Efficacy of Intravenous Mesenchymal Stem Cells for Motor Recovery After Ischemic Stroke: A Neuroimaging Study.

BACKGROUND AND PURPOSE: Stem cell-based therapy is a promising approach to repair brain damage after stroke. This study was conducted to investigate changes in neuroimaging measures using stem cell-based therapy in patients with ischemic stroke. METHODS: In this prospective, open-label, randomized controlled trial with blinded outcome evaluation, patients with severe middle cerebral artery territory infarct were assigned to the autologous mesenchymal stem cell (MSC) treatment or control group. Of 54 patients who completed the intervention, 31 for the MSC and 13 for the control groups were included in this neuroimaging analysis. Motor function was assessed before the intervention and 90 days after randomization using the Fugl-Meyer assessment scale. Neuroimaging measures included fractional anisotropy values of the corticospinal tract and posterior limb of the internal capsule from diffusion tensor magnetic resonance imaging and strength of connectivity, efficiency, and density of the motor network from resting-state functional magnetic resonance imaging. RESULTS: For motor function, the improvement ratio of the Fugl-Meyer assessment score was significantly higher in the MSC group compared with the control group. In neuroimaging, corticospinal tract and posterior limb of the internal capsule fractional anisotropy did not decrease in the MSC group but significantly decreased at 90 days after randomization in the control group. Interhemispheric connectivity and ipsilesional connectivity significantly increased in the MSC group. Change in interhemispheric connectivity showed a significant group difference. CONCLUSIONS: Stem cell-based therapy can protect corticospinal tract against degeneration and enhance positive changes in network reorganization to facilitate motor recovery after stroke. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01716481.

Brain morphological and connectivity changes on MRI after stem cell therapy in a rat stroke model.

In animal models of stroke, behavioral assessments could be complemented by a variety of neuroimaging studies to correlate them with recovery and better understand mechanisms of improvement after stem cell therapy. We evaluated morphological and connectivity changes after treatment with human mesenchymal stem cells (hMSCs) in a rat stroke model, through quantitative measurement of T2-weighted images and diffusion tensor imaging (DTI). Transient middle cerebral artery occlusion rats randomly received PBS (PBS-only), FBS cultured hMSCs (FBS-hMSCs), or stroke patients' serum cultured hMSCs (SS-hMSCs). Functional improvement was assessed using a modified neurological severity score (mNSS). Quantitative analyses of T2-weighted ischemic lesion and ventricular volume changes were performed. Brain microstructure/connectivity changes were evaluated in the ischemic recovery area by DTI-derived microstructural indices such as relative fractional anisotropy (rFA), relative axial diffusivity (rAD), and relative radial diffusivity (rRD), and relative fiber density (rFD) analyses. According to mNSS results, the SS-hMSCs group showed the most prominent functional improvement. Infarct lesion volume of the SS-hMSCs group was significantly decreased at 2 weeks when compared to the PBS-only groups, but there were no differences between the FBS-hMSCs and SS-hMSCs groups. Brain atrophy was significantly decreased in the SS-hMSCs group compared to the other groups. In DTI, rFA and rFD values were significantly higher and rRD value was significant lower in the SS-hMSCs group and these microstructure/connectivity changes were correlated with T2-weighted morphological changes. T2-weighted volume alterations (ischemic lesion and brain atrophy), and DTI microstructural indices and rFD changes, were well matched with the results of behavioral assessment. These quantitative MRI measurements could be potential outcome predictors of functional recovery after treatment with stem cells for stroke.

Efficacy and Safety of Intravenous Mesenchymal Stem Cells for Ischemic Stroke.

OBJECTIVE: To test whether autologous modified mesenchymal stem cells (MSCs) improve recovery in patients with chronic major stroke. METHODS: In this prospective, open-label, randomized controlled trial with blinded outcome evaluation, patients with severe middle cerebral artery territory infarct within 90 days of symptom onset were assigned, in a 2:1 ratio, to receive preconditioned autologous MSC injections (MSC group) or standard treatment alone (control group). The primary outcome was the score on the modified Rankin Scale (mRS) at 3 months. The secondary outcome was to further demonstrate motor recovery. RESULTS: A total of 39 and 15 patients were included in the MSC and control groups, respectively, for the final intention-to-treat analysis. Mean age of patients was 68 (range 28-83) years, and mean interval between stroke onset to randomization was 20.2 (range 5-89) days. Baseline characteristics were not different between groups. There was no significant difference between the groups in the mRS score shift at 3 months (p = 0.732). However, secondary analyses showed significant improvements in lower extremity motor function in the MSC group compared to the control group (change in the leg score of the Motricity Index, p = 0.023), which was notable among patients with low predicted recovery potential. There were no serious treatment-related adverse events. CONCLUSIONS: IV application of preconditioned, autologous MSCs with autologous serum was feasible and safe in patients with chronic major stroke. MSC treatment was not associated with improvements in the 3-month mRS score, but we did observe leg motor improvement in detailed functional analyses. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that autologous MSCs do not improve 90-day outcomes in patients with chronic stroke. CLINICALTRIALSGOV IDENTIFIER: NCT01716481.

Prevalence and Impact of Venous and Arterial Thromboembolism in Patients With Embolic Stroke of Undetermined Source With or Without Active Cancer.

Background An increased risk of acute ischemic stroke is recognized among patients with cancer. However, the mechanism behind cancer-related stroke is unclear. In this study, we determined the presence of associated venous thromboembolism and arterial thromboembolism and their clinical impact on patients with cancer-related stroke. Methods and Results Patients with embolic stroke of undetermined source with or without cancer were evaluated for venous thromboembolism (deep vein thrombosis [DVT] and/or pulmonary embolism) and arterial thromboembolism by using Doppler sonography to determine the presence of lower-extremity DVT and the microembolic signal of the symptomatic cerebral circulation, respectively. Infarct volume was determined by diffusion-weighted magnetic resonance imaging. The multivariable linear regression and Cox proportional hazard analysis were used to investigate the effect of DVT and microembolic signal on infarct volume and 1-year survival, respectively. Of 142 screened patients, 118 were included (37 with, 81 without cancer). Those with cancer had a higher prevalence of DVT or microembolic signal than did the noncancer group (62.2% versus 19.8%; P<0.001). Among patients with cancer-related stroke, DVT was associated with a greater infarct volume in magnetic resonance imaging (beta, 13.14; 95% CI, 1.62-24.66; P=0.028). Presence of DVT (hazard ratio, 16.79; 95% CI, 2.05-137.75; P=0.009) and microembolic signal (hazard ratio, 8.16; 95% CI, 1.36-48.85; P=0.022) were independent predictors of poor 1-year survival. Conclusions Patients with cancer-associated embolic stroke of undetermined source have an elevated risk of associated venous thromboembolism and arterial thromboembolism, both of which have a significant negative impact on 1-year survival. The results of this study may enhance our understanding of cancer-associated stroke and improve risk stratification of patients with this disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov/.Unique identifier: NCT02212496.

Cancer Cell-Derived Extracellular Vesicles Are Associated with Coagulopathy Causing Ischemic Stroke via Tissue Factor-Independent Way: The OASIS-CANCER Study.

BACKGROUND: Cancer and stroke, which are known to be associated with one another, are the most common causes of death in the elderly. However, the pathomechanisms that lead to stroke in cancer patients are not well known. Circulating extracellular vesicles (EVs) play a role in cancer-associated thrombosis and tumor progression. Therefore, we hypothesized that cancer cell-derived EVs cause cancer-related coagulopathy resulting in ischemic stroke. METHODS: Serum levels of D-dimer and EVs expressing markers for cancer cells (epithelial cell adhesion molecule [CD326]), tissue factor (TF [CD142]), endothelial cells (CD31+CD42b-), and platelets (CD62P) were measured using flow cytometry in (a) 155 patients with ischemic stroke and active cancer (116 - cancer-related, 39 - conventional stroke mechanisms), (b) 25 patients with ischemic stroke without cancer, (c) 32 cancer patients without stroke, and (d) 101 healthy subjects. RESULTS: The levels of cancer cell-derived EVs correlated with the levels of D-dimer and TF+ EVs. The levels of cancer cell-derived EVs (CD326+ and CD326+CD142+) were higher in cancer-related stroke than in other groups (P<0.05 in all the cases). Path analysis showed that cancer cell-derived EVs are related to stroke via coagulopathy as measured by D-dimer levels. Poor correlation was observed between TF+ EV and D-dimer, and path analysis demonstrated that cancer cell-derived EVs may cause cancer-related coagulopathy independent of the levels of TF+ EVs. CONCLUSIONS: Our findings suggest that cancer cell-derived EVs mediate coagulopathy resulting in ischemic stroke via TF-independent mechanisms.

Caveolin-1, Ring finger protein 213, and endothelial function in Moyamoya disease.

BACKGROUND: Moyamoya disease is a unique cerebrovascular occlusive disease of unknown etiology. Ring finger protein 213 (RNF213) was identified as a susceptibility gene for Moyamoya disease in East Asian countries. However, the pathogenesis of Moyamoya disease remains unclear. METHODS: We prospectively analyzed clinical data for 139 patients with Moyamoya disease (108 bilateral Moyamoya disease, 31 unilateral Moyamoya disease), 61 patients with intracranial atherosclerotic stroke, and 68 healthy subjects. We compared the genetic (RNF213 variant) and protein biomarkers for caveolae (caveolin-1), angiogenesis (vascular endothelial growth factor (VEGF) and receptor (VEGFR2), and antagonizing cytokine (endostatin)) and endothelial dysfunction (asymmetric dimethylarginine (ADMA), and nitric oxide and its metabolites (nitrite and nitrate)) between patients with Moyamoya disease and intracranial atherosclerotic stroke. We then performed path analysis to evaluate whether a certain protein biomarker mediates the association between genes and Moyamoya disease. RESULTS: Caveolin-1 level was decreased in patients with Moyamoya disease and markedly decreased in RNF213 variant carriers. Circulating factors such as VEGF and VEGFR2 did not differ among the groups. Markers for endothelial dysfunction were significantly higher in patients with intracranial atherosclerotic stroke but normal in those with Moyamoya disease. Path analysis showed that the presence of the RNF213 variant was associated with caveolin-1 levels that could lead to Moyamoya disease. The level of combined marker of Moyamoya disease (caveolin-1) and intracranial atherosclerotic stroke (ADMA, an endothelial dysfunction marker) predicted Moyamoya disease with good sensitivity and specificity. CONCLUSION: Our results suggest that Moyamoya disease is a caveolae disorder but is not related to endothelial dysfunction or dysregulation of circulating cytokines.

Adult Moyamoya Disease: A Burden of Intracranial Stenosis in East Asians?

BACKGROUND: Both Moyamoya disease (MMD) and intracranial atherosclerotic stenosis (ICAS) are more prevalent in Asians than in Westerners. We hypothesized that a substantial proportion of patients with adult-onset MMD were misclassified as having ICAS, which may in part explain the high prevalence of intracranial atherosclerotic stroke in Asians. METHOD: We analyzed 352 consecutive patients with ischemic events within the MCA distribution and relevant intracranial arterial stenosis, but no demonstrable carotid or cardiac embolism sources. Conventional angiography was performed in 249 (70.7%) patients, and the remains underwent MRA. The occurrence of the c.14429G>A (p.Arg4810Lys) variant in ring finger protein 213 (RNF213) was analyzed. This gene was recently identified as a susceptibility gene for MMD in East Asians. RESULTS: The p.Arg4810Lys variant was observed in half of patients with intracranial stenosis (176 of 352, 50.0%), in no healthy control subjects (n = 51), and in 3.2% of stroke control subjects (4 of 124 patients with other etiologies). The presence of basal collaterals, bilateral involvement on angiography, and absence of diabetes were independently associated with the presence of the RNF213 variant. Among 131 patients who met all three diagnostic criteria and were diagnosed with MMD, three-fourths (75.6%) had this variant. However, a significant proportion of patients who met two criteria (57.7%), one criterion (28.6%), or no criteria (20.0%) also had this variant. Some of them developed typical angiographic findings of MMD on follow-up angiography. CONCLUSIONS: Careful consideration of MMD is needed when diagnosing ICAS because differential therapeutic strategies are required for these diseases and due to the limitations of the current diagnostic criteria for MMD.

Lack of Association of Clinical Factors (SAMe-TT2R2) with CYP2C9/VKORC1 Genotype and Anticoagulation Control Quality.

BACKGROUND AND PURPOSE: Advantages of new oral anticoagulations may be greater in atrial fibrillation (AF) patients of poor anticoagulation control with warfarin. The SAMe-TT2R2 scoring system, based on clinical variables, was recently developed to aid in identifying these patients. In this study, we investigated the association of this clinical composite score with genetic factors related warfarin dosing and the quality of anticoagulation control. METHODS: Clinical and genetic data were collected from 380 consecutive Korean patients with AF (CHA2DS2-VASc score, 3.5±1.8) who were followed for an average of 4 years. We evaluated factors associated with time in therapeutic range (TTR, INR 2-3), including the CYP2C9 and VKORC1 genotypes and the SAMe-TT2R2 score (Sex female, Age <60 years, Medical history [>two co-morbidities], Treatment [interacting drugs, e.g., amiodarone], Tobacco use within 2 years [doubled], and Race non-white [doubled]). RESULTS: The average SAMe-TT2R2 score was 3.4±0.9, range 2-7; and 153 patients (40.2%) had SAMe-TT2R2 scores ≥4. Time in specific INR ranges varied depending on the VKORC1 genotype but not with the CYP2C9 genotype or the SAMe-TT2R2 score. TTR was higher in patients with the VKORC1 1173C>T than in VKORC1 TT (61.7±16% vs. 56.7±17.4%, P=0.031). Multivariate testing showed that VKORC1 genotype but not the SAMe-TT2R2 score was significantly associated with labile INRs. There was no correlation between the SAMe-TT2R2 scores and pharmacogenetic data. CONCLUSIONS: A genetic factor, but none of the common clinical and demographic factors, as combined in the SAMe-TT2R2 score, was associated with the quality of anticoagulation control in Korean patients with AF.

Comparison of Enoxaparin and Warfarin for Secondary Prevention of Cancer-Associated Stroke.

Background. The aim of this study was to determine which anticoagulant is superior for secondary prevention of cancer-associated stroke, using changes in D-dimer levels as a biomarker for recurrent thromboembolic events. Methods. We conducted a retrospective, single center observational study including patients with cancer-associated stroke who were treated with either enoxaparin or warfarin. Blood samples for measuring the initial and follow-up D-dimer levels were collected at admission and a median of 8 days after admission, respectively. Multiple logistic regression analysis was conducted to evaluate the factors that influenced D-dimer levels after treatment. Results. Although the initial D-dimer levels did not differ between the two groups, the follow-up levels were dramatically decreased in patients treated with enoxaparin, while they did not change with use of warfarin (3.88 µg/mL versus 17.42 µg/mL, p = 0.026). On multiple logistic regression analysis, use of warfarin (OR 12.95; p = 0.001) and the presence of systemic metastasis (OR 18.73; p = 0.017) were independently associated with elevated D-dimer levels (≥10 µg/mL) after treatment. Conclusion. In cancer-associated stroke patients, treatment with enoxaparin may be more effective than treatment with warfarin for lowering the D-dimer levels. Future prospective studies are warranted to show that enoxaparin is better than warfarin for secondary prevention in cancer-associated stroke.

Intravenous transplantation of mesenchymal stem cells preconditioned with early phase stroke serum: current evidence and study protocol for a randomized trial.

BACKGROUND: Recovery after a major stroke is usually limited, but cell therapy for patients with fixed neurologic deficits is emerging. Several recent clinical trials have investigated mesenchymal stem cell (MSC) therapy for patients with ischemic stroke. We previously reported the results of a controlled trial on the application of autologous MSCs in patients with ischemic stroke with a long-term follow-up of up to 5 years (the 'STem cell Application Researches and Trials In NeuroloGy' (STARTING) study). The results from this pilot trial are challenging, but also raise important issues. In addition, there have been recent efforts to improve the safety and efficacy of MSC therapy for stroke. METHODS AND DESIGN: The clinical and preclinical background and the STARTING-2 study protocol are provided. The trial is a prospective, randomized, open-label, blinded-endpoint (PROBE) clinical trial. Both acute and chronic stroke patients will be selected based on clinical and radiological features and followed for 3 months after MSC treatment. The subjects will be randomized into one of two groups: (A) a MSC group (n = 40) or (B) a control group (n = 20). Autologous MSCs will be intravenously administered after ex vivo culture expansion with autologous ischemic serum obtained as early as possible, to enhance the therapeutic efficacy (ischemic preconditioning). Objective outcome measurements will be performed using multimodal MRI and detailed functional assessments by blinded observers. DISCUSSION: This trial is the first to evaluate the efficacy of MSCs in patients with ischemic stroke. The results may provide better evidence for the effectiveness of MSC therapy in patients with ischemic stroke. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov, number NCT01716481.

Clinical presentation and ischemic zone on MRI in cancer patients with acute ischemic stroke.

AIMS: This study was conducted to evaluate the clinical and MRI profiles in acute cancer strokes, and to demonstrate our experience with thrombolytic therapy in cancer stroke patients. METHODS: We prospectively studied active cancer patients with acute ischemic stroke who underwent MRI within 48 h of the onset of symptoms. Patients were grouped based on the presence of conventional stroke mechanisms (CSM). Clinical characteristics and MRI profiles were evaluated. RESULTS: A total of 70 patients were finally included in this study. Patients without CSM were more frequently presented with encephalopathy than those with CSM (29.4 vs. 2.8%, p = 0.002). The diffusion-perfusion mismatch pattern was more prevalent in patients with CSM (21 patients, 58.3%) than in patients without CSM (8 patients, 23.5%). Patients who had a higher tertiles of D-dimer level were significantly less likely to have the diffusion-perfusion mismatch pattern (p = 0.015). Among patients who presented within 6 h of the onset of stroke, revascularization therapy was performed in 4 of 16 (25%) patients with CSM, but none of the patients without CSM. CONCLUSION: Based on the stroke mechanisms, the optimal strategy of thrombolytic therapy should be considered differently in cancer patients with acute ischemic stroke.

Differential risk factors for lacunar stroke depending on the MRI (white and red) subtypes of microangiopathy.

BACKGROUND: Leukoaraiosis and cerebral microbleeds (CMB), which represent cerebral microangiopathy, commonly coexist in patients with acute lacunar stroke. Since they may have different impacts on stroke prognosis and treatment, it is important to know the factors associated with leukoaraiosis-predominant vs. CMB-predominant microangiopathies. METHODS: We prospectively recruited 226 patients with acute lacunar infarction and divided them into four groups according to the Fazekas' score and the presence of CMB: mild, red (predominant CMB), white (predominant leukoaraiosis) and severe microangiopathy groups. For comparison, we also evaluated 50 patients with intracerebral hemorrhage (ICH). We evaluated the clinical and laboratory findings of microangiopathy subtypes in patients with acute lacunar stroke and then compared them with those of primary ICH. RESULTS: The risk factor profile was different among the groups. Patients with acute lacunar infarct but mild microangiopathy were younger, predominantly male, less hypertensive, and more frequently had smoking and heavy alcohol habits than other groups. The risk factor profile of red microangiopathy was similar to that of ICH but differed from that of white microangiopathy. The subjects in the white microangiopathy group were older and more frequently had diabetes than those in the red microangiopathy or ICH group. After adjustments for other factors, age [odds ratio (OR) 1.13; 95% confidence interval (CI) 1.08-1.18; p<0.001] and diabetes (OR 2.28; 95% CI 1.02-5.13; p = 0.045) were independently associated with white microangiopathy, and age (OR 1.05; 95% CI 1.01-1.08; p = 0.010) was independent predictor for red microangiopathy compared to mild microangiopathy. CONCLUSION: Patients with acute lacunar infarction have a different risk factor profile depending on microangiopathic findings. Our results indicate that diabetes may be an one of determinants of white (leukoaraiosis-predominant) microangiopathy, whereas smoking and alcohol habits in relatively young people may be a determinants of mild microangiopahic changes in patients with lacunar infarction.

Clues to occult cancer in patients with ischemic stroke.

BACKGROUND: We hypothesized that hidden malignancy could be detected in patients with cryptogenic stroke without active cancer when they showed the distinctive characteristics of cancer-related stroke. METHODS AND FINDINGS: Among 2,562 consecutive patients with acute ischemic stroke, patients with cryptogenic stroke were analyzed and categorized into two groups according to the presence of active cancer: cryptogenic stroke with active cancer (cancer-related stroke, CA-stroke) group and without active cancer (CR-stroke) group. Patients with active lung cancer without stroke were also recruited for comparison purposes (CA-control). Clinical factors, lesion patterns on diffusion-weighted MRI (DWI), and laboratory findings were analyzed among groups. A total of 348 patients with cryptogenic stroke were enrolled in this study. Among them, 71 (20.4%) patients had active cancer at the time of stroke. The D-dimer levels were significantly higher in patients with CA-stroke than those with CR-stroke or CA-control (both p<0.001). Regarding lesion patterns, patients with CA-stroke mostly had multiple lesions in multiple vascular territories, while more than 80% of patients with CR-stroke had single/multiple lesions in a single vascular territory (P<0.001). D-dimer levels (OR 1.11 per 1 µg/mL increase; 95% CI 1.06-1.15; P<0.001) and DWI lesion patterns (OR 7.13; 95% CI 3.42-14.87; P<0.001) were independently associated with CA-stroke. Workup for hidden malignancy was performed during hospitalization in 10 patients who showed elevated D-dimer levels and multiple infarcts involving multiple vascular territories but had no known cancer, and it revealed hidden malignancies in all the patients. CONCLUSION: Patients with CA-stroke have distinctive D-dimer levels and lesion patterns. These characteristics can serve as clues to occult cancer in patients with cryptogenic stroke.

Circulating mesenchymal stem cells microparticles in patients with cerebrovascular disease.

Preclinical and clinical studies have shown that the application of CD105(+) mesenchymal stem cells (MSCs) is feasible and may lead to recovery after stroke. In addition, circulating microparticles are reportedly functional in various disease conditions. We tested the levels of circulating CD105(+) microparticles in patients with acute ischemic stroke. The expression of CD105 (a surface marker of MSCs) and CXCR4 (a CXC chemokine receptor for MSC homing) on circulating microparticles was evaluated by flow cytometry of samples from 111 patients and 50 healthy subjects. The percentage of apoptotic CD105 microparticles was determined based on annexin V (AV) expression. The relationship between serum levels of CD105(+)/AV(-) microparticles, stromal cells derived factor-1α (SDF-1α), and the extensiveness of cerebral infarcts was also evaluated. CD105(+)/AV(-) microparticles were higher in stroke patients than control subjects. Correlation analysis showed that the levels of CD105(+)/AV(-) microparticles increased as the baseline stroke severity increased. Multivariate testing showed that the initial severity of stroke was independently associated with circulating CD105(+)/AV(-) microparticles (OR, 1.103 for 1 point increase in the NIHSS score on admission; 95% CI, 1.032-1.178) after adjusting for other variables. The levels of CD105(+)/CXCR4(+)/AV(-) microparticles were also increased in patients with severe disability (r = 0.192, p = 0.046 for NIHSS score on admission), but were decreased with time after stroke onset (r = -0.204, p = 0.036). Risk factor profiles were not associated with the levels of circulating microparticles or SDF-1α. In conclusion, our data showed that stroke triggers the mobilization of MSC-derived microparticles, especially in patients with extensive ischemic stroke.

Biomarkers of asymptomatic carotid stenosis in patients undergoing coronary artery bypass grafting.

BACKGROUND AND PURPOSE: Carotid artery stenosis is an important etiologic factor of stroke related to coronary artery bypass surgery. We evaluated clinical and laboratory factors to identify biomarkers for pre-existing carotid artery stenosis in patients undergoing coronary artery bypass surgery. METHODS: Between June 2006 and September 2008, 811 patients aged ≥50 years underwent preoperative carotid artery duplex scanning as part of a preoperative assessment for nonemergency cardiac procedures. Of these, 54 patients with previous stroke or transient ischemic attack were excluded. The association between various biomarkers and carotid artery stenosis was analyzed by multiple logistic regression analysis. The receiver operating characteristic curves were generated and analyzed to compare diagnostic performance and optimum diagnostic cutoff levels of biomarkers. RESULTS: A total of 757 patients was included in the study. The prevalence of asymptomatic carotid stenosis of ≥50% and ≥70% was 26.4% and 8.6%, respectively. In multivariate analysis, plasma levels of apolipoprotein B (apoB):apoA-I, lipoprotein(a), and homocysteine were independently associated with carotid stenosis of ≥50%: the OR (95% CI) for apoB/apoA-I, lipoprotein(a), and homocysteine in the highest versus lowest quartile was 2.07 (1.18 to 3.66), 2.17 (1.16 to 4.05), and 2.13 (1.20 to 3.79), respectively. Receiver operating characteristic curve analysis indicated area under the curve values of 0.708 (apoB:apoA-I), 0.678 (lipoprotein[a]), and 0.689 (homocysteine). The sensitivity, specificity, positive and negative predictive values (%) for diagnosis of carotid stenosis ≥50% were 80.0, 50.4, 38.0, and 86.9 for apoB:apoA-I; 47.0, 78.9, 46.1, and 79.5 for lipoprotein(a); and 69.3, 62.1, 41.2, and 84.1 for homocysteine, respectively. CONCLUSIONS: Our findings indicated that plasma levels of apoB/apoA-I, lipoprotein(a), and homocysteine can predict asymptomatic carotid stenosis in patients undergoing coronary artery bypass surgery.

Benign oligemia despite a malignant MRI profile in acute ischemic stroke.

BACKGROUND: It has recently been suggested that diffusion and perfusion MRI can identify subgroups likely to benefit or potentially be harmed by reperfusion therapies. CASE REPORT: We investigated serial MRI data of two patients with occlusion of the proximal middle cerebral artery (MCA). In both cases, acute multiple cortical infarcts evident on diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) showed extensive areas of severe perfusion delays, indicating a malignant MRI profile. However, despite the malignant MRI profiles in these cases, no new ischemic lesions or hemorrhage evolved even in the presence of persistent arterial occlusion, and the patients recovered without sequelae. CONCLUSIONS: These two cases suggest that time-domain PWI findings should be interpreted with caution in certain scenarios of acute ischemic stroke.

Characteristics of patients with target magnetic resonance mismatch profile: data from two geographically and racially distinct populations.

BACKGROUND: Recently, the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) and the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) trialists suggested that diffusion-perfusion magnetic resonance imaging (MRI) can classify patients into 4 subgroups likely to differentially experience benefit or harm from reperfusion therapies. However, there is a lack of data comparing MR mismatch profiles between different race-ethnic groups. In addition, clinical factors affecting MR mismatch profiles are not well described. METHODS: We analyzed clinical and pretreatment MRI data of patients from 2 geographically and ethnically distinct study populations (Seoul, South Korea, and Los Angeles, Calif., USA) who are eligible for recanalization therapy. Diffusion-perfusion mismatch regions were classified among the 4 DEFUSE MR profiles: target mismatch, no mismatch, small lesion and malignant. RESULTS: A total of 147 South Korean and 162 Southern Californian subjects (64.2% Whites) were included. Pretreatment MRIs revealed that the MR mismatch profiles were different in the 2 study populations (p < 0.001). Target mismatch was more prevalent in Southern Californian subjects (67.9%) compared with South Korean subjects (58.5%), whereas the small lesion pattern was more prevalent in the latter (9.9 vs. 23.1%). After adjusting for covariables, 3 features independently decreased the likelihood of presence of target mismatch: history of diabetes (OR 0.369, 95% CI 0.196-0.694), small versus large arterial occlusion (OR 0.052, 95% CI 0.01-0.255) and largest size (highest tertile) of diffusion-weighted imaging (DWI) lesion volume (OR 0.516, 95% CI 0.266-0.999). The one feature independently increasing target mismatch likelihood was intermediate size (middle tertile) DWI volume (OR 2.977, 95% CI 1.431-6.195). CONCLUSIONS: Target mismatch profiles are present in 55-70% of patients. Target mismatch is less common in patients with diabetes, small vessel occlusion, Asian ethnicity and extensive DWI lesions, and more common in patients with DWI lesions of intermediate size.

Association of thyroid autoantibodies with moyamoya-type cerebrovascular disease: a prospective study.

BACKGROUND AND PURPOSE: To investigate the association between thyroid autoantibodies and moyamoya disease (MMD) in patients with an apparent euthyroid state. METHODS: We prospectively studied angiographically diagnosed patients with MMD. We compared demographic profiles, thyroid function test, and thyroid autoantibody status between MMD and control groups. RESULTS: A total of 63 patients with MMD, 71 patients with non-MMD stroke, and 200 healthy control subjects were included. The prevalence of elevated thyroid autoantibodies was higher in the MMD group than in other groups (P<0.01 for MMD versus non-MMD; P<0.001 for MMD versus control subjects). After adjusting for covariates, the elevated thyroid autoantibodies (OR, 4.871; 95% CI, 1.588 to 15.277) and smoking habits (OR, 0.206 for current smoker; 95% CI, 0.054 to 0.786) were independently associated with MMD versus non-MMD stroke. CONCLUSIONS: Elevated thyroid autoantibodies were frequently observed in patients with MMD. The results of the present study suggest that immune aberrancies associated with or underlying thyroid autoimmunity are also playing a role in developing MMD.

Isolated tongue tremor after removal of cerebellar pilocytic astrocytoma: Functional analysis with SPECT study.

Tongue tremor is a rare form of focal tremor. Even though the dysfunction of the dentato-rubro-olivary circular pathway has been proposed as its mechanism, the origin of the rhythmic activities remains unknown. We experienced a case of isolated tongue tremor after the removal of a cerebellar pilocytic astrocytoma. To localize the activated structures corresponding to the isolated tongue tremor, we analyzed subtracted ictal SPECT coregistered to MRI (SISCOM). SISCOM demonstrated multiregional hyperperfusion including the Guillain-Mollaret triangular and extratriangular structures. The activation of the inferior olive and red nucleus and accompanying extratriangular structures might be related to the isolated tongue tremor.