Hemispheric Cerebral Blood Flow Research Articles

Abstract TMP12: Large Vessel Vasculopathy is Associated With Oxygen Metabolic Stress in Children and Young Adults With Sickle Cell Disease

Background: Large-vessel vasculopathy (LVV), such as moyamoya syndrome, increases stroke risk with sickle cell disease (SCD). We hypothesized that tissue-based cerebral blood flow (CBF) and oxygen extraction fraction (OEF), as indicators of hemodynamic and metabolic stress, would differ in hemispheres with vs. without LVV. Methods: Patients underwent serial brain MRI and time-of-flight MRA to quantify voxel-wise CBF, OEF, and infarcts. LVV was defined as 75-99% stenosis of a major anterior circulation artery. Hemispheres with large vessel occlusion or revascularization surgery were excluded. Infarcted voxels were removed. Mean hemispheric (hemi-) CBF, OEF of the anterior circulation were extracted based on a vascular territory template. Hemi- OEF was normalized to whole brain OEF (nOEF). Hemi- cerebral metabolic rate of oxygen utilization (CMRO 2 ) was calculated from arterial oxygen content, hemi- CBF, and hemi- OEF. Mann-Whitney U was used to compare hemispheres with vs. without LVV. Effects of age, hemoglobin, and repeated MRIs were adjusted for in linear mixed model. Results: Of 158 patients, 221 MRI and MRAs were performed. At baseline, LVV occurred in 5% of hemispheres. Median infarct volume was larger in hemispheres with vs. without LVV (6.5 vs. 0.04 mL, p <0.001). In baseline univariate analysis, hemispheres with LVV had lower CBF (25.8 vs 31.3 mL/100g/min, p =0.04), non-significantly higher nOEF (0.99 vs. 0.96, p =0.067), and lower CMRO 2 (8.1 vs. 12.4 mL/100g/min, p =0.002) vs. without LVV. In mixed model, with all MRIs included, LVV was independently associated with nOEF (β = 0.03, p =0.04) and showed a trend for association with CBF (β = -5.4, p =0.09) and CMRO 2 (β = -35.2, p =0.08). Discussion: In SCD, hemispheric OEF was increased as a compensatory response to flow-limiting stenosis, yet may be inadequate to prevent infarction as CMRO 2 decreased. Hemispheric OEF, as an indicator of increased stroke risk, may guide medical management and surgical intervention.

Cortex-specific transcriptome profiling reveals upregulation of interferon-regulated genes after deeper cerebral hypoperfusion in mice.

Background: Chronic cerebral hypoperfusion (CCH) is commonly accompanied by brain injury and glial activation. In addition to white matter lesions, the intensity of CCH greatly affects the degree of gray matter damage. However, little is understood about the underlying molecular mechanisms related to cortical lesions and glial activation following hypoperfusion. Efforts to investigate the relationship between neuropathological alternations and gene expression changes support a role for identifying novel molecular pathways by transcriptomic mechanisms. Methods: Chronic cerebral ischemic injury model was induced by the bilateral carotid artery stenosis (BCAS) using 0.16/0.18mm microcoils. Cerebral blood flow (CBF) was evaluated using laser speckle contrast imaging (LSCI) system. Spatial learning and memory were assessed by Morris water maze test. Histological changes were evaluated by Hematoxylin staining. Microglial activation and neuronal loss were further examined by immunofluorescence staining. Cortex-specific gene expression profiling analysis was performed in sham and BCAS mice, and then validated by quantitative RT-PCR and immunohistochemistry (IHC). Results: In our study, compared with the sham group, the right hemisphere CBF of BCAS mice decreased to 69% and the cognitive function became impaired at 4 weeks postoperation. Besides, the BCAS mice displayed profound gray matter damage, including atrophy and thinning of the cortex, accompanied by neuronal loss and increased activated microglia. Gene set enrichment analysis (GSEA) revealed that hypoperfusion-induced upregulated genes were significantly enriched in the pathways of interferon (IFN)-regulated signaling along with neuroinflammation signaling. Ingenuity pathway analysis (IPA) predicted the importance of type I IFN signaling in regulating the CCH gene network. The obtained RNA-seq data were validated by qRT-PCR in cerebral cortex, showing consistency with the RNA-seq results. Also, IHC staining revealed elevated expression of IFN-inducible protein in cerebral cortex following BCAS-hypoperfusion. Conclusion: Overall, the activation of IFN-mediated signaling enhanced our understanding of the neuroimmune responses induced by CCH. The upregulation of IFN-regulated genes (IRGs) might exert a critical impact on the progression of cerebral hypoperfusion. Our improved understanding of cortex-specific transcriptional profiles will be helpful to explore potential targets for CCH.

Whole Brain CT Perfusion Evaluation in Transient Ischaemic Attack: A Cross-sectional Study from a Tertiary Care Centre, New Delhi, India

Introduction: Few studies exist in current literature regarding imaging features in Transient Ischaemic Attack (TIA) and most of the previous studies on Computed Tomography Perfusion (CTP) have used old generation scanners with limited brain coverage. Aim: To study the spectrum of whole brain CTP parameters in patients presenting with TIA using a 256 slice CT scanner. Materials and Methods: This cross -sectional observational study was conducted at tertiary care centre in New Delhi, India over a period of 18 months from October 2017 till March 2019. All patients presenting with the first episode of TIA were evaluated with Non Contrast Computed Tomography (NCCT), Whole brain CTP, and Color doppler of carotid vessels. Quantitative assessment and statistical analysis of the alteration of CT perfusion parameters was done in areas of visualized Focal Perfusion Abnormalities (FPA) and seven predefined locations in bilateral hemispheres on perfusion maps. Results: Five out of 15 patients had FPAs in the colour maps and there was a significant elevation of Cerebral Blood Flow (CBF) and Cerebral Blood Volume (CBV) in the FPA region (p-value= 0.018) suggestive of postischaemic hyperperfusion. The mean hemispheric CBF was increased in the abnormal hemisphere compared to the normal hemisphere (p-value=0.04). Conclusion: CTP parameters are significantly altered in the patients with TIA with predominant increase in CBF and CBV in the patients who have FPA on CTP. CTP shows postischaemic hyperperfusion changes in the form of increased CBF in the hemisphere corresponding to the symptoms.

Long-Term Cognitive Changes after Revascularization Surgery in Adult Patients with Ischemic Moyamoya Disease

Introduction: Revascularization surgery for adult moyamoya disease (MMD) with ischemic presentation changes cognitive function and prevents further cerebral ischemic events. Most studies however repeated neuropsychological evaluation within 1 year after surgery. Our previous prospective cohort study of adult patients with MMD with misery perfusion who underwent direct revascularization surgery showed cognitive improvement and decline in 31% and 44%, respectively, of the patients 2 months after surgery. The present prospective study aimed to elucidate the 5-year cognitive changes after direct revascularization surgery in adult patients with cerebral misery perfusion due to ischemic MMD by following the same patients. Methods: In total, 31 patients were prospectively followed up for 5 years after direct revascularization surgery. Five types of neuropsychological tests were performed preoperatively, 2 months after surgery, and at the end of the 5-year follow-up. Cerebral blood flow (CBF) in the symptomatic cerebral hemisphere relative to that in the ipsilateral cerebellar hemisphere (hemispheric relative CBF [RCBF]) was measured using brain perfusion single-photon emission computed tomography preoperatively and at the end of the 5-year follow-up. Results: Based on results of pre- and postoperative neuropsychological tests, 11, 10, and 10 patients showed cognitive improvement, no change in cognitive function, and cognitive decline, respectively, at the end of the 5-year follow-up. These ratios were not significantly different compared with those 2 months after surgery (cognitive improvement, no change in cognitive function, and cognitive decline in 10, 8, and 13 patients, respectively). Although hemispheric RCBF was significantly greater at the end of the 5-year follow-up than before surgery in patients with cognitive improvement (80.7 ± 6.1% vs. 92.9 ± 5.5%; p = 0.0033) and in those showing no change in cognitive function (85.6 ± 3.5 vs. 91.5 ± 5.2%; p = 0.0093), this value was significantly lower at the end of the 5-year follow-up than before surgery in patients with cognitive decline (83.8 ± 3.7 vs. 81.0 ± 5.8%; p = 0.0367). Conclusion: One-third of adult patients with cerebral misery perfusion due to ischemic MMD who underwent direct revascularization surgery exhibited cognitive improvement, and one-third exhibited decline at the end of the 5-year follow-up. The former and latter patients had increased and decreased CBF, respectively, in the affected cerebral hemisphere at the end of the 5-year follow-up compared with preoperative brain perfusion.

Effect of hematocrit on cerebral blood flow measured by pseudo-continuous arterial spin labeling MRI: A comparative study with 15O-water positron emission tomography

IntroductionIn cerebral blood flow (CBF) quantification with pseudo-continuous arterial spin labeling (pCASL) MRI, arterial blood T1 (T1a) is usually fixed to a typical value (e.g., 1650 ms). However, individual T1a depends strongly on hematocrit (Hct) level. To investigate the utility of Hct-based T1a as an alternative to the fixed T1a method, we performed a comparative study with 15O-water positron emission tomography (PET). MethodsFor patients with unilateral occlusion or stenosis of major arteries, hemispheric CBF on the healthy side was measured using pCASL and 15O-water PET. The pCASL CBFs were calculated with both (a) fixed T1a (1650 ms) and (b) individual T1a estimated from blood-sampled Hct (Hct-based T1a). Correlation coefficients of Hct–CBF were calculated and compared between pCASL and PET. ResultsIn pCASL, CBF with fixed T1a showed a strong negative correlation with Hct (r = −0.568), which was reduced with individual Hct-based T1a (r = −0.341 to −0.190), consistent with the Hct–CBF relation measured with PET (r = −0.349). Discussion and conclusionWe demonstrated that Hct-based T1a resulted in smaller inter-individual variations in pCASL CBF and an inverse Hct–CBF relationship more similar to that of PET. Care must be taken in the interpretation of pCASL CBF imaging in relation to Hct level even in subjects without anemia. Further comparative studies are needed to investigate whether advanced techniques improve pCASL CBF quantification at the individual level.

Hemispheric cerebral blood flow predicts outcome in acute small subcortical infarcts

The association between baseline perfusion measures and clinical outcomes in patients with acute small subcortical infarcts (SSIs) has not been studied in detail. Post-processed acute perfusion CT and follow-up diffusion-weighted imaging of 71 patients with SSIs were accurately co-registered. Relative perfusion values were calculated from the perfusion values of the infarct lesion divided by those of the mirrored contralateral area. The association between perfusion measures with clinical outcomes and the interaction with intravenous thrombolysis were studied. Additionally, the perfusion measures for patients having perfusion CT before and after thrombolysis were compared. Higher contralateral hemispheric cerebral blood flow (CBF) was the only independent predictor of an excellent clinical outcome (modified Rankin Scale of 0-1) at 3 months (OR = 1.3, 95% CI 1.1–1.4, P = 0.001) amongst all the perfusion parameters, and had a significant interaction with thrombolysis (P = 0.04). Patients who had perfusion CT after thrombolysis demonstrated a better perfusion profile (relative CBF ≥1) than those who had perfusion CT before thrombolysis (After:45.5%, Before:21.1%, P = 0.03). This study implies that for patients with SSIs, hemispheric CBF is a predictor of clinical outcome and has an influence on the effect of intravenous thrombolysis.

Non-invasive assessment of cerebral microvascular changes for predicting postoperative cerebral hyperperfusion after surgical revascularisation for moyamoya disease: an arterial spin labelling MRI study

Cerebral hyperperfusion syndrome (CHPS) can result after anastomotic surgery as the reperfusion is established in chronically ischemic cerebral territories in patients of moyamoya disease (MMD). In this study, we have evaluated the feasibility of arterial spin labelling (ASL) perfusion MRI to predict cerebral hyperperfusion syndrome based on changes of cerebral blood flow (CBF) after revascularisation surgery in patients of MMD. Our prospective study included 25 patients with MMD who underwent superficial temporal artery-middle cerebral artery (STA-MCA) bypass with or without dural/muscle synangiosis. ASL MRI was performed before and 1-7days after surgery. On the side planned for operation, 5-mm ROI circle was drawn on the predetermined regions in frontal lobe, temporal lobe, parietal lobe and basal ganglia in proximal and distal territories of MCA to calculate ipsilateral CBF values (CBFi). An attempt was made to select the same location on contralateral side (non-operative) (CBFc) for each measurement for calculation of hemispheric normalised CBF (nCBFh) ratios. To adjust for inter individual variation among MR imagers and CBF, additional regions of interest were drawn within the cerebellum (CBFcbl) for cerebellar CBF normalised ratios (nCBFCbl). Of the 25 patients (26 operated hemispheres), 5 patients showed significant immediate postoperative symptoms suggestive of CHPS. Based on our findings, sensitivity and specificity of ASL perfusion to detect CHPS were evaluated. ASL was found to have 47-100% sensitivity and 45-88% specificity to detect CHPS. We have tried to calculate the prevalence of CHPS in postoperative patients of moyamoya disease, which in our study ranged from 6.83 to 40.70%. Based on our results, we concluded that ASL perfusion is an appropriate alternative to standard nuclear medicine studies to monitor the changes in perfusion after STA-MCA bypass surgery in moyamoya patients. ASL MR perfusion can be used to identify changes in cerebral blood flow (CBF) for early detection of cerebral hyperperfusion syndrome in patients with otherwise normal conventional MRI sequences with very high sensitivity but moderate specificity.

Contralateral Hemispheric Cerebral Blood Flow Measured With Arterial Spin Labeling Can Predict Outcome in Acute Stroke.

Background and Purpose- Imaging is frequently used to select acute stroke patients for intra-arterial therapy. Quantitative cerebral blood flow can be measured noninvasively with arterial spin labeling magnetic resonance imaging. Cerebral blood flow levels in the contralateral (unaffected) hemisphere may affect capacity for collateral flow and patient outcome. The goal of this study was to determine whether higher contralateral cerebral blood flow (cCBF) in acute stroke identifies patients with better 90-day functional outcome. Methods- Patients were part of the prospective, multicenter iCAS study (Imaging Collaterals in Acute Stroke) between 2013 and 2017. Consecutive patients were enrolled after being diagnosed with anterior circulation acute ischemic stroke. Inclusion criteria were ischemic anterior circulation stroke, baseline National Institutes of Health Stroke Scale score ≥1, prestroke modified Rankin Scale score ≤2, onset-to-imaging time <24 hours, with imaging including diffusion-weighted imaging and arterial spin labeling. Patients were dichotomized into high and low cCBF groups based on median cCBF. Outcomes were assessed by day-1 and day-5 National Institutes of Health Stroke Scale; and day-30 and day-90 modified Rankin Scale. Multivariable logistic regression was used to test whether cCBF predicted good neurological outcome (modified Rankin Scale score, 0-2) at 90 days. Results- Seventy-seven patients (41 women) met the inclusion criteria with median (interquartile range) age of 66 (55-76) yrs, onset-to-imaging time of 4.8 (3.6-7.7) hours, and baseline National Institutes of Health Stroke Scale score of 13 (9-20). Median cCBF was 38.9 (31.2-44.5) mL per 100 g/min. Higher cCBF predicted good outcome at day 90 (odds ratio, 4.6 [95% CI, 1.4-14.7]; P=0.01), after controlling for baseline National Institutes of Health Stroke Scale, diffusion-weighted imaging lesion volume, and intra-arterial therapy. Conclusions- Higher quantitative cCBF at baseline is a significant predictor of good neurological outcome at day 90. cCBF levels may inform decisions regarding stroke triage, treatment of acute stroke, and general outcome prognosis. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02225730.

Burden of cerebral hypoperfusion in patients with delayed cerebral ischemia after subarachnoid hemorrhage.

Delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) may result in focal neurological deficits and cerebral infarction, believed to result from critical regional rather than global impairments in cerebral blood flow (CBF). However, the burden of such regional hypoperfusion has not been evaluated by gold-standard voxel-by-voxel CBF measurements. Specifically, the authors sought to determine whether the proportion of brain affected by hypoperfusion was greater in patients with DCI than in SAH controls without DCI and whether the symptomatic hemisphere (in those with lateralizing deficits) exhibited a greater cerebral hypoperfusion burden. Sixty-one patients with aneurysmal SAH underwent 15O PET to measure regional CBF during the period of risk for DCI (median 8 days after SAH, IQR 7-10 days). Regions of visibly abnormal brain on head CT studies, including areas of hemorrhage and infarction, were excluded. Burden of hypoperfusion was defined as the proportion of PET voxels in normal-appearing brain with CBF < 25 ml/100 g/min. Global CBF and hypoperfusion burden were compared between patients with and those without DCI at the time of PET. For patients with focal impairments from DCI, the authors also compared average CBF and hypoperfusion burden in symptomatic versus asymptomatic hemispheres. Twenty-three patients (38%) had clinical DCI at the time of PET. Those with DCI had higher mean arterial pressure (MAP; 126 ± 14 vs 106 ± 12 mm Hg, p < 0.001) and 18 (78%) were on vasopressor therapy at the time of PET study. While global CBF was not significantly lower in patients with DCI (mean 39.4 ± 11.2 vs 43.0 ± 8.3 ml/100 g/min, p = 0.16), the burden of hypoperfusion was greater (20%, IQR 12%-23%, vs 12%, 9%-16%, p = 0.006). Burden of hypoperfusion performed better than global CBF as a predictor of DCI (area under the curve 0.71 vs 0.65, p = 0.044). Neither global CBF nor hypoperfusion burden differed in patients who responded to therapy compared to those who had not improved by the time of PET. Although hemispheric CBF was not lower in the symptomatic versus contralateral hemisphere in the 13 patients with focal deficits, there was a trend toward greater burden of hypoperfusion in the symptomatic hemisphere (21% vs 18%, p = 0.049). The burden of hypoperfusion was greater in patients with DCI, despite hemodynamic therapies, higher MAP, and equivalent global CBF. Similarly, hypoperfusion burden was greater in the symptomatic hemisphere of DCI patients with focal deficits even though the average CBF was similar to that in the contralateral hemisphere. Evaluating the proportion of the brain with critical hypoperfusion after SAH may better capture the extent of DCI than averaging CBF across heterogenous brain regions.

Abstract WP567: The Association Between Decreased Cerebral Blood Flow in Transient Ischemic Attack Patients and Cognition

Patients with transient ischemic attack (TIA) have a 4-fold increase in developing late-life dementia. Cerebral blood flow has shown to be reduced approximately 30% in patients with Alzheimer’s disease (AD). Vascular abnormalities may initiate and aggravate AD pathology prior to the development of clinical symptoms. We hypothesize that middle-aged patients with a history of TIA will have lower cerebral blood flow (CBF) in the hippocampus, thalamus, white matter and grey matter compared to healthy controls. Additionally, we hypothesize that individuals with lower cerebral blood flow in our regions of interest will have lower cognitive scores. Participants between the ages of 45-85 years old without dementia were subject to a clinical brain MRI arterial-spin-labelling CBF sequence accompanied by a cognitive battery. The cognitive battery included the Montreal Cognitive Assessment (MOCA) and a composite memory score created with the Addenbrooke’s Cognitive Examination, the Brief Visuospatial Memory Test Revised, and the Rey Auditory Verbal Learning Test. TIA patients had their assessments within 14-days of ictus. Atlas-based imaging analysis was performed using FSL. Sixty-three (63) healthy controls (63 + 10 years of age) and 51 TIA (69 + 9 years of age) participants were analyzed. In an independent one-tailed t-test, TIA patients had significantly (p&lt;0.05) lower CBF than healthy controls in the left/right hippocampus and thalamus, and right white matter. A multiple regression was performed to predict MOCA and composite memory scores from CBF, while correcting for age, gender and premorbid intelligence. Lower hemispheric CBF in the hippocampus, thalamus, white matter and grey matter each significantly predicted lower MOCA scores (F(4,101), R 2 =[0.1701-0.2013], p&lt;0.05) and lower composite memory scores (F(4,101), R 2 =[0.2429-0.2864], p&lt;0.05) in all participants. In conclusion , TIA patients have significantly lower CBF values in regions of interest compared to healthy control subjects and decreased CBF values in all participants are associated with poorer cognitive scores. By investigating neuroimaging biomarkers associated with cognition in mid-life, we may begin to understand why TIA patients have a higher risk of developing AD in late-life.

Abstract WP339: Arterial Spin Labelling Cerebral Perfusion Measurements Demonstrate Normal Blood Flow in Subacute Intracerebral Hemorrhage Patients

Introduction: Perihematomal hypoperfusion in acute intracerebral hemorrhage (ICH) has been demonstrated using CT perfusion. Although blood pressure (BP) reduction does not appear to impact perihematomal Cerebral Blood Flow (CBF), measurements using contrast are limited to a single time point. It has also been shown that up to 41% of ICH patients develop subacute diffusion-weighted imaging (DWI) lesions on MRI. Arterial Spin Labelling (ASL) is an magnetic resonance imaging (MRI) technique that allows measurement of CBF without a contrast agent, making it suitable for serial measurements. We assessed CBF in ICH patients using ASL and tested the hypothesis that perihematoma perfusion is related to BP. Methods: Patients with CT scan confirmed ICH were prospectively recruited within 6 hours of symptom onset. Acute systolic BP (SBP) targets were randomly assigned as part of an ongoing trial. The SBP target remained blinded for this analysis. Patients were assessed with ASL at 48 hours post ICH. The perihematoma region was defined using co-registered susceptibility weighted images to delineate the hematoma border. Relative CBF (rCBF) was calculated as a ratio of the ipsilateral to contralateral ASL measurements. Results: Perfusion was measured in 6 ICH patients, none of whom had DWI lesions, 55.38 (43.72, 59.75) hours after onset. Median 48 hour hematoma volume was 23.40 (18.10, 99.90) ml. Mean±SD SBP at 48 hours was 140.20 ± 10.64 mmHg. Mean perihematomal rCBF was 0.95±0.37. Mean hemispheric rCBF was 0.95 ± 0.17. Perihematomal and hemispheric CBF was not lower in the side of the hematoma ( p &gt;0.583). Hematoma size was unrelated to rCBF (perihematomal R=0.039, 95% CI [-0.880, 0.959], p =0.682; hemispheric R=0.00, 95% CI [-0.005, 0.006], p =0.932). Systolic BP at the time of the scan, difference between baseline SBP and SBP at the time of the scan, and time spent with SBP &lt;140 mmHg were all not associated with perihematomal or hemispheric rCBF ( p &gt;0.170). Conclusion: It is feasible to measure perihematoma and hemispheric perfusion in ICH patients using ASL, which may be useful for serial CBF assessment, particularly in patients with MRI evidence of ischemia.

Carotid stenting for unilateral stenosis can increase contralateral hemispheric cerebral blood flow

BackgroundThe revascularization of carotid stenosis can increase ipsilateral cerebral blood flow (CBF). Occasionally, elevated CBF is also evident on the contralateral side, but this phenomenon is poorly understood.ObjectiveTo analyze retrospectively...

Modification to the Rice-Vannucci perinatal hypoxic-ischaemic encephalopathy model in the P7 rat improves the reliability of cerebral infarct development after 48 hours

BackgroundThe Rice-Vannucci model of hypoxic-ischaemic encephalopathy (HIE) has been associated with a high degree of variability with respect to the development of cerebral infarction and infarct lesion volume. For this reason, we examined the occurrence of communicational blood flow within the common carotid (CCA), internal (ICA), and external (ECA) carotid arteries following CCA occlusion as a source of variability in the model. New methodWe propose a novel modification to the Rice-Vannucci model, whereby both the CCA and ECA are permanently ligated; mitigating communicational blood flow. ResultsUsing magnetic resonance angiography, phase-contrast velocity encoding, and pulsed arterial spin labelling, the modified Rice-Vannucci model (CCA/ECA occlusion) was demonstrated to mitigate communicational blood flow, whilst significantly reducing ipsilateral hemispherical cerebral blood flow (CBF). Comparatively, the original Rice-Vannucci model (CCA occlusion) demonstrated anterograde and retrograde blood flow within the ICA and CCA, respectively, with a non-significant reduction in ipsilateral CBF. Furthermore, CCA/ECA occlusion plus hypoxia (8% O2/92% N2; 2.5h) resulted in 100% of animals presenting with an infarct (vs 87%), significantly larger infarct volume at 48h (18.5% versus 10.0%; p<0.01), reduced standard deviation (±10% versus ±15%), and significantly worsened functional outcomes when compared to CCA occlusion plus hypoxia. Comparison with existing methodWe compared a modified Rice-Vannucci model (CCA/ECA occlusion±hypoxia) to the commonly used Rice-Vannucci model (CCA occlusion±hypoxia). ConclusionThis study demonstrates that CCA/ECA occlusion in the Rice-Vannucci model of HIE reduces infarct volume variability by limiting communicational blood flow.

Inotropic support against early brain injury improves cerebral hypoperfusion and outcomes in a murine model of subarachnoid hemorrhage.

Early brain injury/ischemia is a recent therapeutic target that contributes to triggering delayed cerebral ischemia (DCI) in the setting of subarachnoid hemorrhage (SAH). This study aimed to determine the role of dobutamine for inotropic cardiac support in improving cerebral blood flow (CBF) and outcomes after experimental SAH, mediated by hypoxia-inducible factor (HIF). Thirty-one mice were subjected to SAH by endovascular perforation, and assigned to either 2% isoflurane postconditioning performed between 1 and 2.5h after SAH induction or concomitant intravenous dobutamine infusion (15μg/kg/min) with or without HIF inhibitor 2-methoxyestradiol (2ME2) (10mg/kg) administered intraperitoneally. Neurobehavioral function was assessed daily by neurological scores and open field testing. DCI was defined 3days later by detecting a new infarction on MRI. Global CBF depression was notable early after SAH, but dobutamine showed significant improvement in CBF, lower incidence of DCI, and better recovery of neuroscores and open field test variables compared with isoflurane postconditioning (P<0.05). CBF over the entire brain on day 1 predicted DCI with a cut-off of 36.5ml/100g/min (80% specificity and 67% sensitivity), with a better area under the curve (0.83 versus 0.75) than the hemispheric CBF measured on the perforated side. The dobutamine-mediated outcomes were attenuated (P<0.05) by 2ME2 pretreatment. The data suggest that cardiac support with dobutamine improves global CBF depression induced by early brain injury, leading to reduced prevalence of DCI and better functional outcomes after experimental SAH, in which HIF may be acting as a critical mediator.

In vivo Monitoring of Cerebral Hemodynamics in the Immature Rat: Effects of Hypoxia-Ischemia and Hypothermia

Background: Neonatal hypoxic-ischemic (HI) encephalopathy occurs in 1-4 per 1,000 live term births and can cause devastating neurodevelopmental disabilities. Currently, therapeutic hypothermia (TH) is the only treatment with proven efficacy. Since TH is associated with decreased cerebral metabolism and cerebral blood flow (CBF), it is important to assess CBF at the bedside. Diffuse correlation spectroscopy (DCS) has emerged as a promising optical modality to noninvasively assess an index of CBF (CBF_i) in both humans and animals. In this initial descriptive study, we employ DCS to monitor the evolution of CBF_i following HI with or without TH in immature rats. We investigate potential relationships between CBF and subsequent cerebral damage. Methods: HI was induced on postnatal day 10 or 11 rat pups by right common carotid artery ligation followed by 60-70 min hypoxia (8% oxygen). After HI, the pups recovered for 4 h under hypothermia (HI-TH group, n = 23) or normothermia (HI-N group, n = 23). Bilateral measurements of hemispheric CBF_i were made with DCS in unanesthetized animals at baseline, before HI, and 0, 1, 2, 3, 4, 5, and 24 h after HI. The animals were sacrificed at either 1 or 4 weeks, and brain injury was scored on an ordinal scale of 0-5 (0 = no injury). Results: Carotid ligation caused moderate bilateral decreases in CBF_i. Following HI, an initial hyperemia was observed that was more prominent in the contralateral hemisphere. After initiation of TH, CBF_i dropped significantly below baseline levels and remained reduced for the duration of TH. In contrast, CBF_i in the HI-N group was not significantly decreased from baseline levels. Reductions in CBF_i after 4 h of TH were not associated with reduced damage at 1 or 4 weeks. However, elevated ipsilateral CBF_i and ipsilateral-to-contralateral CBF_i ratios at 24 h were associated with worse outcome at 1 week after HI. Conclusions: Both HI and TH alter CBF_i, with significant differences in CBF_i between hypothermic and normothermic groups after HI. CBF_i may be a useful biomarker of subsequent cerebral damage.

Acute blood pressure reduction in patients with intracerebral hemorrhage does not result in borderzone region hypoperfusion.

The Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial (ICH ADAPT) demonstrated blood pressure (BP) reduction does not affect mean perihematoma or hemispheric cerebral blood flow. Nonetheless, portions of the perihematoma and borderzones may reach ischemic thresholds after BP reduction. We tested the hypothesis that BP reduction after intracerebral hemorrhage results in increased critically hypoperfused tissue volumes. Patients with Intracerebral hemorrhage were randomized to a target systolic BP (SBP) of <150 or <180 mm Hg and imaged with computed tomographic perfusion 2 hours later. The volumes of tissue below cerebral blood flow thresholds for ischemia (<18 mL/100 g/min) and infarction (<12 mL/100 g/min) were calculated as a percentage of the total volume within the internal and external borderzones and the perihematoma region. Seventy-five patients with intracerebral hemorrhage were randomized a median (interquartile range) of 7.8 (13.3) hours from onset. Acute hematoma volume was 17.8 (27.1) mL and mean SBP was 183±22 mm Hg. At the time of computed tomographic perfusion (2.3 [1.0] hours after randomization), SBP was lower in the <150 mm Hg (n=37; 140±18 mm Hg) than in the <180 mm Hg group (n=36; 162±12 mm Hg; P<0.001). BP treatment did not affect the percentage of total borderzone tissue with cerebral blood flow<18 (14.7±13.6 versus 15.6±13.7%; P=0.78) or <12 mL/100 g/min (5.1±5.1 versus 5.8±6.8%; P=0.62). Similar results were found in the perihematoma region. Low SBP load (fraction of time with SBP<150 mmHg) did not predict borderzone tissue volume with cerebral blood flow<18 mL/100 g/min (β=0.023 [-0.073, 0.119]). BP reduction does not increase the volume of critically hypoperfused borderzone or perihematoma tissue. These data support the safety of early BP reduction in intracerebral hemorrhage. http://www.clinicaltrials.gov. Unique identifier: NCT00963976.

Migraine with Aura Is Associated with an Incomplete Circle of Willis: Results of a Prospective Observational Study

ObjectiveTo compare the prevalence of an incomplete circle of Willis in patients with migraine with aura, migraine without aura, and control subjects, and correlate circle of Willis variations with alterations in cerebral perfusion.MethodsMigraine with aura, migraine without aura, and control subjects were prospectively enrolled in a 1∶1∶1 ratio. Magnetic resonance angiography was performed to examine circle of Willis anatomy and arterial spin labeled perfusion magnetic resonance imaging to measure cerebral blood flow. A standardized template rating system was used to categorize circle of Willis variants. The primary pre-specified outcome measure was the frequency of an incomplete circle of Willis. The association between circle of Willis variations and cerebral blood flow was also analyzed.Results170 subjects were enrolled (56 migraine with aura, 61 migraine without aura, 53 controls). An incomplete circle of Willis was significantly more common in the migraine with aura compared to control group (73% vs. 51%, p = 0.02), with a similar trend for the migraine without aura group (67% vs. 51%, p = 0.08). Using a quantitative score of the burden of circle of Willis variants, migraine with aura subjects had a higher burden of variants than controls (p = 0.02). Compared to those with a complete circle, subjects with an incomplete circle had greater asymmetry in hemispheric cerebral blood flow (p = 0.05). Specific posterior cerebral artery variants were associated with greater asymmetries of blood flow in the posterior cerebral artery territory.ConclusionsAn incomplete circle of Willis is more common in migraine with aura subjects than controls, and is associated with alterations in cerebral blood flow.

Effects of Topical Administration of Nimodipine on Cerebral Blood Flow following Subarachnoid Hemorrhage in Pigs

We sought to explore whether topical administration of nimodipine improves the abnormal cerebral perfusion following subarachnoid hemorrhage (SAH) in pigs. Fourteen pigs were randomly divided into three groups: sham (n=4), SAH (n=5), or SAH + nimodipine (n=5). The SAH model was established by injecting fresh autologous nonheparinized arterial blood into the suprasellae cistern. Nimodipine or saline placebo (0.04 g/mL) were administered to the operative area on the fourth day after the SAH model was established. The cerebral blood flow (CBF) was measured 60 min after topical administration of nimodipine by cranial SPECT/CT scans with 5 mCi 99mTc-ECD injected intravenously. The CCR (corticocebellar ratio) was calculated by dividing the counts/voxel of the whole cerebral hemisphere by the average count/voxel in the cerebellar region of reference and RD (relative dispersion). A predictor for impaired autoregulation of CBF was calculated by dividing standard deviation (SD) of regional perfusion by mean perfusion (RD=SD/Mean). CCR and RD were applied to describe hemisphere CBF and perfusion heterogeneity. Cerebral perfusion significantly decreased in the SAH group (CCR: 1.382±0.192, RD: 0.417±0.015) compared to sham (CCR: 1.988±0.346, RD 0.389±0.015) (p<0.05). Abnormal cerebral perfusion status, however, was not significantly improved in the nimodipine + SAH group (CCR: 1.503±0.107, RD: 0.425±0.018) compared to the SAH group (p>0.05). Topical administration of nimodipine did not significantly improve CBF following SAH. These findings were not consistent with our previous data demonstrating that the topical administration of nimodipine significantly alleviates cerebral vasospasm following SAH detected by TCD. Potential mechanisms governing these disparate outcomes require further investigation.

Ischemic Brain Injury After Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) is the second most common cause of stroke and accounts for 8% to 15% of strokes in Western societies with an estimated incidence of 10 to 25 per 100 000 persons.1–3 Despite advances in the field of stroke and neurocritical care,4 the 30-day mortality has not changed significantly over the past 20 years.3 Indeed, ICH has the highest rates of dependence or death among stroke types and proven treatments are lacking. Clinical trials aimed at limiting hemorrhage growth, procoagulant agents for hemostasis,5 and surgical evacuation6 have not translated into improved clinical outcomes. Antihypertensive therapy for the purpose of reducing hematoma growth has been a mainstay of acute management. Guidelines recommend maintaining mean arterial pressure <130 mm Hg during the acute phase7; however, controversies exist given the lack of randomized clinical trial data and uncertainties about the rapidity and target level of blood pressure (BP)-lowering. Recent Phase 2 clinical trials evaluating acute BP control have shown promise in reducing hematoma expansion with an adequate safety profile and Phase 3 trials are underway.8,9 Besides hematoma growth, other pathophysiological processes occur in the setting of ICH and may serve as potential therapeutic targets. In the acute period after ICH, a rapid rise in intracranial pressure (ICP) from an expanding hematoma may reduce cerebral perfusion pressure. In this setting, interventions aimed at BP-lowering and hemostasis may theoretically induce thrombosis or exacerbate brain ischemia, particularly in patients with pre-existing cerebrovascular disease. A recent publication suggests that aggressive BP-lowering may actually cause acute brain ischemia and worsen outcomes after ICH.10 In this review, we outline the data on secondary acute ischemic injury after ICH, review the prevalence of remote ischemic lesions and risk factors associated with their occurrence, explore potential …

Middle cerebral artery blood velocity during running: interactions of heart and stride impact rates

Vertical movement during running or treadmill exercise generates complex aortic blood pressure waveforms that are developed by the interactions of the cardiac and foot impact pressure pulses (&gt;120bpm). Heart rate (HR) and stride rate (SR) can be synchronized in and out of phase with beat frequencies (difference in the HR and SR). Large variations in phasic aortic pulse pressures (40–120 mmHg) occur during running. Transcranial Doppler (TCD) measures dynamic middle cerebral artery blood velocity (CBFv), an index of hemispheric cerebral blood flow. Due to technical limitations, CBFv during running has not been reported. We hypothesized that running would significantly modulate CBFv. We used a 2 MHz TCD and a form fitting headset to minimize motion artifact in 5 healthy subjects (26 ±8SD) during: upright rest; walking (4 mph, no vertical motion); and running (7 mph, 4–5 inch vertical motion). The resting and walking waveforms were similar to reported ergometer waveforms. Running CBFv waveforms were similar to reported pressure waveforms and exhibited beat frequencies with a range of maximal and minimal CBFv. During in phase HR and SR periods, CBFv was 78±8 cm/s. Out of phase CBFv was 56±6 cm/s (p&lt;0.05). Preliminary data suggest that CBFv is significantly modulated by the convolution of HR and SR during running. Dynamic cerebral blood flow may depend on the mode of exercise, and it could be optimized by timing of stride rate.