Familial transmission of stroke and myocardial infarction (MI) is partially mediated by transmission of cerebrovascular and cardiovascular risk factors. We examined relationships between family risk of stroke and MI with risk factors for these phenotypes.
Cross-sectional association between the stratified log-rank family score (SLFS) for stroke and MI with prevalent risk factors was assessed in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort.
Individuals in the 4th quartile of SLFS scores for stroke were more likely to have prevalent risk factors including hypertension (OR: 1.43; 95% CI: [1.30, 1.58]), left ventricular hypertrophy (OR 1.42; 95% CI: [1.16, 1.42]), diabetes (OR: 1.26; 95% CI: [1.12, 1.43]) and atrial fibrillation (OR 1.23; 95% CI: [1.03, 1.45]) compared to individuals in the 1st quartile. Likewise, individuals in the 4th quartile of SLFS scores for MI were more likely to have prevalent risk factors including hypertension (OR 1.57; 95% CI: [1.27, 1.94]) and diabetes (OR 1.29; 95% CI: [1.12, 1.43]) than the 1st quartile. In contrast to stroke, the family risk score for MI was associated with dyslipidemia (OR 1.38; 95% CI: [1.23, 1.55]) and overweight/obesity (OR 1.22; 95% CI: [1.10, 1.37]).
Family risk of stroke and MI are strongly associated with the majority of risk factors associated with each disease. Family history and genetic studies separating nonspecific contributions of intermediate phenotypes from specific contributions to the disease phenotype may lead to more thorough understanding of transmission for these complex disorders.
stroke; myocardial infarction; cohort studies; family risk; REGARDS
family history studies; genetics; genomewide association; ischemic stroke; pharmacogenomics
Background and Purpose
Hypertension is the most important risk factor associated with intracerebral hemorrhage (ICH). We explored racial differences in blood pressure (BP) control after ICH and assessed predictors of BP control at presentation, 30 days, and 1 year in a prospective cohort study.
Subjects with spontaneous ICH were identified from the DiffErenCes in the Imaging of Primary Hemorrhage based on Ethnicity or Race (DECIPHER) Project. Blood pressure was compared by race at each time point. Multivariable linear regression was used to determine predictors of presenting mean arterial pressure (MAP), and longitudinal linear regression was used to assess predictors of MAP at follow-up.
A total of 162 patients were included (mean age 59, 53% male, 77% black). MAP at presentation was 9.6 mmHg higher in blacks than whites despite adjustment for confounders (p=0.065). Fewer than 20% of patients had normal blood pressure (<120/80 mmHg) at 30 days or 1 year. While there was no difference at 30 days (p=0.331), blacks were more likely than whites to have Stage I/II hypertension at one year (p=0.036). Factors associated with lower MAP at follow-up in multivariable analysis were being married at baseline (p=0.032) and living in a facility (versus personal residence) at the time of BP measurement (p=0.023).
Long-term blood pressure control is inadequate in patients following ICH, particularly in blacks. Further studies are needed to understand the role of social support and barriers to control to identify optimal approaches to improve blood pressure in this high-risk population.
Intracerebral hemorrhage; hypertension; secondary prevention; racial differences
Background and Purpose
Long noncoding RNAs (lncRNAs) play a significant role in cellular physiology. We evaluated the effect of focal ischemia on the expression of 8,314 lncRNAs in rat cerebral cortex using microarrays.
Ischemia was induced by transient middle cerebral artery occlusion. Genomic and transcriptomic correlates of the stroke-responsive lncRNAs and the transcription factor binding sties in their promoters were evaluated with bioinformatics.
359 lncRNAs were upregulated (>2-fold) and 84 were downregulated (<0.5 fold) at 3h to 12h of reperfusion following MCAO compared to sham. 62 stroke-responsive lncRNAs showed >90% sequence homology with exons of protein-coding genes. Promoters of stroke-responsive lncRNA genes and their homologous protein-coding genes showed highly overlapping transcription factor binding sites. Despite presence of ORFs, lncRNAs did not form any product when subjected to in vitro translation.
Stroke significantly alters cerebral lncRNA expression profiles.
Stroke; Noncoding RNA; Transcription Factor; exon mimicry
Background and Purpose
The pattern of antenatal brain injury varies with gestational age at the time of insult. Deep brain nuclei are often injured at older gestational ages. Having previously shown postnatal hypertonia following preterm fetal rabbit hypoxia-ischemia (H-I), the objective of this study was to investigate the causal relationship between the dynamic regional pattern of brain injury on MRI and the evolution of muscle tone in the near-term rabbit fetus.
Serial MRI was performed on New Zealand White rabbit fetuses to determine equipotency of fetal H-I during uterine ischemia comparing 29 days gestation (E29, 92% gestation) with E22 and E25. E29 postnatal kits at 4, 24, 72 hours after H-I underwent T2- and diffusion weighted imaging. Quantitative assessments of tone were made serially using a torque apparatus in addition to clinical assessments.
Based on the brain apparent diffusion coefficient (ADC), 32 min of uterine ischemia was selected for E29 fetuses. At E30, 58% of the survivors manifested hind limb hypotonia. By E32, 71% of the hypotonic kits developed dystonic hypertonia. Marked and persistent ADC reduction in basal ganglia, thalamus and brainstem was predictive of these motor deficits.
MRI observation of deep brain injury 6–24 hours following near-term H-I predicts dystonic hypertonia postnatally. Torque-displacement measurements indicate that motor deficits in rabbits progressed from initial hypotonia to hypertonia, similar to human CP, but in a compressed time-frame. The presence of deep brain injury and quantitative shift from hypo- to hypertonia may identify patients at risk for developing CP.
hypoxic-ischemic encephalopathy; hypertonia; diffusion-weighted imaging
Background and Purpose
Enrollment in the SAMMPRIS trial was halted due to the high risk of stroke or death within 30 days of enrollment in the percutaneous transluminal angioplasty and stenting (PTAS) arm relative to the medical arm. This analysis focuses on the patient and procedural factors that may have been associated with peri-procedural cerebrovascular events in the trial.
Bivariate and multivariate analyses were performed to evaluate whether patient and procedural variables were associated with cerebral ischemic or hemorrhagic events occurring within 30 days of enrollment (termed peri-procedural) in the PTAS arm.
Of 224 patients randomized to PTAS, 213 underwent angioplasty alone (n=5) or with stenting (n=208). Of these, 13 had hemorrhagic strokes (7 parenchymal, 6 subarachnoid), 19 had ischemic stroke, and 2 had cerebral infarcts with temporary signs (CITS) within the peri-procedural period. Ischemic events were categorized as perforator occlusions (13), embolic (4), mixed perforator and embolic (2), and delayed stent occlusion (2). Multivariate analyses showed that higher percent stenosis, lower modified Rankin score, and clopidogrel load associated with an activated clotting time above the target range were associated (p ≤ 0.05) with hemorrhagic stroke. Non-smoking, basilar artery stenosis, diabetes, and older age were associated (p ≤ 0.05) with ischemic events.
Peri-procedural strokes in SAMMPRIS had multiple causes with the most common being perforator occlusion. Although risk factors for peri-procedural strokes could be identified, excluding patients with these features from undergoing PTAS to lower the procedural risk would limit PTAS to a small subset of patients. Moreover, given the small number of events, the present data should be used for hypothesis generation rather than to guide patient selection in clinical practice.
Intracranial stenosis; angioplasty and stenting; clinical trial
The Critical Access Hospital (CAH) designation was established to provide rural residents local access to emergency and inpatient care. CAHs, however, have poorer short-term outcomes for pneumonia, heart failure, and myocardial infarction compared to other hospitals. We assessed whether 30-day risk-standardized mortality rates (RSMRs) and readmission rates (RSRRs) after ischemic stroke differ between CAHs and non-CAHs.
The study included all fee-for-service Medicare beneficiaries ≥65 years old with a primary discharge diagnosis of ischemic stroke (ICD-9 433, 434, 436) in 2006. Hierarchical generalized linear models calculated hospital-level RSMRs and RSRRs, adjusting for patient demographics, medical history, and comorbid conditions. Non-CAHs were categorized by hospital volume quartiles and the RSMR and RSRR posterior probabilities in comparison to CAHs were determined using linear regression with Markov chain Monte Carlo simulation.
There were 10,267 ischemic stroke discharges from 1,165 CAHs and 300,114 discharges from 3,381 non-CAHs. The RSMRs of CAHs were higher than non-CAHs (11.9%±1.4% vs. 10.9%±1.7%, p<0.001), but the RSRRs were comparable (13.7%±0.6% vs. 13.7%±1.4%, p=0.3). The RSMRs for the two higher volume quartiles of non-CAHs were lower than CAHs (posterior probability of RSMRs higher than CAHs=0.007 for quartile 3, probability<0.001 for quartile 4), but there were no differences for lower volume hospitals; RSRRs did not vary by annual hospital volume.
Critical Access Hospitals had higher RSMRs compared with non-CAHs, but readmission rates were similar. The observed differences may be partly explained by patient characteristics and annual hospital volume.
ischemic stroke; outcomes; critical access hospital; mortality; readmission
Background and Purpose
Memory impairment is both a predictor and a consequence of stroke, but memory decline is common even in healthy elderly. We compared the long-term trajectory of memory functioning before and after stroke to memory change in stroke-free elderly.
Health and Retirement Study participants age 50+ (n=17,340) with no stroke history at baseline were interviewed biennially up to 10 years for first self- or proxy-reported stroke (n=1,574). Age-, sex-, and race- adjusted segmented linear regression models were used to compare annual rates of change in a composite memory score before and after stroke among three groups: 1,189 stroke survivors; 385 stroke decedents; and 15,766 cohort members who remained stroke-free.
Before stroke onset, individuals who later survived stroke had significantly (p<0.001) faster average annual rate of memory decline (-0.143 points/year) than those who remained stroke-free throughout follow-up (-0.101 points/year). Stroke decedents had even faster pre-stroke memory decline (-0.212 points/year). At stroke onset, memory declined an average of -0.369 points among stroke survivors, comparable to 3.7 years of age-related decline in stroke-free cohort members. Following stroke, memory in stroke survivors continued to decline at -0.142 points/year, similar to their pre-stroke rate (p=0.93). Approximately 50% of the memory difference between stroke survivors shortly after stroke and age-matched stroke-free individuals was attributable to pre-stroke memory.
Although stroke onset induced large decrements in memory, memory differences were apparent years before stroke. Memory declines before stroke, especially among those who did not survive the stroke, were faster than declines among stroke-free adults.
Memory functioning change; memory impairment; stroke
Background and Purpose
Remote ischemic conditioning is cardioprotective in myocardial infarction and neuroprotective in mechanical occlusion models of stroke. However, there is no report on its therapeutic potential in a physiologically relevant embolic stroke model (eMCAO) in combination with intravenous (IV) tissue plasminogen activator (tPA).
We tested remote ischemic perconditioning therapy (RIPerC) at 2 hours after eMCAO in the mouse with and without IV tPA at 4 hours. We assessed cerebral blood flow (CBF) up to 6 hours, neurologic deficits, injury size and phosphorylation of Akt (Serine473; p-Akt) as a pro-survival signal in the ischemic hemisphere at 48 hours post stroke.
RIPerC therapy alone improved the CBF and neurologic outcomes. tPA alone at 4 hours did not significantly improve the neurologic outcome even after successful thrombolysis. Individual treatments with RIPerC and IV tPA reduced the infarct size (25.7% and 23.8%, respectively). Combination therapy of RIPerC and tPA resulted in additive effects in further improving the neurologic outcome, and reducing the infarct size (50%). All the therapeutic treatments upregulated p-Akt in the ischemic hemisphere.
RIPerC is effective alone after eMCAO and has additive effects in combination with IV tPA. RIPerC may be a simple, safe and inexpensive combination therapy with IV tPA.
Embolic stroke; Remote Ischemic Conditioning; IV tPA
Intracranial stenosis; angioplasty and stenting; clinical trial
White matter hyperintensity (WMH), or leukoaraiosis, is a radiological finding generally assumed to reflect diseased small cerebral vasculature. WMH has significant functional impact through its relationship to cognitive decline and risk of ischemic and hemorrhagic stroke. Accumulating evidence suggests that some manifestations of small vessel disease such as intracerebral hemorrhage (ICH) are associated with low levels of cholesterol. We sought to determine the relationship between hyperlipidemia (HL) and WMH severity in patients with acute ischemic stroke (AIS).
We analyzed two independent hospital-based AIS cohorts. Demographic and clinical data were collected prospectively. WMH was measured using semi-automated volumetric image analysis and a semi-quantitative visual grading scale. Univariate and multivariable regression analyses were used to assess the relationship between WMH severity and study variables.
A total of 631 and 504 subjects in the first and second cohorts, respectively, were included. In univariate analyses, advancing age and hypertension were associated with severity of WMH (p<0.001) in both cohorts. In the multivariable analysis, after controlling for age, gender, and those significant risk factors in the univariate and age-adjusted analyses, patients with a history of HL had less severe WMH in both cohorts (p<0.01).
Results from two independent cohorts demonstrate that AIS patients with a history of HL have less severe WMH at the time of stroke. These data support the hypothesis that HL may play a relatively protective role on cerebral small vessel disease.
white matter disease; leukoaraiosis; hyperlipidemia; risk factors
Background and Purpose
Neighborhood characteristics may influence the risk of stroke and contribute to socioeconomic disparities in stroke incidence. The objectives of this study were to examine the relationship between neighborhood socioeconomic status (NSES) and incident ischemic stroke and examine potential mediators of these associations.
We analyzed data from 3834 whites and 785 African Americans enrolled in the Cardiovascular Health Study, a multicenter, population-based, longitudinal study of adults ages ≥65 years from four U.S. counties. The primary outcome was adjudicated incident ischemic stroke. NSES was measured using a composite of six census tract variables. Race-stratified multilevel Cox proportional hazard models were constructed, adjusted for sociodemographic, behavioral, and biologic risk factors.
Among whites, in models adjusted for sociodemographic characteristics, stroke hazard was significantly higher among residents of neighborhoods in the lowest compared to the highest NSES quartile (Hazard Ratio [HR] =1.32; 95% CI 1.01-1.72), with greater attenuation of the HR after adjustment for biologic risk factors (HR=1.16; 0.88-1.52) than for behavioral risk factors (HR=1.30; 0.99-1.70). Among African Americans, we found no significant associations between NSES and ischemic stroke.
Higher risk of incident ischemic stroke was observed in the most disadvantaged neighborhoods among whites, but not among African Americans. The relationship between NSES and stroke among whites appears to be mediated more strongly by biologic than behavioral risk factors.
Background and Purpose
This scientific statement provides an overview of the evidence on
vascular contributions to cognitive impairment and dementia. Vascular
contributions to cognitive impairment and dementia of later life are common.
Definitions of vascular cognitive impairment (VCI), neuropathology, basic
science and pathophysiological aspects, role of neuroimaging and vascular
and other associated risk factors, and potential opportunities for
prevention and treatment are reviewed. This statement serves as an overall
guide for practitioners to gain a better understanding of VCI and dementia,
prevention, and treatment.
Writing group members were nominated by the writing group co-chairs
on the basis of their previous work in relevant topic areas and were
approved by the American Heart Association Stroke Council Scientific
Statement Oversight Committee, the Council on Epidemiology and Prevention,
and the Manuscript Oversight Committee. The writing group used systematic
literature reviews (primarily covering publications from 1990 to May 1,
2010), previously published guidelines, personal files, and expert opinion
to summarize existing evidence, indicate gaps in current knowledge, and,
when appropriate, formulate recommendations using standard American Heart
Association criteria. All members of the writing group had the opportunity
to comment on the recommendations and approved the final version of this
document. After peer review by the American Heart Association, as well as
review by the Stroke Council leadership, Council on Epidemiology and
Prevention Council, and Scientific Statements Oversight Committee, the
statement was approved by the American Heart Association Science Advisory
and Coordinating Committee.
The construct of VCI has been introduced to capture the entire
spectrum of cognitive disorders associated with all forms of cerebral
vascular brain injury—not solely stroke—ranging from mild
cognitive impairment through fully developed dementia. Dysfunction of the
neurovascular unit and mechanisms regulating cerebral blood flow are likely
to be important components of the pathophysiological processes underlying
VCI. Cerebral amyloid angiopathy is emerging as an important marker of risk
for Alzheimer disease, microinfarction, microhemorrhage and macrohemorrhage
of the brain, and VCI. The neuropathology of cognitive impairment in later
life is often a mixture of Alzheimer disease and microvascular brain damage,
which may overlap and synergize to heighten the risk of cognitive
impairment. In this regard, magnetic resonance imaging and other
neuroimaging techniques play an important role in the definition and
detection of VCI and provide evidence that subcortical forms of VCI with
white matter hyperintensities and small deep infarcts are common. In many
cases, risk markers for VCI are the same as traditional risk factors for
stroke. These risks may include but are not limited to atrial fibrillation,
hypertension, diabetes mellitus, and hypercholesterolemia. Furthermore,
these same vascular risk factors may be risk markers for Alzheimer disease.
Carotid intimal-medial thickness and arterial stiffness are emerging as
markers of arterial aging and may serve as risk markers for VCI. Currently,
no specific treatments for VCI have been approved by the US Food and Drug
Administration. However, detection and control of the traditional risk
factors for stroke and cardiovascular disease may be effective in the
prevention of VCI, even in older people.
Vascular contributions to cognitive impairment and dementia are
important. Understanding of VCI has evolved substantially in recent years,
based on preclinical, neuropathologic, neuroimaging, physiological, and
epidemiological studies. Transdisciplinary, translational, and transactional
approaches are recommended to further our understanding of this entity and
to better characterize its neuropsychological profile. There is a need for
prospective, quantitative, clinical-pathological-neuroimaging studies to
improve knowledge of the pathological basis of neuroimaging change and the
complex interplay between vascular and Alzheimer disease pathologies in the
evolution of clinical VCI and Alzheimer disease. Long-term vascular risk
marker interventional studies beginning as early as midlife may be required
to prevent or postpone the onset of VCI and Alzheimer disease. Studies of
intensive reduction of vascular risk factors in high-risk groups are another
important avenue of research.
AHA Scientific Statements; vascular dementia; Alzheimer disease; risk factors; prevention; treatment
Background and Purpose
We examined effects of isoflurane, volatile anesthetics, on blood-brain barrier (BBB) disruption in the endovascular perforation model of subarachnoid hemorrhage (SAH) in mice.
Animals were assigned to sham-operated, SAH+vehicle-air, SAH+1% or 2% isoflurane groups. Neurobehavioral function, brain water content, Evans blue dye extravasation and Western blotting for sphingosine kinases (SphKs), occludin, claudin-5, junctional adhesion molecule and vascular endothelial cadherin were evaluated at 24 hours post-SAH. Effects of SphK (DMS) or sphingosine-1-phosphate receptor-1/3 (S1P1/3) inhibitors (VPC23019) on isoflurane's action were also examined.
SAH aggravated neurological scores, brain edema and BBB permeability, which were prevented by 2% but not 1% isoflurane posttreatment. 2% isoflurane increased SphK1 expression and prevented a post-SAH decrease in expressions of the BBB-related proteins. Both DMS and VPC23019 abolished the beneficial effects of isoflurane.
2% isoflurane can suppress post-SAH BBB disruption, which may be mediated by SphK1 expression and S1P1/3 activation.
subarachnoid hemorrhage; early brain injury; isoflurane; blood-brain barrier; sphingosine kinase-1; sphingosine-1-phosphate receptor
Background and Purpose
An increasing number of unruptured intracranial aneurysms are being detected, partly due to the increased use of brain imaging techniques. Pharmacological stabilization of aneurysms for the prevention of aneurysmal rupture could potentially be an attractive alternative approach to clipping or coiling in patients with unruptured intracranial aneurysms. We have developed a mouse model of intracranial aneurysm that recapitulates key features of intracranial aneurysms. In this model, subarachnoid hemorrhage from aneurysmal rupture causes neurological symptoms that can be easily detected by a simple neurological examination. Using this model, we tested whether anti-inflammatory agents such as tetracycline derivatives, or a selective inhibitor of matrix metalloproteinases-2 and -9 (SB-3CT) can prevent the rupture of intracranial aneurysms.
Aneurysms were induced by a combination of induced hypertension and a single injection of elastase into the cerebrospinal fluid in mice. Treatment with minocycline, doxycycline, or SB-3CT was started six days after aneurysm induction. Aneurysmal rupture was detected by neurological symptoms and confirmed by the presence of intracranial aneurysm with subarachnoid hemorrhage.
Minocycline and doxycycline significantly reduced rupture rates (vehicle vs. doxycycline = 80 vs. 35%, P < 0.05; vehicle vs. minocycline = 73 vs. 24%, P < 0.05) without affecting the overall incidence of aneurysms. However, SB-3CT did not affect the rupture rate (62 vs. 55%, P = 0.53).
Our data established the feasibility of using a mouse model of intracranial aneurysm to test pharmacological stabilization of aneurysms. Tetracycline derivatives could be potentially effective in preventing aneurysmal rupture.
intracranial aneurysm; subarachnoid hemorrhage; intracranial hemorrhage; animal model; tetracycline; matrix metalloproteinase; inflammation
Evidence suggests that the protease-activated receptor-1 (PAR-1), a thrombin receptor, mediates neuronal injury in experimental cerebral ischemia. The present study investigated whether PAR-1 plays a role in brain injury after global cerebral ischemia.
Adult male wild type (WT) or PAR-1 knockout mice underwent a 20-minute bilateral common carotid artery occlusion (BCCAO) or a sham operation. Behavior tests were performed before ischemia, and 1, 2 and 3 days after BCCAO. Mice were euthanized at different time points for thrombin activity, brain edema, Western blot analysis and brain histology.
Thrombin activity and PAR-1 expression were increased in the brain after BCCAO. Compared with WT mice, PAR-1 knockout mice had less brain edema formation, neuronal death and behavior impairment after BCCAO. In addition, BCCAO-induced activation of mitogen-activated protein kinases was absent in PAR-1 knockout mice.
PAR-1 contributes to the brain injury induced by global cerebral ischemia, which may be related to activation of mitogen-activated protein kinases.
brain edema; global cerebral ischemia; mitogen-activated protein kinases; protease activated receptor-1(PAR-1); thrombin
Background and purpose
Tissue plasminogen activator (tPA) is the only approved therapy for acute ischemic stroke. However, tPA has a brief therapeutic window. Its side effects include intracerebral bleeding and neurotoxicity. Therefore, a combination therapy with tPA and agents that can extend the therapeutic window of tPA and/or counteract its side effects are warranted. Here, we studied whether 3K3A-APC, a neuroprotective analog of activated protein C (APC) with reduced anticoagulant activity, can enhance the therapeutic effects of tPA in models of ischemic stroke in rodents.
Human recombinant tPA (10 mg/kg), alone or in combination with human recombinant 3K3A-APC (2 mg/kg), was given intravenously 4 hours after proximal or distal transient middle cerebral artery occlusion (MCAo) in mice and embolic stroke in rats. 3K3A-APC was additionally administered for 3–4 consecutive days after stroke. The neuropathological and neurological analyses were performed at 1 to 7 days after stroke.
In all models, tPA alone had no effects on the infarct volume or behavior (i.e., neurological score, foot-fault, forelimb asymmetry, adhesive removal) compared to vehicle. tPA and 3K3A-APC combination therapy reduced the infarct volume 24 hours and 7 days after proximal or distal transient MCAo in mice and 7 days after embolic stroke in rats by 65%, 63% and 52%, respectively, improved significantly (P<0.05) behavior, and eliminated tPA-induced intracerebral microhemorrhages.
3K3A-APC extends the therapeutic window of tPA for ischemic stroke in rodents. Therefore, this combination therapy should also be considered for treating stroke in humans.
thrombolytic therapy; ischemic stroke; proteases; neuroprotection
Background and Purpose
The harsh host brain microenvironment caused by production of reactive oxygen species after ischemic reperfusion injury offers a significant challenge to survival of transplanted neural stem cells (NSCs) after ischemic stroke.
Copper/zinc-superoxide dismutase (SOD1) is a specific antioxidant enzyme that counteracts superoxide anions. Here, we have investigated whether genetic manipulation to overexpress SOD1 enhances survival of grafted stem cells and accelerates amelioration of ischemic stroke.
NSCs genetically modified to overexpress or downexpress SOD1 were administered intracerebrally 2 days after transient middle cerebral artery occlusion. Histological and behavioral tests were examined from Days 0 to 28 after stroke.
Overexpression of SOD1 suppressed production of superoxide anions after ischemic reperfusion injury and reduced NSC death after transplantation. In contrast, downexpression of SOD1 promoted superoxide generation and increased oxidative stress-mediated NSC death. Transplantation of SOD1-overexpressing NSCs enhanced angiogenesis in the ischemic border zone through up-regulation of vascular endothelial growth factor. Moreover, grafted SOD1-overexpressing NSCs reduced infarct size and improved behavioral performance, compared with NSCs that were not genetically modified.
Our findings reveal a strong involvement of SOD1 expression in NSC survival after ischemic reperfusion injury. We propose that conferring antioxidant properties on NSCs by genetic manipulation of SOD1 is a potential approach for enhancing the effectiveness of cell transplantation therapy in ischemic stroke.
neural stem cell; ischemic stroke; copper/zinc-superoxide dismutase; neuroprotection
Background and Purpose
Maternal cigarette smoking increases the risk of neonatal morbidity. We tested the hypothesis that perinatal nicotine exposure causes heightened brain vulnerability to hypoxic-ischemic (HI) injury in neonatal rats via aberrant expression patterns of angiotensin II type 1 (AT1R) and type 2 (AT2R) receptors in the developing brain.
Nicotine was administered to pregnant rats via subcutaneous osmotic minipumps. HI brain injury was determined in 10-day-old pups. AT1R and AT2R expression patterns were assessed via Western blotting, q-PCR, immunofluorescence and confocal imaging.
Perinatal nicotine exposure significantly increased HI brain infarct size in male, but not female, pups. In fetal brains, nicotine caused a decrease in mRNA and protein abundance of AT2R, but not AT1R. The downregulation of AT2R persisted in brains of male pups, and nicotine treatment resulted in a significant increase in methylation of CpG locus three bases upstream of TATA-box at AT2R gene promoter. In female brains, there was an increase in AT2R, but a decrease in AT1R expression. Both AT1R and AT2R expressed in neurons but not in astrocytes in the cortex and hippocampus. Central application of AT1R antagonist losartan or AT2R antagonist PD123319 increased HI brain infarct size in both male and female pups. In male pups, AT2R agonist CGP42112 abrogated nicotine-induced increase in HI brain infarction. In females, PD123319 uncovered the nicotine’s effect on HI brain infarction.
Perinatal nicotine exposure causes epigenetic repression of AT2R gene in the developing brain resulting in heightened brain vulnerability to HI injury in neonatal male rats in a sex-dependent manner.
nicotine; AT1R/AT2R; neonatal rat; hypoxic-ischemic brain injury
Background and Purpose
Fractalkine (CX3CL1) is a unique chemokine that is constitutively expressed on neurons where it serves as an adhesion molecule for lymphocytes and monocytes. CX3CL1 may also be cleaved from the surface of these cells and enter the circulation to act as a traditional chemokine. CX3CL1 could thus influence the inflammatory response following stroke. We hypothesized that patients with higher plasma CX3CL1 after stroke would have a more robust inflammatory response and experience worse outcome.
Plasma CX3CL1 concentrations were assessed in 85 patients who were part of a larger study evaluating immune responses following ischemic stroke; CX3CL1 values were available from day 1 to day 180 after stroke onset. CX3CL1 was correlated to measures of inflammation and its effect on outcome assessed.
At 1 day after stroke, CX3CL1 was lower in patients with severe strokes. At 180 days after stroke, CX3CL1 concentrations were lower in patients with poor outcome. The association of CX3CL1 and outcome at 180 days was independent of initial stroke severity. Plasma CX3CL1 at 180 days was inversely associated with systemic markers of inflammation, including white blood cell counts and high sensitivity C reactive protein.
In contrast to our original hypothesis, lower concentrations of CX3CL1 are associated with worse stroke outcome. In light of recent studies suggesting an immunomodulatory and neuroprotective role for CX3CL1 in a variety of neurodegenerative diseases, a therapeutic role for CX3CL1 in stroke recovery should be considered.
fractalkine; CX3CL1; stroke; inflammation; outcome
Background and Purpose
Enhanced angiogenesis facilitates neurovascular remodeling processes and promotes brain functional recovery after stroke. Previous studies from our laboratory demonstrated that valproate (VPA), a histone deacetylase (HDAC) inhibitor, protects against experimental brain ischemia. The present study investigated whether VPA could enhance angiogenesis and promote long-term functional recovery after ischemic stroke.
Male rats underwent middle cerebral artery occlusion (MCAO) for 60 minutes followed by reperfusion for up to 14 days. Assessed parameters were: locomotor function via rotarod test; infarct volume via T2-weighted magnetic resonance imaging; microvessel density via immunohistochemistry; relative cerebral blood flow (rCBF) via perfusion-weighted imaging; protein levels of pro-angiogenic factors via Western blotting; and matrix metalloproteinase (MMP)-2/9 activities via gelatin zymography.
Post-ischemic VPA treatment robustly improved the rotarod performance of MCAO rats on days 7 and 14 after ischemia, and significantly reduced brain infarction on day 14. Concurrently, VPA markedly enhanced microvessel density, facilitated endothelial cell proliferation, and increased rCBF in the ipsilateral cortex. The transcription factor hypoxia-inducible factor (HIF)-1α and its downstream pro-angiogenic factors, vascular endothelial growth factor (VEGF) and MMP-2/9, were upregulated after MCAO and significantly potentiated by VPA in the ipsilateral cortex. Acetylation of histone-H3 and H4 was robustly increased by chronic VPA treatment. The beneficial effects of VPA on rotarod performance and microvessel density were abolished by HIF-1α inhibition.
Chronic VPA treatment enhances angiogenesis and promotes functional recovery after brain ischemia. These effects may involve HDAC inhibition and upregulation of HIF-1α and its downstream pro-angiogenic factors VEGF and MMP-2/9.
angiogenesis; cerebral ischemia; hypoxia-inducible factor-1; matrix metalloproteinase; MRI; valproate; vascular endothelial growth factor
Background and Purpose
Few studies have addressed outcomes among patients ≥80 years treated with acute stroke therapy. In this study, we outline in-hospital outcomes in (1) patients ≥80 years compared to their younger counterparts, and (2) those over age 80 receiving intra-arterial therapy (IAT) compared to those treated with intravenous recombinant tissue plasminogen activator (IVrtPA).
Stroke centers within the Specialized Program of Translational Research in Acute Stroke (SPOTRIAS) prospectively collected data on all patients treated with IVrtPA or IAT from 1/1/2005 to 12/31/2010. IAT was defined as receiving any endovascular therapy; IAT was further divided into bridging therapy (BT) when the patient received both IAT and IVrtPA, and endovascular therapy alone (ETA). In-hospital mortality was compared in (1) all patients age ≥80 versus younger counter-parts, and (2) IAT, BT, and ETA versus IVrtPA only among those age ≥80 using multivariable logistic regression. An age-stratified analysis was also performed.
A total of 3768 patients were included in the study; 3378 were treated with IVrtPA alone, 808 with IAT (383 with ETA and 425 with BT). Patients ≥80 (n=1182) had a higher risk of in-hospital mortality compared to younger counterparts regardless of treatment modality (OR 2.13, 95%CI 1.60–2.84). When limited to those age ≥80, IAT (OR 0.95, 95%CI 0.60–1.49), BT (OR 0.82, 95%CI 0.47–1.45), or ETA (OR 1.15, 95%CI 0.64–2.08) versus IVrtPA were not associated with increased in-hospital mortality
IAT does not appear to increase the risk of in-hospital mortality among those over age 80 compared to intravenous thrombolysis alone.
Our recently proposed point scoring model includes the widely-used Spetzler-Martin (SM)-5 variables, along with age, unruptured presentation, and diffuse border (SM-Supp). Here we evaluate the SM-Supp model performance compared to SM-5, SM-3, and Toronto prediction models using net reclassification index (NRI), which quantifies the correct movement in risk reclassification, and validate the model in an independent dataset.
Bad outcome was defined as worsening between preoperative and final postoperative modified Rankin Scale score. Point scores for each model were used as predictors in logistic regression, and predictions evaluated using NRI at varying thresholds (10–30%) and any threshold (continuous NRI>0). Performance was validated in an independent dataset (n=117).
Net gain in risk reclassification was better using the SM-Supp model over a range of threshold values (NRI=9–25%) and significantly improved overall predictions for outcomes in the development dataset, yielding a continuous NRI of 64% versus SM-5, 67% versus SM-3, and 61% versus Toronto (all P<0.001). In the validation dataset, the SM-Supp model again correctly reclassified a greater proportion of patients versus SM-5 (82%), SM-3 (85%), and Toronto models (69%).
The SM-Supp model demonstrated better discrimination and risk reclassification than several existing models and should be considered for clinical practice to estimate surgical risk in BAVM patients.
receiver operator curve; Modified Rankin Scale; net reclassification
Toward the goal of designing a clinical trial using imaging parameters to treat stroke patients with unknown onset time, we investigated the timing of changes on MRI in patients with well-defined stroke onset.
Hypothesis generating (n=85) and confirmatory (n=111) samples were scored by blinded readers for FLAIR hyperintensity in diffusion-positive regions. Reader measured signal intensity ratio (SIR) of the lesion to contralateral tissue was compared with SIR measured by co-registration.
Lesion conspicuity increased with time on FLAIR (p=0.006). Qualitative assessment of FLAIR-negative vs FLAIR hyperintensity (k= 0.7091, 95% CI 0.61–0.81) showed good interrater agreement. Subtle hyperintensity was less reliably categorized (k=0.59, 95% CI 0.47–0.71). Reader measured SIR <1.15 can identify patients within the treatable time window of 4.5 hours (positive predictive value= 0.90). The SIR was greater for right hemisphere lesions (p=0.04) for a given reported time from stroke symptom onset.
The SIR on FLAIR provides a quantitative tool to identify early ischemic strokes. In developing SIR thresholds, right hemisphere lesions may confound the accurate estimate of stroke onset time. Image co-registration for thrombolytic trial enrollment is not necessary. A SIR < 1.15 on FLAIR yields a practical estimate of stroke onset within 4.5 hours.
DWI= Diffusion Weighted Imaging; FLAIR= Fluid Attenuation Inversion Recovery; Thrombolysis; Stroke