Recurrent Hemispheric Stroke Syndromes in Symptomatic Atherosclerotic Internal Carotid Artery Occlusions: The Carotid Occlusion Surgery Study Randomized Trial.

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 < .01) and to have TIA as the entry event (59% vs 21%, P < .01). All primary endpoints were ipsilateral ischemic strokes. There were no significant differences in occurrence of the primary endpoint between nonsurgical and surgical participants in rHEMI+ (26.3% vs 22.4%, P = .660) and rHEMI- (18.9% vs 19.5%, P = .943). For nonsurgical participants, there was no significant difference in the primary endpoint for rHEMI+ vs rHEMI- patients (P = .410). CONCLUSION: Patients with recurrent hemispheric stroke syndromes enrolled in the COSS trial did not show benefit from EC-IC bypass compared to medical treatment. Early aggressive risk factor measures should be prioritized to reduce recurrent strokes in these patients.

Relative Mean Transit Time Predicts Subsequent Stroke in Symptomatic Carotid Occlusion.

BACKGROUND: Mean transit time (MTT) measurements to assess cerebral hemodynamics are easily obtained by computed tomography and magnetic resonance imaging. We reviewed hemodynamic and clinical outcome data from the St. Louis Carotid Occlusion Study to determine if increased MTT was associated with an increased risk of stroke in patients with symptomatic complete carotid artery occlusion. METHODS: Positron emission tomography (PET) studies of cerebral blood volume-to-cerebral blood flow ratios were used to calculate MTTs. Mean ipsilateral (side of the occluded internal carotid artery)-to-contralateral ratios of MTTs in the middle cerebral artery territories were determined. MTT was tested as a predictor of stroke risk using Cox regression analysis. Receiver operating characteristic curves for stroke risk prediction were generated by varying the mean ispilateral-to-contralateral MTT ratio to identify an optimal cutpoint. RESULTS: Increased MTT ratio was associated with an increased risk of ipsilateral stroke (P < .001). The maximum combination of sensitivity (.778) and specificity (.763) was obtained at a cutpoint ratio of 1.387 or higher. Subjects with a MTT ratio of 1.387 or higher had a 29.3% 2-year risk of ipsilateral stroke compared to 4.6% for those without (P < .001). CONCLUSIONS: PET relative MTT ratio identified patients with symptomatic complete internal artery occlusion who were at high risk for subsequent ipsilateral stroke. Confirmation using measurements of relative MTT from other imaging modalities in a patient cohort receiving contemporary medical management is needed.

Lower stroke risk with lower blood pressure in hemodynamic cerebral ischemia.

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).

Randomized Evaluation of Carotid Occlusion and Neurocognition (RECON) trial: main results.

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.

Striatal dopamine D1-like receptor binding is unchanged in primary focal dystonia.

BACKGROUND: Multiple studies have demonstrated decreases in striatal D2-like (D2, D3) radioligand binding in primary focal dystonias. Although most investigations have focused on D2-specific receptors (D2R), a recent study suggests that the decreased D2-like binding may be due to a D3-specific (D3R) abnormality. However, only limited data exist on the role of D1-specific receptors (D1R) and the D1R-mediated pathways within basal ganglia in dystonia. Metabolic positron emission tomography (PET) data in primary generalized dystonia suggest resting state over activity in the D1R-mediated direct pathway, leading to excessive disinhibition of motor cortical areas. This work investigated whether striatal D1-like receptors are affected in primary focal dystonias. METHODS: Striatal-specific (caudate and putamen) binding of the D1-like radioligand [(11)C]NNC 112 was measured using PET in 19 patients with primary focal dystonia (cranial, cervical, or arm) and 18 controls. RESULTS: No statistically significant difference was detected in striatal D1-like binding between the two groups. The study had 91% power to detect a 20% difference, indicating that false-negative results were unlikely. CONCLUSIONS: Because [(11)C]NNC 112 has high affinity for D1-like receptors, very low affinity for D2-like receptors, and minimal sensitivity to endogenous dopamine levels, we conclude that D1-like receptor binding is not impaired in these primary focal dystonias.

Principal component analysis of PiB distribution in Parkinson and Alzheimer diseases.

OBJECTIVE: To use principal component analyses (PCA) of Pittsburgh compound B (PiB) PET imaging to determine whether the pattern of in vivo ß-amyloid (Aß) in Parkinson disease (PD) with cognitive impairment is similar to the pattern found in symptomatic Alzheimer disease (AD). METHODS: PiB PET scans were obtained from participants with PD with cognitive impairment (n = 53), participants with symptomatic AD (n = 35), and age-matched controls (n = 67). All were assessed using the Clinical Dementia Rating and APOE genotype was determined in 137 participants. PCA was used to (1) determine the PiB binding pattern in AD, (2) determine a possible unique PD pattern, and (3) directly compare the PiB binding patterns in PD and AD groups. RESULTS: The first 2 principal components (PC1 and PC2) significantly separated the AD and control participants (p < 0.001). Participants with PD with cognitive impairment also were significantly different from participants with symptomatic AD on both components (p < 0.001). However, there was no difference between PD and controls on either component. Even those participants with PD with elevated mean cortical binding potentials were significantly different from participants with AD on both components. CONCLUSION: Using PCA, we demonstrated that participants with PD with cognitive impairment do not exhibit the same PiB binding pattern as participants with AD. These data suggest that Aß deposition may play a different pathophysiologic role in the cognitive impairment of PD compared to that in AD.

Validation of nigrostriatal positron emission tomography measures: critical limits.

OBJECTIVE: Molecular imaging and clinical endpoints are frequently discordant in Parkinson disease clinical trials, raising questions about validity of these imaging measures to reflect disease severity. We compared striatal uptake for 3 positron emission tomography (PET) tracers with in vitro measures of nigral cell counts and striatal dopamine in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. METHODS: Sixteen macaques had magnetic resonance imaging and baseline PETs using 6-[18F]fluorodopa (FD), [11C]dihydrotetrabenazine (DTBZ), and 2beta-[11 C]carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT). MPTP (0-0.31 mg/kg) infused unilaterally via the internal carotid artery produced stable hemiparkinsonism by 3 weeks. After 8 weeks, PETs were repeated and animals were euthanized for striatal dopamine measurements and unbiased counts of tyrosine hydroxylase-stained nigral cells. RESULTS: Striatal uptake for each radiotracer (FD, DTBZ, CFT) correlated with stereologic nigral cell counts only for nigral loss<50% (r2=0.84, r2=0.86, r2=0.87, p<0.001 respectively; n=10). In contrast, striatal uptake correlated with striatal dopamine over the full range of dopamine depletion (r2=0.95, r2=0.94, r2=0.94, p<0.001; n=16). Interestingly, indices of striatal uptake of FD, DTBZ, and CFT correlated strongly with each other (r2=0.98, p<0.001). INTERPRETATION: Tracer uptake correlated with nigral neurons only when nigral loss was <50%. This along with previous work demonstrating that nigral cell counts correlate strongly with parkinsonism ratings may explain discordant results between neuroimaging and clinical endpoints. Furthermore, strong correlations among striatal uptake for these tracers support lack of differential regulation of decarboxylase activity (FD), vesicular monoamine transporter type 2 (DTBZ), and dopamine transporter (CFT) within 2 months after nigrostriatal injury.

Surgical results of the Carotid Occlusion Surgery Study.

OBJECT: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Thalamic activation during slightly subphysiological glycemia in humans.

OBJECTIVE: The central nervous system mechanisms of defenses against falling plasma glucose concentrations, and how they go awry and result in iatrogenic hypoglycemia in diabetes, are not known. Hypoglycemic plasma glucose concentrations of 55 mg/dL (3.0 mmol/L) cause symptoms, activate glucose counterregulatory systems, and increase synaptic activity in a network of brain regions including the dorsal midline thalamus in humans. We tested the hypothesis that slightly subphysiological plasma glucose concentrations of 65 mg/dL (3.6 mmol/L), which do not cause symptoms but do activate glucose counterregulatory systems, also activate brain synaptic activities. RESEARCH DESIGN AND METHODS: We measured relative regional cerebral blood flow (rCBF), an index of synaptic activity, in predefined brain regions with [(15)O]water positron emission tomography, symptoms, and plasma epinephrine and glucagon concentrations during a 2-h euglycemic (90 mg/dL) to hypoglycemic (55 mg/dL) clamp (n = 20) or a 2-h euglycemic to slight subphysiological (65 mg/dL) clamp (n = 9) in healthy humans. RESULTS: Clamped plasma glucose concentrations of 65 mg/dL did not cause hypoglycemic symptoms, but raised plasma epinephrine and glucagon concentrations and increased rCBF (P = 0.007) only in the dorsal midline thalamus. CONCLUSIONS: Slightly subphysiological plasma glucose concentrations increase synaptic activity in the dorsal midline thalamus in humans.

Characterization of extrastriatal D2 in vivo specific binding of [¹8F](N-methyl)benperidol using PET.

PET imaging studies of the role of the dopamine D2 receptor family in movement and neuropsychiatric disorders are limited by the use of radioligands that have near-equal affinities for D2 and D3 receptor subtypes and are susceptible to competition with endogenous dopamine. By contrast, the radioligand [¹8F]N-methylbenperidol ([¹8F]NMB) has high selectivity and affinity for the D2 receptor subtype (D2R) and is not sensitive to endogenous dopamine. Although [¹8F]NMB has high binding levels in striatum, its utility for measuring D2R in extrastriatal regions is unknown. A composite MR-PET image was constructed across 14 healthy adult participants representing average NMB uptake 60 to 120 min after [¹8F]NMB injection. Regional peak radioactivity was identified using a peak-finding algorithm. FreeSurfer and manual tracing identified a priori regions of interest (ROI) on each individual's MR image and tissue activity curves were extracted from coregistered PET images. [¹8F]NMB binding potentials (BP(ND) s) were calculated using the Logan graphical method with cerebellum as reference region. In eight unique participants, extrastriatal BP(ND) estimates were compared between Logan graphical methods and a three-compartment kinetic tracer model. Radioactivity and BP(ND) levels were highest in striatum, lower in extrastriatal subcortical regions, and lowest in cortical regions relative to cerebellum. Age negatively correlated with striatal BP(ND) s. BP(ND) estimates for extrastriatal ROIs were highly correlated across kinetic and graphical methods. Our findings indicate that PET with [¹8F]NMB measures specific binding in extrastriatal regions, making it a viable radioligand to study extrastriatal D2R levels in healthy and diseased states.

Reduced uptake of FDOPA PET in end-stage liver disease with elevated manganese levels.

OBJECTIVE: To investigate whether manganese toxicity secondary to end-state liver disease is associated with nigrastriatal dysfunction as measured by 6-[(18)F]fluoro-L-DOPA (FDOPA) positron emission tomographic (PET) imaging. DESIGN: Observational case report. SETTING: The Movement Disorder Center at Washington University, St Louis, Missouri. PATIENT: An individual with manganese toxicity secondary to end-stage liver disease. His FDOPA PET was compared with those of 10 idiopathic Parkinson disease patients and 10 age- and sex-matched healthy controls. MAIN OUTCOME MEASURE: The average estimated net FDOPA uptake by Patlak graphical analysis for caudate, anterior putamen, and posterior putamen. RESULTS: The FDOPA uptake for the patient with secondary manganese toxicity was reduced across all regions by more than 2 SDs compared with healthy controls: caudate (reduced 24.7%), anterior putamen (28.0%), and posterior putamen (29.3%). The ratio of uptake between the caudate/posterior putamen was 0.99 and was different from that of idiopathic Parkinson disease patients, in whom the greatest reduction of FDOPA was in the posterior putamen (mean [SD] ratio, 1.65 [0.41]). CONCLUSIONS: Reduce striatal uptake of FDOPA uptake indicates dysfunction of the nigrostriatal pathways in manganese toxicity secondary to end-stage liver disease. The pattern of striatal involvement with equal reduction of FDOPA uptake in the caudate compared with posterior putamen appears different from those previously reported in individuals with occupational manganese toxicity and idiopathic Parkinson disease and may be specific to manganese toxicity secondary to end-stage liver disease.

Mood response to deep brain stimulation of the subthalamic nucleus in Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus (STN DBS) in Parkinson's disease (PD) improves motor functioning but has variable effects on mood. Little is known about the relationship between electrode contact location and mood response. The authors identified the anatomical location of electrode contacts and measured mood response to stimulation with the Visual Analog Scale in 24 STN DBS PD patients. Participants reported greater positive mood and decreased anxiety and apathy with bilateral and unilateral stimulation. Left DBS improved mood more than right DBS. Right DBS-induced increase in positive mood was related to more medial and dorsal contact locations. These results highlight the functional heterogeneity of the STN.

Effect of osmotic agents on regional cerebral blood flow in traumatic brain injury.

PURPOSE: Cerebral blood flow (CBF) is reduced after severe traumatic brain injury (TBI) with considerable regional variation. Osmotic agents are used to reduce elevated intracranial pressure (ICP), improve cerebral perfusion pressure, and presumably improve CBF. Yet, osmotic agents have other physiologic effects that can influence CBF. We sought to determine the regional effect of osmotic agents on CBF when administered to treat intracranial hypertension. MATERIALS AND METHODS: In 8 patients with acute TBI, we measured regional CBF with positron emission tomography before and 1 hour after administration of equi-osmolar 20% mannitol (1 g/kg) or 23.4% hypertonic saline (0.686 mL/kg) in regions with focal injury and baseline hypoperfusion (CBF <25 mL per 100 g/min). RESULTS: The ICP fell (22.4 ± 5.1 to 15.7 ± 7.2 mm Hg, P = .007), and cerebral perfusion pressure rose (75.7 ± 5.9 to 81.9 ± 10.3 mm Hg, P = .03). Global CBF tended to rise (30.9 ± 3.7 to 33.1 ± 4.2 mL per 100 g/min, P = .07). In regions with focal injury, baseline flow was 25.7 ± 9.1 mL per 100 g/min and was unchanged; in hypoperfused regions (15% of regions), flow rose from 18.6 ± 5.0 to 22.4 ± 6.4 mL per 100 g/min (P < .001). Osmotic therapy reduced the number of hypoperfused brain regions by 40% (P < .001). CONCLUSION: Osmotic agents, in addition to lowering ICP, improve CBF to hypoperfused brain regions in patients with intracranial hypertension after TBI.

Effect of mannitol on cerebral blood volume in patients with head injury.

BACKGROUND: Mannitol has traditionally been the mainstay of medical therapy for intracranial hypertension in patients with head injury. We previously demonstrated that mannitol reduces brain volume in patients with cerebral edema, although whether this occurs because of a reduction in brain water, blood volume, or both remains poorly understood. OBJECTIVE: To test the hypothesis that mannitol acts by lowering blood viscosity leading to reflex vasoconstriction and a fall in cerebral blood volume (CBV). METHODS: We used O positron emission tomography to study 6 patients with traumatic brain injuries requiring treatment for intracranial hypertension. Cerebral blood flow (CBF), CBV, and cerebral metabolic rate for oxygen (CMRO2) were measured before and 1 hour after administration of 1.0 g/kg 20% mannitol. RESULTS: CBV rose from 4.1 ± 0.4 to 4.2 ± 0.2 mL/100 g (P = .3), while intracranial pressure fell from 21.5 ± 4.9 to 13.7 ± 5.1 mm Hg (P < .003) after mannitol. Blood pressure, PaCO2, oxygen content, CBF, and CMRO2 did not change. CONCLUSION: A single bolus of 1 g/kg of 20% mannitol does not acutely lower CBV. Another mechanism, such as a reduction in brain water, may better explain mannitol's ability to lower intracranial pressure and reduce mass effect.

Comparison of induced hypertension, fluid bolus, and blood transfusion to augment cerebral oxygen delivery after subarachnoid hemorrhage.

OBJECT: Critical reductions in oxygen delivery (DO(2)) underlie the development of delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH). If DO(2) is not promptly restored, then irreversible injury (that is, cerebral infarction) may result. Hemodynamic therapies for DCI (that is, induced hypertension [IH] and hypervolemia) aim to improve DO(2) by raising cerebral blood flow (CBF). Red blood cell (RBC) transfusion may be an alternate strategy that augments DO(2) by improving arterial O(2) content. The authors compared the relative ability of these 3 interventions to improve cerebral DO(2), specifically their ability to restore DO(2) to regions where it is impaired. METHODS: The authors compared 3 prospective physiological studies in which PET imaging was used to measure global and regional CBF and DO(2) before and after the following treatments: 1) fluid bolus of 15 ml/kg normal saline (9 patients); 2) raising mean arterial pressure 25% (12 patients); and 3) transfusing 1 U of RBCs (17 patients) in 38 individuals with aneurysmal SAH at risk for DCI. Response between groups in regions with low DO(2) (< 4.5 ml/100 g/min) was compared using repeated-measures ANOVA. RESULTS: Groups were similar except that the fluid bolus cohort had more patients with symptoms of DCI and lower baseline CBF. Global CBF or DO(2) did not rise significantly after any of the interventions, except after transfusion in patients with hemoglobin levels < 9 g/dl. All 3 treatments improved CBF and DO(2) to regions with impaired baseline DO(2), with a greater improvement after transfusion (23%) than hypertension (14%) or volume loading (10%); p < 0.001. Transfusion also resulted in a nonsignificantly greater (47%) reduction in the number of brain regions with low DO(2) when compared with fluid bolus (7%) and hypertension (12%) (p = 0.33). CONCLUSIONS: The IH, fluid bolus, and blood transfusion interventions all improve DO(2) to vulnerable brain regions at risk for ischemia after SAH. Transfusion appeared to provide a physiological benefit at least comparable to IH, especially among patients with anemia, but transfusion is associated with risks. The clinical significance of these findings remains to be established in controlled clinical trials.

Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial.

CONTEXT: Patients with symptomatic atherosclerotic internal carotid artery occlusion (AICAO) and hemodynamic cerebral ischemia are at high risk for subsequent stroke when treated medically. OBJECTIVE: To test the hypothesis that extracranial-intracranial (EC-IC) bypass surgery, added to best medical therapy, reduces subsequent ipsilateral ischemic stroke in patients with recently symptomatic AICAO and hemodynamic cerebral ischemia. DESIGN: Parallel-group, randomized, open-label, blinded-adjudication clinical treatment trial conducted from 2002 to 2010. SETTING: Forty-nine clinical centers and 18 positron emission tomography (PET) centers in the United States and Canada. The majority were academic medical centers. PARTICIPANTS: Patients with arteriographically confirmed AICAO causing hemispheric symptoms within 120 days and hemodynamic cerebral ischemia identified by ipsilateral increased oxygen extraction fraction measured by PET. Of 195 patients who were randomized, 97 were randomized to receive surgery and 98 to no surgery. Follow-up for the primary end point until occurrence, 2 years, or termination of trial was 99% complete. No participant withdrew because of adverse events. INTERVENTIONS: Anastomosis of superficial temporal artery branch to a middle cerebral artery cortical branch for the surgical group. Antithrombotic therapy and risk factor intervention were recommended for all participants. MAIN OUTCOME MEASURE: For all participants who were assigned to surgery and received surgery, the combination of (1) all stroke and death from surgery through 30 days after surgery and (2) ipsilateral ischemic stroke within 2 years of randomization. For the nonsurgical group and participants assigned to surgery who did not receive surgery, the combination of (1) all stroke and death from randomization to randomization plus 30 days and (2) ipsilateral ischemic stroke within 2 years of randomization. RESULTS: The trial was terminated early for futility. Two-year rates for the primary end point were 21.0% (95% CI, 12.8% to 29.2%; 20 events) for the surgical group and 22.7% (95% CI, 13.9% to 31.6%; 20 events) for the nonsurgical group (P = .78, Z test), a difference of 1.7% (95% CI, -10.4% to 13.8%). Thirty-day rates for ipsilateral ischemic stroke were 14.4% (14/97) in the surgical group and 2.0% (2/98) in the nonsurgical group, a difference of 12.4% (95% CI, 4.9% to 19.9%). CONCLUSION: Among participants with recently symptomatic AICAO and hemodynamic cerebral ischemia, EC-IC bypass surgery plus medical therapy compared with medical therapy alone did not reduce the risk of recurrent ipsilateral ischemic stroke at 2 years. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00029146.

Poor correlation between perihematomal MRI hyperintensity and brain swelling after intracerebral hemorrhage.

BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Metabolic control of resting hemispheric cerebral blood flow is oxidative, not glycolytic.

Although the close regional coupling of resting cerebral blood flow (CBF) with both cerebral metabolic rate of oxygen (CMRO(2)) and cerebral metabolic rate of glucose (CMRglc) within individuals is well documented, there are few data regarding the coupling between whole brain flow and metabolism among different subjects. To investigate the metabolic control of resting whole brain CBF, we performed multivariate analysis of hemispheric CMRO(2), CMRglc, and other covariates as predictors of resting CBF among 23 normal humans. The univariate analysis showed that only CMRO(2) was a significant predictor of CBF. The final multivariate model contained two additional terms in addition to CMRO(2): arterial oxygen content and oxygen extraction fraction. Notably, arterial plasma glucose concentration and CMRglc were not included in the final model. Our data demonstrate that the metabolic factor controlling hemispheric CBF in the normal resting brain is CMRO(2) and that CMRglc does not make a contribution. Our findings provide evidence for compartmentalization of brain metabolism into a basal component in which CBF is coupled to oxygen metabolism and an activation component in which CBF is controlled by another mechanism.

Platelet mitochondrial complex I and I+III activities do not correlate with cerebral mitochondrial oxidative metabolism.

Assays of mitochondrial electron transport system (ETS) activity in circulating blood platelets have been used to investigate the cause of neurodegenerative diseases. However, the correspondence between platelet ETS function and cerebral mitochondrial metabolism is not well characterized. To assess the validity of using platelet ETS activity to infer cerebral mitochondrial metabolism, we measured platelet ETS activity (complex I and complex I+III), cerebral metabolic rate of oxygen (CMRO(2)), and the CMRO(2)/cerebral metabolic rate for glucose ratio in 40 subjects: 7 with never-medicated Parkinson's disease, 13 with genetically proved Huntington's disease, and 20 normal controls. We found no correlation between in vivo measures of cerebral mitochondrial oxidative metabolism and ex vivo assays of platelet complex I and complex I+III activity performed on blood collected immediately before cerebral metabolism studies. We saw no evidence of a threshold effect when comparing platelet complex I and complex I+III activity with cerebral oxidative metabolism across a 4- to 10-fold range of platelet ETS activity. On the basis of these data, we conclude that measures of mitochondrial complex I and I+III activity in platelets within the ranges we have studied do not correlate with oxidative function of cerebral mitochondria.

Cerebral hemodynamic and metabolic effects of equi-osmolar doses mannitol and 23.4% saline in patients with edema following large ischemic stroke.

INTRODUCTION: Cerebral edema after ischemic stroke is frequently treated with mannitol and hypertonic saline (HS); however, their relative cerebrovascular and metabolic effects are incompletely understood, and may operate independent of their ability to lower intracranial pressure. METHODS: We compared the effects of 20% mannitol and 23.4% saline on cerebral blood flow (CBF), blood volume (CBV), oxygen extraction fraction (OEF), and oxygen metabolism (CMRO(2)), in nine ischemic stroke patients who deteriorated and had >2 mm midline shift on imaging. (15)O-PET was performed before and 1 h after administration of randomly assigned equi-osmolar doses of mannitol (1.0 g/kg) or 23.4% saline (0.686 mL/kg). RESULTS: Baseline CBF values (ml/100g/min) in the infarct core, periinfarct region, remaining ipsilateral hemisphere, and contralateral hemisphere in the mannitol group were 5.0 ± 3.9, 25.6 ± 4.4, 35.6 ± 8.6, and 45.5 ± 2.2, respectively, and in the HS group were 8.3 ± 9.8, 35.3 ± 10.9, 38.2 ± 15.1, and 35.2 ± 12.4, respectively. There was a trend for CBF to rise in the contralateral hemisphere after mannitol from 45.5 ± 12.2 to 57.6 ± 21.7, P = 0.098, but not HS. CBV, OEF, and CMRO(2) did not change after administration of either agent. Change in CBF in the contralateral hemisphere after osmotic therapy was strongly correlated with baseline blood pressure (R (2)= 0.879, P = 0.002). CONCLUSIONS: We conclude that at higher perfusion pressures, osmotic agents may raise CBF in non-ischemic tissue. We conclude that at higher perfusion pressures, osmotic agents may raise CBF in non-ischemic tissue.