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NEUROLOGICAL REVIEW

Brain-Immune Interactions and Ischemic Stroke

Clinical Implications

Hooman Kamel, MD; Costantino Iadecola, MD

Increasing evidence shows that the central nervous system and the immune system interact

in complex ways, and better insight into these interactions may be relevant to the treat-

ment of patients with stroke and other forms of central nervous system injury. Atheroscle-

rosis, autoimmune disease, and physiological stressors, such as infection or surgery, cause

inflammation that contributes to vascular injury and increases the risk of stroke. In addition, the

immune system actively participates in the acute pathogenesis of stroke. Thrombosis and hypoxiatrigger an intravascular inflammatory cascade, which is further augmented by the innate immune

response to cellular damage occurring in the parenchyma. This immune activation may cause sec-

ondary tissue injury, but it is unclear whether modulating the acute immune response to stroke

can produce clinical benefits. Attempts to dampen immune activation after stroke may have ad-

verse effects because central nervous system injury causes significant immunodepression that places

patients at higher risk of infections, such as pneumonia. The activation of innate immunity after

stroke sets the stage for an adaptive immune response directed against brain antigens. The patho-

genic significance of adaptive immunity and its long-term effects on the postischemic brain re-

mains unclear, but it cannot be ruled out that a persistent autoimmune response to brain antigens

has deleterious and long-lasting consequences. Further research will be required to determine what

role, if any, immunity has in long-term outcomes after stroke, but elucidation of potential mecha-

nisms may open promising avenues for the development of new therapeutics to improve neuro-

logical recovery after brain injury. Arch Neurol. 2012;69(5):576-581

Mounting evidence indicates that the im-mune system has a key role in brain in-jury. A better understanding of the inter-actions betweentheimmunesystemand thebrain can aid physicians who care for pa-tients with stroke and other forms of cen-tral nervous system (CNS) injury. In addi-tion, advancing our understanding of theimmunology of stroke promises to gener-ate novel clinical strategies, as well as di-agnosticand therapeutic approaches. In thisbrief review, we discuss selected aspects ofthe interactions between CNS injury andimmunity, focusing on its implications fornew diagnostic tools to identify patients at

risk of stroke and the potential for noveltherapeutic agents to modify the immuneresponse to stroke. In addition, we high-light the many gaps in our understandingof the role of the immune system in CNSinjury and examine promising avenues offuture investigation. Although relevant tothe concept of immunity and stroke, pri-mary and secondary CNS vasculitides falloutside thescope of this brief overview andwill not be discussed.

IMMUNE ACTIVATIONAND THE RISK OF STROKE

Several lines of evidence suggest that acti-vationof theimmune system mayincreasetheriskof stroke (Table). Numerous pro-

Author Affiliations:Department of Neurology and Neuroscience (Drs Kamel andIadecola) and Division of Neurobiology (Dr Iadecola), Weill Cornell MedicalCollege, New York, New York.

ARCH NEUROL/ VOL 69 (NO. 5), MAY 2012 WWW.ARCHNEUROL.COM576

2012 American Medical Association. All rights reserved.

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spective population-based investigations demonstrated acorrelation between levels of inflammatory biomarkers(such as white blood cell count, fibrinogen, D-dimer, andC-reactive protein) and the risk of incident and recurrentstroke.1 Biomarkers may allow identification of patientsubgroups who derive greater or lesser degrees of ben-efit from standardmedications, such asantiplatelet or lipid-modifying agents. In addition, improvedknowledge aboutthe link between inflammation and stroke may lead tobetter and more timely recognition of specially vulner-

able populations, such as patients with recent infectionor surgery whofacea transiently heightened risk ofstroke.These patients may be at increased risk from inappro-priate cessation of antithrombotic medications,2 andrec-ognition of their vulnerability to stroke will help to en-sure that antithrombotic drugs are stopped only ifabsolutely necessary and as briefly as possible.

The association between stroke and antecedent in-flammatory states, such as infection or surgery, comple-ments recent findings of a correlation between stroke andthe duration of chronic inflammatory diseases, such assystemic lupus erythematosus and rheumatoid arthri-tis. The increased risk of stroke and coronary artery dis-ease seen in patients with lupus seems to be out of pro-

portion to traditional vascular risk factors, implying anadditive effect of underlying inflammation. Further-more, animal models demonstrate that atherosclerosis hasan inflammatory component, and inhibition of the im-mune response to lipoproteins seems to reduce the pro-gression of atherosclerosis. These observations suggestthat inflammation may have a causal role in vascular in-jury and subsequent stroke, which would open the doorfor immunomodulatory agents as new tools to preventstroke in these patients. However, observational data arenotoriously prone to confounding, and animal models

often do not apply well to humans. Clearly, a more de-tailed understanding of the complex relationship be-tween inflammation and stroke is required to better as-sess the feasibility of immunomodulation as a potentialtool for stroke prevention.

Inflammation is increasingly recognized as a possiblepathway in the pathogenesis of atrial fibrillation, whichis a leading cause of stroke.3 Levels of C-reactive proteinare elevated in patients with atrial fibrillation and are as-sociated with incident atrial fibrillation and with its re-

currence after ablation or cardioversion. Inflammatorypathways may promote atrial fibrillation by interactingwith cell signaling cascades, causing ion channel dys-function, impairing myocyte gap junctions, promotingatrial fibrosis, and recruiting leukocytes to cardiac tis-sue. The relationship between inflammation and atrialfibrillation is most likely bidirectional, with atrial fibril-lation causing some degree of immune activation andinflammation. The prothrombotic state seen in atrial fi-brillation may reflect this inflammation, and anticoagu-lation with heparinoids seems to reduce biomarkers ofinflammation in patients with atrial fibrillation. On theother hand, perioperative treatment with glucocorti-coids reduces the incidence of atrialfibrillation after car-

diac surgery, which suggests that inflammation may alsohave a causal role in the pathogenesis of atrial fibrilla-tion. Once patients develop atrial fibrillation, their riskof stroke varies in proportion to known clinical risk fac-tors, such as congestive heart failure, hypertension, age,diabetes mellitus, prior stroke, and peripheral vasculardisease. However, levels of the proinflammatory cyto-kine interleukin 6 are also associated with stroke risk,suggesting that inflammation is an additional biomarkerof stroke risk within this population. Given these data,physicians should be mindful that periods of heightened

Table. Examples of Brain-Immune Interactions and Their Clinical Implications in the Care of Patients With Stroke

Examples Potential Clinical Implications

Interaction of Inflammation and Stroke Risk

Biomarkers of stroke risk include white blood cell count, fibrinogen, D-dimer,and C-reactive protein. Duration of systemic lupus erythematosus andrheumatoid arthritis correlates with risk of stroke. A transient increased riskof stroke occurs after infection or surgery. A link exists betweeninflammation and atrial fibrillation.

Clinical implications include the following capabilities: predict favorableresponse to lipid-modifying agents, identify patients at high risk of strokeafter cessation of antithrombotic drugs, stratify risk of stroke and determineappropriate antithrombotic strategy in patients with atrial fibrillation, useproven measures for stroke prevention in patients with underlyinginflammatory disease and after infection or surgery, and control inflammationas a pathway to reducing vascular injury or occurrence of atrial fibrillation.

Interaction of Acute Infarction and Immune Activation

Intravascular hypoxia from thrombosis activates complement and endothelialcells. Oxidative stress reduces nitric oxide, promoting platelet and leukocyteaggregation. Platelet activation generates proinflammatory signals. Spreadof inflammation into perivascular space activates resident macrophages.Dying cells release signals that promote inflammation. Loss of neuronsremoves the anti-inflammatory check on adjacent microglia.

Inhibition of the complement cascade reduces ischemic brain damage.Lymphocyte depletion protects against penumbral ischemia in experimentalanimal models of stroke. Timely use of statin therapy during acute strokeseems to improve outcomes, potentially in part from anti-inflammatoryproperties.

Interaction of Central Nervous System Injury and Immunosuppression

Stroke results in lymphopenia, upregulation of anti-inflammatory cytokines,and splenic atrophy. Pneumonia and urinary tract infections occurfrequently after stroke. Cortisol and catecholamine levels correlate withsusceptibility to infection after stroke.

Vigilance should be exercised for early signs of infection after stroke.Prophylactic antibiotic use after stroke may reduce infectious complicationsand improve outcomes. Modulation of sympathetic activation may reducepoststroke immunodepression.

Interaction of Adaptive Immunity and Outcomes After Stroke

Inflammatory brain infiltrates persist for years after stroke. Abnormal

blood-brain barrier permeability may be associated with radiographic whitematter disease.

Immunomodulation may reduce the burden of long-term sequelae of ischemic

stroke.




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inflammation(such as acute medical illness or recent sur-gery) place patients at higher risk of atrial fibrillation andstroke. Withfurther development, biomarkers of inflam-mation may help to stratify patients risk of developingatrial fibrillation and stroke, allowing targeted screen-ing,risk factor modification, and timely treatment. A bet-ter understanding of the interactions among atrial fibril-lation, inflammation, and thromboembolism may leadtothe development of therapeutic agents that modulate in-

flammatory pathways to reduce the risk of atrial fibril-lation and stroke.

IMMUNE SIGNALINGDURING ACUTE INFARCTION

Besides its background role in stroke risk, the immunesystem actively participates in the acute pathogenesis ofstroke4 (Figure). Independent of any immune re-sponse, brain ischemia quickly causes failure of ionpumps, overaccumulation of intracellular sodium and cal-cium, loss of membrane integrity, and necrotic cell death.In addition, arterial occlusion immediately leads to in-travascular hypoxia, changes in shear stress, and the pro-

duction of reactive oxygen species, all of which in turnactivate the coagulation cascade, complement, plate-lets, and endothelial cells. This results in a vicious cycle,with fibrin formation entrapping platelets and leuko-cytes and causing further vascular occlusion. In addi-tion, oxidative stress reduces the bioavailability of nitricoxide, undermining its protective role in promoting va-sodilation and inhibiting platelet aggregation and leu-kocyte adhesion, causing further vascular occlusion andischemia. Central in this cascade of events is the trans-location of P-selectin, an adhesion molecule whose ex-

pression on the surface of platelets and endothelial cellsrapidly leads to cell adhesion. Trafficking of inflamma-tory cells into theperivascular spaceis facilitatedby down-regulation of junctional proteins that maintain the in-tegrity of the endothelial lining and the blood-brainbarrier. Involvement of the perivascular space then ac-tivates resident macrophages and mast cells, leading tothe release of vasoactive mediators and proinflamma-tory cytokines, which in turn recruit and promote the

infiltration of more leukocytes.As cells die of ischemia, they release signals that fur-ther activate the immune system. Extracellular accumu-lation of adenosine triphosphate released from dying cellsactivates microglia, which develop characteristics of mac-rophages and release proinflammatory mediators. Nu-merous normally intracellular components serve asdanger-associated molecular pattern molecules on theirrelease from dying cells, and these molecules activate toll-like receptors and scavenger receptors on microglia, peri-vascular macrophages, dendritic and endothelial cells, andinfiltrating leukocytes. This activation induces the ex-pression of proinflammatory molecules and primes den-dritic cells for antigen presentation. Such proinflamma-

tory changes are initially counterbalanced by the releaseof neurotransmitters, which activate anti-inflammatoryreceptors on microglia, and by the presence of cell-cellinteractions between microglia and adjacent neurons,which usually keep microglia quiescent. However, as is-chemic cell death progresses, neurons die and neurotrans-mitters are depleted, releasing this brake on proinflam-matory signaling.

The clinical implications of the immediate immuneinvolvement in the ischemic cascade are unclear. On theface of it, proinflammatory signals seem to promote mi-

Minutes Hours DaysYears

LDLoxidation andaggregation

Recentinfection

or surgery

Chronicinflammatory

disease

Weeks Months Yearsays Weeks

Immunodepression

Risk factors Acute stroke Sequelae

Hypoxia

activatesinflammation

Cellular damagetriggers innate

immunity

Adaptiveimmunityengaged

Resolution of inflammation,clearing of dead cells, and

promotion of cellular regrowth

Chronic CNS inflammationand immune activation?

LDL

Lipidaccumulation

Thrombus formation

Persistent autoimmuneresponse to brain antigens?

Leukocytes respond to hypoxiaand tissue damage

Tissuedamage

Complementactivation

Vessellumen

Figure.Progression of inflammation and immune activation in the development of stroke. Chronic inflammation from atherosclerosis, autoimmune disease, andphysiological stress results in progressive vascular injury that increases the risk of stroke. Acute occlusion of the cerebral vasculature produces intravascularhypoxia that triggers a rapid inflammatory response. As tissue damage proceeds, cellular components activate the innate immune response and set the stage forthe engagement of adaptive immunity. Questions remain about whether this immune activation after stroke causes autoimmunity that affects neurologicalrecovery. CNS indicates central nervous system; LDL, low-density lipoprotein.




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crovascular occlusionand shouldtend to increase the sizeof the resulting infarct. In fact, in experimental modelsof stroke, mice deficient in adhesion receptors or comple-ment subunits seem to be protected from acute ische-mia, and healthy mice treated with inhibitors of adhe-sion molecules or the complement cascade also developless ischemic brain injury. In addition, mice engineeredto lack selected T-cell subgroups are protected from is-chemic damage to the penumbral zone around areas of

infarction.

5

Available data indicate that the protective ef-fect of lymphocyte suppression does not stem from aninability to propagate thrombus and that no significantdifferences in cerebral blood flow exist between healthyand lymphocyte-deficient mice.6 It is possible that lym-phocytes instead produce cell damagedirectly or throughproinflammatory signaling and activation of down-stream microglia and macrophages. Or, the early dam-age associated with lymphocyte infiltration of the ische-mic brain may be due to the natural killer T-cell subtypethat harbors a simplified T-cell receptor and may not re-quire antigen processing. The available data do not pro-vide a clear picture of how lymphocytes participate inacute infarction.

Clinical attempts to explicitly modify the immune re-sponse after stroke (such as trials of recombinant neu-trophil inhibitory factor or antibodies against adhesionmolecules) have been ineffective to date, and these fail-ures highlight thecomplexity andredundancyof thepath-ways involved in the immune response to stroke. On theother hand, observational data and a randomized clini-cal trial indicate that acute use of statin medications atthe time of stroke improves long-term outcomes and re-duces mortality. Because this time window is not con-sistent with the lipid-lowering effects of statin medica-tions, the benefit of their use during the acute stage ofstroke hasbeen attributedto their anti-inflammatory prop-erties. This suggests that, despite the absence of specific

clinical strategies or drugs proven to beneficially modu-late immune functioning during acute brain infarction,further elucidation of this complex interplay may yieldmore sophisticated and pleiotropic therapeutics to aug-mentthe limitedrepertoire of antithrombotic agents avail-able to physicians today.

THE ROLE OF ADAPTIVE IMMUNITYAFTER STROKE

The inflammatory processes detailed thus far occur in ashort time window after infarction and rely on the in-nate immune system, which involves the rapid activa-tion of low-affinity receptors that recognize a wide range

of targets. The immediate onset of this inflammatory cas-cade and the available experimental data on patterns ofsignaling during early immune activation do not sup-port a substantial role in this process for the adaptive im-mune system, which relieson theclonal expansion of spe-cific lymphocytes with high-affinity receptors to specificantigens. However, the general immune activation causedby cerebral ischemia raises the questions of whether theadaptive immune system is eventually activated and howit may contribute to the propagation and repair of braininjury after stroke.

After stroke, the number of antigen-presenting cellsin the brain increases, along with costimulatory mol-ecules required for antigen presentation to lympho-cytes. This antigen presentation results in the produc-tion of antibodies against brain antigens and T cellssensitizedto brain antigens. Furthermore, successive mu-cosal administration of myelin antigens in experimentalmodels results in the development of immune toleranceand protection from subsequent ischemic injury, sug-

gesting that this immune response involves adaptive im-munity and that modulating it may be protective. On theother hand, although lymphocyte-deficient mice are pro-tected from ischemic brain damage, reconstituting themwith T cells directed against non-CNS antigens worsensischemic damage. In addition, mice lacking the neces-sary costimulatory molecules for antigen-specific T-cellresponses are nevertheless vulnerable to ischemic dam-age. Therefore, it is unclear whether the release and pre-sentation of CNS antigens during and after stroke resultin an adaptive immune responsedirectedagainst theCNS.

If such an autoimmune response was directed againstthe brain after stroke, its long-term implications wouldpotentially be significant (Table). Such immune activity

wouldbe expected to impair neuronal plasticity andfunc-tional recovery and contribute to the frequent incidenceof poststroke dementia. Such concerns are supported bythe presence of inflammatory infiltrates in damaged areasof the brain years after stroke, as well as by persistentlyelevated titers of antibodies to brain antigens. Abnor-malpermeability of theblood-brain barrier hasbeen linkedto the radiographic white matter changes frequently as-sociated with vascular disease and cognitive decline, andlevelsof inflammatory biomarkers such as C-reactive pro-tein are associated with white matter changes, lacunarstrokes, and loss of microstructural integrity as mea-sured by diffusion-tensor imaging.7 Therefore, it cannotbe discounted that immune activation contributes to the

alterations in this endothelial permeability and vasculardysfunction. On the other hand, immune cells such asmicroglia may be important for clearing deleterious cel-lular debris that can cause neurodegeneration. Furtherresearch will be required to determine what role, if any,immunity hasin long-term outcomesafter stroke, butelu-cidation of any potential mechanisms may open prom-ising avenues for the development of new therapeuticsto improve neurological recovery after brain injury.

RESOLUTION OF INFLAMMATIONAND THE ROLE OF THE IMMUNE SYSTEM

IN TISSUE REPAIR

The inflammation unleashed by cerebral infarction is fol-lowed by a carefully orchestrated process to clear ne-crotic debris and foster tissue repair. This reparativeprocess releases mediatorsthat actively bringthe inflam-matory process to a close. Phagocytosis of dead cells bymicroglia and macrophages promotes the production ofimmunomodulatory cytokines, such as transforminggrowth factor and interleukin 10. Although transform-ing growth factor has numerous proinflammatory ef-fects, in this context it helps to suppress inflammationby inhibitinghelper T-cell responsesand promotingregu-




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latory T-cell development. Interleukin 10 has neuropro-tective and anti-inflammatory properties, and its releasehelps to facilitate the resolution of inflammation and pro-motes the survival of remaining viable neurons.

In this evolving process, the same cells that were ini-tially recruited in the inflammatory phase serve as im-portant sources of growth factors required for neuronalsprouting, neurogenesis, angiogenesis, gliogenesis, andmatrix reorganization. For example, microglia are re-

quired for the full expression of insulinlike growth fac-tor 1, which promotes neuronal sprouting after injury.Reactive astrocytes produce vascular endothelial growthfactor, which is required for angiogenesis. CirculatingCD34 immune progenitor cells promote revasculariza-tion in infarcted brain tissue. This reparative aspect ofimmune cells raises expectations that they can be har-nessedto augment neuronal repair and recoveryafter CNSinjury. However, experimental efforts so far provide cau-tionary tales; for example, increasing vascular endothe-lial growth factor levels early after ischemia or in exces-sive amounts actually worsens injury. Such findingshighlight the complexity of the immune response to CNSinjury and indicate that attempts to modify these inter-

actions must be undertaken with care.

BRAIN INJURY AND IMMUNOSUPPRESSION

Thus far, we have focused on the effects exerted by theimmune system on the CNS after stroke. However, thisinteraction is bidirectional, and CNS injury has pro-found effects on immune function (Table). Within daysof stroke, patients develop significant immunodepres-sion, marked by lymphopenia, upregulation of anti-inflammatory cytokines, and splenic atrophy.8 This im-munodepression clinically manifests in the high rate ofsystemic infections seen in the immediate poststroke pe-riod. Patients with stroke are especially at risk of pneu-

monia and urinary tract infections, and such infectionsmay independently worsen neurological outcomes andincrease mortality. Immunodepression may account forthe inability of other factors (such as dysphagia) to fullyaccount for the high rates of pneumonia seen in survi-vors of stroke.

Poststroke immunodepression seems to be mediatedby catecholamines and steroids released by sympatheticactivation after stroke. Cortisol and serum catechol-amine levels correlate with susceptibility to infection af-ter stroke, and experimental models have shown that ste-roid and adrenergic antagonists counteract lymphocyteapoptosis and reduce rates of infection after brain in-jury. Intriguing clinical observations associate-blocker

use with lower rates of pneumonia and mortality afterstroke,9 but given the sparse nature of these data and thepleiotropic effects of-blockers, further research will berequired to determine the usefulness of such widely avail-able drugs to modulate the immune response after stroke.

Other efforts to counteract poststroke immunode-pression have involved the prophylactic administrationof antibiotics after stroke to protect patients from com-mon infections. Several randomized trials investigatedwhether this strategy improvesoutcomesafter stroke, anda meta-analysis10 of their results indicates that antibi-

otic use reduced the rate of infections but not mortality.However, these studies were underpowered to detect ameaningful difference in mortality rates, andfurther largetrials will be required to answer this question. If antibi-otic use is eventually shown to improve outcomes afterstroke, questions will remain about the effects of such astrategy on microbial resistance patterns. Nevertheless,it is possible that a strategy of prudent poststroke anti-biotic use may emerge as a cost-effective and safe strat-

egy for improving outcomes in these vulnerable pa-tients. In the meantime, physicians should be cognizantof the immunosuppressed state of their patients withstroke and should remain vigilant to expeditiously iden-tify and appropriately treat infections in these patients.

RELATIONSHIP BETWEEN POSTSTROKEIMMUNODEPRESSION AND ADAPTIVE IMMUNITY

In speculating about why poststroke immunodepres-sion occurs, on the surface it would seem to harm pa-tients by increasing their risk of infectious complica-tions. Although it may simply be a maladaptive responsethat stems from inherent aspects of thedesign of theCNS

andimmunesystem, immunodepressionmayserve to pro-tect the CNS from the development of adaptive immuneresponses directed against self. Recent data indicate thatthe CNS undergoes regular immune surveillance by cir-culating lymphocytes. Central nervous system compo-nents are not routinely presented to these lymphocytesin such a way as to sensitize them and launch an im-mune response against the CNS. However, in the ab-sence of countervailing factors, such antigen presenta-tion would be expected to occur after CNS injury andcompromise of the blood-brain barrier. Therefore, the im-munodepression seen after stroke may serve a benefi-cial purpose in limiting the development of such auto-immunity. Such considerations suggest that a detailed

understanding of the many facets of the interactions be-tween the CNS and the immune system is needed to guideany interventions to modify these interactions and im-prove outcomes.

CONCLUSIONS

The relationship between the CNS and the immune sys-tem is complex and remains incompletely understood.It has particular salience after stroke and other forms ofCNS injury, which trigger immune processes that seemto be both beneficial and harmful. A major frontier instrokeresearch involves efforts to better understand theseinteractions to develop new strategies and drugs that will

prevent and reduce the burden of stroke. Based on cur-rent knowledge, physicians should be mindful that un-derlying inflammation is a biomarker of stroke risk andshould carefully consider antithrombotic, statin, and an-tihypertensive therapy in vulnerable populations. Fur-ther work will be neededto delineate precise clinical strat-egies for risk factor modification based on specificbiomarkers. In addition, it would be reasonable to ad-minister statin drugs to patients with acute stroke givendata suggesting that this improves outcomes, possibly asa result of anti-inflammatory properties. Furthermore,




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physicians caring for patients with stroke should recog-nize that poststroke immunodepression increases the riskof infection and should adjust their clinical suspicion andtreatment strategies accordingly. Whether a strategy ofroutine prophylacticantibiotic administration after strokeis beneficial remains unknown, but it holds promise asa simple method for improving poststroke outcomes. Fi-nally, the care of patients with stroke may be improvedby advances in specific areas, including investigation of

whether modulating inflammatory pathways can re-duce the risk of stroke and decrease penumbral ische-mia during acute stroke, whether immunity has a rolein poststroke functional recovery and dementia, andwhether strategies to prevent poststroke immunodepres-sion can reduce the incidence of infection after strokewithout increasing dangerous autoimmunity against thebrain. The immune system has not traditionally been thesubject of therapeutic manipulation in patients withstroke,butgiven itsintertwined relationship with the CNS,it promises to be an exciting avenue for future attemptsto reduce the high burden of disability and death fromstroke.

Accepted for Publication:December 9, 2011.Correspondence:Costantino Iadecola, MD, Division ofNeurobiology, Department of Neurology and Neurosci-ence, 407 E 61st St, PO Box 64, Room RR303, New York,NY 10065 ([email protected]).Author Contributions:Drafting of the manuscript: Ka-mel and Iadecola.Critical revision of the manuscript for

important intellectual content: Kamel and Iadecola. Ob-tained funding:Iadecola.Financial Disclosure:None reported.Funding/Support:This study was supported by grantsNS34179 and NS73666 from the National Institute ofNeurological Disorders and Stroke, National Institutesof Health.

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