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BACKGROUND: There are limited data on outcomes of extracranial-intracranial (EC-IC) bypass in patients with recurrent hemispheric syndromes due to atherosclerotic internal carotid artery occlusion (AICAO). OBJECTIVE: To compare clinical outcomes and efficacy of EC-IC bypass surgery in patients with and without recurrent hemispheric syndromes associated with AICAO in the Carotid Occlusion Surgery Study (COSS). METHODS: In patients enrolled in the COSS trial, we compared baseline characteristics and clinical outcomes for participants with (rHEMI+) and without recurrent hemispheric ischemia (rHEMI−) prior to randomization into surgical vs medical groups. The primary outcome was all stroke and death from randomization through 30 d and ipsilateral ischemic stroke within 2 yr. RESULTS: Of 195 randomized participants, 100 were rHEMI+ (50 in each group). Baseline characteristics between rHEMI+ and rHEMI− participants were similar except rHEMI+ were more likely to have had previous stroke prior to randomization (61% vs 20%, P

Background Human immunodeficiency virus (HIV)-infected individuals are at high risk for ischemic stroke. To investigate the physiological basis for this risk, we used magnetic resonance imaging (MRI) to measure oxygen extraction fraction (OEF) and cerebral blood flow (CBF) in treatment-naive asymptomatic HIV-infected subjects and controls. Methods In treatment-naive asymptomatic HIV-infected subjects and age-, gender-, and race-matched controls, OEF was measured by MRI asymmetric spin–echo echo-planar imaging sequences and CBF was measured by MRI pseudocontinuous arterial spin labeling. Results Twenty-six treatment-naive HIV-infected subjects and 27 age-, gender-, race-matched controls participated. Whole-brain, gray matter (GM), and white matter OEF were not different between the groups (all P > .70). Unexpectedly, HIV-infected subjects had significantly higher CBF in cortical GM (72.9 ± 16.2 mL/100 g/min versus 63.9 ± 9.9 mL/100 g/min; P = .01) but not in subcortical GM ( P = .25). Conclusions The observed increase in cortical GM CBF in treatment-naive HIV-infected subjects is unexpected, contrary to CBF decreases reported in HIV-infected subjects on treatment, and may represent an initial increase in metabolic activity due to an HIV-mediated inflammation.

Background and Purpose— Penumbral biomarkers promise to individualize treatment windows in acute ischemic stroke. We used a novel magnetic resonance imaging approach that measures oxygen metabolic index (OMI), a parameter closely related to positron emission tomography–derived cerebral metabolic rate of oxygen utilization (CMRO2), to derive a pair of ischemic thresholds: (1) an irreversible-injury threshold that differentiates ischemic core from penumbra and (2) a reversible-injury threshold that differentiates penumbra from tissue not-at-risk for infarction. Methods— Forty patients with acute ischemic stroke underwent magnetic resonance imaging at 3 time points after stroke onset: Results— The optimal OMI ischemic thresholds were found to be 0.28 and 0.42 of normal values in the contralateral hemisphere. Using the 10-fold cross-validation method, median infarct probabilities were 90.6% for core, 89.7% for nonreperfused penumbra, 9.95% for reperfused penumbra, and 6.28% for not-at-risk tissue. Conclusions— OMI thresholds, derived using voxel-based, reperfusion-dependent infarct probabilities, delineated the ischemic penumbra with high predictive ability. These thresholds will require confirmation in an independent patient sample.

Objective: To determine whether strict blood pressure (BP) control is the best medical management for patients with symptomatic carotid artery occlusion and hemodynamic cerebral ischemia. Methods: In this prospective observational cohort study, we analyzed data from 91 participants in the nonsurgical group of the Carotid Occlusion Surgery Study (COSS) who had recent symptomatic internal carotid artery occlusion and hemodynamic cerebral ischemia manifested by ipsilateral increased oxygen extraction fraction. The target BP goal in COSS was ≤130/85 mm Hg. We compared the occurrence of ipsilateral ischemic stroke during follow-up in the 41 participants with mean BP ≤130/85 mm Hg to the remaining 50 with higher BP. Results: Of 16 total ipsilateral ischemic strokes that occurred during follow-up, 3 occurred in the 41 participants with mean follow-up BP of ≤130/85 mm Hg, compared to 13 in the remaining 50 participants with mean follow-up BP >130/85 mm Hg (hazard ratio 3.742, 95% confidence interval 1.065–13.152, log-rank p = 0.027). Conclusion: BPs ≤130/85 mm Hg were associated with lower subsequent stroke risk in these patients. Classification of evidence: This study provides Class III evidence that control of hypertension ≤130/85 mm Hg is associated with a reduced risk of subsequent ipsilateral ischemic stroke in patients with recently symptomatic carotid occlusion and hemodynamic cerebral ischemia (increased oxygen extraction fraction).

Objective: To determine whether extracranial-intracranial (EC-IC) bypass can improve cognition over 2 years compared to best medical therapy alone in patients with symptomatic internal carotid artery (ICA) occlusion and increased oxygen extraction fraction (OEF) on PET. Methods: Patients underwent 15 O PET and were randomized if OEF ratio was >1.13 on the occluded side. Using blinded baseline and 2-year cognitive assessments, age-adjusted composite z scores were generated from subtests sensitive to right/left hemisphere plus global cognitive functioning. Multiple regression predicted 2-year cognitive change. Results: Eighty-nine patients were enrolled; 41 had increased OEF and were randomized. Two died, 2 were lost to follow-up, and 2 refused 2-year testing. Of the 35 remaining, 6 had ipsilateral stroke or death, leaving 13 surgical and 16 medical patients. Controlling for age, education, and depression, there was no difference in 2-year cognitive change between the medical and surgical arms (95% confidence interval −0.5 to 0.5, p = 0.9). In post hoc analysis of 26 patients with no stroke in the follow-up period, cognitive improvement was associated with less impaired PET OEF at baseline ( p = 0.045). Conclusion: Cognitive improvement following bypass surgery was not superior to medical therapy among patients with recently symptomatic carotid occlusion and increased OEF. Among those with no recurrent stroke, less hemodynamic impairment at baseline was associated with greater cognitive gain in both groups. Reversing cognitive impairment in hemodynamic failure remains an open challenge. Classification of evidence: This study provides Class II evidence that for patients with symptomatic ICA occlusion and increased OEF on PET, EC-IC bypass compared to no bypass does not improve cognitive function after 2 years.

Since the approval of tissue-type plasminogen activator (tPA) for the treatment of acute ischemic stroke by the Food and Drug Administration,1 the search for means to identify patients who may benefit from this treatment beyond the approved therapeutic window has been actively pursued. One of the most successful examples is the European Cooperative Acute Stroke Study III (ECASS III) trial,2,3 which demonstrated that efficacy of tPA treatment could be extended from the original 3 hours to 4.5 hours from onset. In addition, with an accumulating arsenal of mechanical clot retrieval devices, promising to achieve more effective reperfusion than intravenous-tPA,4–6 it is likely that the therapeutic windows for these retrieval devices will differ from that of intravenous-tPA. Different collateral flow patterns, comorbidities, and intrinsic tissue vulnerabilities among individual patients further complicate the use of a fixed therapeutic time-window for all patients and different treatments. Therefore, insights into brain tissue viability at the time of presentation may aid in the management of acute stroke. Toward this end, imaging approaches have been actively sought to provide a potential signature for tissue viability.7 Specifically, the diffusion/perfusion mismatch (DPM) concept has been widely advocated as a potential approach to depict the presence or absence of ischemic penumbra.8–10 The underlying hypothesis is that lesions defined by abnormal diffusion most likely reflect irreversible injury, whereas regions defined by abnormal perfusion represent critically hypoperfused tissue. The region of DPM with normal diffusion but abnormal perfusion is, in theory, the region at risk of evolving to infarction if reperfusion-promoting therapies are not administered. Although the overall hypothesis of DPM is straightforward and diffusion weighted images (DWI) and perfusion-weighted images (PWI) are readily available, the means by which DWI and PWI lesions are defined vary widely, leading to, potentially, …

The Carotid Occlusion Surgery Study (COSS) was conducted to determine if superficial temporal artery-middle cerebral artery (STA-MCA) bypass, when added to the best medical therapy, would reduce subsequent ipsilateral stroke in patients with complete internal carotid artery (ICA) occlusion and an elevated oxygen extraction fraction (OEF) in the cerebral hemisphere distal to the occlusion. A recent publication documented the methodology of the COSS in detail and briefly outlined the major findings of the trial. The surgical results of the COSS are described in detail in this report.The COSS was a prospective, parallel-group, 1:1 randomized, open-label, blinded-adjudication treatment trial. Participants, who had angiographically demonstrated complete occlusion of the ICA causing either a transient ischemic attack or ischemic stroke within 120 days and hemodynamic cerebral ischemia indicated by an increased OEF measured by PET, were randomized to either surgical or medical treatment. One hundred ninety-five patients were randomized: 97 to the surgical group and 98 to the medical group. The surgical patients underwent an STA-MCA cortical branch anastomosis.In the intention-to-treat analysis, the 2-year rates for the primary end point were 21% for the surgical group and 22.7% for the medical group (p = 0.78, log-rank test). Fourteen (15%) of the 93 patients who had undergone an arterial bypass had a primary end point ipsilateral hemispheric stroke in the 30-day postoperative period, 12 within 2 days after surgery. The STA-MCA arterial bypass patency rate was 98% at the 30-day postoperative visit and 96% at the last follow-up examination. The STA-MCA arterial bypass markedly improved, although it did not normalize, the level of elevated OEF in the symptomatic cerebral hemisphere. Five surgically treated and 1 nonsurgically treated patients in the surgical group had a primary end point ipsilateral hemispheric stroke after the 30-day postoperative period. No baseline characteristics or intraoperative variables revealed those who would experience a procedure-related stroke.Despite excellent bypass graft patency and improved cerebral hemodynamics, STA-MCA anastomosis did not provide an overall benefit regarding ipsilateral 2-year stroke recurrence, mainly because of a much better than expected stroke recurrence rate (22.7%) in the medical group, but also because of a significant postoperative stroke rate (15%). Clinical trial registration no.: NCT00029146.

SUMMARY: The Kety-Schmidt technique provides quantitative measurement of whole-brain CBF. CBF is measured as the area between the arterial and venous washout curves of a diffusible tracer. Oxygen extraction and metabolism may be calculated from arterial and venous samples. In this report, we present a method for performing these measurements in an MR imaging environment. This technique could be useful for validation of MR imaging methods of hemodynamic and metabolic measurements in humans.

The perihematomal hyperintensity (PHH) is commonly interpreted to represent cerebral edema following intracerebral hemorrhage (ICH), but the accuracy of this interpretation is unknown. We therefore investigated the relationship between the changes in PHH and the changes in hemispheric brain volume as a measure of edema during the first week after ICH. Fifteen individuals aged 66 ± 13 with baseline hematoma size of 13.1 ml (range 3–43) were prospectively studied with sequential MRI 1.0 ± 0.5, 2.6 ± 0.9, and 6.5 ± 1.0 days after spontaneous supratentorial ICH. Changes in hemispheric brain volume were assessed on MPRAGE using the Brain-Boundary Shift Integral (BBSI). Hematoma and PHH volumes were measured on T2-weighted images. Brain volume increased a small but statistically significant amount (6.3 ± 8.0 ml, 0.6 ± 0.7%) between the first and second scans relative to 10 normal controls (−0.9 ± 4.1 ml, P = 0.02) and returned toward baseline at the third scan (1.5 ± 9.5 ml vs. controls 0.9 ± 4.0 ml, P = 0.85). There were no significant differences in the volume changes between the two hemispheres at scan 2 or scan 3. At both scan 2 (P = 0.04) and scan 3 (P = 0.004), the change in PHH was significantly greater than and poorly correlated with the change in ipsilateral hemispheric volume. There were no significant correlations between the change in NIH Stroke Scale (NIHSS) and the change in PHH, ipsilateral, or total brain volume at scan 2 or scan 3 (all P > 0.05). In patients with small-to-moderate-sized hematomas, change in PHH was a poor measure of brain edema in the first week following ICH. A small degree of bihemispheric brain swelling occurred, but was of little clinical significance.

Studies in transgenic mice overexpressing amyloid precursor protein (APP) demonstrate impaired autoregulation of cerebral blood flow (CBF) to changes in arterial pressure and suggest that cerebrovascular dysfunction may be critically important in the development of pathological Alzheimer's disease (AD). Given the relevance of such a finding for guiding hypertension treatment in the elderly, we assessed autoregulation in individuals with AD. Twenty persons aged 75±6 years with very mild or mild symptomatic AD (Clinical Dementia Rating 0.5 or 1.0) underwent 15O-positron emission tomography (PET) CBF measurements before and after mean arterial pressure (MAP) was lowered from 107±13 to 92±9 mm Hg with intravenous nicardipine; 11C-PIB-PET imaging and magnetic resonance imaging (MRI) were also obtained. There were no significant differences in mean CBF before and after MAP reduction in the bilateral hemispheres (−0.9±5.2 mL per 100 g per minute, P=0.4, 95% confidence interval (CI)=−3.4 to 1.5), cortical borderzones (−1.9±5.0 mL per 100 g per minute, P=0.10, 95% CI=−4.3 to 0.4), regions of T2W-MRI-defined leukoaraiosis (−0.3±4.4 mL per 100 g per minute, P=0.85, 95% CI=−3.3 to 3.9), or regions of peak 11C-PIB uptake (−2.5±7.7 mL per 100 g per minute, P=0.30, 95% CI=−7.7 to 2.7). The absence of significant change in CBF with a 10 to 15 mm Hg reduction in MAP within the normal autoregulatory range demonstrates that there is neither a generalized nor local defect of autoregulation in AD.

Hemispheric ratios of oxygen extraction fraction (OEF), a proven methodology for the detection of severe hemodynamic impairment and stroke risk, are not sensitive for detecting bilateral hemispheric increases in OEF. The aim of this study was to investigate the use of cerebellum as the reference normal. We analyzed positron emission tomographic (PET) measurements of count-based OEF and clinical data from 57 patients with unilateral atherosclerotic carotid occlusion and 13 controls enrolled in a prospective study of stroke risk. The ipsilateral, contralateral, and total cerebellum were each evaluated as possible reference regions, and the ratios of the middle cerebral artery (MCA) hemispheric OEF counts against those in each reference region were determined. A statistically significant correlation ( P

SUMMARY: One of the goals of neuroimaging in acute ischemic stroke is to identify those patients whose outcome will be improved by therapeutic intervention. This article will discuss the design, analysis, and interpretation of clinical research studies carried out to establish the accuracy and clinical value of neuroimaging to select such patients.

Abnormal cerebral energy metabolism owing to dysfunction of mitochondrial electron transport has been implicated in the pathogenesis of Parkinson's disease (PD). However, in vivo data of mitochondrial dysfunction have been inconsistent. We directly investigated mitochondrial oxidative metabolism in vivo in 12 patients with early, never-medicated PD and 12 age-matched normal controls by combined measurements of the cerebral metabolic rate of oxygen (CMRO2) and the cerebral metabolic rate of glucose (CMRglc) with positron emission tomography. The primary analysis showed a statistically significant 24% increase in bihemispheric CMRO2 and no change in CMRO2/CMRglc. These findings are inconsistent with a defect in mitochondrial oxidative phosphorylation owing to reduced activity of the mitochondrial electron transport system (ETS). Because PD symptoms were already manifest, deficient energy production owing to a reduced activity of the mitochondrial ETS cannot be a primary mechanism of neuronal death in early PD. Alternatively, this general increase in CMRO2 could be due not to an increased metabolic demand but to an uncoupling of ATP production from oxidation in the terminal stage of oxidative phosphorylation. Whether this is the case in early PD and whether it is important in the pathogenesis of PD will require further study.

The recent “Advanced Neuroimaging for Acute Stroke Treatment” meeting on September 7 and 8, 2007 in Washington DC, brought together stroke neurologists, neuroradiologists, emergency physicians, neuroimaging research scientists, members of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Biomedical Imaging and Bioengineering (NIBIB), industry representatives, and members of the US Food and Drug Administration (FDA) to discuss the role of advanced neuroimaging in acute stroke treatment. The goals of the meeting were to assess state-of-the-art practice in terms of acute stroke imaging research and to propose specific recommendations regarding: (1) the standardization of perfusion and penumbral imaging techniques, (2) the validation of the accuracy and clinical utility of imaging markers of the ischemic penumbra, (3) the validation of imaging biomarkers relevant to clinical outcomes, and (4) the creation of a central repository to achieve these goals. The present article summarizes these recommendations and examines practical steps to achieve them.

Animal studies have suggested that the reduction in stroke risk observed with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) therapy is owing to an increase in basal cerebral blood flow (CBF). The purpose of the study was to determine if statin therapy was associated with increased CBF in humans with cerebrovascular atherosclerotic disease. Quantitative measurements of CBF were obtained on study entry in 97 patients with carotid artery occlusion enrolled in a prospective study of cerebral hemodynamics and stroke risk. This study represents a post hoc analysis of CBF measurements based on whether patients were receiving statin therapy at the time of CBF measurement. Global and regional CBF (including hemispheric, basal ganglia, and arterial borderzones), and baseline clinical, epidemiologic, and laboratory stroke risk factors were compared between the two groups. Nineteen of the 97 patients were on a statin agent on study entry. The statin group was younger, had significantly lower LDL levels and included more women. Statin therapy was not associated with higher baseline values of CBF in global or regional analyses. Mean middle cerebral artery territory CBF (± s.d.) ipsilateral to the occluded carotid artery was 37.6 ± 12.7 mL/100 g min for the statin group ( n = 19) compared with 38.6 ± 12.7 mL/100 g min for the nonstatin group ( n = 78). Contralateral values were 42.9 ± 13.5 and 44.2 ± 13.3 mL/100 g min for the statin and nonstatin groups, respectively. We conclude that the stroke risk reduction observed with statin therapy in humans likely involves mechanisms other than an increased basal CBF.

Recent antecedent hypoglycemia has been found to shift glycemic thresholds for autonomic (including adrenomedullary epinephrine), symptomatic, and other responses to subsequent hypoglycemia to lower plasma glucose concentrations. This change in threshold is the basis of the clinical syndromes of hypoglycemia unawareness and, in part, defective glucose counterregulation and the unifying concept of hypoglycemia-associated autonomic failure in type 1 diabetes. We tested in healthy young adults the hypothesis that recent antecedent hypoglycemia increases blood-to-brain glucose transport, a plausible mechanism of this phenomenon. Eight subjects were studied after euglycemia, and nine were studied after approximately 24 h of interprandial hypoglycemia ( approximately 55 mg/dl, approximately 3.0 mmol/l). The latter were shown to have reduced plasma epinephrine (P = 0.009), neurogenic symptoms (P = 0.009), and other responses to subsequent hypoglycemia. Global bihemispheric blood-to-brain glucose transport and cerebral glucose metabolism were calculated from rate constants derived from blood and brain time-activity curves-the latter determined by positron emission tomography (PET)-after intravenous injection of [1-(11)C]glucose at clamped plasma glucose concentrations of 65 mg/dl (3.6 mmol/l). For these calculations, a model was used that includes a fourth rate constant to account for egress of [(11)C] metabolites. Cerebral blood flow was measured with intravenous [(15)O]water using PET. After euglycemia and after hypoglycemia, rates of blood-to-brain glucose transport (24.6 +/- 2.3 and 22.4 +/- 2.4 micromol. 100 g(-1). min(-1), respectively), cerebral glucose metabolism (16.8 +/- 0.9 and 15.9 +/- 0.9 micromol. 100 g(-1). min(-1), respectively) and cerebral blood flow (56.8 +/- 3.9 and 53.3 +/- 4.4 ml. 100 g(-1). min(-1), respectively) were virtually identical. These data do not support the hypothesis that recent antecedent hypoglycemia increases blood-to-brain glucose transport during subsequent hypoglycemia. They do not exclude regional increments in blood-to-brain glucose transport. Alternatively, the fundamental alteration might lie beyond the blood-brain barrier.

To determine whether coronary thrombi can be detected scintigraphically after acute myocardial infarction, 24 patients were studied with a new method employing indium-111-labeled platelets and technetium-99m-labeled red blood cells. Nine patients with suspected infarction were evaluated initially within 9 hours of the onset of symptoms and again 18 to 24 hours after onset. Eight patients with neurologic symptoms but without overt cardiac disease and seven patients with angina but without infarction served as unmatched control subjects. Foci of net indium accumulation were detected after image processing that incorporated subtraction of blood pool activity. Carotid and pulmonary artery reference regions, in which blood pool activity is high and active platelet deposition unlikely, were used to correct digitized cardiac scintigrams for indium-111 platelet activity in the blood pool. In patients with infarction, distinct foci of net indium accumulation were present in regions corresponding to the coronary artery supplying ischemic zones. This occurred in seven of eight patients at the time of the earliest evaluation (5.6 +/- 3.3 hours [mean +/- SD] after the onset of symptoms) and in eight of nine patients at the time of subsequent imaging (23.6 +/- 1.9 hours after onset). Only 1 of the 15 control patients exhibited a cardiac focus of net indium accumulation. The percent of indium excess (100 [total indium-111 activity-blood pool indium-111 activity]/blood pool indium-111 activity) within the cardiac region measured (+/- SD) 16.8 +/- 11.6% in all patients with myocardial infarction (19.1 +/- 11.2% in those with visually identified foci) compared with 0.4 +/- 4.3% in control patients (p less than 0.001). This method permits early detection and sequential assessment of coronary artery thrombi. It should permit improved characterization of the role of platelets in the pathogenesis of acute manifestations of coronary vascular disease and improved evaluation of interventions designed to prevent or lyse coronary thrombi.