the brain
(review in the study by Strong (2009)). Thus,
the increased metabolic workload coupled with
limited O2 supply leads to transient episodes of
worse hypoxia and stepwise increases in lactate
with each depolarization, loss of ionic gradients,
and other molecular disturbances that increase
cell death (Mies et al, 1993; Hossmann, 2006).
(3) A delayed phase of injury evolution occurs that
can last for several days to weeks. Using multiparametric imaging techniques for differentiation
between the core and the penumbra, by 1 hour

after proximal MCA occlusion in the cat, the

penumbra approximately predicts the size of the
final infarct if flow is not restored (Heiss et al,
1994). However, after 3 hours, > 50% of the
penumbra progresses to infarction, and between
6 and 8 hours, almost all of the penumbra
disappears and is converted into the irreversibly
damaged infarct core (see Figure 5 below).
The flow values for irreversible damage and for
functional impairment from experimental models of
ischemia in cats correspond to those observed in
humans. Considerable variability exists (damage
below 4.8 to 17.3 mL/100 g per min, penumbra below
14.1 to 35.4 mL/100 g per min), which depends on
the definition of damage/penumbra, the methods
used for flow determination, the time of measurement after stroke, and whether occlusion was
permanent or temporary (for review see the study
by Heiss (2000)).

Molecular Characteristics of the

Ischemic Penumbra and the Core
During focal ischemia, the molecular events that
correspond best to the physiologic and imaging
definitions of the penumbra are: (1) regions of
decreased protein synthesis with preserved ATP
and (2) regions of Hsp70 induction in neurons. Many
molecular events occur well outside the clinically
defined penumbra of ischemia-induced injury that
does not lead to detectable infarction. These are
associated with vascular changes during noninjurious decreases in blood flow, inflammation with loss
of cells and their processes in the core, and synaptic/
brain reorganization.
Kleihues and Hossmann (1971) and Hossmann
(1993) first described decreased cerebral protein
synthesis following focal cerebral ischemia. As rCBF
decreases to B30% to 50% of baseline (Mies et al,
1990), blockade of translation and decreased protein
synthesis are observed (Dienel et al, 1980; Kiessling
et al, 1986; Bergstedt et al, 1993; Hossmann, 1994).
Within the core region of ischemic injury, protein
synthesis decreases early and is associated with ATP
loss and irreversible translation blockade, whereas
in the penumbra, protein synthesis is initially
depressed, ATP remains normal, and then protein
synthesis recovers over time (Hossmann, 1993, 1994).
The Unfolded Protein Response

The decrease in protein synthesis in the ischemic

core is mediated in part by the unfolded protein
response within the cell endoplasmic reticulum.
Translation blockade proceeds through initiation,
maintenance, and termination (DeGracia and Hu,
2007). Initiation of the translation blockade in part
involves the PKR-like endoplasmic reticulum kinase
that phosphorylates eukaryotic initiation factor-2a
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GJ del Zoppo et al
1840

and blocks translation in the endoplasmic reticulum.

If eukaryotic initiation factor-2a is phosphorylated,
the initiation complex is disrupted and translation
is slowed or blocked (Hu and Wieloch, 1993). This
is associated with disaggregation of polysomes,
followed by the appearance of stress granules
(DeGracia and Hu, 2007). The PKR-like endoplasmic
reticulum kinase knockouts only show early translation blocks after ischemia, so that eukaryotic
initiation factor-2a is related to the early, but not
prolonged, blockade of protein synthesis following
ischemia. After the initial translation blockade, other
transcription factors, including eukaryotic initiation
factor-4(E,F,G), likely maintain decreased protein
synthesis for 4 to 24 hours and perhaps longer. This
maintenance phase is followed either by (1) recovery
of translation or by (2) permanent translation blockade and cell death, which constitute the termination
phase (DeGracia et al, 2008). The proximate stimuli
for the unfolded protein response in cerebral ischemia are still unknown, but may include increased
Ca + 2 in the endoplasmic reticulum, impaired aminoacid or glucose delivery, abnormal glycosylation
of proteins, and other factors (Paschen, 1996, 1998;
Kaufman et al, 2002, 2004; Schroder and Kaufman,
2005). It has been suggested by several groups that
protein synthesis is arrested following ischemia
to prevent formation of partially denatured or
improperly processed proteins, which is probably
protective. How protein synthesis resumes in the
penumbra that will be salvaged and why protein
synthesis remains suppressed in regions of penumbra that infarct are still not understood, but are under
study.

Heat-Shock Protein Induction

Another major molecular responder to ischemia is

the family of Hsps. The Hsps, expressed in every
living cell and organism, are induced in cells during
periods of ischemia and other stresses that produce
intercellular denatured proteins (Lindquist and
Craig, 1988; Craig et al, 1993; Lindquist and Kim,
1996; Massa et al, 1996; Yenari, 2002).
Now, Hsp70, the major inducible Hsp, is expressed
at almost undetectable levels in normal brain cells.
After heat stress, ischemia, and other stresses, Hsp70
is massively induced and becomes the most abundant protein in the cell because it binds denatured
proteins directly and attempts to refold them
(Beckmann et al, 1990, 1992; Welch, 1993; Welch
and Brown, 1996). Denatured proteins induce heatshock transcription factors that bind to heat-shock
elements in the Hsp genes and induce Hsp40, Hsp70,
Hsp90, and others. At this point, the injured cell
appears to make a decision: Hsp70 can promote
protein refolding and cell survival or allow protein
degradation and progression to cell death (Hohfeld
et al, 2001). Importantly, cells that synthesize Hsp70
mRNA but cannot synthesize Hsp70 protein likely
Journal of Cerebral Blood Flow & Metabolism (2011) 31, 18361851

die. Most cells that express both Hsp70 mRNA and

Hsp70 protein appear to survive.
After MCA occlusion, Hsp70 mRNA is expressed
throughout the MCA territory, both within the infarction and in regions adjacent to the infarction (Kinouchi
et al, 1993a, b, 1994). Hata et al (1998) have shown that
Hsp70 transcription (RNA) and Hsp70 translation
(protein) occur in regions of decreased protein synthesis, but preserved ATP. This is the area where blood
flow is 18% to 20% normal and in which infarction
would occur if reperfusion did not occur (Hata et al,
2000a, b, 1998). Under conditions in which Hsp70
transcripts are induced in the MCA distribution, the
Hsp70 protein is only synthesized in neurons peripheral to the ischemic core, whereas there is no or very
little Hsp70 protein synthesized in the core (Kinouchi
et al, 1993a). Thus, the ischemic core corresponds to a
region of either no Hsp70 mRNA induction or induction of Hsp70 mRNA, but without translation into the
Hsp70 protein. This contrasts with the molecular
events within the penumbra: regions of Hsp70 mRNA
induction and Hsp70 protein synthesis in the regions
of denatured proteins where cells can effectively refold
proteins (Figure 3). This also correlates with differential cellular vulnerability to ischemia because blood
vessels that synthesize Hsp70 mRNA and Hsp70
protein may well survive in areas of infraction where
neurons and glia succumb. Although the regions of
Hsp70 mRNA and Hsp70 protein induction at 24 hours
appear to correlate well with the clinical definition of
the penumbra, it is not known whether the volume of
tissue destined to infarction corresponds exactly to that
represented by the Hsp70 protein, because there is no
known independent molecular marker of tissue at risk
for infarction.
The degree and duration of ischemia affect
the regional expression of Hsp70. For example,
10 minutes of focal ischemia in the MCA distribution
(using the suture model), which does not infarct rat
brain, induces Hsp70 protein in neurons throughout
the MCA distribution 4 to 24 hours later. Thus, the
regions of Hsp70 protein induction indicate the
penumbra because this is the region at risk for
infarction, but which did not infarct because blood
flow was restored after 10 minutes of focal ischemia
(Zhan et al, 2008). In contrast, at 24 hours after
3-hour (suture-induced) MCA occlusion infarction
occurs in the MCA territory, and the small area of
Hsp70 induction indicates a small penumbra located
between the middle and anterior, and the posterior
cerebral arteries (Zhan et al, 2008). The expression
of Hsp70 in neurons outside areas of infarction is
presumed to protect these cells from further protein
denaturation, as overexpression of the Hsp70 protein
in transgenic mice markedly protects the brain
against infarction (Rajdev et al, 2000).
Heterogeneity of the Molecular Responses

The boundary of the penumbra reflects the

degree and duration of decreased cerebral perfusion.

Heterogeneity in the penumbra

GJ del Zoppo et al
1841

penumbra

*
mini-core

*
mini-penumbra

Figure 3 Development of mini-penumbra and mini-core. (A) Coronal section of the adult rat brain that shows Hsp70 protein
(stain) 24 hours after occlusion of the right middle cerebral artery (MCA) for 10 minutes. Hsp70 immunoreactivity in the cortex, basal
ganglia, and ventral thalamus and dorsal hypothalamus in the MCA distribution must be noted. Hsp70 staining delineates the entire
penumbra, because this region of brain did not infarct, but would have infarcted if MCA occlusion had persisted for 2 hours. (B) The
region of the cortex within the box in panel A shows a central area of little Hsp70 expression surrounded by a large number of
Hsp70-stained cells that are predominantly microglia (two are denoted with green stars). For the purposes of this review, we have
designated the central area that represents a possible microscopic infarct as the mini-core and the surrounding area of Hsp70stained glia and some neurons as the mini-penumbra. This figure is adapted from the study by Zhan et al (2008). Hsp70, heatshock protein 70.

Outside this region, the hypoperfused ischemic brain

tissue contains neurons, glia, and vascular elements
together with inflammatory cells that are associated
with gliosis, synaptic pruning, and other structural
and molecular changes presaging recovery after
stroke.
In contrast to a central zone of hypoperfused brain
at risk for infarction, the pattern and evolution of the
penumbra can be quite variable. For example, in
some models of cerebral infarction, there are no
zones that correspond to decreased protein synthesis
and Hsp70 proteinand thus there is no penumbra.
In other models, there are small islands of the
infarcted brain (mini-cores) surrounded by neurons
and glial cells that express Hsp70 (mini-penumbras) (Figure 3). The most-stressed cells at the
margins of these islands are sometimes neurons and
sometimes microglia. The features that determine
this heterogeneity are unknown, but likely reflect a
dynamic interplay between adjacent microvascular
beds and complex interactions between the microvessels and the adjacent glia and neurons that differ
over regions of 30 to 40 mm. How this relates to
infarction without the intervening surviving tissue is
still unknown. Indeed, although neurons are more
vulnerable than glia to ischemia, there is eventually
a discrete demarcation between the infarcted brain
and the surviving brain where both viable neurons
and glia exist at the margin and where their
companions have perished on the infarcted side of
the margin. The factors that define such a sharp
margin are unknown, but may reflect interdependent survival growth factors responsible for the
survival of all members of a given neurovascular
unit, or regions lacking adequate microvascular
supply.
The data in Figure 3 strongly support the idea
of mini-penumbras and mini-cores based on the

pattern of stress gene response. Histologic data

obtained from the study by Hughes et al (2010) also
support this concept because they found patchy
neuronal loss and associated microglial activation in
the salvaged cortical penumbra after brief MCA
occlusion. In addition, we have shown very patchy
areas of microinfarction in the striatum and occasionally in the cortex after 5- and 10-minute periods
of focal ischemia produced with the suture technique in rats (Zhan et al, 2008). These mini-cores
were microscopic and defined by contiguous loss
of NeuN-immunostained neurons associated with
contiguous loss of glial fibrillary acidic protein
(GFAP)-stained astrocytes in the same region.

Vascular Characteristics of the

Ischemic Penumbra and the Core
Heterogeneity in the development of cortical neuron
injury has been shown in a rodent model of focal
cerebral ischemia (Dawson and Hallenbeck, 1996).
One provocative view has suggested that vascular
and hemostatic responses vary depending on the
specific organ, although little information was available about the cerebral vasculature (Rosenberg and
Aird, 1999). It is now known that cellular and
molecular responses of cerebral microvessels to focal
ischemia are heterogeneously distributed in space
and time very early in the ischemic territory.
After MCA occlusion in the nonhuman primate,
neuron injury and the microvessel responses are
rapid and are distributed in a characteristic topographical arrangement with regard to the development of the ischemic core. Tagaya et al (1997) have
shown that in the evolving core early after injury
(defined by evidence of DNA strand breaks or repair),
80.0%6.6% of injured cells were neurons at
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Heterogeneity in the penumbra

GJ del Zoppo et al
1842

2 hours after MCA occlusion, but there is a much

lower proportion of injured endothelial cells at later
times ( < 2% of cells at 27 hours). This is consistent
with the notion that neurons are most sensitive to
ischemia, whereas vascular endothelial cells are
most resistant. However, microvessels within the
territories of injury are rapidly reactive, participating
in inflammatory cell adhesion, and displaying
changes in barrier permeability and matrix integrity.
These observations indicate heterogeneity in cell
vulnerability to injury within the developing core
and adjacent penumbra. Indeed, in the primate
corpus striatum after proximal MCA occlusion,
microvessel alterations and injury within the regions
of the ischemic core are distributed heterogeneously
(Tagaya et al, 2001).
Microvessel Matrix Receptor Responses

This heterogeneity in the evolution of injury is also

shown by the response of integrin a1b1 expression by
microvessel endothelial cells in regions of the
territory at risk that become the core. Integrin a1b1
is a common receptor for endothelial cell adhesion to
laminin, collagen IV, and perlecan in the microvessel
basal lamina. The b1 integrins on the cerebral endothelium, and the integrin a6b4 as well as ab-dystroglycan on astrocyte end-feet all decrease significantly
within 2 hours after MCA occlusion (Wagner et al,
1997; Abumiya et al, 1999; Tagaya et al, 2001).
Tagaya et al (2001) have shown that the distributions
and density of microvessels suffering loss of a1 and
b1 subunits were heterogeneously distributed, in a
pattern that depended on the vascular supply.
Microvessels in the ischemic striatum expressed
increased b1 subunit transcripts in boundaries
around central regions devoid of b1 integrin transcription. To help explain these observations, in vitro
integrin b1 subunit mRNA expression increased
when murine brain endothelial cells (grown on
collagen type IV, laminin, or perlecan) were exposed
to moderate oxygenglucose deprivation (experimental ischemia) (Milner et al, 2008). Hence, the regions
of endothelial cell response in the striatum of the
nonhuman primate can be interpreted as multiple
mini-penumbras made up of areas of b1 integrin
mRNA upregulation on the edges of each core region
and absent b1 integrin expression in mini-cores
because of the failure of transcription and translation
in the areas of infarction (Figure 4A) (Tagaya et al,
1997, 2001).

responsible for the upregulation of integrin avb3,

and stimulates proliferation, migration, and increased permeability of the endothelium (Senger
et al, 1996). Abumiya et al have shown that during
striatal ischemia, VEGF mRNA was detectable in
noncapillary microvessels in relationship to the avb3
expression. Colocalization studies, involving microvessels reconstructed over 100 mm of their length in
regions of dUTP incorporation (the core), showed
a significant colocalization among proliferating cell
nuclear antigen (PCNA), the integrin avb3, and VEGF
along the length of activated microvessels (Abumiya
et al, 1999). Integrin avb3 was upregulated mainly on
7.5- to 30.0-mm diameter microvessels within the
core region. Microvessel-associated PCNA, VEGF,
and integrin avb3 were all upregulated in this region
(Figure 4B). Using a hierarchical log-linear model for
the categorical data analysis, tests for pairwise
interactions at different times showed that the
interaction with time was not significant. Therefore,
coexpression of PCNA, VEGF, and integrin avb3 by
microvessels within the ischemic core indicated a
highly significant interaction that was independent
of time, and was therefore heterogeneous within the
core regions.
An interesting observation in this respect suggests
that in some settings, cerebral microvessels in a
territory could be variously primed for response,
such that their response is heterogeneous. Ruetzler
et al (2001) have shown segmental heterogeneity of
central nervous system vascular responses in normoxic spontaneously hypertensive stroke-prone rats
exposed to lipopolysaccharide, in which circular
decoration of brain tissue by manganese superoxide
dismutase was seen around some microvessels
and not others. This is possibly relevant to the observations made by Mabuchi et al (2005) of an ordered,
but heterogeneously distributed, neuron injury
within 2 hours of MCA occlusion that is related to
the microvessel supply (the neurovascular unit).
Of importance, these observations are not simply
explained by the dependence of local injury on the
fall-off of O2 diffusion as applied to cerebral
capillaries (the Krogh cylinder), but suggest other
mechanisms (Quistorff et al, 1977; Mabuchi et al,
2005). Whether the coordinated expression of PCNA,
integrin avb3, and VEGF by cerebral microvessels
during focal ischemia is an intrinsic characteristic
of some vessels of a size class, or the heterogeneity of
the injury, is not yet certain.

Heterogeneity of the Microvascular Responses

Angiogenesis

Another example of vascular response heterogeneity

to focal ischemia is the increased expression of
integrin avb3 and vascular endothelial growth factor
(VEGF) by cerebral microvessels within the ischemic
core during MCA occlusion (Abumiya et al, 1999).
Vascular endothelial growth factor expression is
Journal of Cerebral Blood Flow & Metabolism (2011) 31, 18361851

Responses of the microvasculature in the territory at

risk (striatum) to focal ischemia are very rapid,
nearly as rapid as those of the neurons they supply.
Within the core regions, in the first minutes after
ischemia onset, microvessel obstruction, endothelial
cell receptor presentation, matrix degradation, and
detachment of astrocyte end-feet occur initially in

Heterogeneity in the penumbra

GJ del Zoppo et al
1843

Figure 4 Expression of microvessel-related gene products at 2 hours after MCA occlusion in the striatum. (A) Expression of the
integrin b1 subunit mRNA by microvessels in the striatum of three nonhuman primate subjects (ac) after MCA:O (Tagaya et al,
2001). Around mini-cores of absent b1 subunit mRNA, significant upregulation of the b1 subunit gene product was observed. The
cores and boundary zones of b1 subunit upregulation corresponded to the regions where cells incorporated dUTP (i.e., dUTP + )
(Tagaya et al, 1997). (B) Regions of VEGF expression (black), an subunit (gray), and expression of both products (hatched) by
activated microvessels in the striata of nonhuman primates that were subject to various periods of MCA occlusion (each image
represents a separate animal) (Abumiya et al, 1999). The mini-cores of integrin or VEGF expression by microvessels must also be
noted. MCA, middle cerebral artery; VEGF, vascular endothelial growth factor.

a heterogeneous manner in pockets (mini-cores).

The initial microvessel responses are neither simultaneous nor homogeneous. This suggests that in the
early moments after arterial occlusion, the entire

core is studded with pockets of penumbra, and

that these mini-cores and their mini-penumbras
evolve dynamically and heterogeneously depending
on local differences of microvessel perfusion.
Journal of Cerebral Blood Flow & Metabolism (2011) 31, 18361851

Heterogeneity in the penumbra

GJ del Zoppo et al
1844

Imaging the Ischemic Penumbra and

Core
Noninvasive brain imaging modalities have evolved
greatly since the first descriptions of the core
penumbra relationships in large animal models.
The use of PET and MR imaging techniques in
humans is now beginning to confirm and even
extend observations of the core and penumbra
defined in animal models.
Positron Emission Tomography Imaging

Positron emission tomography techniques have

permitted classification of three regions within the
disturbed vascular territory: (1) the core of ischemia
which usually undergoes necrosis with a flow rate
< 12 mL/100 g per min, (2) a penumbra region (12 to
22 mL/100 g per min) of still viable tissue, but
with uncertain chances for infarction or recovery
depending on reflow, and (3) a hypoperfused area
( > 22 mL/100 g per min) not primarily damaged by
decreased blood supply that will not proceed to
infarction (see Figure 5). In humans, the brain tissue
with rCBF < 12 mL/100 g per min and rCMRO2
< 65 mmol/100 g per min (often measured several
hours after stroke) usually displays eventual evidence
of infarction on late computerized tomographic scans
(Ackerman et al, 1981; Baron et al, 1981a; Lenzi et al,
1982; Powers et al, 1985). Relatively preserved CMRO2
in regions of severely reduced CBF has been taken as
an indicator of maintained neuronal function in
regions with severely reduced CBF. This pattern,
coined misery perfusion, has served as a PET-derived
definition of the penumbra (Baron et al, 1981b). It is
characterized as the area of increased OEF ( > 80%
from the normal value of B40%). Positron emission
tomography investigations imply that the extent of the
penumbra depends on the time of measurement
relative to the onset of ischemia. The volume is large
and rCBF is low if the penumbra is defined in the first
hours of ischemia; the penumbra volume is small, if
defined later (Heiss et al, 1992). The heterogeneity in
the core of ischemia and in the penumbra over time
can be seen in the occurrence of OEF especially in
animal studies (Figure 5), but also seen repeatedly in
human PET studies (e.g., Heiss et al, 1992).
As these measurements require arterial blood
sampling and complex logistics, a marker of neuronal integrity is preferable. The central benzodiazepine receptor ligand flumazenil (FMZ) binds to the
GABA receptor that is abundant in the cerebral
cortex. These receptors are sensitive to ischemic
damage and can identify early neuronal loss. Flumazenil, validated in the cat MCA occlusion model,
predicted the size of final infarction in patients with
acute ischemic stroke, and showed the efficacy of
thrombolytic treatment (Heiss, 2000). Another marker of the penumbra, 18F misonidazol is trapped in
viable hypoxic tissue (Takasawa et al, 2007). In early
Journal of Cerebral Blood Flow & Metabolism (2011) 31, 18361851

stroke, increased 18F misonidazol uptake surrounds

the core, and there is a strong association between
the extent of 18F misonidazol-binding tissue that survives and functional outcome (Markus et al, 2003).
18
F misonidazol uptake also assesses hypoxia in the
white matter, where progression of ischemic damage
is slower (Heiss et al, 2000; Spratt et al, 2007).
As PET methodology has improved, higher resolution with shorter time sequences have detected
temporal and spatial heterogeneity of the core and
penumbra (Kidwell et al, 2003), which were especially evident in sequential studies in animal models
of focal and reversible cerebral ischemia (Heiss et al,
1994).

Magnetic Resonance Imaging

Although PET remains the imaging gold standard for

identification of tissue in the penumbra in human
stroke patients, MR studies using diffusion and
perfusion imaging by MR have provided valuable
insights into the relationships between the core and
the penumbra. More than a decade ago, it was
hypothesized that the early diffusion-weighted imaging (DWI) lesion estimates the ischemic core in
ischemic stroke patients and adjacent critically
hypoperfused tissue could be identified with perfusion-weighted imaging (PWI) (Baird et al, 1997;
Barber et al, 1998). Therefore, brain regions with a
PWI lesion that did not show restricted diffusion
(PWI/DWI mismatch) were hypothesized to represent the penumbra. Subsequent studies have
extended this notion by showing that appropriate
quantification of perfusion and diffusion imaging
can provide a reasonable estimate of the penumbra.
Problems with the MRI definition of the penumbra
include the fact that there is no threshold within a
region of oligemia (Kidwell et al, 2003; Kane et al,
2007; Toth and Albers, 2009), and that the PWI
abnormality often overestimates the final infarction
volume, and hence the amount of tissue at risk
(Parsons et al, 2001). In addition, the initial diffusion
lesion does not necessarily define the core of
infarcted tissue because some diffusion lesions can
be transiently or permanently reversed if blood flow
is rapidly restored (Kidwell et al, 2000; Parsons et al,
2002; Chalela et al, 2004).
Kidwell et al (2003) proposed a modified model of
ischemia-compromised tissue in which the penumbra includes the region of perfusiondiffusion mismatch, minus the region of benign oligemia plus a
portion of the initial diffusion abnormality itself.
Although several attempts have been made to
identify perfusion or apparent diffusion coefficient
(ADC) thresholds so as to better differentiate these
regions, consensus on the best method has been
hampered by the lack of methodological standardization of image postprocessing and analysis. These
restrict the pooling of data and cross-comparison of
results across studies (Kane et al, 2007).

Heterogeneity in the penumbra

GJ del Zoppo et al
1845

Figure 5 Sequential PET images of CBF, CMRO2, and OEF of permanent MCA occlusion in cats (left columns) compared with images
of patients 12 hours after stroke (right columns). Two different cat subjects are shown (efficient and nonefficient perfusion) and three
different patients are shown (A: early OEF defect with corresponding infarction on MRI, B: effective reperfusion without infarction,
and C: ineffective/delayed reperfusion with large final partially hemorrhagic infarction). In the cat, the progressive decrease of CMRO2
and the reduction of OEF predict infarction. In the patient, the area with preserved OEF is not infarcted (outside region on late MRI,
upper part of figure A). If reperfusion occurs before OEF is reduced, tissue can be salvaged (left: cat, and left: patient in the lower part
of the figure B). If reperfusion is achieved after this therapeutic window, tissue cannot be salvaged (right: cat, and right: patient
in lower part of the figure C). CBF, cerebral blood flow; CMRO2, cerebral metabolic rate for oxygen; MCA, middle cerebral artery;
MRI, magnetic resonance imaging; OEF, oxygen extraction fraction; PET, positron emission tomography.

Validation of MR signatures with regard to PET

measurements might help in the interpretation of
the respective findings and in the assessment of
the accuracy of the various measures for predicting
tissue outcome. Comparisons of PET and MR imaging
have been performed in small groups of patients to
assess perfusion, and the delineation of tissue in the
penumbra (Figure 5).
To predict irreversible cortical damage, results
from sequential early DWI and 11C-FMZ-PET outcomes were compared with infarct extension 24 to
48 hours later on T2-weighted MRI in 12 acute stroke
patients (Heiss et al, 2004). When the volumes of
tissue beyond the defined thresholds of FMZ binding
and DWI intensity were compared, close correlations
(1) between volumes with FMZ and DWI beyond
threshold and (2) between predicted and final infarct
volumes were obtained, but the volumes did not
completely overlap. Whereas false-positive results
were observed for 25.9% of the total volume of DWI

increase, they were negligible with FMZ-PET. A

time-to-peak delay of 4 seconds correlated with flow
decreases below 20 mL/100 g per min as identified
by H2 15O-PET (Zaro-Weber et al, 2009).
For demarcation of the volume of the penumbra,
the areas of PWI/DWI mismatch were compared with
those of increased OEF. Using PWI/DWI mismatch,
there was considerable variability in penumbra
volume, and all patients (13/13) showed areas of
mismatch. However, PET detected OEF in only 8 of
13 patients. The areas of OEF elevation were always
located within the areas of time-to-peak prolongation, and were significantly smaller and covered only
1% to 75% (median, 33%) of the time-to-peak area
on MRI. These data show a high sensitivity, and a
low specificity of the chosen thresholds to identify
the penumbra as defined by PET. This suggests that
the PWI/DWI volume ratios depicted by time to peak
do not reliably reflect the penumbra as defined
by PET.
Journal of Cerebral Blood Flow & Metabolism (2011) 31, 18361851

Heterogeneity in the penumbra

GJ del Zoppo et al
1846

Advances in Perfusion-Weighted Imaging Techniques

Nonetheless, the spatial correspondence between

early DWI and PWI lesions, in conjunction with
knowledge of whether reperfusion of the supply
artery(ies) occurs, allow a reasonable (but not a
highly accurate) prediction of the final infarction
volume. More advanced PWI techniques, including
deconvolution sequences that account for differences
in arterial input to vessels with normal flow, appear
to produce more accurate estimates of the regions of
hypoperfusion that define the outer boundaries of
the penumbra. Although PWI provides a number of
parameters including mean transit time and cerebral
blood volume, recently there has been focus on the
maximum of the tissue residue function (Tmax)
obtained by deconvolution (Zaro-Weber et al, 2010).
Although the physiologic interpretation of Tmax is
complex, it reflects the degree of lag between the
arterial input and the tissue response, as well as
dispersion and mean transit time (Calamante et al,
2010). This parameter appears to correlate with CBF
values determined by Xenon computerized tomographic scans and has performed well in two
prospective clinical stroke trials (Albers et al, 2006;
Davis et al, 2008).
Thresholding techniques that restrict the volume
of PWI lesions to brain regions where there are
substantial delays in contrast arrival or transit times
have also been used. This reduces the volume of
benign oligemia captured by the PWI map. Prediction of the final infarction volume and salvage of the
penumbra seems to be more accurate using Tmax
maps with higher thresholds. In the DEFUSE (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution) study, for instance, the
correlation between infarct growth and the volume
of penumbra salvaged was significantly better for
PWI lesions defined by Tmax > 6 seconds compared
with > 2 seconds (Olivot et al, 2009). In addition, in
patients who did not experience early reperfusion,
the > 4-second threshold was a more accurate
predictor of final infarction volume than Tmax
> 2 seconds. Similarly, in EPITHET (Echoplanar
Imaging Thrombolytic Evaluation Trial), both the
size and the severity of PWI lesions correlated with
clinical outcomes (Parsons et al, 2010). Recent data
have suggested a B90% sensitivity and specificity
for Tmax > 5.5 seconds to identify the PET-defined
penumbra rCBF threshold of 20 mL/100 g per min
(Zaro-Weber et al, 2010). These results suggest that
quantification of the severity of PWI lesions can
improve accuracy for identification of tissue that is
in the penumbra.
Advances in Diffusion-Weighted Imaging Techniques

Progress has been made in quantification of DWI

using ADC measurements. Animal studies and
human trials are congruent, both showing correlations between CBF and the severity of ADC decline
Journal of Cerebral Blood Flow & Metabolism (2011) 31, 18361851

(Kohno et al, 1995; Hoehn-Berlage et al, 1995;

Dijkhuizen et al, 1997; Thijs et al, 2002; Lin et al,
2003). With increasing time from symptom onset,
ADC values become progressively reduced in a
critically low CBF environment. Recent data have
shown that only a small volume of the acute DWI
lesion is reversible (Chemmanam et al, 2010).
Diffusion-weighted imaging lesions are most likely
to reverse if they have modest reductions in ADC and
there is early reperfusion (Olivot et al, 2009).
However, observations in both animal models and
in human stroke patients show that reperfusion is
associated with a rapid increase in ADC values, and
that this increase is not necessarily reflective of
tissue salvage. Therefore, an isolated ADC map can
be an unreliable predictor of eventual infarct volume
(Ringer et al, 2001).
The fact that early DWI lesions are not uniformly
incorporated into the final infarction has an important implication: it is likely that some part of the
ischemic penumbra is contained within the acute
DWI lesion. Additional research is required to more
accurately determine which regions of the acute DWI
lesions are most likely to be salvageable, i.e., part of
the penumbra.

The Core and Penumbra are Dynamic

Experimental data from vascular and molecular

modeling studies, as well as recent imaging work
indicate that the penumbra is dynamic. There appear
to be substantial fluctuation in volumes, locations,
and structures of DWI and PWI lesions during the
early hours after stroke onset (Ma et al, 2009).
Coregistration of acute DWI lesions with PET
imaging has shown that DWI lesions are heterogeneous and include regions of variable metabolic
disruption and flow-metabolism coupling (Guadagno
et al, 2006). These findings are compatible with the
observations discussed above regarding the relationship among rCBF, ADC, and DWI. Therefore, predicting the fate of ischemic brain tissue based on data
obtained from any single imaging modality performed at only one early time point may not have
high specificity and sensitivity for prediction of the
core and penumbra.
Visualization of the spatial relationships between
PWI and DWI lesions at different times after stroke
onset can be achieved by coregistration of sequential
MRI scans in stroke patients. Three-dimensional
analyses have shown that a central volume of restricted diffusion (core) surrounded by a hypoperfused
penumbra is not present in the majority of stroke
patients imaged 3 to 6 hours after symptom onset
(before administration of thrombolytic therapy).
Multiple discrete regions of restricted diffusion or
perfusion were documented in one-third of the
patients enrolled in the DEFUSE study (Figure 6).
Surprisingly, a substantial proportion of the acute
DWI lesions (54%) did not have a superimposed

Heterogeneity in the penumbra

GJ del Zoppo et al
1847

Figure 6 Heterogeneity of DWI and PWI lesion structure. (A) Examples of the three-dimensional structure of DWI and PWI lesions in
acute stroke patients. Left, a single PWI lesion; center, a DWI lesion with multiple individual lesion components; right, a PWI lesion
with multiple components. (B) Three-dimensional imaging of DWI and PWI lesions in acute stroke patients reveals intertwined
regions of mismatch, DWI/PWI overlap, and early reperfusion. Regions that contain DWI lesions without superimposed PWI lesions
(early reperfusion) are shown in blue; areas where DWI lesions have superimposed PWI lesions are shown in purple. The red areas
are PWI lesions without superimposed DWI lesions (regions of mismatch). Reprinted from Stroke with permission from Olivot et al
(2009). DWI, diffusion-weighted imaging; PWI, perfusion-weighted imaging.

perfusion lesion (Olivot et al, 2009). These regions

of restricted diffusion without superimposed PWI
lesions are assumed to represent regions where
perfusion deficits have resolved or shifted to adjacent brain regions. The term RADAR (Reversible
Acute Diffusion lesion Already Reperfused) has been
used to describe these regions (Olivot et al, 2009).
The RADAR regions appear to have an increased rate
of DWI reversal. These findings emphasize the
heterogeneity and complexity of the relationships
between acute PWI and DWI lesions.

mini-cores

normal
+
mini-penumbras

normal

core

penumbra

The Penumbra Revisited

The original notion that occlusion of a brainsupplying artery produces a central core of tissue
injury destined for infarction that is surrounded by a
penumbra of metabolically metastable tissue with
the potential for full recovery still has great merit.
This model is strongly supported by the pathologic
findings of stroke that show confluent regions of
tissue infarction in animal models and patients.
Recent experimental and imaging work offer the
refinement that in the early minutes and hours after
ischemia onset, the core contains pockets of injury

Figure 7 A new hypothetical construct of the penumbra. The

architecture and reversibility depend on time and location of
rCBF reduction in the territory at risk after occlusion of a brainsupplying artery. The outside boundary represents the territory at
risk of cerebral tissue that functions normally until rCBF is
reduced for an extended period. Mini-cores coalesce with the
duration of rCBF reduction devouring micro-penumbras. The
period of evolution from normal function to the final state of the
territory at risk may depend on a number of factors, including
tissue location, depth of reduction of rCBF, inflammatory state at
baseline and/or degree of inflammatory response, and other
factors. The location of the mini-cores and mini-penumbras
appear heterogeneously distributed. However, they in fact reflect
the microvascular supply of tissue and cell vulnerabilities. rCBF,
regional cerebral blood flow.
Journal of Cerebral Blood Flow & Metabolism (2011) 31, 18361851

Heterogeneity in the penumbra

GJ del Zoppo et al
1848

which we characterize as mini-cores, surrounded

by mini-penumbras. We hypothesize that unless
salvaged, such embedded mini-penumbras are
consumed by the expanding mini-cores of metabolic
and functional failure to generate a lesion that is
ultimately homogenous and can grow into the surrounding injured tissue (Figure 7). Furthermore, it is
hypothesized that the mini-cores contain tissues in
which neurovascular units have been irreversibly
damaged because of flow cessation and its consequences, whereas the mini-penumbras have a proportion of neurovascular units that are viable. The separate
networks of microvessels, neurons, and glia associate
the mini-cores with the mini-penumbras. In this
way, if unimpeded, these mini-cores can grow into
their respective mini-penumbras to encompass a larger
region of injury.
This refined view has several implications:
1. Multiple mini-penumbras are apparent at the
molecular, cellular, and microvessel levels, such
that higher imaging resolution will be necessary to
follow their fate in patients,
2. these cell and microvessel events are related to
local microvascular flow,
3. serial imaging studies are required to show the
evolution of this dynamic core and penumbra,
4. inflammatory cellendothelial interactions, periinfarct depolarization, flow changes, and other
processes contribute to the engulfment of minipenumbras into the evolving ischemic core,
5. these observations underscore the need for
extremely early interventions, and
6. depending on the vascular territory involved and
the timing and severity of the ischemic event,
injury evolution may occur at different speeds
within different mini-cores/mini-penumbras,
such that certain interventions might have benefit
later.
Future studies will need to determine whether the
presence or absence of mini-cores and minipenumbras might affect the efficacy of different
types of treatment, the timing of treatment, or impact
ultimate prognosis.

Acknowledgement
The authors thank G Berg for manuscript preparation.

Disclosure/Conflict of interest
The authors declare no conflict of interest.

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