Elevated Oxygen Extraction Fraction Research Articles

Abstract 109: Non-invasive Detection of Capillary Arteriovenous Shunting in Patients With Sickle Cell Anemia

Introduction: High blood velocity can cause rapid erythrocyte transit through capillaries, reducing efficiency of oxygen delivery to tissue (capillary arteriovenous shunting). Arterial spin labeling (ASL) is an MRI technique that utilizes magnetic labeling of arterial blood water for CBF quantitation. Labeled water that traverses capillaries without exchanging with tissue leads to hyperintense venous signal indicative of arteriovenous shunting. We hypothesized that venous hyperintensity is present in sickle cell anemia (SCA) adults, correlates with flow velocity, and corresponds with clinical impairment and oxygen extraction fraction (OEF). Methods: ASL for shunting determination, TRUST for OEF measurement, phase contrast angiography for velocity assessment, and FLAIR / MRA for infarct / vasculopathy evaluation were performed at 3T in adults with SCA (n=36) and age- and race-matched controls (n=11). Three reviewers assessed for hyperintensity in the superior sagittal sinus on ASL images (Fig) and assigned scores of 0 (none), 1 (mild, focal), 2 (significant, focal), or 3 (significant, diffuse). Shunting scores were compared with the presence of clinical impairment (prior infarcts, stenosis>50%, or severe disease requiring transfusions) and OEF. Results: Interobserver agreement was excellent (Fleiss’ κ=0.91). Consensus shunting score in SCA adults (1.2±1.1) was higher (p<0.01) than controls (0.1±0.3), Median age 27.6 y, 57% F. Elevated shunting scores were observed in SCA adults with (1.23±1.07) vs. without (1.07±1.16) clinical impairment. A trend (p=0.068) for elevated OEF was observed in those with shunting scores ≥2 (0.44±0.07) vs. those with shunting scores ≤1 (0.40±0.07). Cervical flow velocity was elevated in subjects with shunting scores ≥2 (30.2±4.8 cm/s) vs. ≤1 (25.3±4.8 cm/s). Conclusion: Venous hyperintensity in ASL images may indicate capillary arteriovenous shunting and may reflect higher clinical impairment and elevated OEF.

Hemodynamic mechanisms underlying elevated oxygen extraction fraction (OEF) in moyamoya and sickle cell anemia patients

Moyamoya is a bilateral, complex cerebrovascular condition characterized by progressive non-atherosclerotic intracranial stenosis and collateral vessel formation. Moyamoya treatment focuses on restoring cerebral blood flow (CBF) through surgical revascularization, however stratifying patients for revascularization requires abilities to quantify how well parenchyma is compensating for arterial steno-occlusion. Globally elevated oxygen extraction fraction (OEF) secondary to CBF reduction may serve as a biomarker for tissue health in moyamoya patients, as suggested in patients with sickle cell anemia (SCA) and reduced oxygen carrying capacity. Here, OEF was measured (TRUST-MRI) to test the hypothesis that OEF is globally elevated in patients with moyamoya (n = 18) and SCA (n = 18) relative to age-matched controls (n = 43). Mechanisms underlying the hypothesized OEF increases were evaluated by performing sequential CBF-weighted, cerebrovascular reactivity (CVR)-weighted, and structural MRI. Patients were stratified by treatment and non-parametric tests applied to compare study variables (significance: two-sided P < 0.05). OEF was significantly elevated in moyamoya participants (interquartile range = 0.38–0.45) compared to controls (interquartile range = 0.29–0.38), similar to participants with SCA (interquartile range = 0.37–0.45). CBF was inversely correlated with OEF in moyamoya participants. Elevated OEF was only weakly related to reductions in CVR, consistent with basal CBF level, rather than vascular reserve capacity, being most closely associated with OEF.

Abstract WMP97: Regional Cerebral Oxygen Extraction is Elevated in Tissue at High Risk of Stroke in Pediatric Sickle Cell Disease

Introduction: Children with sickle cell disease (SCD) are at high risk of stroke. Hemispheric oxygen extraction fraction (OEF) is a predictor of stroke in adults with carotid occlusion, but OEF has not been evaluated as a predictor of stroke in children with SCD. Hypothesis: OEF is elevated in SCD children compared to controls within a region at high risk of stroke as defined by an infarct heat-map created from a separate retrospective SCD cohort. Methods: A prospective MRI study enrolled 37 children aged 5-21: 17 with SCD and no stroke, 12 with SCD and silent infarcts (median infarct volume=0.3ml), and 8 sibling controls. None were on transfusions or had overt stroke history. Voxel-wise OEF was measured using an asymmetric spin echo sequence. In a separate retrospective cohort of 67 SCD children with overt and silent stroke, infarct regions on FLAIR were manually outlined and coregistered to an average T1 map to create an infarct heat-map (Fig A) which was used to define a “high risk” ROI (defined by &gt;3% infarct density). This ROI was aligned to individual OEF maps from the prospective cohort (Fig B, average OEF map). OEF within the “high risk” ROI was compared between SCD children and controls; and between SCD children with and without infarction using Mann Whitney U tests. Results: The infarct heat-map from the retrospective cohort (Fig A) and the average OEF map from the prospective SCD cohort (Fig B) demonstrate striking co-localization of infarct density and elevated OEF. Within the “high risk” ROI, OEF was higher in SCD children compared to controls (39% [36, 46] vs. 23% [22, 27], p&lt;0.0001 (Fig C). OEF within this “high risk” ROI did not differ between SCD children with and without infarcts (40% [38, 47] vs. 38% [35, 46], p=0.6). Conclusion: OEF in SCD children is elevated in the internal borderzone, a region with high stroke risk in SCD. Regional OEF may be a marker of cerebral metabolic stress that could be exploited to stratify stroke risk in this vulnerable population.

Abstract 35: Transfusion Relieves Cerebral Metabolic Stress in Children with Sickle Cell Disease

Introduction: Transfusions (Tx) are the mainstay of stroke prevention in children with sickle cell disease (SCD), but the pathophysiology conferring this neuroprotection is not well understood. Hypothesis: Tx relieves cerebral metabolic stress by improving arterial oxygen content, thereby lowering chronically-elevated cerebral blood flow (CBF) and oxygen extraction fraction (OEF) in children with SCD at risk for stroke. Methods: Children with SCD on chronic Tx therapy underwent two brain MRIs with measurement of CBF via pseudocontinuuous arterial spin labeling and OEF via asymmetric spin echo sequence within 24 hours of exchange Tx. To determine how Tx may reduce regions of elevated OEF, we set absolute OEF thresholds (45, 47.5, 50%) and compared tissue volumes above each threshold pre- and post-Tx using nonparametric paired statistics. Results: Twelve children with SCD (6-21 yrs) underwent MRIs. Tx raised Hb and lowered CBF and OEF (Figure), suggesting that elevated CBF and OEF may be markers of metabolic stress relieved by Tx. While CBF correlates with age in healthy children, pre-Tx CBF correlation with age was lost (τ= -0.42, p=0.07), but regained post-Tx (τ= -0.76, p=0.001). Also, absolute change in OEF diminished with increasing age (τ=. -0.75, p=0.003). Regions with very high OEF were found in the periventricular white matter, a common area of infarcts in SCD (Figure, average OEF maps pre- and post-Tx). Tx reduced the volume of these brain regions defined by all three OEF thresholds (Table), suggesting that Tx reduces brain regions at high risk for stroke. Conclusion: Tx in SCD children improves arterial oxygen content by increasing Hb, allowing CBF and OEF to fall, thus relieving metabolic stress globally and regionally. The absolute change in OEF correlates with age, suggesting that the efficacy of Tx may be age-dependent.

Abstract TMP93: Elevated Oxygen Extraction Fraction Measured With Noninvasive MRI may be Discriminatory for Stroke Risk in Adults With Sickle Cell Anemia

Introduction: No screening procedures exist for evaluating stroke risk in adults with sickle cell anemia (SCA). Reduced oxygen carrying capacity is present in SCA, which may initially be compensated for by an increase in cerebral blood flow (CBF) and then by increased oxygen extraction fraction (OEF). Hypothesis: OEF and CBF can be measured noninvasively and reproducibly with MRI using clinically-available equipment in adults with SCA; elevated OEF provides added discriminatory capacity for clinical impairment relative to vasculopathy extent and CBF alone. Methods: Structural, CBF-weighted, and MRA imaging, together with a noninvasive OEF-weighted T 2 -relaxation-under-spin-tagging (TRUST)-MRI method was applied in SCA adults (n=26) and race and age-matched controls (n=11). A Kruskal-Wallis test was applied to evaluate mean differences between SCA and control parameters. Linear regression assessed how elevated OEF correlated with increasing clinical impairment defined by presence of infarct, vasculopathy, or use of regular blood transfusions for SCA. Results: OEF had high reproducibility within the same scan session, n=37 (ICC = 0.989). Whole-brain OEF and CBF were increased in SCA adults (OEF=0.46±0.08; CBF=52.4±8.3 ml/100g/min) versus controls (OEF=0.35±0.06; CBF=43.6±5.1 ml/100g/min). Hematocrit and OEF were inversely correlated (R 2 =0.72; p&lt;0.01). Linear regression revealed a stronger relationship of OEF than CBF with clinical impairment. In SCA adults without impairment (n=12) CBF and OEF have an inverse relationship (R 2 =0.41; p=0.01, Fig. 1A) but with clinical impairment (infarct, vasculopathy or severe pain requiring regular transfusions, n=14) CBF and OEF become uncoupled (R 2 =0.08; p=0.16; Fig. 1B) as CBF may not be able to increase further and may plateau or decline. Conclusion: TRUST-MRI OEF is a rapid, reproducible measure. OEF shows promise as screening tool for hemodynamic impairment and stroke risk in adults with SCA.

Non-invasive imaging of oxygen extraction fraction in adults with sickle cell anaemia.

Sickle cell anaemia is a monogenetic disorder with a high incidence of stroke. While stroke screening procedures exist for children with sickle cell anaemia, no accepted screening procedures exist for assessing stroke risk in adults. The purpose of this study is to use novel magnetic resonance imaging methods to evaluate physiological relationships between oxygen extraction fraction, cerebral blood flow, and clinical markers of cerebrovascular impairment in adults with sickle cell anaemia. The specific goal is to determine to what extent elevated oxygen extraction fraction may be uniquely present in patients with higher levels of clinical impairment and therefore may represent a candidate biomarker of stroke risk. Neurological evaluation, structural imaging, and the non-invasive T2-relaxation-under-spin-tagging magnetic resonance imaging method were applied in sickle cell anaemia (n = 34) and healthy race-matched control (n = 11) volunteers without sickle cell trait to assess whole-brain oxygen extraction fraction, cerebral blood flow, degree of vasculopathy, severity of anaemia, and presence of prior infarct; findings were interpreted in the context of physiological models. Cerebral blood flow and oxygen extraction fraction were elevated (P < 0.05) in participants with sickle cell anaemia (n = 27) not receiving monthly blood transfusions (interquartile range cerebral blood flow = 46.2-56.8 ml/100 g/min; oxygen extraction fraction = 0.39-0.50) relative to controls (interquartile range cerebral blood flow = 40.8-46.3 ml/100 g/min; oxygen extraction fraction = 0.33-0.38). Oxygen extraction fraction (P < 0.0001) but not cerebral blood flow was increased in participants with higher levels of clinical impairment. These data provide support for T2-relaxation-under-spin-tagging being able to quickly and non-invasively detect elevated oxygen extraction fraction in individuals with sickle cell anaemia with higher levels of clinical impairment. Our results support the premise that magnetic resonance imaging-based assessment of elevated oxygen extraction fraction might be a viable screening tool for evaluating stroke risk in adults with sickle cell anaemia.

Quantitative MRI of Hemodynamic Compromise in Children with Sickle Cell Disease: New Insights into Pathophysiology

Introduction:Sickle cell disease (SCD) is the leading cause of overt stroke in children, resulting in increased morbidity and mortality (Prengler et al. 2002). Neurologic injury in SCD is caused by a cascade of complex physiological processes that may manifest as abnormal cerebral blood flow (CBF), abnormal oxygen extraction fraction (OEF), and ultimately lead to oxygen deprivation of the brain tissue (Adams et al. 2007., Cheung et al. 2002), however, the underlying pathophysiology is not well understood. While much research has focused on the role of vasculopathy in neurologic injury in SCD, over one third of children with sickle cell disease who suffer an overt ischemic event do not present with arterial stenosis (Hulbert et al. 2011). Extending the work of Nur et al. (2009), we have recently shown in children without stenosis in SCD that elevated cerebral blood flow and diminished cerebrovascular reserve is associated with the severity of anemia (Kosinski et al. 2015). However, to date, little is known about the relative contributions of non-vasculopathic hemodynamic compromise that may occur in children with SCD. Therefore, a comprehensive model of pathophysiology in this population will help stratify stroke risk and guide therapeutic strategies.Aim:To noninvasively quantify both CBF and OEF in children with SCD using magnetic resonance imaging.Methods:11 patients (7M/4F; age 14 ± 2.7 years (mean ± SD)) with SCD and no history of stroke nor arterial stenosis were imaged on a 3T MRI system. 9 patients were on hydroxyurea (average dose: 19.7 ± 3 mg/kg/day). Hematological parameters were acquired at a clinic visit no more than one month prior to the MRI scan (Table 1). Pulsed arterial spin labelling MRI was used to noninvasively assess grey matter cerebral blood flow according to a standard kinetic model. A T2*-weighted flow-compensated image provided phase information, with the phase signal difference between the sagittal sinus and surrounding tissue used to quantify venous oxygenation (SvO2) (Driver et al. 2014). Arterial oxygen saturation (SaO2) was measured via peripheral pulse oximetry and OEF was determined by (SaO2 - SvO2/SaO2) according to Fick's principle of arteriovenous difference.Results:A significant positive association was observed between CBF and OEF (p = 0.82, p = 0.02, pearson product moment correlation coefficient), as shown in Figure 1. Mean values (± SD) were 0.75 ± 0.08, 0.23 ± 0.08 and 54.1 ± 11 ml/min/100g for SvO2, OEF and CBF respectively.Discussion:The observed correlation between CBF and OEF suggests that children with SCD who do not present with vasculopathy, utilize both the perfusion and metabolic reserve in order to meet the cerebral demand for O2. This allows CBF and OEF to increase simultaneously rather than sequentially as proposed by Powers et al. (1991). This non-sequential hemodynamic compromise is in agreement with previous literature in cerebrovascular disease (Kanno et al. 1988) and may serve to minimise increases in cardiac output (Varat et al. 1972). This data suggests that elevated OEF may serve as an early risk marker for overt stroke in addition to elevated blood flow velocity and thus may help better screen for those who will most benefit from transfusion therapy.Table 1SCD PatientsSample Size (N)11Gender (M/F)7/4Age (y)13.7 ± 2.7BMI (Kg/m2)18.8 ± 3.0Hematocrit0.282 ± 0.03Hemoglobin (g/L)100 ± 10.3SaO20.99 ± 0.02SvO20.75 ± 0.08Absolute Reticulocyte (K/uL)205 ± 72Neutrophil Count (K/uL)5.3 ± 3.7Clinical parameters acquired within 30 days of the MRI session [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Oxygen extraction fraction measurement using quantitative susceptibility mapping: Comparison with positron emission tomography

The purposes of this study are to establish oxygen extraction fraction (OEF) measurements using quantitative susceptibility mapping (QSM) of magnetic resonance imaging (MRI), and to compare QSM–OEF data with the gold standard 15O positron emission tomography (PET). Twenty-six patients with chronic unilateral internal carotid artery or middle cerebral artery stenosis or occlusion, and 15 normal subjects were included. MRI scans were conducted using a 3.0 Tesla scanner with a three-dimensional spoiled gradient recalled sequence. QSM images were created using the morphology-enabled dipole inversion method, and OEF maps were generated from QSM images using extraction of venous susceptibility induced by deoxygenated hemoglobin. Significant correlation of relative OEF ratio to contra-lateral hemisphere between QSM–OEF and PET–OEF was observed (r = 0.62, p < 0.001). The local (intra-section) correlation was also significant (r = 0.52, p < 0.001) in patients with increased PET–OEF. The sensitivity and specificity of OEF increase in QSM was 0.63 (5/8) and 0.89 (16/18), respectively, in comparison with PET. In conclusion, good correlation was achieved between QSM–OEF and PET–OEF in the identification of elevated OEF in affected hemispheres of patients with unilateral chronic steno-occlusive disease.

Elevated global cerebral blood flow, oxygen extraction fraction and unchanged metabolic rate of oxygen in young adults with end-stage renal disease: an MRI study.

To noninvasively assess global cerebral blood flow (CBF), oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) in young adults with end-stage renal disease (ESRD). Thirty-six patients and 38 healthy volunteers were included and took part in MR examinations, blood and neuropsychological tests. CBF and OEF were measured by phase-contrast and T2-relaxation-under-spin-tagging MRI techniques, respectively. CMRO2 was computed from CBF, OEF and hematocrit according to Fick's principle. Correlations were performed between MR measurements, blood biochemistry measurements and neuropsychological test scores. Compared with controls, ESRD patients had elevated CBF (72.9 ± 12.5 vs. 63.8 ± 8.5mlmin(-1) 100g(-1), P < 0.001), elevated OEF (47.2 ± 10.2 vs. 35.8 ± 5.4%, P < 0.001), but unaffected CMRO2 (199.5 ± 36.4 vs. 193.8 ± 28.6μmol O2 min(-1) 100g(-1), P = 0.879). Hematocrit negatively correlated with CBF (r = -0.640, P < 0.001) and OEF (r = -0.701, P < 0.001), but not with CMRO2. Altered neuropsychological test scores of ESRD patients were associated with OEF and CBF, but not with CMRO2. There were weak relationships between eGFR and hematocrit (r = 0.308, P = 0.068) or CBF (r = 0.318, P = 0.059). Our findings suggested that anaemic young adults with ESRD may afford higher CBF and OEF to maintain a normal CMRO2. Despite this compensatory process, however, cognitive function was still impaired and its severity was correlated with their CBF and OEF abnormality. • Anaemic young adults with ESRD may afford higher CBF and OEF. • Anaemic young adults with ESRD maintain a normal CMRO 2 . • Cognitive function was still impaired in young ESRD adults. • The severity of cognitive dysfunction correlated with CBF and OEF changes.

Neurovascular coupling during cortical spreading depolarization and -depression.

Cortical spreading depolarizations (CSDs) are self-propagating waves of transient loss of neuronal transmembrane ion gradients, followed by prolonged suppression of neuronal activity (spreading depression). CSDs emerge spontaneously in animal models of traumatic brain injury,1 subarachnoid hemorrhage,2 and in focal ischemia3 where they are associated with infarct growth.4 In humans, CSDs have been demonstrated in traumatic brain injury,5 subarachnoid hemorrhage,6,7 and malignant hemispheric stroke,8 and they are believed to be the brain mechanism underlying migraine aura.9 CSDs are associated with dramatic changes in cerebral blood flow (CBF). During the depolarization phase of CSDs induced in healthy and well-perfused brain tissue in animal models, an early hyperemic response is observed, typically followed by prolonged oligemia after the neuronal repolarization. Despite the initial CBF increase, tissue hypoxia may develop in more distant territories of capillary supply.10,11 Similar CBF changes have been observed in patients with migraine aura.12–14 In the injured brain, CSDs can be accompanied by severe initial CBF reduction instead of a CBF increase during the depolarization phase, termed spreading ischemia.15 When this inverse hemodynamic response is observed, the energy-dependent recovery from CSD is delayed in a characteristic fashion, indicating a severe mismatch between oxygen supply and demand2 and a high risk of tissue damage.16 In rat and cat models of focal ischemia, CSD-related CBF transients range from monophasic, positive CBF responses in peri-ischemic tissue, over biphasic transients in mildly ischemic tissue, to negative CBF transients in more severe ischemia.17–19 During CSD in animal models, capillary flow patterns become severely disturbed.10,20,21 The passage of a CSD causes erythrocytes in some capillaries to reduce their speed, whereas other capillaries reveal 4-fold increases in flow or higher. …

Hypoxic viable tissue in human chronic cerebral ischemia because of unilateral major cerebral artery steno-occlusive disease.

Positron emission tomography (PET) with radiolabeled 2-nitroimidazoles directly detects hypoxic but viable tissue present in an acute ischemic area in the human brain. This study using PET with 1-(2-(18)F-fluoro-1-[hydroxymethyl]ethoxy) methyl-2-nitroimidazole ((18)F-FRP170) aimed to determine whether tissue with an abnormally elevated uptake of (18)F-FRP170 exists in human chronic cerebral ischemia because of unilateral atherosclerotic major cerebral artery steno-occlusive disease. (18)F-FRP170 PET was performed, and cerebral blood flow and metabolism were assessed using (15)O-gas PET in 20 healthy subjects and 52 patients. A region of interest (ROI) was automatically placed in 3 segments of the middle cerebral artery territory in both cerebral hemispheres with a 3-dimensional stereotaxic ROI template using SPM2, and each PET value was determined in each ROI. The ratio of values in the affected versus contralateral hemispheres was calculated for the (18)F-FRP170 PET image. A significant correlation was observed between oxygen extraction fraction and (18)F-FRP170 ratios (ρ=0.509; P<0.0001) in a total of 156 ROIs in 52 patients. The specificity and positive-predictive value for a combination of an elevated oxygen extraction fraction and a moderately reduced cerebral oxygen metabolism for detection of an abnormally elevated (18)F-FRP170 ratio (19 ROIs: 12%) were significantly greater than those for the individual categories (elevated oxygen extraction fraction, moderately reduced cerebral oxygen metabolism, or reduced cerebral blood flow). Tissues with abnormally elevated uptake of (18)F-FRP170 exist in human chronic cerebral ischemia characterized by a combination of misery perfusion and moderately reduced oxygen metabolism because of unilateral atherosclerotic major cerebral artery steno-occlusive disease.

Clinical significance of STA-MCA double anastomosis for hemodynamic compromise in post-JET/COSS era

Even after the recent randomized clinical trials JET and COSS, it is still unclear that impaired cerebrovascular reactivity (CVR) to acetazolamide and oxygen extraction fraction (OEF) can identify the candidates for superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis. This prospective study was aimed to evaluate the benefits of STA-MCA "double" anastomosis on long-term outcome in patients with reduced cerebral blood flow (CBF) and CVR (Type 3 ischemia) and elevated OEF attributable to occlusive carotid diseases. This study included 49 patients with reduced CBF and CVR on SPECT in the ipsilateral MCA area. Using (15)O-gas PET, OEF was also measured in all patients. STA-MCA double anastomosis was recommended to the patients with Type 3 and elevated OEF. Those with Type 3 but normal OEF were medically treated. Of 36 patients with Type 3 and elevated OEF, 25 consented to surgery. No perioperative morbidity or mortality were noted. The other 11 patients with Type 3 and elevated OEF were medically treated. Annual incidence of ipsilateral stroke was 0.7% and 6.5% in surgically and medically treated patients with Type 3 and elevated OEF, respectively (P = 0.0188). None of patients with Type 3 but normal OEF developed ipsilateral stroke during follow-up periods. STA-MCA "double" anastomosis significantly decreased OEF. STA-MCA "double" anastomosis may still have the potential to reduce the risk of recurrent ipsilateral stroke in hemodynamically compromised patients. Further studies would be essential to advance diagnosis, surgical procedures, and perioperative managements to bring out maximal effects of bypass surgery.

Ivy sign, misery perfusion, and asymptomatic moyamoya disease: FLAIR imaging and 15O-gas positron emission tomography

The prevalence of ivy sign on fluid-attenuated inversion recovery (FLAIR) imaging in patients with asymptomatic moyamoya disease is unclear. The aim of this study was to clarify the incidence of ivy sign in these patients, as well as the correlation between MRI and (15)O gas PET findings. A retrospective analysis including 16 consecutive patients with asymptomatic moyamoya disease enrolled between 2001 and 2010 in a single center. FLAIR imaging at the initial visit was categorized as ivy sign present, negative, or equivocal. Hemodynamic and metabolic parameters were quantified in 11 of 16 patients by (15)O-gas positron emission tomography, and the relationship between ivy sign and (15)O-gas PET parameters was analyzed. Cerebrovascular events within the follow-up period (54 ± 28 months) were also examined. Five of 16 asymptomatic moyamoya patients (31.3 %) had positive ivy sign (6/30 hemispheres, 20 %). In (15)O-gas PET examinations, 18 % of 22 hemispheres had elevated oxygen extraction fraction values that were significantly associated with positive ivy sign. Of these 16 asymptomatic moyamoya patients, six patients (37.5 %) underwent combined surgical revascularization. In this series, no patients experienced ischemic stroke, but one had intraventricular bleeding 1 year after surgery. Ivy sign on FLAIR imaging is still not rare in patients with moyamoya disease, even when asymptomatic. Although optimal management is still under debate, ivy sign may be an indicator of misery perfusion, and patients with asymptomatic moyamoya disease and ivy sign on FLAIR imaging will benefit from more careful follow-up.

Surgical results of the Carotid Occlusion Surgery Study.

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.

Oxygen Imaging by MRI

Mapping the ischemic penumbra (ie, the neurophysiologically silent but still viable ischemic tissue) is increasingly part of routine assessment in suspected acute stroke, although whether this approach is cost-effective is still unclear.1,2 The penumbra is characterized by both low cerebral blood flow (CBF; <20 mL · 100 g−1 · min−1) and elevated oxygen extraction fraction (OEF).3 The latter is considered a critical marker of tissue viability and is therefore a key imaging target. The penumbra was originally documented in humans using positron emission tomography (PET),2,3 a validated method to map CBF, OEF and cerebral metabolic rate of oxygen (CMRO2),4 but clinical access to PET is scarce. Consequently, MR-based diffusion and perfusion imaging (PWI) and CT-based perfusion imaging are widely used as substitutes.1 However, both methods have limitations for penumbra imaging2 and do not directly assess oxygen metabolism. A method combining the advantages of MR and the ability to map OEF would therefore be highly desirable. Blood oxygen level-dependent (BOLD) imaging has recently emerged as a possible candidate for this purpose. However, several BOLD techniques with different levels of validation, accuracy, and clinical applicability are in concurrent development, making the situation somewhat confusing. This review aims to clarify whether BOLD imaging might be of use to map oxygen in the clinical setting. We systematically review and critically discuss all studies published to date in English language, both experimental and clinical, that have applied BOLD in acute stroke. Because our focus is tissue oxygen metabolism, we do not address the T2*-weighted method to visualize leptomeningeal vessels,5 the mapping of ΔCMRO2 during physiological challenges,6 or the emerging 17O imaging method.7 ### Principles of BOLD MRI Oxyhemoglobin is diamagnetic, whereas deoxyhemoglobin (DHb) is paramagnetic. Transverse relaxation is sensitive to paramagnetic …

Abstract 2941: Wide Variability of Cerebral Blood Volume Response in the Area with Impaired Cerebrovascular Reactivity to Acetazolamide due to Occlusive Carotid Artery Disease

Background and Purpose - Recent studies have suggested that hemodynamic and metabolic responses to reduced cerebral perfusion pressure (CPP) are not so simple in patients with occlusive carotid artery disease. Autoregulatory vasodilation reaches maximal and cerebral blood flow (CBF) starts to fall, when CPP critically falls beyond autoregulatory capacity. Theoretically, cerebral blood volume (CBV) is expressed as maximally elevated in the conditions that cerebrovascular reactivity (CVR) to acetazolamide (ACZ) is impaired. However, there are almost no studies that denote whether CBV is maximally elevated in the area with reduced CBF and CVR to ACZ (Kuroda’s Type 3 ischemia). Therefore, this study was aimed to investigate the CBV response to ACZ in the area with reduced CBF and CVR due to occlusive carotid artery disease. Methods- This study included totally 24 hemispheres of 20 patients with reduced CBF and CVR on 15 O-gas PET due to occlusive carotid artery disease. There were 8 men and 12 women with a mean age of 57.9 years ranging from 33 to 72 years. All of them were admitted to our hospital between 2004 and 2010. In all 20 patients, CBF, CBV, cerebral metabolic rate for oxygen (CMRO 2 ) and oxygen extraction fraction (OEF) were quantitatively measured, using 15 O-gas PET. Subsequently, ACZ was intravenously injected to determine the reactivity of CBF and CBV. Results- Both CBF and CVR were reduced in all 24 hemispheres (Type 3). Of these, OEF was elevated in 7 hemispheres (29%). Compared with normal control (3.4 ± 0.5 mL/100g), baseline CBV were significantly elevated both in elevated OEF group (5.2 ± 1.2 mL/100g) and normal OEF group (4.5 ± 0.9 mL/100g). Intravenous administration of ACZ further increased CBV in 4 of 7 hemispheres with elevated OEF and in all 17 hemispheres with normal OEF. %CBV reactivity was 9.5 ± 12% in elevated OEF group, being significantly lower than 22 ± 13% in normal OEF group (P = 0.04, un-paired t). CBV did not increase in patients with steal phenomenon after ACZ injection in elevated OEF group, but increased in normal OEF group. Conclusion- These findings strongly suggest that baseline CBV increases, but does not reach maximal in the area with reduced CBF and CVR due to occlusive carotid artery disease, indicating that CBF response to ACZ may imply more complicated mechanisms in the severe ischemic brain.

Change in cortical vein appearance on susceptibility-weighted MR imaging before and after carotid artery stenting

<title/>Objectives: Susceptibility-weighted (SW) magnetic resonance (MR) imaging is a sensitive test to detect intravenous deoxygenated blood. On SW images, dilated appearing draining veins in tissue with perfusion impairment occur due to an increase in intravenous deoxyhemoglobin levels, and could indicate poor perfusion areas in which there is an elevated oxygen extraction fraction. In this study, patients with possible chronic ischemia caused by internal carotid artery stenosis underwent carotid artery stenting (CAS). Changes in cortical vein diameters were evaluated before and after CAS using SW imaging.Methods: Twenty-two patients with 25 lesions underwent 3 T SW imaging before and after CAS. The diameters of cortical veins were measured on SW images. Blood flow reduction and cerebrovascular reserve were examined before CAS using a single-photon emission computed tomography (SPECT) study, including an acetazolamide stress test.Results: Two of six patients with both decreased blood flow and reduced cerebrovascular reserve on SPECT showed significantly increased cortical vein diameters on pre-CAS SW images (P<0·05). After CAS, these same two patients demonstrated a significant decrease in their cortical vein diameters (P<0·05).Discussion: The present study demonstrates that dilated cortical veins as seen on SW imaging may reflect areas of altered oxygen extraction fraction due to chronic ischemia in patients with carotid artery stenosis, and that cortical venous dilatation is reversed after successful CAS. In the future, estimations of the cortical vein diameters on SW imaging may help to qualitatively evaluate areas of poor perfusion in chronic ischemia.

Central Benzodiazepine Receptor Binding Potential and CBF Images on SPECT Correlate with Oxygen Extraction Fraction Images on PET in the Cerebral Cortex with Unilateral Major Cerebral Artery Occlusive Disease

Oxygen extraction fraction (OEF) is a key predictor of stroke recurrence in patients with symptomatic major cerebral arterial occlusive disease. The purpose of the present study was to compare central benzodiazepine receptor binding potential (BRBP) and cerebral blood flow (CBF) images on SPECT with OEF images on PET in patients with chronic unilateral middle cerebral artery (MCA) or internal carotid artery (ICA) occlusive disease. OEF, CBF, and BRBP were assessed using (15)O PET and N-isopropyl-p-(123)I-iodoamphetamine and (123)I-iomazenil SPECT, respectively, in 20 healthy subjects and in 34 patients with unilateral MCA or ICA occlusive disease. All images were transformed into the standard brain size and shape by linear and nonlinear transformation using statistical parametric mapping for anatomic standardization. A region of interest (ROI) was automatically placed according to the arterial supply using a 3-dimensional stereotactic ROI template, and the ratio of the value in the affected side to that in the contralateral side was calculated in each image. Among patients with occlusive disease, a significant positive correlation was observed between PET OEF and SPECT BRBP/CBF ratios in 3 cerebral cortical regions (r = 0.851, P < 0.0001, for anterior cerebral artery [ACA] ROI; r = 0.807, P < 0.0001, for MCA ROI; and r = 0.774, P < 0.0001, for posterior cerebral artery [PCA] ROI), but there were no correlations between these 2 parameters in the basal ganglia or the cerebellum. When an abnormally elevated PET OEF ratio was defined as a value greater than the mean + 2 SDs obtained in healthy subjects, sensitivity and specificity were, respectively, 100% and 96% for the ACA ROI, 100% and 89% for the MCA ROI, and 100% and 93% for the PCA ROI for the SPECT BRBP/CBF ratio for detecting an abnormally elevated PET OEF ratio. BRBP/CBF images on SPECT correlate with OEF images on PET in a specific clinical setting-that is, in the cerebral cortex of patients with chronic unilateral MCA or ICA occlusive disease.

Cerebellum as the Normal Reference for the Detection of Increased Cerebral Oxygen Extraction

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<0.0001) was observed with all three MCA-to-cerebellar ratios when compared with the gold standard of ipsilateral-to-contralateral MCA hemispheric ratio. Kaplan-Meier analyses showed all MCA-to-cerebellar ratios to be predictive of stroke. By using the total cerebellum method, 7 strokes were found to have occurred in 20 patients with increased OEF (P=0.0007), compared with 7 strokes out of 16 patients with elevated OEF using the ipsilateral or contralateral cerebellum methods (P<0.0001). These methods may be useful for categorizing the hemodynamic status of patients with bilateral cerebral occlusive diseases, including atherosclerosis and moyamoya, to determine the association with the risk of subsequent stroke.

Brain Temperature Measured Using Proton MR Spectroscopy Detects Cerebral Hemodynamic Impairment in Patients With Unilateral Chronic Major Cerebral Artery Steno-Occlusive Disease

Brain temperature is determined by the balance between heat produced by cerebral energy turnover and heat removed by cerebral blood flow. The purpose of the present study was to investigate whether brain temperature measured noninvasively using proton MR spectroscopy can detect cerebral hemodynamic impairment in patients with unilateral chronic internal carotid or middle cerebral artery occlusive disease when compared with positron emission tomography. Brain temperature, cerebral blood flow, and metabolism were measured using proton MR spectroscopy and (15)O-positron emission tomography, respectively, in 21 normal subjects and 37 patients. Positron emission tomography images were coregistered with MR images and resliced automatically using image analysis software. Regions of interest placed in both cerebral hemispheres on MR images were automatically superimposed in these resliced positron emission tomography images. A significant correlation was observed between brain temperature difference (affected hemisphere-contralateral hemisphere) and both cerebral blood volume and oxygen extraction fraction ratio (affected hemisphere/contralateral hemisphere; r=0.607; P=0.0004 and r=0.631; P=0.0002). With abnormally elevated cerebral blood volume or oxygen extraction fraction ratio defined as higher than the mean +2 SDs obtained from normal subjects, brain temperature difference provided 86% or 92% sensitivity and 87% or 84% specificity with 80% or 73% positive and 91% or 95% negative predictive values for detecting abnormally elevated cerebral blood volume or oxygen extraction fraction ratios, respectively. Brain temperature measured using proton MR spectroscopy can detect cerebral hemodynamic impairment in patients with unilateral chronic major cerebral artery steno-occlusive disease.