Low CBF Research Articles

Association between CT Perfusion Parameters and Hemorrhagic Transformation after Endovascular Treatment in Acute Ischemic Stroke: Results from the ESCAPE-NA1 Trial.

Hemorrhagic transformation can occur as a complication of endovascular treatment for acute ischemic stroke. This study aimed to determine whether ischemia depth as measured by admission CTP metrics can predict the development of hemorrhagic transformation at 24 hours. Patients with baseline CTP and 24-hour follow-up imaging from the ESCAPE-NA1 trial were included. RAPID software was used to generate CTP volume maps for relative CBF, CBV, and time-to-maximum at different thresholds. Hemorrhage on 24-hour imaging was classified according to the Heidelberg system, and volumes were calculated. Univariable and multivariable regression analyses assessed the association between CTP lesion volumes and hemorrhage/hemorrhage subtypes. Among 408 patients with baseline CTP, 142 (35%) had hemorrhagic transformation at 24-hour follow-up, with 89 (63%) classified as hemorrhagic infarction (HI1/HI2), and 53 (37%), as parenchymal hematoma (PH1/PH2). Patients with HI or PH had larger volumes of low relative CBF and CBV at each threshold compared with those without hemorrhage. After we adjustied for baseline and treatment variables, only increased relative CBF <30% lesion volume was associated with any hemorrhage (adjusted OR, 1.14; 95% CI, 1.02-1.27 per 10 mL), as well as parenchymal hematoma (adjusted OR, 1.23; 95% CI, 1.06-1.43 per 10 mL). No significant associations were observed for hemorrhagic infarction. Larger "core" volumes of relative CBF <30% were associated with an increased risk of PH following endovascular treatment. This particular metric, in conjunction with other clinical and imaging variables, may, therefore, help estimate the risk of post-endovascular treatment hemorrhagic complications.

Abstract TP66: Optimizing CT Perfusion Thresholds for Identification of Ischemic Core in Hyperacute Stroke

Objective: CT perfusion (CTP) estimates of infarct core are typically based on identifying regions of very low CBF (typically &lt;30% of normal). These thresholds were optimized in patient populations that typically did not include patients scanned in the hyper-acute phase (&lt; 60 minutes from stroke onset). Our aim was to determine if these thresholds apply to the hyper-acute phase. Methods: We conducted a retrospective review (2012 to 2017) of patients who met the following inclusion criteria: acute ischemic stroke due to an ICA or M1 occlusion, baseline CTP core (rCBF &lt;30%) &gt;20ml, and underwent endovascular therapy with TICI2b/3 reperfusion. Baseline ischemic core volumes were compared to final infarct volumes, measured on follow-up CT or MRI obtained &gt;24 hours after stroke onset. Results: In 7 of 21 included patients, the ischemic core assessed on baseline CTP overestimated the final infarct by at least 10 ml. Five of these patients had witnessed onset and two were unwitnessed. The mean time from stroke onset to CTP was 0.96 hours for the seven patients with core overestimation and 3.4 hours in the 14 patients without core overcall. 6 of the 7 patients with core overcall had good outcomes (mRS of 0 to 2 at 90 days) compared to 4/14 without core overcall (p-value 0.01). For patients with core overcall, 2 additional CTP thresholds (rCBF &lt;20% and &lt;15%) were assessed. rCBF&lt;20% produced core volume estimates that most closely matched the final infarct volume and did not overcall the final infarct volume. The median difference between baseline core and final infarct volume with the &lt;20% threshold was 27 ml compared to 35 ml with &lt;30%. Conclusion: A rCBF threshold of &lt;30% tends to overestimate the ischemic core in patients imaged within 60 minutes of symptom onset. A threshold of &lt;20% may be more appropriate for patients imaged in the hyper-acute phase of stroke.

Abstract WP58: Enhancement of Acute Stroke Lesions on Non-Contrast CT Using Relative Signal Intensity Maps

Purpose: Early ischemic changes on non-contrast CT (NCCT) are often subtle, which makes the detection of early infarct signs challenging. To accentuate early ischemic changes and facilitate the interpretation of the NCCT scan, we aimed to develop a novel, automated post-processing technique that generates NCCT ratio-maps in relative Hounsfield Units to highlight regions that are hypodense. Materials and Methods: Relative signal intensities were calculated by dividing the signal intensity of each voxel by the signal intensity of a corresponding region in the contralateral hemisphere. Relative signal intensities were visualized as a heat map ranging from dark blue (for ratios equal to 0.95) to red (for ratios less than or equal to .8). The heat map was overlaid on the NCCT for visual clarity (figure). Voxels with a ratio below 0.95 were designated as infarct. The NCCT ratio-map technique was tested on the first six cases enrolled in the CRISP study at a single center and were compared to the baseline CT perfusion maps and the day 5 follow-up FLAIR scan. Results: The median time from symptom onset to CT was 5.2 hours (IQR 3.8-6.6), median NIHSS was 16, and all patients achieved TICI 2b or 3 reperfusion. In all six cases, the territory of early infarct signs on the NCCT ratio-map was more extensive than on the conventional NCCT scan, and corresponded with the region of low CBF on the baseline CT perfusion map and the final infarct on the day 5 FLAIR (figure). In 3 cases, the CT ratio-map identified ischemic tissue that an experienced vascular neurologist did not identify during prospective review of the conventional NCCT. Limitations included false positives on the ratio-map due to asymmetric CSF and white matter disease. Conclusion: The NCCT ratio-map markedly increases sensitivity for detection of early infarct signs. This novel method will assist clinicians in the interpretation of the NCCT and serves as a major milestone towards fully automated CT volumetric lesion quantification.

Increased Volume and Distinct Pattern of Silent Cerebral Infarcts in Healthy, Young Adults with Sickle Cell Trait

▪Background: Sickle cell trait (SCT) is common, affecting 7-8% of African Americans. Previously thought to be of little clinical consequence except under conditions of severe hypoxic/metabolic stress, recent studies have shown that SCT is independently associated with chronic vascular diseases including kidney disease, coronary artery disease, overt stroke, and pulmonary embolism. It has been postulated that SCT underlies the increased prevalence of cerebrovascular disease in African-Americans after adjusting for excess risk factors. Prospective imaging studies evaluating the natural history of cerebral ischemia in SCT are lacking; thus, the true disease burden is unknown. In this study, we hypothesized that individuals with SCT are at increased risk of silent cerebral infarctions (SCI) compared to healthy young adults, but with a lower risk of SCIs compared to young adults with sickle cell anemia (SCA). We further evaluated and compared the patterns of SCIs within SCT and SCA.Methods: Three cohorts were prospectively recruited from a tertiary care referral center for pediatric and adult SCA: (1) young adults with SCA, (2) healthy, young adults with SCT, and (3) healthy, age- and race-matched, controls. Control and SCT subjects were excluded for history of hypertension, diabetes, anemia, dyslipidemia, chronic medical or neurological illness, or severe trauma; individuals with SCA were excluded if on chronic transfusion therapy or history of overt stroke, vasculopathy, or chronic neurological illness. Brain MRI T1 and FLAIR maps were evaluated for the presence of two lesion types (defined in Wardlaw et al, Lancet Neurol, 2013): (a) FLAIR lesions were defined as FLAIR hyperintensity > 3mm in diameter; (b) SCIs were defined as FLAIR lesions with the additional requirement of CSF-like hypointensity on T1. Thus, SCIs represented a subset of all FLAIR lesions. FLAIR lesions were outlined by a vascular neurologist using MIPAV (Medical Image Processing, Analysis and Visualization, https://mipav.cit.nih.gov/) from which individual lesion volumes were calculated. Baseline characteristics, prevalence of SCIs, and volume of FLAIR lesions in SCT were compared to controls and SCA (Fishers Exact for categorical variables; Mann-Whitney U for continuous variables). To evaluate the distribution of SCIs in SCT relative to healthy controls and SCA, three lesion density maps were created. Lesions drawn on FLAIR 5mm slice thickness were stretched in the z-direction to 10mm for display of SCI pattern on few slices.Results: Control, SCT, and SCA adults were similar with respect to baseline characteristics, except SCA subjects were younger and fewer female than SCT (Table). Ten (45%) of the SCA subjects were on hydroxyurea. We acquired LDL, glucose, and blood pressure to ensure that SCT participants did not have higher risk of SCIs compared to controls due to ongoing comorbidities (Table). Imaging Outcomes: We found greater FLAIR lesion volumes in SCT than controls (292 vs. 90 mm3, p=0.02) and a trend towards greater prevalence of SCIs – 5 of 11 (45%) in SCT compared to 1 of 11 (9%) in controls (p=0.15). FLAIR lesion volumes and SCI prevalence were higher in SCA compared to SCT (p=0.01 and p=0.02, respectively). Lesion density maps (Figure) were created to evaluate SCI patterns in SCT and SCA. In the SCA cohort, lesion density was highest within the internal borderzone (where cerebral blood flow is at a nadir), while this region was relatively unaffected in SCT. In contrast, a distinct pattern of small cortical/subcortical strokes distributed in a stochastic pattern (not following any particular vascular territory) were found in both SCT and SCA.Conclusions: We found greater FLAIR lesion volumes and a trend towards a greater prevalence of SCIs in healthy individuals with SCT. We postulate that SCIs found in SCT may represent an etiologic subtype of SCIs found in SCA, representing microembolic events or a microvasculopathy, in contrast to the etiology of internal borderzone infarction which likely represents a heightened ischemic vulnerability within low CBF regions in the setting of chronic, severe anemia. Larger studies are necessary to determine if SCT carries a heightened risk of silent cerebral ischemia, which would impact society at large given the high prevalence of SCT and the known effects of SCIs on cognitive disability. [Display omitted] DisclosuresFields:Proclara Biosciences: Equity Ownership. Hulbert:Pfizer: Other: Spouse employment at Pfizer.

Low cerebral blood flow after cardiac arrest is not associated with anaerobic cerebral metabolism

Aim of the studyEstimation of cerebral anaerobic metabolism in survivors and non-survivors after cardiac arrest. MethodsWe performed an observational study in twenty comatose patients after cardiac arrest and 19 healthy control subjects. We measured mean flow velocity in the middle cerebral artery (MFVMCA) by transcranial Doppler. Arterial and jugular blood samples were used for calculation of the jugular venous-to-arterial CO2/arterial to-jugular venous O2 content difference ratio. ResultsAfter cardiac arrest, MFVMCA increased from 26.0[18.6–40.4]cm/sec on admission to 63.9[48.3–73.1]cm/sec after 72h (p<0.0001), with no significant differences between survivors and non-survivors (p=0.4853). The MFVMCA in controls was 59.1[52.8–69.0]cm/sec. The oxygen extraction fraction (O2EF) was 38.9[24.4–47.7]% on admission and decreased significantly to 17.3[12.1–26.2]% at 72h (p<0.0001). The decrease in O2EF was more pronounced in non-survivors (p=0.0173). O2EF in the control group was 35.4[32.4–38.7]%. The jugular bulb-arterial CO2 to arterial-jugular bulb O2 content difference ratio was >1 at all time points after cardiac arrest and did not change during admission, with no differences between survivors and non-survivors. Values in cardiac arrest patients were similar to those in normal subjects. ConclusionsIn this study, low CBF after cardiac arrest is not associated with anaerobic metabolism. Hypoperfusion appears to be the consequence of a decrease of neuronal functioning and metabolic needs. Alternatively, hypoperfusion may decrease cerebral metabolism. Subsequently, metabolism increases in survivors, consistent with resumption of neuronal activity, whereas in non-survivors lasting low metabolism reflects irreversible neuronal damage.

In Vivo T1 of Blood Measurements in Children with Sickle Cell Disease Improve Cerebral Blood Flow Quantification from Arterial Spin-Labeling MRI.

Children with sickle cell disease have low hematocrit and elevated CBF, the latter of which can be assessed with arterial spin-labeling MR imaging. Quantitative CBF values are obtained by using an estimation of the longitudinal relaxation time of blood (T1blood). Because T1blood depends on hematocrit in healthy individuals, we investigated the importance of measuring T1blood in vivo with MR imaging versus calculating it from hematocrit or assuming an adult fixed value recommended by the literature, hypothesizing that measured T1blood would be the most suited for CBF quantification in children with sickle cell disease. Four approaches for T1blood estimation were investigated in 39 patients with sickle cell disease and subsequently used in the CBF quantification from arterial spin-labeling MR imaging. First, we used 1650 ms as recommended by the literature (T1blood-fixed); second, T1blood calculated from hematocrit measured in patients (T1blood-hematocrit); third, T1blood measured in vivo with a Look-Locker MR imaging sequence (T1blood-measured); and finally, a mean value from T1blood measured in this study in children with sickle cell disease (T1blood-sickle cell disease). Quantitative flow measurements acquired with phase-contrast MR imaging served as reference values for CBF. T1blood-measured (1818 ± 107 ms) was higher than the literature recommended value of 1650 ms, was significantly lower than T1blood-hematocrit (2058 ± 123 ms, P < .001), and, most interesting, did not correlate with hematocrit measurements. Use of either T1blood-measured or T1blood-sickle cell disease provided the best agreement on CBF between arterial-spin labeling and phase-contrast MR imaging reference values. This work advocates the use of patient-specific measured T1blood or a standardized value (1818 ms) in the quantification of CBF from arterial spin-labeling in children with SCD.

Prevalence and Prognostic Significance of c-KIT Mutations in Core Binding Factor Acute Myeloid Leukemia: A Comprehensive Large-Scale Study from a Single Chinese Center

Introduction CBF-acute myeloid leukemia (AML) is a heterogeneous disease that requires prognostic factors for patient differentiation. c-KIT mutations are predominantly detected in CBF-AML among AML cases, and reported frequencies vary significantly. To date, the clinical significance of c-KIT mutations in CBF-AML has been intensively studied; however, the results are controversial and a final conclusion has not been reached. Large-scale studies with subgroup analysis should be performed to elucidate the clinical effects of c-KIT mutations in CBF-AML.Methods A total of 351 patients with CBF-AML [t(8;21) (n = 253) or inv(16) (n = 98)] were included in this study. Overall, 250 patients [42 pediatric t(8;21);146 adult t(8;21); 11 pediatric inv (16) and 51 adult inv (16)] received standard treatment and underwent follow up. Induction therapy consisted of one or two cycles of combined anthracycline and cytarabine for adult patients, whereas cytarabine, idarubicin, and etoposide were used for pediatric patients. 131, 17, and 93 of the patients further received intermediate-dose cytarabine-based chemotherapy, chemotherapy with auto-hematopoietic stem cell transplantation (HSCT), and chemotherapy with allogeneic (allo)-HSCT for consolidation, respectively. c-KIT mutations in exon 8 and 17 were screened by direct sequencing. Patients who received allo-HSCT were censored at the time of transplantation for relapse and survival analysis to exclude the effects of allo-HSCT on outcome. The median follow up time was 10 months (3 to 93 months) for the 211 living patients.Results Overall, 36.5% (128/351) of the patients were found to have a c-KIT mutation. The frequencies of c-KIT mutations were similar between pediatric and adult patients with t(8;21) AML (41.7% vs. 38.5%, P > 0.05), whereas pediatric patients tended to have higher frequency of c-KIT mutations than the adult patients with inv(16) AML (53.8% vs 25.9%, P = 0.053). In adults, the frequency of c-KIT mutations was significantly higher in patients with t (8;21) than those with inv(16) (P = 0.043). In adults, the frequency of mutations in exon 17 was significantly higher in t(8;21) than inv(16) AML (P < 0.0001). In pediatric group, the frequencies of mutations in exon 17 and exon 8 were similar for t(8;21) and inv(16) AML (P > 0.05). The low PLT count (¡Ü 30∙109/L) in pediatric t(8;21) AML tended to be associated with the presence of c-KIT mutations ( P = 0.063). High white blood cell (WBC) count (>10∙109/L), WBC index, and AML1-ETO transcript levels in adult t(8;21) AML patients were significantly correlated with the presence of c-KIT mutations (P = 0.015, 0.0051, and 0.030, respectively). Moreover, low CBF¦Â-MYH11 transcript levels in adult inv(16) AML tended to be significantly related to c-KIT mutations (P = 0.059). No difference was observed in CR rates between patients with and without c-KIT mutations (P > 0.05). c-KIT mutations were significantly associated with less reduction in fusion transcript levels after the first induction therapy in adult inv(16) patients (P = 0.021). c-KIT mutations in adult t(8;21) AML patients (n = 137) significantly correlated with higher CIR rates at 2 years and low 2-year DFS and OS rates (73.2% vs. 46.2%, P = 0.0070; 26.8% vs. 49.1%, P = 0.013; 48.9% vs. 65.7%, P = 0.0055, respectively. Figure 1). In contrast, c-KIT mutations had no impact on CIR, DFS, and OS rates in pediatric t(8; 21)(n = 42), as well as in adult inv (16) (n = 51; all P > 0.05. Figure 1). Multivariate analysis demonstrated that c-KIT mutation was the only independent prognostic factor for relapse (hazard ratio (HR) = 2.47, 95% CI = 1.25 to 4.86, P = 0.009) and DFS (HR = 2.23, 95% CI = 1.17 to 4.41, P = 0.016). Moreover, c-KIT mutation and PLT count were independent prognostic factors for OS (HR = 3.68, 95% CI = 1.57 to 8.63, P = 0.003; HR = 0.37, 95% CI = 0.16 to 0.87, P = 0.023).Conclusion CBF-AML is a heterogeneous disease with regard to c-KIT mutations. c-KIT mutations have a strong adverse impact on relapse and survival in adult t(8;21) AML.Grant support Nature Science Foundation of China (81170483 and 81370639) and Beijing Municipal Science & Technology Commission£¨Z141100000214011). [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Effects of background suppression on the sensitivity of dual-echo arterial spin labeling MRI for BOLD and CBF signal changes

Dual-echo arterial spin labeling (DE-ASL) enables the simultaneous acquisition of BOLD and CBF fMRI data and is often used for calibrated BOLD and cerebrovascular CO2 reactivity measurements. DE-ASL, like all ASL techniques, suffers from a low intrinsic CBF SNR, which can be improved by suppressing the background signal via the inclusion of additional inversion pulses. However, until now this approach has been considered to be undesirable for DE-ASL, because the BOLD signal is extracted from the background signal and attenuating the background signal could decrease the sensitivity of DE-ASL scans for BOLD changes. In this study, the effect of background suppression on the sensitivity of DE-ASL MRI for BOLD and CBF signal changes with a visual stimulation paradigm was studied. Results showed that with an average background suppression level of 70% the BOLD sensitivity of DE-ASL MRI decreases slightly (15%), while the CBF sensitivity of the scans increased by almost a factor-of-two (81%). These findings support the conclusion that the gains in CBF sensitivity of DE-ASL MRI due to background suppression outweigh the slight decrease in sensitivity of these scans for BOLD changes, and thus that background suppression is highly recommended for DE-ASL.

Abstract WP33: Reduced Cerebral Blood Flow on Acute Whole Brain CT Perfusion Best Predicts Hemorrhagic Transformation

Objective: Hemorrhagic transformation in ischemic stroke is a potentially life threatening complication of thrombolysis. Using perfusion MRI, very low cerebral blood volume (VLCBV) strongly predicts hemorrhagic transformation after reperfusion. CT perfusion (CTP) is currently more widely accessible than MRI and recent data have shown that CT relative cerebral blood flow (relCBF) provides a better estimate of infarct core than CBV. We aimed to determine the optimal parameter to predict hemorrhagic transformation using whole brain CTP. Methods: Patients with ischemic stroke were imaged with whole brain CTP within 6hrs of symptom onset. Hemorrhagic transformation was assessed on CT/MRI within 7 days of stroke using ECASS grade. CBF and CBV were analyzed within a relative time to peak &gt;4sec region of interest. Results were expressed as volumes below a given percentile relative to the contralateral hemisphere (relCBF and relCBV). Receiver operating characteristic (ROC) and logistic regression analysis were performed to determine the optimal parameter and percentile threshold correlating with parenchymal hemorrhage (PH). Results: 128 patients with acute CTP were analyzed, median age 76yr (IQR 66-83), median NIHSS 13 (IQR 9-16), 59% received IV thrombolysis. 11 patients had PH on follow-up. On ROC analysis, the optimal threshold for very low CBF (VLCBF) was at the &lt;0 th centile. VLCBF was significantly associated with PH in ROC analysis (AUC=0.760, p&lt;0.01) whereas VLCBV (AUC 0.638 at &lt;5 th centile, 0.618 at &lt;2.5 th centile, 0.440 at &lt;0 th centile) was not significant. Using VLCBF, the optimal lesion volume to predict PH was &gt;3mL with OR 12.0 (95%CI 2.4-58), sensitivity 0.82 (95%CI 0.48-0.98), specificity 0.73 (95%CI 0.64-0.80), negative predictive value 0.98 (95%CI 0.92-1.0) and positive predictive value 0.22 (95%CI 0.11-0.38). In logistic regression, PH was associated with increased VLCBF (p&lt;0.01) but not with VLCBV (p=0.08). The Bayesian information criterion for VLCBF compared to VLCBV was +5 indicating improved model fit. Conclusions: VLCBF appears to be more reliably associated with hemorrhagic transformation than VLCBV when CT perfusion is used. This may be due to reduced ability of VLCBV to distinguish regions of ischemia from normal white matter.

Abstract WP50: Defining the Hyper-acute Infarct Core in Porcine Model of Cerebral Ischemia: A Multi-modality Imaging Study

Background: Defining the hyper-acute infarct core can inform thrombolysis treatment. Clinical outcome and hemorrhagic transformation are correlated with infarct volume at admission. CT perfusion (CTP)-derived parameters and MR-diffusion weighted imaging (DWI) are currently used to delineate infarct volume; however, reversibility of such defects has been shown for both modalities. Methods: Six domestic pigs (mean weight 34.7kg) had a CTP scan prior to intracranial injection of endothelin-1 (ET-1; 0.01mL/kg) into the left striatum. Subsequent CTP scans at 30min, 1hr, 1.5hrs were done to monitor stroke progression. A second dose of ET-1 (0.01mL/kg) was injected at 2hrs from the first injection. Twenty minutes after the second ET-1 injection, 18F-FDG was injected. The animal was moved to a 3T MRI scanner where MR-DWI was performed. The animal was then moved back to the CT scanner for a final CTP/PET acquisition. The brain was quickly removed, cut into 10mm slices and stained with tetrazolium-chloride (TTC), the gold standard for defining final infarct volume. Using custom software, the infarct volume defined by low intensity TTC stain, low CBF (&lt; 9.3ml•min-1•100g-1), low CBV (&lt; 1.07ml•100g-1), DWI hyper-intensity and low F-18 FDG uptake were determined. A linear regression model was used to correlate the infarct volume measured by each imaging modality to that by the histological gold standard and the coefficients of correlation (R2) compared. Results: R2 values for CBF, CBV, DWI and FDG versus TTC-histology were 0.83, 0.69, 0.95 and 0.61, respectively. For the CBF and DWI parameters the slope of the fitted line was greater than 1, while the slope of the fitted line for the CBV and CBFxCBV parameters was less than 1. Mean normalized (relative to the histologically defined infarct) values were 1.38, 0.82, 0.99, and 0.67 for CBF, CBV, DWI and FDG, respectively. Conclusion: In this small sample study, the CTP-CBF and the imaging gold standard DWI both overestimated the TTC-infarct in 100% and 50% of cases, while CTP-CBV and FDG-PET both underestimated the final infarct volume in 100% of animals.

Comparison of Computed Tomography Perfusion and Magnetic Resonance Imaging Perfusion-Diffusion Mismatch in Ischemic Stroke

Perfusion imaging has the potential to select patients most likely to respond to thrombolysis. We tested the correspondence of computed tomography perfusion (CTP)-derived mismatch with contemporaneous perfusion-diffusion magnetic resonance imaging (MRI). Acute ischemic stroke patients 3 to 6 hours after onset had CTP and perfusion-diffusion MRI within 1 hour, before thrombolysis. Relative cerebral blood flow (relCBF) and time to peak of the deconvolved tissue residue function (Tmax) were calculated. The diffusion lesion (diffusion-weighted imaging) was registered to the CTP slabs and manually outlined to its maximal visual extent. Volumetric accuracy of CT-relCBF infarct core (compared with diffusion-weighted imaging) was tested. To reduce false-positive low CBF regions, relCBF core was restricted to voxels within a relative time-to-peak (relTTP) >4 seconds for lesion region of interest. The MR-Tmax >6 seconds perfusion lesion was automatically segmented and registered to CTP. Receiver-operating characteristic analysis determined the optimal CT-Tmax threshold to match MR-Tmax >6 seconds. Agreement of these CT parameters with MR perfusion-diffusion mismatch in coregistered slabs was assessed (mismatch ratio >1.2, absolute mismatch >10 mL, infarct core <70 mL). In analysis of 49 patients (mean onset to CT, 213 minutes; mean CT to MR, 31 minutes), constraining relCBF <31% within the automated relTTP perfusion lesion region of interest reduced the median magnitude of volumetric error (vs diffusion-weighted imaging) from 47.5 mL to 15.8 mL (P<0.001). The optimal CT-Tmax threshold to match MR-Tmax >6 seconds was 6.2 seconds (95% confidence interval, 5.6-7.3 seconds; sensitivity, 91%; specificity, 70%; area under the curve, 0.87). Using CT-Tmax >6 seconds "penumbra" and relTTP-constrained relCBF "core," CT-based and MRI-based mismatch status was concordant in 90% (kappa=0.80). Quantitative CTP mismatch classification using relCBF and Tmax is similar to perfusion-diffusion MRI. The greater accessibility of CTP may facilitate generalizability of mismatch-based selection in clinical practice and trials.

Abstract 3200: Comparison of CT Perfusion Mismatch with Perfusion-Diffusion MRI in Ischemic Stroke - a Reliable Alternative?

Background and purpose: CT-perfusion (CTP) is widely and rapidly accessible for imaging acute ischemic stroke. However, there has been limited validation of CTP parameters against the more intensively studied MRI perfusion-diffusion mismatch paradigm. We tested the correspondence of CTP with contemporaneous perfusion-diffusion MRI. Methods: Acute ischemic stroke patients &lt;6hr after onset had CTP and perfusion-diffusion MRI within 1hr, before reperfusion therapies. Relative cerebral blood flow (relCBF) and time-to-peak of the deconvolved tissue-residue-function (Tmax) were calculated (standard singular value decomposition deconvolution). The diffusion lesion was registered to the CTP slabs and manually outlined to its maximal visual extent. CT-infarct core was defined as relCBF&lt;31% contralateral mean as previously published using this software. The volumetric accuracy of relCBF core compared to the diffusion lesion was tested in isolation, but also when restricted to pixels with relative time-to-peak (TTP) &gt;4sec, to reduce artifactual false positive low CBF (eg in leukoaraiosis). The MR Tmax&gt;6sec perfusion lesion (previously validated to define penumbral tissue at risk of infarction) was automatically segmented and registered to the CTP slabs. Receiver operating characteristic (ROC) analysis determined the optimal CT-Tmax threshold to match MR-Tmax&gt;6sec, confidence intervals generated by bootstrapping. Agreement of these CT parameters with MR perfusion-diffusion mismatch on co-registered slabs was assessed (mismatch ratio &gt;1.2, absolute mismatch&gt;10mL, infarct core&lt;70mL). Results: In analysis of 98 CTP slabs (54 patients, median onset to CT 190min, median CT to MR 30min), volumetric agreement with the diffusion lesion was substantially improved by constraining relCBF&lt;31% within the automated TTP perfusion lesion ROI (median magnitude of volume difference 9.0mL vs unconstrained 13.9mL, p&lt;0.001). ROC analysis demonstrated the best CT-Tmax threshold to match MR-Tmax&gt;6sec was 6.2sec (95% confidence interval 5.6-7.3sec, ie not significantly different to 6sec), sensitivity 91%, specificity 70%, AUC 0.87. Using CT-Tmax&gt;6s “penumbra” and relCBF&lt;31% (restricted to TTP&gt;4s) “core”, volumetric agreement was sufficient for 90% concordance between CT and MRI-based mismatch status (kappa 0.80). Conclusions: Automated CTP mismatch classification using relCBF and Tmax is similar to perfusion-diffusion MRI. CTP may allow more widespread application of the “mismatch” paradigm in clinical practice and trials.

Low Residual CBF Variability in Alzheimer's Disease after Correction for CO(2) Effect.

We tested the claim that inter-individual CBF variability in Alzheimer’s disease (AD) is substantially reduced after correction for arterial carbon dioxide tension (PaCO2). Specifically, we tested whether the variability of CBF in brain of patients with AD differed significantly from brain of age-matched healthy control subjects (HC). To eliminate the CO2-induced variability, we developed a novel and generally applicable approach to the correction of CBF for changes of PaCO2 and applied the method to positron emission tomographic (PET) measures of CBF in AD and HC groups of subjects. After correction for the differences of CO2 tension, the patients with AD lost the inter-individual CBF variability that continued to characterize the HC subjects. The difference (ΔK1) between the blood-brain clearances (K1) of water (the current measure of CBF) and oxygen (the current measure of oxygen clearance) was reduced globally in AD and particularly in the parietal, occipital, and temporal lobes. We then showed that oxygen gradients calculated for brain tissue were similar in AD and HC, indicating that the low residual variability of CBF in AD may be due to low functional demands for oxidative metabolism of brain tissue rather than impaired delivery of oxygen.

A comparison of the low temperature transcriptomes and CBF regulons of three plant species that differ in freezing tolerance: Solanum commersonii, Solanum tuberosum, and Arabidopsis thaliana

Solanum commersonii and Solanum tuberosum are closely related plant species that differ in their abilities to cold acclimate; whereas S. commersonii increases in freezing tolerance in response to low temperature, S. tuberosum does not. In Arabidopsis thaliana, cold-regulated genes have been shown to contribute to freezing tolerance, including those that comprise the CBF regulon, genes that are controlled by the CBF transcription factors. The low temperature transcriptomes and CBF regulons of S. commersonii and S. tuberosum were therefore compared to determine whether there might be differences that contribute to their differences in ability to cold acclimate. The results indicated that both plants alter gene expression in response to low temperature to similar degrees with similar kinetics and that both plants have CBF regulons composed of hundreds of genes. However, there were considerable differences in the sets of genes that comprised the low temperature transcriptomes and CBF regulons of the two species. Thus differences in cold regulatory programmes may contribute to the differences in freezing tolerance of these two species. However, 53 groups of putative orthologous genes that are cold-regulated in S. commersonii, S. tuberosum, and A. thaliana were identified. Given that the evolutionary distance between the two Solanum species and A. thaliana is 112–156 million years, it seems likely that these conserved cold-regulated genes—many of which encode transcription factors and proteins of unknown function—have fundamental roles in plant growth and development at low temperature.

Attenuation of Cerebral Venous Contrast in Susceptibility-Weighted Imaging of Spontaneously Breathing Pediatric Patients Sedated with Propofol

SWI is known for its detailed visualization of the cerebral venous system and seems to be a promising tool for early detection of cerebrovascular pathologies in children, who are frequently sedated for MR imaging. Because sedation influences cerebral hemodynamics, we hypothesized that it would affect cerebral venous contrast in SWI. SWI (125 examinations) of 26 patients (age, 2-16 years) was reviewed in this study. Images were acquired of patients sedated with propofol. Reviewers classified the images by weak or strong venous contrast. Physiologic data, such as etCO(2), BP, age, and CBF by arterial spin-labeling, were monitored and collected during MR imaging. A generalized estimating equation approach was used to model associations of these parameters with venous contrast. EtCO(2) and CBF were found to correlate with venous contrast, suggesting that patients with high etCO(2) and CBF have weak contrast and patients with low etCO(2) and CBF have strong contrast. BP was also found to correlate with the venous contrast of SWI, suggesting that patients with high BP have strong venous contrast. No significant correlations were found for any other physiologic parameters. We found that the venous contrast in SWI is affected by propofol sedation in spontaneously breathing patients. We also found that low etCO(2), low CBF, and high BP are associated with strong venous contrast. Reviewing SWI data in light of physiologic measures may therefore help prevent potential misinterpretations of weak venous contrast in SWI examinations under propofol sedation.

Brain Edema after Carotid Revascularization: Benign Syndrome or Prelude to Hemorrhage?

Brain edema (BE) post carotid revascularization (CR) is considered a benign presentation of the hyperperfusion syndrome. Its physiopathology has been related to production of vasogenic edema that tends to progressive spontaneous resolution. Its relation with post-CR hemorrhage remains unclear. Three cases of BE post-CR are described and compared to controls. Clinical evolution, medical management, and plain-CT and perfusion-CT (PCT) results are analysed. Two cases of BE had a benign course, with a progressive resolution of edema and disappearance of neurologic deficits. Effective blood pressure control was achieved in these patients. The third case suffered massive hemorrhage 24h after initial BE and died. This patient reached peak systolic levels of 220 mmHg before conversion to hemorrhage. Plain-CT and PCT findings were similar in the three patients with BE. CT showed signs of hemispheric brain swelling ipsilateral to CR. PCT showed low MTT and high CBF values on the hemisphere ipsilateral to CR compared to the contralateral hemisphere, with symmetric CBV values. Plain-CT and PCT in controls showed no abnormalities. BE post CR can be reversible but may also herald a hemorrhagic complication. A common physiopathology of post-CR BE and hemorrhage is suggested by PCT findings, related to failure of auto-regulation and secondary blood-brain-barrier dysfunction. Spontaneous resolution of BE post-CR should not be routinely expected in clinical practice. Conversion to hemorrhage might be related with deficient blood pressure control and secondary rupture of the already damaged vessel wall.

Monitoring of Cerebrovascular Autoregulation: Facts, Myths, and Missing Links

The methods for continuous assessment of cerebral autoregulation using correlation, phase shift, or transmission (either in time- or frequency-domain) were introduced a decade ago. They express dynamic relationships between slow waves of transcranial Doppler (TCD), blood flow velocity (FV) and cerebral perfusion pressure (CPP), or arterial pressure (ABP). We review a methodology and clinical application of indices useful for monitoring cerebral autoregulation and pressure-reactivity in various scenarios of neuro-critical care. Poor autoregulation and loss of pressure-reactivity are independent predictors of fatal outcome following head injury. Autoregulation is impaired by too low or too high CPP when compared to autoregulation with normal CPP (usually between 60 and 85 mmHg; and these limits are highly individual). Hemispheric asymmetry of the bi-laterally assessed autoregulation has been associated with asymmetry of CT scan findings: autoregulation was found to be worse ipsilateral to contusion or lateralized edema causing midline shift. The pressure-reactivity (PRx index) correlated with a state of low CBF and CMRO2 revealed using PET studies. The PRx is easier to monitor over prolonged periods of time than the TCD-based indices as it does not require fixation of external probes. Continuous monitoring with the PRx can be used to direct CPP-oriented therapy by determining the optimal CPP for pressure-reactivity. Autoregulation indices are able to reflect transient changes of autoregulation, as seen during plateau waves of ICP. However, minute-to-minute assessment of autoregulation has a poor signal-to-noise ratio. Averaging across time (30 min) or by combining with other relevant parameters improves the accuracy. MYTHS: It is debatable whether the TCD-based indices in head injured patients can be calculated using ABP instead of CPP. Thresholds for functional and disturbed autoregulation dramatically depends on arterial tension of CO2--therefore, comparison between patients cannot be performed without comparing their PaCO2. The TCD pulsatility index cannot accurately detect the lower limit of autoregulation. MISSING LINKS: We still do not know whether autoregulation-oriented therapy can be understood as a consensus between CPP-directed protocols and the Lund-concept. What are the links between endothelial function and autoregulation indices? Can autoregulation after head injury be improved with statins or EPO, as in subarachnoid hemorrhage? In conclusion, monitoring cerebral autoregulation can be used in a variety of clinical scenarios and may be helpful in delineating optimal therapeutic strategies.

Cerebral ischemia due to compression of the brain by ossified and hypertrophied muscle used for encephalomyosynangiosis in childhood moyamoya disease

Background Encephalomyosynangiosis is one of the indirect method in which ischemic brain surface is covered by temporal muscle for the treatment of moyamoya disease. Case Descriptions A 14-year-old girl who had been treated with bilateral STA-MCA anastomosis and EMS in 1999 was admitted on January 5, 2005. She showed transient incomplete palsy on the left side of the face and the ipsilateral upper extremity. On the day of admission, MRIs/MRA and 3-dimensional regional CBF measurement using stable xenon and CT scanning were conducted after performance of plain CT scanning. The MRI and CT studies showed that ossified and hypertrophied temporal muscle used for EMS to the right MCA territory compressed the brain just under the muscle. MRA demonstrated well-developed collaterals to the territories of the bilateral MCAs via the previously performed anastomosis. The CBF studies disclosed a low CBF value just under ossified and hypertrophied muscle used for EMS on the right side. She showed same transient ischemic attacks repetitively after January 5, 2005. Conclusions The repetitive attacks with the transient motor palsy on her left side was thought to be caused by direct compression of the brain by the ossified and hypertrophied muscle used for EMS and decrease in CBF just under it, and its removal was thought to be the treatment of choices. However, the patient and her parents refused the surgical procedure, and she is treated conservatively at present.

Functional Magnetic Resonance Imaging in Conscious Animals: A New Tool in Behavioural Neuroscience Research

Functional magnetic resonance imaging (fMRI) is a unique window to the brain, enabling scientists to follow changes in brain activity in response to hormones, ageing, environment, drugs of abuse and other stimuli. There are two features that make fMRI unique when compared with other imaging modalities used in behavioural neuroscience. First, it can be entirely noninvasive: each animal can serve as its own control over the natural course of its life, vital for following neuroadaptation and other developmental processes critical to understanding behaviour. Second, fMRI has the spatial and temporal resolution to observe patterns of neuronal activity across the entire brain in less than a minute. Although fMRI does not have the cellular spatial resolution of immunostaining, nor the millisecond temporal resolution of electrophysiology, synchronised changes in neuronal activity across multiple brain areas seen with functional MRI can be viewed as functional neuroanatomical circuits coordinating the thoughts, memories and emotions for particular behaviours. Thus, fMRI affords a systems approach to the study of the brain, complementing and building from other neurobiological techniques to understand how behaviour is organised across multiple brain regions. In this review, we present a general background to fMRI and the different imaging modalities that can be used in fMRI studies. Included are examples of the application of fMRI in behavioural neuroscience research, along with discussion of the advantages and disadvantages of this technology.

A comparison of FAIR and CASL perfusion imaging in mice

We present a quantitative comparison of continuous and pulsed spin labelling (CASL and FAIR respectively) in the mouse brain. The quantification of perfusion measurements is complicated by several physiological parameters such as the arterial transit time; also these parameters may change during abnormal conditions. The aim of this study is to compare the performance of the two sequences in mice, both for normal flow rates and during ischemia, when perfusion is low. Eight mice were anaesthetised and maintained on 1.3–1.7% isoflurane with 100% oxygen. The middle cerebral artery was occluded, and animals were scanned at 2 and 24 hours after occlusion. Coronal EPI images were obtained on a 2.35 T SMIS MRI scanner. FAIR: Short repetition time FAIR sequence 1, non-selective inversion or a selective FOCI inversion pulse, delay time 1300 ms, TR 1.5 s, and 22 averages. CASL: transit time insensitive CASL 2, interleaved adiabatic inversion labelling and control measurements, post-labelling delay time 500 ms, TR 1 s, and 22 averages. T1sat and T1 were also measured. Data processing: 4 ROIs were selected in each animal for further analysis. FAIR: the ssIR data were used to fit M0, T1app and a. These values were then used to fit the magnetisation difference for CBF 1. CASL: T1, T1sat and M0 were fitted using the IR data; subsequently these values were used to fit the magnetisation difference according to Alsop et al. 2 for CBF. FAIR was assumed to be transit time insensitive. For CASL: arterial transit time cortex 440 ms, basal ganglia 290 ms (previous results; data not shown). Transit time correction (see results): CASL: cortex 800 ms, basal ganglia 600 ms, based on previous rat studies 3. FAIR: cortex 500 ms, basal ganglia 500 ms. For normal perfusion rates (>100 ml/100g/min) there was an excellent correlation between the CASL and FAIR data (r = 0.96). The mean difference between the techniques was negligible, with a 95% confidence interval of -30 to +31 ml/100 g/min between the two methods for any given measurement. In the case of compromised CBF however, there was a marked discrepancy between the techniques, with FAIR showing little sensitivity to different flow rates, in agreement with earlier reports 1. This is most likely due to increased arterial transit times during occlusion, which would render the assumption that the technique is transit-time insensitive invalid. A transit time correction in the FAIR and CASL calculations for the ROIs with low CBF improved the correspondence between the techniques, though there was still a difference, indicating that either the FAIR transit time during occlusion is even larger than estimated, or there are other confounding factors influencing the measurement. Further studies using transit-time insensitive sequences such as multi-TI FAIR or QUIPSS II 4 are needed to investigate this phenomenon.