Methods— We studied 61 consecutive patients with diffusion-weighted imaging–mean transit time mismatch. All patients were scanned twice within 12 hours of symptom onset and between days 4 and 30. We explored the relationship between the volume of white matter regions with LA on acute images and the proportion of diffusion-weighted imaging–mean transit time mismatch tissue that progressed to infarction (percentage mismatch lost).

Results— Bivariate analyses showed a statistically significant correlation between percentage mismatch lost and LA volume (r=0.33, P<0.01). A linear regression model with percentage mismatch lost as response and LA volume, acute diffusion-weighted imaging and mean transit time volumes, age, admission blood glucose level, admission mean arterial blood pressure, etiologic stroke subtype, time to acute MRI, and time between acute and follow-up imaging as covariates revealed that LA volume was an independent predictor of infarct growth (P=0.04). The adjusted percentage mismatch lost in the highest quartile of LA volume was 1.9-fold (95% CI: 1.2 to 3.1) greater than the percentage mismatch lost in the lowest quartile.

Conclusion— LA volume at the time of acute ischemic stroke is a predictor infarct growth. Because LA is associated with factors that modulate tissue perfusion as well as tissue capacity for handling of ischemia, LA volume appears to be a composite predictive marker for the fate of acutely ischemic tissue.

Methods— Baseline and repeat MRI (3-year follow-up) were collected within the multicenter, multinational Leukoaraiosis and Disability study (n=396). Baseline WMH were scored on MRI by the Fazekas scale and the Scheltens scale. WMH progression was assessed using the modified Rotterdam Progression scale (absence/presence of progression in 9 brain regions). Baseline and new lacunes were counted per region. WMH and lacunes at baseline and vascular risk factors were evaluated as predictors of WMH progression and new lacunes.

Results— WMH progressed (mean±SD=1.9±1.8) mostly in the subcortical white matter, where WMH was also most prevalent at baseline. The majority of new lacunes, which were found in 19% of the subjects (maximum=9), also appeared in the subcortical white matter, mainly of the frontal lobes, whereas most baseline lacunes were located in the basal ganglia. Baseline WMH and lacunes predicted both WMH progression and new lacunes. Furthermore, previous stroke, diabetes, and blood glucose were risk factors for WMH progression. Male sex, hypertension, systolic blood pressure, previous stroke, body mass index, high-density lipoprotein, and triglyceride levels were risk factors for new lacunes.

Conclusion— WMH and lacunes progressed over time, predominantly in the subcortical white matter. Progression was observed especially in subjects with considerable WMH and lacunes at baseline. Moreover, the presence of vascular risk factors at baseline predicted WMH progression and new lacunes over a 3-year period.

Methods— In the Rotterdam Study, 6347 participants were classified at baseline (1990 to 1993) into those with recognized MI (subdivided into Q-wave and non-Q-wave MI), with unrecognized MI, and without MI based on electrocardiography and interview and were followed for incident dementia (n=613) until January 1, 2005. In the Rotterdam Scan Study, 436 nondemented persons were similarly classified based on electrocardiography and interview and underwent brain MRI for the assessment of white matter lesions and brain infarction.

Results— In men, unrecognized MI was associated with an increased risk of dementia (compared with men without MI hazard ratio, 2.14; 95% CI, 1.37 to 3.35) and with more white matter lesions and more often brain infarction on MRI. In women, no associations were found with unrecognized MI. Recognized MI was not associated with the risk of dementia in either sex. Men, but not women, with recognized MI had more often any brain infarction or asymptomatic brain infarction, especially if they had Q-wave MI. No consistent associations were found between recognized Q-wave or non-Q-wave MI and severity of white matter lesions. Additional adjustment for cardiovascular risk factors did not change the results.

Conclusions— Men with unrecognized MI have an increased risk of dementia and more cerebral small vessel disease.

Methods— Forty patients (26 men; mean [SD] age 62.1 [13.7] years) undergoing intracardiac surgery (7 also with coronary artery bypass grafting) were studied. Neurological, neuropsychological, and MRI examinations were performed 24 hours before surgery and 5 days (MRI and neurology) and 6 weeks (neuropsychology and neurology) after surgery. Cognitive decline from baseline was determined using the Reliable Change Index.

Results— Two of 40 (5%) patients had perioperative strokes and 22 of 35 (63%) tested had cognitive decline in at least one measure (range, 1 to 4). Sixteen of 37 participants (43%) with postoperative imaging had new ischemic lesions (range, 1 to 17 lesions) with appearances consistent with cerebral embolization. Cognitive decline was seen in all patients with, and 35% of those without, postoperative ischemic lesions (P<0.001), and there was an association between the number of abnormal cognitive tests and ischemic burden (P<0.001).

Conclusion— We have provided a reliable estimate of the rate of stroke, postoperative ischemia, and cognitive impairment at 6 weeks after cardiac valve surgery. Cognitive impairment is associated with perioperative ischemia and is more severe with greater ischemic load.

Methods— Multiplex families having at least 2 individuals with "definite" or "probable" IA were ascertained through an international consortium. First-degree relatives of individuals with IA who were at increased risk of an IA because of a history of hypertension or present smoking were offered cerebral magnetic resonance angiography. A genome screen was completed using the Illumina 6K SNP system, and the resulting data from 192 families, containing 1155 genotyped individuals, were analyzed. Narrow and broad disease definitions were used when testing for linkage using multipoint model-independent methods. Ordered subset analysis was performed to test for a genexsmoking (pack-years) interaction.

Results— The greatest evidence of linkage was found on chromosomes 4 (LOD=2.5; 156 cM), 7 (LOD=1.7; 183 cM), 8 (LOD=1.9; 70 cM), and 12 (LOD=1.6; 102 cM) using the broad disease definition. Using the average pack-years for the affected individuals in each family, the genes on chromosomes 4 (LOD=3.5; P=0.03), 7 (LOD=4.1; P=0.01) and 12 (LOD=3.6; P=0.02) all appear to be modulated by the degree of smoking in the affected members of the family. On chromosome 8, inclusion of smoking as a covariate did not significantly strengthen the linkage evidence, suggesting no interaction between the loci in this region and smoking.

Conclusions— We have detected possible evidence of linkage to 4 chromosomal regions. There is potential evidence for a genexsmoking interaction with 3 of the loci.

Methods— Mononuclear cells were isolated from the peripheral blood of 75 patients with acute stroke, 45 patients with chronic stroke, and 40 age-matched healthy volunteers. CFU numbers were counted after culturing them for 7 days, and outgrowth cell appearance was measured during the 2 months of culture. Endothelial progenitor cell function was also evaluated by matrigel plate assays. Independent parameters predicting CFU number and outgrowth cell yield were assessed using logistic regression analysis.

Results— The CFU numbers and tube formation abilities in matrigel assays were significantly reduced in patients with acute stroke compared with patients with chronic stroke or healthy control subjects. Moreover, patients with large artery atherosclerosis had much lower CFU numbers and functional activities than ones with cardioembolism. Outgrowth cells were isolated from 10% of healthy control subjects and 22% of patients with chronic stroke during the cultures, but from 71% of patients with stroke. Multivariate analysis identified glycosylated hemoglobin and National Institutes of Health Stroke Scale on admission as significant independent predictors of a low CFU number and a high isolation frequency of outgrowth cells, respectively.

Conclusion— CFU number may thus represent an accumulated endothelial progenitor cell dysfunctional status, whereas outgrowth cell appearance may reflect the resilience of the systemic circulation to acute ischemic stress.

Methods— The expression of Lp-PLA₂ in 167 carotid artery plaques was determined by immunoblotting and immunostaining. Plaque oxidative stress, inflammation, and stability were quantified by NAD(P)H oxidase p67phox and MMP-2 immunoblotting, oxidized LDL (oxLDL) immunoreactivity, macrophage and Sirius red collagen staining. Lysophosphatidylcholine 16:0 (lysoPC) concentration was measured in 55 plaques using liquid chromatography tandem mass spectrometry.

Results— Lp-PLA₂ expression was significantly higher in plaques of symptomatic patients than asymptomatic patients (1.66±0.19 versus 1.14±0.10, P<0.05) and localized mainly to shoulder and necrotic lipid core areas in colocalization with oxLDL and macrophage content. Similarly, Lp-PLA₂ expression was related to collagen content, which was lower in plaques from symptomatic patients than in plaques from asymptomatic patients (9.1±2.2 versus 18.5±1.7% of staining/field, P<0.001). LysoPC plaque concentration was significantly higher in plaques of symptomatic than asymptomatic patients (437.0±57.91 versus 228.84±37.00 mmol/L, P<0.05).

Conclusions— Symptomatic carotid artery plaques are characterized by increased levels of Lp-PLA₂ and its product lysoPC in correlation with markers of tissue oxidative stress, inflammation, and instability. These findings strongly support a role for Lp-PLA2 in the pathophysiology and clinical presentation of cerebrovascular disease.

Methods— Seventy-five consecutive patients with first-ever symptomatic intracranial atherostenosis were studied. Blood levels of C-reactive protein (CRP), E-selectin, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, matrix metalloproteinases 1, 2, 3, 8, 9, 10, and 13, plasminogen activator inhibitor-1 (PAI-1), and lipoprotein(a) were measured 3 months after the qualifying stroke or transient ischemic attack. Thereafter, patients underwent long-term transcranial Doppler follow-up to detect progression of ILA.

Results— During a median follow-up time of 23 months, 25 (33%) patients showed ILA progression. Multivariable adjusted Cox regression models and Kaplan–Meier curves showed that high baseline level of CRP, E-selectin, intercellular adhesion molecule-1, matrix metalloproteinase 9, PAI-1, and lipoprotein(a) predicted ILA progression independently of vascular risk factors. Of them, only CRP (CRP>5.5 mg/L; HR, 5.4 [2.3 to 12.7]; P=0.0001) and PAI-1 (PAI-1>23.1 ng/mL; HR, 2.4 [1.0 to 5.8]; P=0.05) predicted ILA progression also independently of the other studied molecules.

Conclusion— Progression of symptomatic ILA is associated with a proinflammatory state, as reflected by high levels of inflammatory markers, and with defective fibrinolysis, as indicated by raised concentrations of endogenous fibrinolysis inhibitors.

Methods— Stroke subjects treated within 3 hours had abnormal Thrombolysis in Brain Ischemia (TIBI) residual flow grades 0 to 3 before tPA on transcranial Doppler (TCD). Randomization included Controls (tPA+TCD) or Target (tPA+TCD+2.8 mL µS). The primary safety end point was symptomatic intracranial hemorrhage (sICH) with worsening by ≥4 NIHSS points within 72 hours.

Results— Fifteen subjects were randomized 3:1 to Target, n=12 or Control, n=3. After treatment, asymptomatic ICH occurred in 3 Target and 1 Control, and sICH was not seen in any study subject. µS reached MCA occlusions in all Target subjects at velocities higher than surrounding residual red blood cell flow: 39.8±11.3 vs 28.8±13.8 cm/s, P<0.001. In 75% of subjects, µS permeated to areas with no pretreatment residual flow, and in 83% residual flow velocity improved at a median of 30 minutes from start of µS infusion (range 30 s to 120 minutes) by a median of 17 cm/s (118% above pretreatment values). To provide perspective, current study recanalization rates were compared with the tPA control arm of the CLOTBUST trial: complete recanalization 50% versus 18%, partial 33% versus 33%, none 17% versus 49%, P=0.028. At 2 hours, sustained complete recanalization was 42% versus 13%, P=0.003, and NIHSS scores 0 to 3 were reached by 17% versus 8%, P=0.456.

Conclusions— Perflutren µS reached and permeated beyond intracranial occlusions with no increase in sICH after systemic thrombolysis suggesting feasibility of further µS dose-escalation studies and development of drug delivery to tissues with compromised perfusion.

Methods— Subjects with acute middle cerebral artery main stem occlusion were randomized into a target group receiving 1-hour transcranial continuous insonation using a 1.8-MHz Doppler ultrasound (US) probe or a control group. All underwent standard thrombolysis with intravenous recombinant tissue-type plasminogen activator.

Results— Thirty-seven subjects were included; 19 subjects were treated in the target (US) group and 18 in the control (no-US) group, all with no residual flow in the middle cerebral artery main stem occlusion (Thrombolysis in Brain Ischemia recanalization grade 0). Compared with the no-US group, the US group showed greater improvement in National Institutes of Health Stroke Scale values at days 1 and 4 and a higher median Thrombolysis in Brain Ischemia grade 1 hour after recombinant tissue-type plasminogen activator initiation. Recanalization (complete or partial) after 1 hour occurred in 57.9% of the US group and 22.2% of the no-US group (P=0.045). After 90 days, 4 subjects from the US group had a modified Rankin Score ≤1 (none from the no-US group) and 8 had a Barthel Index ≥95 (none from the no US group; P=0.106 and P=0.003, respectively). Three subjects from the US group (15.8%) developed a symptomatic intracranial hemorrhage as did one (5.6%) in the no-US group (P=0.60).

Conclusions— This small randomized study indicates a beneficial impact of transcranial ultrasound on recanalization and short-term outcome in subjects with middle cerebral artery main stem occlusion and recombinant tissue-type plasminogen activator treatment.

Methods— A double-blind, interobserver-validated analysis of multi-gate power-motion Doppler µS traces included large (>8µ) µS from agitated saline injections in the right-to-left shunt (RLS) positive stroke patients and small (<5µ) µS from acute patients without shunts receiving thrombolysis and perflutren-lipid µS.

Results— In 101 µS traces from 50 RLS-positive and 10 thrombolysis+µS treated patients, a large µS passage had median maximum duration 30.8 ms (interquartile range [IQR] 22.0ms), multi-gate travel time (MGTT) 58.6±19.3 ms versus small µS: duration 8.3ms (IQR 4.3ms), MGTT 43.2±13.9ms, P<0.001. Small µS had higher embolus-to-blood ratio (EBR): 17.5 (IQR 9.3) versus 7.5 (IQR 4), P<0.001. Receiver-operating curve areas were: duration 0.989 (95% CI 0.968 to 1.000), MGTT 0.766 (0.672 to 0.859), and EBR (Embolus-to-Blood Ratio) 0.927 (0.871 to 0.982), P<0.001. A 15.1-ms duration discriminated size ranges with 98% to 99% accuracy. On average, 130 sequential large (range 51 to 260) and 500 (265–588) small µS can produce continuous flow enhancement for 4 seconds. Small µS velocities on m-mode in obstructed vessels (39.8±11.3 cm/s) were similar to large µS in patent vessels (40.8±11.5 cm/s; P=0.719) and higher than surrounding red blood cell velocities (28.8±13.8 cm/s, P<0.001).

Conclusions— With normal or reduced flow, activated µS passage duration through a small power motion Doppler gate can quantify the dose of delivered µS. Ultrasound can determine a minimum number of µS needed to achieve constant flow enhancement and targeted drug delivery. Propagation speed of µS smaller than red blood cells may reflect plasma flow velocities around acute occlusions.

Methods— Participants were risk-stratified with the widely-used CHADS₂ scheme. Treatment-specific rates of stroke and major bleeding were calculated for patients with a CHADS₂=1 and compared to those with a CHADS₂>1.

Results— Observed stroke rates for those with a CHADS₂=1 were 1.25% per year on C+A and 0.43% per year on OAC (RR=2.96, 95% CI: 1.26 to 6.98, P=0.01). Among patients with a CHADS₂>1, the stroke rates were 3.15% per year on C+A and 2.01% per year on OAC (RR=1.58, 95% CI: 1.11 to 2.24, P=0.01) (P for interaction between stroke risk category and efficacy of OAC=0.19). The risk of major bleeding during OAC was significantly lower among patients with CHADS₂=1 (1.36% per year) compared with CHADS₂>1 (2.75% per year) (RR=0.49, 95% CI 0.30 to 0.79, P=0.003).

Conclusions— In this clinical trial, patients with a CHADS₂=1 had a low risk of stroke, yet still derived a modest (<1% per year) but statistically significant absolute reduction in stroke with OAC and had low rates of major hemorrhage on OAC.

Methods— Prospective case series. Patients with sinus thrombosis were selected for thrombolysis if they had an altered mental status, coma, straight sinus thrombosis, or large space-occupying lesions. Urokinase was infused into the sinuses (bolus 120 to 600x10³ U; then 100x10³ U/h) via a jugular catheter, in 15 cases combined with mechanical thrombus disruption or removal.

Results— We treated 20 patients (16 women), mean age 32 years. Twelve patients were comatose and 14 had hemorrhagic infarcts before thrombolysis. Twelve patients recovered (Rankin score 0 to 2), 2 survived with handicaps, and 6 died. Factors associated with a fatal outcome were leukemia (3/6 versus 0/14, P=0.02) and large hemorrhagic infarcts (4/6 versus 2/14, P=0.04). Seizures were less frequent in the fatal cases (P=0.05). Patients who died had a larger mean lesion surface than survivors (30.5 versus 13.6 cm²; P=0.03), larger midline shift (5.2 versus 1.7 mm; P=0.02), and a more rapid course (2.7 versus 8.2 days; P=0.01). Five patients who died had large hemispheric infarcts and edema before thrombolysis, causing herniation. Five patients had increased cerebral hemorrhage (3 minor, 2 major) after thrombolysis.

Conclusions— Thrombolysis can be effective for severe sinus thrombosis, but patients may deteriorate because of increased cerebral hemorrhage. Patients with large infarcts and impending herniation did not benefit.

Methods— We analyzed clinical radiological findings and functional outcomes in consecutive patients 3 months after treatment with IAT for peri-procedural strokes occurring during neuroendovascular or cardiac catheter interventions. To measure outcome, the modified Rankin scale score was used.

Results— Of a total of 432 patients treated with IAT, 12 (4 women and 8 men; mean age, 60 years) were treated because of an ischemic stroke after a neuro-endovascular procedure (n=6) or coronary angiography (n=6). The median baseline National Institutes of Health Stroke Scale score was15. Recanalization was complete (thrombolysis in myocardial infarction grade 3) in 6, partial (thrombolysis in myocardial infarction 2) in 5, and minimal (thrombolysis in myocardial infarction 1) in 1. Nine patients (75%) had a favorable outcome (modified Rankin scale score, 0 to 2), and 3 had a poor outcome (modified Rankin scale score, 3 or 4). All patients with complete recanalization had a favorable outcome, whereas only 3 of 6 patients with partial or minimal recanalization (P=0.18) had a favorable outcome. Follow-up brain imaging was normal in 2 and showed new ischemic lesions in 10 patients. Two patients (17%) had a symptomatic intracerebral hemorrhage.

Conclusion— In acute stroke attributable to arterial catheter interventions, IAT is feasible and has the potential to improve outcome in these patients. A high recanalization rate could be achieved.

Methods— Starting in January 2006, we treated all eligible patients with acute BAO admitted to our academic stroke center or one of our cooperating community hospitals after a standardized protocol combining IVT with consecutive on-demand EMT. Inclusion criteria were: (1) presence of predefined symptoms clearly suggestive of BAO; (2) exclusion of intracerebral hemorrhage on CT scan; (3) evidence of BAO on CT angiography; (4) start of therapy within 6 hours after symptom onset; and (5) no contraindications for IVT. If CT angiography showed persistent BAO after IVT, EMT was performed.

Results— Since January 2006, 16 patients have been treated. All patients received IVT; in 7 of them, EMT became necessary because of persistent BAO. Final recanalization was achieved in 15 patients. Three months after therapy, 12 of 16 patients were still alive; 7 of them had a good outcome (modified Rankin score ≤2).

Conclusions— Our data suggest that the combination of IVT with on-demand consecutive EMT in BAO is feasible, allows for early treatment, and provides excellent recanalization rates.

Methods— Potential predictors of IPR were evaluated in patients treated in the Cerebral Aneurysm Rerupture After Treatment (CARAT) study using multivariate logistic regression with stepwise elimination stratified by treatment modality. Periprocedural death or disability was defined as death or a change of ≥2 points on the Modified Rankin Scale at discharge compared to before treatment.

Results— IPR occurred in 14.6% of 1010 patients (299 coiled, 711 clipped): 19% with clipping and 5% with coiling (P<0.001). Among those clipped, 31% with IPR had periprocedural death or disability compared to 18% without IPR (P=0.001); among those coiled, 63% with IPR had periprocedural death or disability compared to 15% without IPR (P<0.001). Overall, coronary artery disease and initial lower Hunt and Hess Grade were independent predictors of IPR. For those undergoing coiling, independent predictors of IPR were Asian race, black race, COPD, and lower initial Hunt and Hess Grade. Among those undergoing clipping, hyperlipidemia and lower initial Hunt and Hess Grade were both independent predictors of IPR.

Conclusions— IPR was common in patients undergoing treatment of ruptured aneurysms, particularly with surgical clipping. The frequency of IPR with new disability was similar in the surgical and endovascular treatment groups. Coronary artery disease, hyperlipidemia, race, COPD, and lower Hunt and Hess Grade were associated with greater risk of IPR, which may reflect differences in vessel fragility but requires further confirmation.

Methods— Eighteen subjects were selected with chronic residual gait impairment due to a single subcortical ischemic stroke. Functional MRI scans were obtained at 3.0 T during active and passive ankle dorsiflexion in the patients (8 females, 10 males; mean age, 59.9±13.5 years; range, 32 to 74 years) and 18 age-matched healthy control subjects.

Results— We observed substantial neocortical activity associated with foot movement both in the patients with stroke and in the healthy control subjects. Our primary finding was increased cortical activation with increasing functional impairment. The extent of activation (particularly in the primary sensorimotor cortex and the supplementary motor area of the unlesioned hemisphere) increased with disability. The changes were most prominent with the active movement task.

Conclusions— Using ankle movement, we observed increased activation in the unlesioned hemisphere associated with worse function of the paretic leg, consistent with studies on movement of paretic upper limbs. We interpret this finding as potentially adaptive recruitment of undamaged ipsilateral motor control pathways from the supplementary motor area and (possibly maladaptive) disinhibition of the ipsilateral sensorimotor cortex.

Methods— A retrospective analysis was conducted of 161 692 patients from the Uniform Data System for Medical Rehabilitation who received inpatient medical rehabilitation after a first stroke in 2002 and 2003. Multivariable models examined the effects of race and ethnicity on length of stay, functional status, rehabilitation efficiency, and discharge setting.

Results— The mean age was 70.97 years (SD=12.87), 53% were female, and 76% were non-Hispanic white. Mean length of stay was similar for all groups ranging from 17.39 days (SD=10.86) to 17.93 (SD=10.59). Non-Hispanic white patients had higher admission and discharge functional status ratings compared with patients in the minority groups (P<0.01). Differences in functional status across racial/ethnic groups were related to age (F=20.49, P<0.001); the older the comparison group, the greater the difference in functional status. Non-Hispanic whites were discharged home less often than blacks (OR=0.64, 95% CI=0.62 to 0.66), Hispanics (OR=0.58, 95% CI=0.55 to 0.62), or other minority groups (OR=0.67, 95% CI=0.57 to 0.67).

Conclusions— The findings suggest racial and ethnic disparities exist in postacute care outcomes for persons with stroke.

Methods— Chronic stroke patients were randomly assigned to receive either constraint-induced movement therapy (n=16) or a comparison therapy (n=20). Longitudinal voxel-based morphometry was performed on structural MRI scans obtained immediately before and after patients received therapy.

Results— The group receiving constraint-induced movement therapy exhibited far greater improvement in use of the more affected arm in the life situation than the comparison therapy group. Structural brain changes paralleled these improvements in spontaneous use of the more impaired arm for activities of daily living. There were profuse increases in gray matter in sensory and motor areas both contralateral and ipsilateral to the affected arm that were bilaterally symmetrical, as well as bilaterally in the hippocampus. In contrast, the comparison therapy group failed to show gray matter increases. Importantly, the magnitude of the observed gray matter increases was significantly correlated with amount of improvement in real-world arm use.

Conclusions— These findings suggest that a previously overlooked type of brain plasticity, structural remodeling of the human brain, is harnessed by constraint-induced movement therapy for a condition once thought to be refractory to treatment: motor deficit in chronic stroke patients.

Methods— The third Auckland Regional Community Stroke (ARCOS) study was a prospective, population-based, stroke incidence study undertaken in Auckland, New Zealand during 2002 to 2003. After a baseline assessment early after stroke, data were collected on all survivors at 1 and 6 months follow-up. Multiple variable logistic regression was used to determine predictors of return to paid work. Data are reported with odds ratios (OR) and 95% confidence intervals (CI).

Results— Among 1423 patients registered with first-ever strokes, there were 210 previously in paid employment who survived to 6 months, of whom 155 (74%) completed the GHQ-28 and 112 (53%) had returned to paid work. Among those cognitively competent, psychiatric morbidity at 28 days was a strong independent predictor of not returning to work (Odds Ratio 0.39; 95% CI 0.22 to 0.80). Non–New Zealand European ethnicity (OR 0.40; 95% CI 0.17 to 0.91), prior part-time, as opposed to full-time, employment 0.36 (0.15 to 0.89), and not being functionally independent soon after the stroke 0.28 (0.13 to 0.59) were the other independent age- and gender-adjusted predictors of not successfully returning to paid work.

Conclusions— About half of previously employed people return to paid employment after stroke, with psychiatric morbidity and physical disability being independent, yet potentially treatable, determinants of this outcome. Appropriate management of both emotional and physical sequelae would appear necessary for optimizing recovery and return to work in younger adults after stroke.

Methods— Stroke-free participants in the Health and Retirement Study (n=19 565) were followed for an average of 8.5 years. Total wealth, income, and education assessed at baseline were used in Cox proportional hazards models to predict time to stroke. Separate models were estimated for 3 age-strata (50 to 64, 65 to 74, and ≥75), and incorporating risk factor measures (smoking, physical activity, body mass index, hypertension, diabetes, and heart disease).

Results— 1542 subjects developed incident stroke. Higher education predicted reduced stroke risk at ages 50 to 64, but not after adjustment for wealth and income. Wealth and income were independent risk factors for stroke at ages 50 to 64. Adjusted hazard ratios comparing the lowest decile with the 75th-90th percentiles were 2.3 (95% CI 1.6, 3.4) for wealth and 1.8 (95% CI 1.3, 2.6) for income. Risk factor adjustment attenuated these effects by 30% to 50%, but coefficients for both wealth (HR=1.7, 95% CI 1.2, 2.5) and income (HR=1.6, 95% CI 1.2, 2.3) remained significant. Wealth, income, and education did not consistently predict stroke beyond age 65.

Conclusions— Wealth and income are independent predictors of stroke at ages 50 to 64 but do not predict stroke among the elderly. This age patterning might reflect buffering of the negative effect of low socioeconomic status by improved access to social and health care programs at old ages, but may also be an artifact of selective survival.

Methods— Male Wistar rats (n=22) were subjected to 60 minutes MCA occlusion. MR images (T2- and T2*-weighted) were obtained weekly between weeks 1 and 7 after reperfusion, and at weeks 10, 14, 20, and 24. Histological iron detection and immunohistochemical examination for different markers (NeuN, GFAP, OX-42, HO-1, and APP) were performed at the 3 survival time points (3, 7, and 24 weeks).

Results— Infarcts affecting MCA territory were evident on T2-weighted imaging, and all animals showed deficits on behavioral tests. In the thalamus, T2 hyperintensity was detected 3 weeks after stroke, and disappeared around week 7 when T2*-weighted images showed a marked hypointensity in that area. Histology revealed neuronal loss in the thalamus, accompanied by strong microglial reactivity and microglial HO-1 expression. APP deposits were detected in the thalamus from week 3 on and persisted until week 24. Iron storage was detected in microglia at week 3, in the parenchyma at week 7, and around APP deposits at week 24.

Conclusions— T2*-weighted MRI allows the detection of secondary damage in the thalamus after MCAO. Iron accumulation in the thalamus is mediated by HO-1 expression in reactive microglia.

Methods— Cerebral blood flow, oxyhemoglobin, and cerebral metabolic rate of oxygen were measured noninvasively using simultaneous multispectral reflectance imaging and laser speckle flowmetry during distal middle cerebral artery occlusion in mice. Hypertension was induced by phenylephrine infusion starting 10 or 60 minutes after ischemia to raise blood pressure by 30% for the duration of ischemia; control groups received saline infusion.

Results— Mild induced hypertension rapidly increased cerebral blood flow, oxyhemoglobin, and cerebral metabolic rate of oxygen in both the core and penumbra and prevented the expansion of cerebral blood flow deficit during 1 hour distal middle cerebral artery occlusion. Induced hypertension also diminished the deleterious effects of periinfarct depolarizations on cerebral blood flow, oxyhemoglobin, and cerebral metabolic rate of oxygen without altering their frequency. Consistent with this, mild induced hypertension reduced infarct volume by 48% without exacerbating tissue swelling when measured 2 days after 1 hour transient distal middle cerebral artery occlusion.

Conclusions— Our data suggest that mild induced hypertension increases collateral cerebral blood flow and oxygenation and improves cerebral metabolic rate of oxygen in the core and penumbra, supporting its use as bridging therapy in acute ischemic stroke until arterial recanalization is achieved.

Methods— We studied the cortical microcirculation of physiologically monitored rats in vivo by two-photon laser-scanning microscopy after plasma-labeling with fluorescein-dextran. We induced focal thrombosis in 30- to 50-µm cortical arterioles by laser irradiation and measured arteriolar flow velocity by repeated line-scanning. At 30 minutes post-thrombosis, we treated animals with the thrombolytic agent, reteplase, which was coadministered with either human albumin, 2 g/kg, or with saline control.

Results— Baseline arteriolar flow velocity averaged 3.8±0.7 mm/s, was immediately reduced by thrombosis to 22% to 25% of control values, and remained unchanged before treatment. Subthrombolytic doses of reteplase combined with saline led to a median increase in flow velocity to 37% of control distal to the thrombus (P=nonsignificant versus pretreatment). By contrast, reteplase combined with albumin therapy resulted in a prompt, highly significant increase of median flow velocity to 58% of control levels (P=0.013 versus reteplase+saline), which remained significantly higher than the reteplase+saline group at multiple time-points over the subsequent hour.

Conclusions— The beneficial effect of subthrombolytic doses of reteplase on microvascular hemodynamics distal to a cortical arteriolar thrombosis is markedly enhanced by the coadministration of high-dose albumin therapy; these results have important clinical implications for the management of patients with acute ischemic stroke.

Method— Male Wistar rats were subjected to embolic stroke and treated with saline (n=10) or with sildenafil (n=11), with treatment initiated at 24 hours and continued daily for 7 days after onset of ischemia. T2*WI measurements were performed at 24 hours after embolization and weekly up to 6 weeks using a 7-Tesla system. Histological measurements were obtained at 6 weeks after MRI scans.

Results— Using T2*WI, cerebral angiogenesis was detected starting from 4 weeks and from 2 weeks after onset of embolic stroke in saline and sildenafil treated rats, respectively. Significant differences in the temporal and spatial features of angiogenesis after embolic stroke up to 6 weeks after onset of stroke were found between saline and sildenafil treated rats and were identified with T2*WI. MRI permeability parameter, K_i, complementarily detected angiogenesis after ischemia in embolic stroke rats. Sildenafil treatment of stroke rats significantly enhanced the angiogenesis, as confirmed histologically.

Conclusions— T2*WI can quantitatively measure the temporal evolution of angiogenesis in rats subjected to embolic stroke. Compared to control rats, sildenafil treatment significantly increased angiogenesis in treated animals up to 6 weeks after stroke.

Methods— Transient cerebral ischemia was induced in adult Wistar rats (n=25) followed by IA or intravenous (IV) injection of mesenchymal stem cells (MSCs) labeled with superparamagnetic iron oxide. Cell infusion was monitored in real time with transcranial laser Doppler flowmetry while cellular delivery was assessed with MRI in vivo (4.7T) and ex vivo (9.4T).

Results— Successful delivery of magnetically labeled MSCs could be readily visualized with MRI after IA but not IV injection. IA stem cell injection during acute stroke resulted in a high variability of cerebral engraftment. The amount of LDF reduction during cell infusion (up to 80%) was found to correlate well with the degree of intracerebral engraftment, with low LDF values being associated with significant morbidity.

Conclusions— High cerebral engraftment rates are associated with impeded cerebral blood flow. Noninvasive dual-modality imaging enables monitoring of targeted cell delivery, and through interactive adjustment may improve the safety and efficacy of stem cell therapy.

Methods— Male Lewis rats were tolerized to myelin basic protein (MBP) or ovalbumin by intranasal administration before middle cerebral artery occlusion. At the time of reperfusion, all animals received lipopolysaccharide (1 mg/kg intraperitoneal). Behavioral tests were performed at set time intervals.

Results— One month after middle cerebral artery occlusion, lymphocytes from the spleens of MBP-tolerized animals were less likely to evidence an autoimmune response and more likely to evidence a regulatory response (Treg) toward MBP than those from ovalbumin-tolerized animals. Animals that had an inflammatory response toward MBP (a Th1 response) performed worse on behavioral tests than those that did not. Fractalkine, a surrogate marker of inflammation, was elevated in animals with a Th1 response to MBP.

Conclusions— These data extend our previous findings and suggest that deleterious autoimmunity to brain antigens can be prevented by prophylactically inducing regulatory T-cell responses to those antigens.

Methods— Participants were recruited after each mass on a single weekend from 2 Catholic churches in Corpus Christi, Texas. Questionnaires about personal stroke risk factors and interest in program participation were completed, and blood pressure screening was performed.

Results— A total of 150 individuals participated (63% Mexican American, median age 62). A substantial majority (84%) were interested in being part of a long-term church-based health education project. Blood pressure was >139/89 mm Hg in 50 of 78 (64%) of individuals with a self-reported history of hypertension, and in 17 of 69 (25%) of individuals without known hypertension, with no ethnic differences in blood pressure. Mexican Americans were younger, had a higher BMI, and were more likely to have diabetes than non-Hispanic whites.

Conclusions— There is substantial burden of stroke risk factors in these predominantly Mexican American church communities. Church-based health interventions may be a way to reduce stroke in this at-risk population.

Methods— We recently initiated a whole genome analysis of ischemic stroke and published the first stage of a case control study using >400 000 SNPs from Illumina Infinium Human-1 and HumanHap300 assays. We focused on SNPs recently associated with heart disease by Helgadottir and colleagues and SNPs from the same haplotype block.

Results— In analyses both unadjusted and adjusted for stroke risk factors, significant associations with ischemic stroke were observed for SNPs from the same haplotype block previously associated with myocardial infarction. Significant association was also seen between disease and haplotypes involving these SNPs, both with and without adjustment for stroke risk factors (odd ratios: 1.01 to 2.65).

Conclusions— These data are important for 3 reasons: first, they suggest a genetic association for stroke; second, they suggest that this association shares pathogenic mechanisms with heart disease and diabetes; and third, they illustrate, that public release of data can facilitate rapid risk locus discovery.

Methods— Six haplotype block-tagging single nucleotide polymorphisms (rs962458, rs6152, rs1204038, rs2361634, rs1337080, rs1337082), as well as the cysteine, adenine, guanine (CAG) microsatellite in exon 1, of the AR gene were evaluated among 300 white postmenopausal women who developed CVD (158 myocardial infarctions and 142 ischemic strokes) and an equal number of matched controls within the Women’s Health Study.

Results— Genotype distributions were similar between cases and controls, and genotypes were not significantly related to risk of CVD, myocardial infarctions or ischemic stroke in conditional logistic regression models. Seven common haplotypes were observed, but distributions did not differ between cases and controls nor were significant associations observed in logistic regression analysis. The median CAG repeat length was 21. In conditional logistic regression, there was no association between the number of alleles with CAG repeat length ≥21 (or ≥22) and risk of CVD, myocardial infarctions or ischemic stroke.

Conclusions— No association between AR genetic variation, as measured by haplotype-tagging single nucleotide polymorphisms and CAG repeat number, and risk of CVD was observed in women.

Methods— Twenty-six single nucleotide polymorphisms in the EPHX2 gene region were genotyped in 601 patients with ischemic stroke and 736 matched controls. Cases were subtyped according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification system. Analyses were done on single markers and haplotypes using a sliding-window approach.

Results— Three single nucleotide polymorphisms showed associations with an increased risk for ischemic stroke (allelic models; all P≤0.01). One of them retained statistical significance after correction for multiple testing. Associations were observed with large-vessel stroke and stroke of undetermined etiology but not with other stroke subtypes.

Conclusions— Our findings confirm and extend previous studies suggesting that genetic variation in or near the EPHX2 gene contributes to the risk of ischemic stroke. This association seems to be mediated predominantly by large-vessel disease.

Methods— The study population consisted of 104 stable patients with CAD who had preserved left ventricular function (left ventricular ejection fraction ≥45%). All patients underwent carotid ultrasound for evaluation of carotid artery plaque score defined by the sum of plaque thickness, maximum percent area stenosis, and carotid arterial stiffness index β calculated by a combination of changes in carotid arterial diameter and blood pressure.

Results— Plaque score and percent area stenosis correlated with the extent of CAD defined as the number of diseased coronary vessels (P<0.001 and 0.002, respectively), but arterial stiffness β did not (P=0.39). Using logistic regression analyses adjusting for confounding coronary risk factors and arterial stiffness β, plaque score and percent area stenosis were independently correlated with multivessel CAD (P=0.001 and 0.004, respectively).

Conclusions— Carotid artery plaque burden, but not arterial stiffness, is associated with the extent of CAD, suggesting morphological rather than functional changes in the carotid artery may be a more accurate predictor of the extent of CAD and multivessel CAD independent of left ventricular function.

Methods— Brain MRI was performed in 1043 participants (151 DM2) with symptomatic arterial disease. Brain volumes were obtained through automated segmentation.

Results— Patients with arterial disease and DM2 had more global and subcortical brain atrophy (–1.20% brain/intracranial volume [95%CI –1.58 to –0.82], P<0.0005 and 0.20% ventricular/intracranial volume [0.05 to 0.34], P<0.01), larger WMH volumes (0.22 logtransformed volume [0.07 to 0.38], P<0.005), and more lacunar infarcts (OR 1.75 [1.13 to 2.69], P<0.01) than identical patients without DM2. In patients with DM2, high glucose levels (B–0.12% per mmol/L [–0.23 to –0.01], P<0.05) and diabetes duration (B–0.05% per year [–0.10 to –0.001], P<0.05) were associated with global brain atrophy.

Conclusion— In patients with symptomatic arterial disease, DM2 has an added detrimental effect on the brain. In patients with DM2, hyperglycemia and diabetes duration contribute to brain atrophy.

Methods— We used 3-dimensional time-of-flight MR angiography with a radiofrequency coil optimized for 7.0T MRI. We examined the LSAs of 6 healthy subjects and compared 7.0T MR angiography images with 1.5T ones to examine the potentials of ultrahigh-field MRI for angiography.

Results— The results show clear details of LSAs and their distribution in the normal healthy subjects with large variations in the shapes, the number of branches and the sites of origin. We also observed substantial differences between the left and right sides within each subject. Although we studied only 6 subjects, we found no age- or gender-related differences in the LSAs.

Conclusions— The visualization of microvasculature of the brain, such as LSAs, using 7.0T MR angiography, is possible in in vivo human studies noninvasively. We, therefore, believe that it could play a major role in the study of small vascular abnormalities, such as the early stages of cerebral strokes.

Methods— We conducted a cross-sectional study in 1151 Japanese healthy subjects. Three types of silent lesions were assessed by MRI scans. MetS was diagnosed using the criteria by the National Cholesterol Education Adult Treatment Panel III.

Results— After adjusting for age and other factors, MetS was significantly associated with silent brain infarction, periventricular hyperintensity and subcortical white matter lesions. Among the MetS components, elevated blood pressure was commonly associated with all types of lesions. Dyslipidemia and elevated fasting glucose levels were associated with subcortical white matter lesions and periventricular hyperintensities, respectively. Positive trends were observed between the number of MetS components and prevalence of silent lesions.

Conclusions— MetS is associated with the prevalence of silent lesions independent of other risk factors. The clustering of MetS components tends to increase the prevalence of silent lesions.

Methods— We prospectively measured cerebrospinal fluid TN-C levels in 7 control patients with unruptured cerebral aneurysms and in 29 consecutive patients with aneurysmal SAH on days 1 to 12.

Results— Cerebrospinal fluid TN-C levels were less than the diagnostic threshold level in control patients but markedly increased after SAH. Higher TN-C levels were observed in patients with more severe SAH on admission CT, ventricular drainage for acute obstructive hydrocephalus, and a worse outcome. Independent of these factors, however, cerebrospinal fluid TN-C levels were significantly higher in patients with than without subsequent chronic shunt-dependent hydrocephalus on days 1 to 9.

Conclusions— These findings suggest the possible involvement of TN-C in the development of chronic hydrocephalus after SAH and encourage further studies.

Methods— After femoral artery cutdown, a microcatheter was advanced from the internal carotid artery to the MCA. MCA occlusion was achieved by IA thrombin and reperfusion by IA plasmin.

Results— The terminal internal carotid artery was successfully catheterized in 12 of 13 animals. Stable (2-hour) MCA occlusion was induced and verified angiographically in all 12 animals; 2 animals also had distal internal carotid artery thrombus. Recanalization was achieved rapidly after IA plasmin in 3 of 3 animals.

Conclusions— We describe a new animal model of selective MCA occlusion documented by real-time angiography and used to demonstrate recanalization with IA plasmin.

Methods— We analyzed data of MRI-selected acute ischemic stroke patients treated with intravenous tissue plasminogen activator within 6 hours. Initial perfusion and diffusion lesion volumes were calculated. Final infarct volume was as