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Background and Purpose: Different studies have pointed that CT perfusion (CTP) could overestimate ischemic core in early time window. We aim to evaluate the influence of time and collateral status on ischemic core overestimation. Methods: Retrospective single-center study including patients with anterior circulation large-vessel stroke that achieved reperfusion after endovascular treatment. Ischemic core and collateral status were automatically estimated on baseline CTP using commercially available software. CTP-derived core was considered as tissue with a relative reduction of cerebral blood flow 6 seconds with time to maximum of tissue residue function >10 seconds). Final infarct volume was measured on 24 to 48 hours noncontrast CT. Ischemic core overestimation was considered when CTP-derived core was larger than final infarct. Results: Four hundred and seven patients were included in the analysis. Median CTP-derived core and final infarct volume were 7 mL (interquartile range, 0–27) and 20 mL (interquartile range, 5–55), respectively. Median hypoperfusion intensity ratio was 0.46 (interquartile range, 0.23–0.59). Eighty-three patients (20%) presented ischemic core overestimation (median overestimation, 12 mL [interquartile range, 41–5]). Multivariable logistic regression analysis adjusted by CTP-derived core and confounding variables showed that poor collateral status (per 0.1 hypoperfusion intensity ratio increase; adjusted odds ratio, 1.41 [95% CI, 1.20–1.65]) and earlier onset to imaging time (per 60 minutes earlier; adjusted odds ratio, 1.14 [CI, 1.04–1.25]) were independently associated with core overestimation. No significant association was found with imaging to reperfusion time (per 30 minutes earlier; adjusted odds ratio, 1.17 [CI, 0.96–1.44]). Poor collateral status influence on core overestimation differed according to onset to imaging time, with a stronger size of effect on early imaging patients( P interaction Conclusions: In patients with large-vessel stroke that achieve reperfusion after endovascular therapy, poor collateral status might induce higher rates of ischemic core overestimation on CTP, especially in patients in earlier window time. CTP reflects a hemodynamic state rather than tissue fate; collateral status and onset to imaging time are important factors to consider when estimating core on CTP.

Supplemental Digital Content is available in the text., Background and Purpose— Breath holding (BH) and hyperventilation are used to assess abnormal cerebrovascular reactivity, often in relation to severity of small vessel disease and risk of stroke with carotid stenosis, but responses may be confounded by blood pressure (BP) changes. We compared effects of BP and end-tidal carbon dioxide (etCO2) on middle cerebral artery mean flow velocity (MFV) in consecutive transient ischemic attack and minor stroke patients. Methods— In the population-based, prospective OXVASC (Oxford Vascular Study) phenotyped cohort, change in MFV on transcranial Doppler ultrasound (ΔMFV, DWL-DopplerBox), beat-to-beat BP (Finometer), and etCO2 was measured during 30 seconds of BH or hyperventilation. Two blinded reviewers independently assessed recording quality. Dependence of ΔMFV on ΔBP and ΔetCO2 was determined by general linear models, stratified by quartiles. Results— Four hundred eighty-eight of 602 (81%) patients with adequate bone windows had high-quality recordings, more often in younger participants (64.6 versus 68.7 years; P

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 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.

Recent histological analyses of human brains show that small vessel–type injuries in the setting of type-2 diabetes colocalize with deposits of amylin, an amyloid-forming hormone secreted by the pancreas. Amylin inclusions are also identified in circulating red blood cells in people with type-2 diabetes and stroke or cardiovascular disease. In laboratory models of type-2 diabetes, accumulation of aggregated amylin in blood and the cerebral microvasculature induces brain microhemorrhages and reduces cerebral blood flow leading to white matter ischemia and neurological deficits. At the cellular level, aggregated amylin causes cell membrane lipid peroxidation injury, downregulation of tight junction proteins, and activation of proinflammatory signaling pathways which, in turn, induces macrophage activation and macrophage infiltration in vascular areas positive for amylin deposition. We review each step of this cascade based on experimental and clinical evidence and propose the hypothesis that systemic amylin dyshomeostasis may underlie the disparity between glycemic control and stroke risk and may be a therapeutic target to reduce the risk of small vessel ischemic stroke in patients with type-2 diabetes.

Supplemental Digital Content is available in the text., Background and Purpose— Computed tomography (CT) perfusion (CTP) provides potentially valuable information to guide treatment decisions in acute stroke. Assessment of interobserver reliability of CTP has, however, been limited to small, mostly single center studies. We performed a large, internet-based study to assess observer reliability of CTP interpretation in acute stroke. Methods— We selected 24 cases from the IST-3 (Third International Stroke Trial), ATTEST (Alteplase Versus Tenecteplase for Thrombolysis After Ischaemic Stroke), and POSH (Post Stroke Hyperglycaemia) studies to illustrate various perfusion abnormalities. For each case, observers were presented with noncontrast CT, maps of cerebral blood volume, cerebral blood flow, mean transit time, delay time, and thresholded penumbra maps (dichotomized into penumbra and core), together with a short clinical vignette. Observers used a structured questionnaire to record presence of perfusion deficit, its extent compared with ischemic changes on noncontrast CT, and an Alberta Stroke Program Early CT Score for noncontrast CT and CTP. All images were viewed, and responses were collected online. We assessed observer agreement with Krippendorff-α. Intraobserver agreement was assessed by inviting observers who reviewed all scans for a repeat review of 6 scans. Results— Fifty seven observers contributed to the study, with 27 observers reviewing all 24 scans and 17 observers contributing repeat readings. Interobserver agreement was good to excellent for all CTP. Agreement was higher for perfusion maps compared with noncontrast CT and was higher for mean transit time, delay time, and penumbra map (Krippendorff-α =0.77, 0.79, and 0.81, respectively) compared with cerebral blood volume and cerebral blood flow (Krippendorff-α =0.69 and 0.62, respectively). Intraobserver agreement was fair to substantial in the majority of readers (Krippendorff-α ranged from 0.29 to 0.80). Conclusions— There are high levels of interobserver and intraobserver agreement for the interpretation of CTP in acute stroke, particularly of mean transit time, delay time, and penumbra maps.

Background and Purpose— Many patients with acute ischemic stroke are not eligible for thrombolysis or mechanical reperfusion therapies due to contraindications, inaccessible vascular occlusions, late presentation, or large infarct core. Sphenopalatine ganglion (SPG) stimulation to enhance collateral flow and stabilize the blood-brain barrier offers an alternative, potentially more widely deliverable, therapy. Methods— In a randomized, sham-controlled, double-masked trial at 41 centers in 7 countries, patients with anterior circulation ischemic stroke not treated with reperfusion therapies within 24 hours of onset were randomly allocated to active SPG stimulation or sham control. The primary efficacy outcome was improvement beyond expectations on the modified Rankin Scale of global disability at 90 days (sliding dichotomy), assessed in the modified intention-to-treat population. The initial planned sample size was 660 patients, but the trial was stopped early when technical improvements in device placement occurred, so that analysis of accumulated experience could be conducted to inform a successor trial. Results— Among 303 enrolled patients, 253 received at least one active SPG or sham stimulation, constituting the modified intention-to-treat population (153 SPG stimulation and 100 sham control). Age was median 73 years (interquartile range, 64–79), 52.6% were female, deficit severity on the National Institutes of Health Stroke Scale was median 11 (interquartile range, 9–15), and time from last known well median 18.6 hours (interquartile range, 14.5–22.5). For the primary outcome, improved 3-month disability beyond expectations, rates in the SPG versus sham treatment groups were 49.7% versus 40.0%; odds ratio, 1.48 (95% CI, 0.89–2.47); P =0.13. A significant treatment interaction with stroke location (cortical versus noncortical) was noted, P =0.04. In the 87 patients with confirmed cortical involvement, rates of improvement beyond expectations were 50.0% versus 27.0%; odds ratio, 2.70 (95% CI, 1.08–6.73); P =0.03. Similar response patterns were observed for all prespecified secondary efficacy outcomes. No differences in mortality or serious adverse event safety end points were observed. Conclusions— SPG stimulation within 24 hours of onset is safe in acute ischemic stroke. SPG stimulation was not shown to statistically significantly improve 3-month disability above expectations, though favorable outcomes were nominally higher with SPG stimulation. Beneficial effects may distinctively be conferred in patients with confirmed cortical involvement. The results of this study need to be confirmed in a larger pivotal study. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT03767192.

Background and Purpose— Cellular Fn-EDA (fibronectin containing extra domain A) is expressed in activated endothelial cells and elevated in circulation in patients with cardiovascular diseases. Although global deficiency of Fn-EDA in mice improves stroke outcome, the specific contribution of plasma versus endothelium Fn-EDA in stroke outcome is currently unknown. We investigated the role of plasma versus endothelial Fn-EDA in stroke exacerbation in the comorbid condition of hyperlipidemia. Methods— We generated novel plasma Fn-EDA −/− ( Fn-EDA fl/fl Alb Cre ) and endothelial Fn-EDA −/− ( Fn-EDA fl/fl Tie2 Cre ) strains on hyperlipidemic apolipoprotein E-deficient ( ApoE −/− ) background. By following the Stroke Therapy Academic Industry Roundtable guidelines, we evaluated stroke outcome in male and female mice. Susceptibility to ischemia/reperfusion injury was evaluated in 2 different models of stroke: intraluminal monofilament and embolic model on days 1, 3, and 7. Quantitative assessment of stroke outcome was evaluated by measuring infarct volume (by magnetic resonance imaging), cerebral blood flow (by laser speckle imaging), neurological and sensory-motor outcome, and postischemic thrombo-inflammation (platelet thrombi, fibrin, neutrophil, phospho-NFκB [nuclear factor κB], TNFα [tumor necrosis factor α], and IL1β [interleukin 1β]). Results— Stroke outcome was comparable in ApoE −/− Fn-EDA fl/fl Tie2 Cre and control ApoE −/− Fn-EDA fl/fl mice suggesting endothelial Fn-EDA does not contribute to stroke. ApoE −/− Fn-EDA fl/fl Alb Cre mice exhibited significantly smaller infarcts and improved neurological and sensory-motor outcome at days 1, 3, and 7 in monofilament and embolic models of stroke. Improved stroke outcome was concomitant with enhanced survival, and decreased postischemic thrombo-inflammatory response ( P ApoE −/− Fn-EDA fl/fl ). No sex-based differences were observed. Laser speckle imaging revealed significantly improved regional cerebral blood flow at 1 hour in ApoE −/− Fn-EDA fl/fl Alb Cre mice suggesting plasma Fn-EDA promotes postischemic secondary thrombosis. Coinfusion of anti–Fn-EDA antibody with r-tPA (recombinant tissue-type plasminogen activator) in ApoE −/− mice, 1 hour after embolization, improved stroke outcome with enhanced survival, and improved neurological outcome ( P Conclusions— Genetic evidence suggests that plasma Fn-EDA exacerbates stroke outcome by promoting postischemic thrombo-inflammation. Interventions targeting plasma Fn-EDA may reduce brain damage after reperfusion.

Introduction: Clinical reports show that cerebral blood flow conditions are indicative of cerebral vascular disease. While methods for characterizing cerebral vascular flow have been extensively reported in the past, comparative analyses between direct flow measurements (DM) and computational flow dynamic (CFD) analysis remain limited. We hypothesize that flow data can be reliably measured both directly and through CFD in normal vessels. Methods: A left heart replicator was used as a realistic cardiac pump which maintained systolic pressure at 120 mmHg and diastolic pressure at 80 mmHg. A stenotic model with 50% stenosis for the ICA was connected to the replicator. A ComboWire was used for DM and recorded flow pressure and velocity. CFD was used to study flow. Results: In areas at the proximal end of the stenosis, the pressure and flow velocity derived from DM and CFD were in good agreement. At the end of systole and diastole, DM pressure were 145.42 mmHg and 73.53 mmHg, respectively. CFD simulation for the same system obtained the pressure at the end of systole and diastole of 147.16 mmHg and 74.64 mmHg, respectively. The velocity data collected from DM was at 15.40 cm/s and 7.74 cm/s for systolic flow and mean flow velocity. CFD measured flow was 17.85 cm/s and 11.37 cm/s, respectively. In areas at the distal end of the stenosis, pressure data showed good agreement between DM and CFD analysis. The DM were 138 and 70.81 mmHg at the end of systole and diastole, respectively; CFD simulation yielded 145.95 and 74.51 mmHg, respectively. Variations in the velocity data were observed at this location (Fig, pink arrows). Conclusion: DM of pressure showed good agreement with CFD simulation in all areas of the vessel. DM of velocity using the flow wire were highly affected by location of the measurement. CFD analysis can provide more consistent flow data for flow information collection along the vasculature.

Purpose: The purpose of this study was to assess the relationship between relative cerebral blood flow (rCBF) by MRI and leptomeningeal collateral recruitment in an experimental acute ischemic stroke model. Methods: This study was approved by the local IACUC. Eight mongrel canines (20-30kg) underwent endovascular middle cerebral artery occlusion (MCAO). Anesthetics were chosen not to interfere with cerebrovascular reactivity. Physiologic parameters were maintained within normal ranges. Pial collateral recruitment was angiographically assessed using a previously published 11-point scale. After the MCAO, subjects underwent DSC and DTI MRI (3T Achieva, Philips Healthcare, Best, Netherlands) in order to derive rCBF and infarct volume by diffusion restriction on mean diffusivity maps. DSC images were imported into Visage software (Visage Imaging; Richmond Australia). The region of interest was drawn on the penumbra and infarct core and corresponding contralateral side. Infarct volume was calculated by using a quantitative voxel-wise threshold by setting a threshold of 1.5 SD relative to normal values based on an ROI drawn to cover the entire contralateral normal hemisphere exclusive of the ventricles. Results: The pial collateral recruitment was strongly correlated with the rCBF on the penumbral region (r 2 = 0.7823, P-value= 0.003), and with the infarct volume measured two hours following occlusion (r 2 = 0.933376, P value= 0.00009.). There was a poor correlation between the pial collateral recruitment and the rCBF ratio on the core region (R 2 =0.4447, p-value= 0.07.) Conclusion: Preliminary data from this study suggests rCBF from the penumbral regions in experimental MCAO has a closer association with pial collateral recruitment relative to rCBF in the core infarct zone. This information has the potential to affect the interpretation of angiographic studies in acute ischemic stroke and underscores the importance of assessing regional differences in rCBF.

Introduction: Systemic blood pressure (BP) should be strictly monitored and adjusted during the initial stages of stroke. Due to the impairment of cerebral autoregulation, cerebral blood flow is directly affected by systemic BP and some degree of permissive hypertension might be beneficial prior to reperfusion treatments to ensure an adequate perfusion in the ischemic tissue. However, after generalization of endovascular treatment (EVT) the rate of successful recanalization has skyrocketed and it is not well established if, once achieved, BP control should be stricter given its potential risks. We aim to explore the relation between BP and outcome among patients who underwent EVT. Methods: This is a retrospective study of a prospectively acquired unicentric database that includes patients who underwent EVT with successful recanalization measured by a mTICI ≥2b. Hourly measuring of systolic and diastolic BP was conducted during the first 24 hours post-procedure. BP variation was measured using standard deviation (SD) and range. We explored the effects of BP on functional outcome at 3 months and safety variables. Results: The study included 351 subjects with a mean age of 72.7+/-13.1 and 51.6% were men. The 3-months mRS was ≤2 in 50.4% of patients, 66 subjects (19.2%) presented hemorrhagic transformation and 67 (19.1%) were dead in the 3-months follow-up period. Both systolic BP SD (15.6+/-9.9 vs. 12.9+/-4.3; p2). Subjects with hemorrhagic transformation presented higher range of DBP (35.7+/-12.4 vs. 32.0+/-11.9; p=0.03) and SBP (56.8+/-17.0 vs. 51.4+/-18.1; p=0.03) and higher diastolic DBP SD (9.3+/-4.1 vs. 8.2+/-2.7; p Conclusions: Major fluctuations in systolic and diastolic BP predict increased risk of hemorrhagic complications and poor functional outcome. Minimizing BP fluctuations may improve outcome of EVT patients after recanalization.

Introduction: The Extracranial-Intracranial bypass (EC-IC) surgery is performed to restore blood flow to the brain and prevent both hemorrhagic and ischemic strokes in Moyamoya disease (MMD) patients. There is a lack of contemporary data regarding EC-IC utilization, racial disparities, related mortality, and disability in the US. Method: Using ICD 9-CM codes 437.5 and 39.28, MMD and EC-IC procedures were extracted from National Inpatient Sample 2005-2015. The weighted discharge was used to generate national estimates. Predictors of revascularization utilization were evaluated using multivariable logistic regression analysis to avoid confounding effect. Disability was defined as non-home discharges, after excluding mortality. Results: Of total 24,484 admissions for MMD, 3,965 (16.2%) underwent revascularization. The mean age of revascularization patients was (SE) ~42 (0.52) years and F: M ratio of 3:1. After multivariable logistic model analysis, higher utilization rates were found in 40-59 year age group (48.3%, OR:1.29; P=0.02), who had ischemic strokes (9.2%, OR:1.38; P=0.03), and conventional cerebral angiography (30.2%, OR:1.80; P=0.001). Lower utilization rates were found in African Americans (14.9%, OR: 0.66; P=0.004), Hispanics (5.7%, OR: 0.60; P=0.03), Medicare recipients (13.6%, OR: 0.55; P=0.009), Northeast (11.5%, OR: 0.47; P= 0.003), Midwest (22.7%, OR: 0.55; P= 0.02), and South (24.8%, OR: 0.46; P=0.0002) compared to the West region. There is no utilization difference in gender female (72.4%, OR: 0.89; P=0.36). After EC-IC surgery, 79% were discharged home, 21% discharged to assistive facilities, and 0.6% died. After adjusting for hospital characteristics and associated comorbidities, lower disability (OR: 0.75; P=0.04) and the mortality rate was reported (OR: 0.80; P=0.71) among revascularization. Conclusions: This nationally representative date within the US suggests that though there is no gender disparity in utilization of EC-IC bypass surgery, there is a significant racial and regional disparity in the utilization of the procedure. Patients undergoing revascularization had better functional outcomes. Further research is needed to identify potential predictors for underutilization in these cohorts.

Sovateltide (IRL-1620, PMZ-1620), an endothelin-B receptor agonist, administered intravenously following acute cerebral ischemic stroke increased cerebral blood flow, had anti-apoptotic activity and produced neurovascular remodeling. Its safety and tolerability were confirmed in healthy human volunteers (CTRI/2016/11/007509). A prospective, multi-centric, randomized, double-blind, parallel, controlled clinical study to compare efficacy of sovateltide with standard treatment in patients with acute cerebral ischemic stroke (CTRI/2017/11/010654; NCT04046484) was conducted in 40 patients, of which 36 completed 90-day follow-up. Patients received saline (n=18; 11 male and 7 female) or sovateltide (n=18; 15 male and 3 female) within 24 hours of onset of stroke. Standard treatment in both cohorts was similar. Mean age in saline and sovateltide cohorts was 58.34±1.73 and 49.83±2.79 years, respectively. Number of patients receiving investigational drug within 20 hours of onset of stroke were 14/18 in saline and 10/18 in sovateltide cohorts. National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) on day 6 when compared to day 1 showed P values of 0.0495, 0.0859 and 0.3948, respectively in saline cohort, whereas the P value in sovateltide cohort was less than 0.0001 of all three indices in sovateltide cohort. An improvement of 6 or more in NIHSS at 90 day of treatment was 57% in sovateltide and 43% patients in saline cohort (P=0.2714; Odds ratio 2.275). mRS improvement of 2 or more was observed in 60% and 40% patients in sovateltide and saline cohorts, respectively (P=0.0519; Odds ratio 5.25). BI improvement of 40 or more was 64% and 36% in sovateltide and saline cohorts, respectively (P=0.0112; Odds ratio 12.44). Number of patients with full recovery achieving NIHSS score of 0 and BI of 100 were significantly (P

Introduction: Cerebrovascular reserve capacity (CVRC), an important predictor and prognostic factor for patients with moyamoya disease (MMD), can be derived by measuring cerebral blood flow (CBF) before and after administration of acetazolamide (ACZ). Commonly, a single CBF measurement is performed after ACZ injection at a time point varying between 5 to 20 minutes, whereas the dynamic temporal response using sequential CBF measurements has not been studied extensively. Furthermore, current literature reports group averaged CVRCs with high standard deviations indicating a patient-specific CVRC is spread over a wide range of values. The aim of this study was to assess the temporal dynamic response of CBF and derived CVRC during the ACZ challenge using arterial spin labeling in patients with MMD. Methods: Ten patients with MMD were included before and/or after revascularisation surgery and examined on a 3T MR scanner. CBF maps, based on 3D-pseudocontineous arterial spin labeling, were acquired before and 5, 15 and 25 minutes after an i.v. ACZ injection and registered to each patient’s 3D-T1-weighted image. A vascular territory template was spatially normalised to patient-specific space, defined by the 3D-T1-weighted image, including bilateral ACA, MCA and PCA. A post label delay of 2500 ms and large regions-of-interests were used to account for possible arterial transit time artefacts. CVRC was calculated as CBF augmentation post-ACZ injection relative to baseline. Results: A total of sixteen examinations were analysed. Average peak CBF augmentation occurred at 5 min post-ACZ injection, successively decreasing at 15 - and 25 min post-ACZ injection . CVRC followed a similar pattern. Peak CBF augmentation mostly occurred at 5 min for all vascular regions (frequency distribution 5 min: 64 %, 15 min: 23 %, 25 min: 13 %). Average ratio between CVRC calculated using 15 min CBF augmentation and CVRC using true peak CBF augmentation (5, 15 or 25 min) was 0.80 to 0.90 for all vascular regions. Conclusion: CVRC assessed using 15 min as a single post-ACZ injections time point may underestimate CVRC in average by 10 % to 20 % because of individual temporal patient response. The use of multiple post-injection time points is warranted.

Purpose: Existing CT perfusion (CTP) techniques are limited in accurate assessment of stroke. The purpose of this study is to validate a novel low-dose whole-brain first-pass analysis (FPA) technique as compared with gold standard microsphere measurement in a swine model. Materials and Methods: Contrast-enhanced CTP of 5 Yorkshire swine (55 ± 24 kg) was performed over 30 seconds at baseline and following incremental brain embolization. For each acquisition, gold standard fluorescent microspheres, IV contrast, and saline were injected (5 ml/s), followed by dynamic CTP imaging in a 320-slice CT scanner. Scan parameters were 320 x 0.5 mm collimation, 100 kVp, 200 mA, and 350 ms gantry rotation time. On average, 47 contrast-enhanced volume scans were acquired per acquisition to capture the entire time attenuation curve (TAC) of the carotid artery. For each acquisition, only two retrospectively selected volume scans were used to quantify brain perfusion with the low-dose FPA technique. Specifically, the first volume scan was selected at the base, while the second volume scan was selected at the peak of the TAC. Regional low-dose FPA CTP measurements from different lobes were then quantitatively compared to gold standard microsphere perfusion of corresponding tissue samples by using linear regression and Bland-Altman analysis. The CT dose index (CTDI) and dose-length product (DLP) of two-volume FPA technique were also determined. Results: Low-dose FPA perfusion measurements (P FPA ) were related to gold standard microsphere perfusion measurements (P MICRO ) by P FPA = 1.14 P MICRO - 0.01 (r = 0.93, p < 0.01). The CTDI and DLP per two-volume FPA CTP were estimated to be 25.6 mGy and 409.6 mGy, respectively. Conclusion: Low dose FPA CTP technique was retrospectively validated in a swine model and has the potential to be used for accurate diagnostic assessment and follow up of patients with stroke and vasospasm.

Background: Cerebral hemodynamic dysfunction is associated with brain small artery disease and poorer cognition. With aging, systemic arteries stiffen, magnifying the spread of pulsatility to distal organs. The brain is especially susceptible to pulsatility due to low impedance to flow. Increased pulsatility causes abnormal brain arteriolar remodeling in animal models. Therefore, we hypothesize that measures of aortic stiffness relate to poorer cerebral autoregulation, an in-vivo measure of arteriolar function. Methods: We recruited participants in the Washington Heights-Inwood Community Aging Project for this study. For autoregulation, both middle cerebral arteries were insonated at a depth of 50-58 mm. End-tidal CO2 (EtCO2) was measured continuously with a facemask. After ten minutes of baseline recording, a mixture of air enriched with 5% CO2 was administered through the facemask for 2 minutes. Cerebrovascular reactivity was calculated as % change in mean CBFV (mCBFV) per 1 mm increase in mean EtCO2 during CO2 inhalation. We averaged the right and left CO2 reactivity percentage. For aortic stiffness, we acquired carotid-femoral pulse wave velocity (cfPWV) with non-invasive oscillometry using the Vicorder system (Skidmore Medical Limited, Bristol, UK). We used generalized linear model to obtain beta estimates of the association between CO2 reactivity and cfPWV. Results: We included 158 participants (mean age 77±6.4 years, 67% women, 40% non-Hispanic black, 38% non-Hispanic white, and 20% Hispanic). Hypertension was present in 54% of the participants. cfPWV was associated with poorer CO2 reactivity (B=-0.038, P=0.047), independent of age, sex, ethnicity, and hypertension. Brachial pulse pressure (B=0.007, P=0.38) and mean arterial pressure (B=-0.017, P=0.21) were not associated with CO2 reactivity, and adding brachial pulse pressure and mean arterial pressure to the adjusted model did not change the association between cfPWV and poorer CO2 reactivity. Conclusions: Aortic stiffness is associated with poorer CO2 reactivity independent of traditional measures of hypertension, a marker of cerebral autoregulation and arteriolar health. Poorer CO2 reactivity may mediate the reported effects of aortic stiffness on brain outcomes.

Diabetes is the primary pathological factor attributed to Alzheimer’s disease and vascular cognitive impairment. Previous studies demonstrated that hyperglycemia promoted oxidative stress in the cerebral vasculature. Cerebrovascular pericytes contribute to maintaining blood-brain barrier (BBB) integrity and regulating cerebral blood flow (CBF). However, whether hyperglycemia diminishes the contractile capability of pericytes, impairs CBF autoregulation and increases BBB permeability are unclear. In the present study, we examined the role of pericytes in cerebrovascular function and cognition in diabetes using cell culture in vitro , isolated penetrating arterioles ex vivo and CBF autoregulation in vivo . Reactive oxygen species were elevated in high glucose (HG, 30 mM) treated vs. normal glucose (NG, 5.5 mM) treated pericytes. Further, mitochondrial superoxide production was increased in HG-treated vs. NG-treated group (13.24 ± 1.01 arbitrary unit (a.u.)/30min vs. 6.98 ± 0.36 a.u./30min). Mitochondrial respiration decreased in HG-treated vs. NG-treated pericytes (3718 ± 185.9 pmol/min/mg, n=10 vs. 4742 ± 284.5 pmol/min/mg, n=10) as measured by a Seahorse XFe24 analyzer. HG-treated pericytes displayed fragmented mitochondria in association with increased fission protein (DRP1) and decreased fusion protein (OPA1) expression. HG-treated pericytes displayed lower contractile capability than NG-treated cells (20.23 ± 7.15% vs. 29.46 ± 9.41%). The myogenic response was impaired in penetrating arterioles isolated from diabetic rats in comparison with non-diabetic rats. Autoregulation of CBF measured by a laser Doppler flowmeter was impaired in diabetic rats compared with non-diabetic rats. Diabetic rats exhibited greater BBB leakage than control rats. The cognitive function was examined using an eight-arm water maze. Diabetic rats took longer time to escape than the non-diabetic rats indicating learning and memory deficits. In conclusion, hyperglycemia induces pericyte dysfunction by altering mitochondrial dynamics and diminishing contractile capability, which promotes BBB leakage, decreases CBF autoregulation and contributes to diabetes-related dementia.

Introduction: Human immunodeficiency virus (HIV)-infected individuals are at high risk for ischemic stroke. We measured cerebral blood flow (CBF), oxygen extraction fraction (OEF), and autoregulation in HIV infected subjects and controls. Methods: In treatment-naive HIV infected subjects and age-, gender-, and race-matched controls, OEF was measured by using MRI T2*-weighted echo-planar imaging sequences and CBF was measured by MRI pulsed arterial spin labeling (PASL) approach. Static cerebral autoregulation was determined by measuring changes in CBF and OEF, in response to ≈10% reductions in MAP induced by using IV Nicardipine infusion. All images were acquired using a Siemens 3T MR scanner (Treo, Siemens Medical Systems Inc). Cerebral autoregulation was measured globally and regionally in gray matter (GM), white matter (WM) and subcortical GM. Autoregulatory Index (AI) was computed using the equation AI = %CBF change/% MAP change supplemented by CBF associated OEF changes. Nominal p-values are uncorrected for multiple comparisons. Results: Forty-one treatment naive HIV-infected subjects and 47 age-, gender-, race-matched controls participated. HIV-infected subjects had higher CBF in cortical GM compared to the controls (76.8± 12 mL/100 g/min versus 71.6 ± 11 mL/100 g/min; p= 0.04), but not in white matter (30.9± 8 mL/100 g/min versus 30.0 ± 8 mL/100 g/min; p = 0.60) or subcortical GM (62.8± 13 mL/100 g/min versus 61.3 ± 13 mL/100 g/min; p = 0.57). Whole brain (WB), GM, WM, and subcortical GM, OEF were similar between the groups (p > .05). The median AI were similar between cases and controls in WB (0.40 vs 0.18, p=0.86), GM (0.10 vs. 0.16, p=0.87), WM (0.80 vs. 0.87, p=0.31), and subcortical GM (1.65 vs. 1.77, p=0.26). A 12-month follow-up (N=30) in HIV-subjects on antiretroviral therapy did not produce a significant change in CBF or OEF in the WB, GM, WM, or subcortical GM (Paired sample t test p>0.05). Similarly, no changes were noted on the AI (Wilcoxon Match Rank test p>0.05). Conclusions: AI was similar between HIV cases and control and remained so after 12-months of antiretroviral therapy. We found no evidence of a defect in autoregulation to explain the high-risk of ischemic stroke documented in other studies.

Background and aims: In patients with severe hypertension, or history of stroke, the lower limit of cerebral blood flow (CBF) autoregulation is shifted to a higher blood pressure (BP) than in healthy subjects. The aim of this study was to compare the effects of olmesartan/azelnidipine combination (OLM/AZ) vs high-dose of olmesartan on ambulatory blood pressure (ABPM), cognitive function, and rehabilitation outcome in the post-stroke patients with hypertension. Methods: A total of 36 patients, 20 men and 16 women, aged 58-72 years, with sitting diastolic BP >90mmHg and systolic BP >140mmHg were eligible for participation in the present study. We randomly assigned 36 patients to either the OLM/AZ group or high-dose olmesartan group for 12 weeks. At the end of a 2-week wash-out period and after 12 weeks of active treatment, 24-h noninvasive ambulatory BP monitoring (ABPM) was performed, and cognitive function was evaluated through neuropsychological testing. In addition, rehabilitation outcome measurements were also collected during study period. Results: Both treatments significantly reduced ambulatory BP. However, the OLM/AZ produced a greater reduction in 24-h, day-time and night time ABPM values. High-dose olmesartan did not induce significant changes in any of the cognitive function test scores, whereas at 12 weeks OLM/AZ significantly improved the neuropsychological test score (Digid span test, Token test, Digital symbol test, Trail making test part A and B) (p< 0.01). Patients treated with OLM/AZ showed effective rates of improvement in hand (38.9%), upper extremities (55.6%) and lower extremities (72.2%), measured by Brunnstrom stage; these improvements were significantly different from those in high-dose olmesartan group for the total (P< 0.05) scores. Conclusions: These results suggest that in hypertensive post-stroke patients treatment with OLM/AZ produces a slightly greater reduction in ambulatory BP than high-dose olmesartan, and unlike this latter, improves some of the components of cognitive function, particularly psychomotor speed, attention and mentation. Our results suggest that OLM/AZ may improve cognitive function and rehabilitation outcome in hypertensive stroke patients in whom CBF autoregulation is impaired.

Background: Raised intracranial pressure (ICP) following severe strokes can impede blood flow to the brain, causing injury or death. There are compensatory mechanisms regulating ICP, but they are often inadequate. Interestingly, our recent observations in intracerebral hemorrhage (ICH) suggest that a volume reduction in remaining brain may serve a compensatory role after large strokes. We observed neurons well outside the hematoma reduce their volume and intercellular space 7 days after the bleed. Here, we tested the hypotheses that this volume reduction would occur sooner in both ischemic and hemorrhagic insults. Methods: Rats received either an ICH via stereotaxic infusion of collagenase or a sham procedure. Euthanasia and perfusion fixation occurred either 1 (N=12), 3 (N=12), or 7 (N=12) days following the ICH. Following histological processing, cellular volume, density, and cortical thickness were assessed with stereological techniques in representative brain regions such as hippocampus, striatum, and primary somatosensory cortex (S1). In a separate experiment, rats received either a middle cerebral artery occlusion (MCAO) via intraluminal suture occlusion (N=8), or a sham procedure (N=7). Rats were euthanized and perfusion fixed 1 day following the MCAO, with brains processed and assessed as described above. Results: After ICH, the decrease in neuronal volume (up to 60%) compared to shams had the largest effect one day following the insult in hippocampal layers CA1 and CA3 (p Discussion: Our data challenges the assumption that ‘healthy’ brain tissue outside the injured area maintains its volume after stroke. Given the magnitude of cell volume reductions, we posit that this is an important intracranial compliance mechanism invoked after severe strokes.

Purpose: We aimed to investigate whether external counterpulsation (ECP) may enhance endothelial metabolic and neurogenic activity by analyzing cerebral blood flow oscillation in transcranial Doppler (TCD) signals, and propose a new indicator for quantifying the enhancement. Methods: Twenty-seven patients with unilateral ischemic stroke in the anterior circulation territory (15 ones with 35 daily 1 h ECP treatment sessions and 12 ones without ECP treatment) were recruited. TCD monitoring of bilateral middle cerebral arteries was performed before and after ECP at day 1 and week 7. The index I, for quantitatively evaluating the enhancement of endothelial metabolism and neurogenic activity, was defined as the ratio of the oscillation amplitude of TCD signal in the dedicated frequency interval at different time points with wavelet analysis. TCD data were analyzed using wavelet analysis based on ipsilateral or contralateral to the infarct side. An overall change in National Institutes of Health Stroke Scale (NIHSS) and Barthel Index (BI) scores were recorded. Results: The index I at baseline of week 7 compared with day 1 were significantly higher on both ipsilateral and contralateral sides in ECP group (ipsilateral, 1.28±0.30; contralateral, 1.28±0.30) than those in No-ECP group (ipsilateral, 1.02±0.06; contralateral, 1.00±0.06) (all P I during ECP of week 7 compared with day 1 also increased on both sides in ECP group (ipsilateral, 1.31±0.36; contralateral, 1.29±0.34) than those in No-ECP group (ipsilateral, 0.99±0.06; contralateral, 1.00±0.07) (all P I with favorable changes in NIHSS and BI in ECP group. Conclusions: ECP treatment can enhance endothelial metabolic and neurogenic activity. The index I may be used as an indicator of enhancement of endothelial metabolic and neurogenic activity, as well as clinical outcome, in ischemic stroke following ECP treatment.

On CT perfusion (CTP), cerebral blood flow < 30% than the contralateral hemisphere (CBF Methods: Retrospective analysis of a prospective database of acute ischemic strokes who underwent CTP on admission and immediately after endovascular thrombectomy (EVT). CC was graded on CT angiography (CTA) by the modified Tan scale (good CC: 2-3 grades). Complete recanalization was defined by modified Thrombolysis in Cerebral Ischemia ≥ 2B. Final infarct volume (FIV) was semi-automatically measured on 48-72h CT; ghost core was defined as: admission CBF 10cc. Results: We included 494 patients; median time from onset to CT: 137 min (IQR 68-238). Median CBF10cc)). Even in recanalized patients, baseline CBF Conclusion: CBF

Background: Children with sickle cell anemia (SCA) invoke compensatory mechanisms to meet cerebral oxygen demand in the setting of low oxygen carrying capacity. Whereas cerebral blood flow (CBF) is largely regulated by cerebral arterioles as one compensatory mechanism, we sought to determine if the cross-sectional area of the large in-flow arteries was also increased. Methods: Children and young adults with SCA underwent 3 Tesla magnetic resonance angiography (MRA) and imaging (MRI) with pseudocontinuous arterial spin labeling (pCASL) and asymmetric spin echo sequence to measure CBF and oxygen extraction fraction (OEF) respectively. Using the double oblique method, we measured artery diameters and calculated the area (A) of the vessel as A=πr 2 . The total inflow area (A T-inflow ) was the summation of the areas of distal portions of both internal carotid arteries and basilar artery. CBF, OEF, arterial oxygen content [(CaO 2 ) = 1.36*Hemoglobin*%saturation on pulse oximetry] and A T-inflow were compared between groups with nonparametric statistics. Spearman’s correlation determined relationship of A T-inflow with other variables. Results: Data was available for 29 subjects with SCA (median age 15 years (range 9-26), 45% male) and 17 age-matched controls (15y (range 9-18), 47% male) underwent scanning. Children with SCA had larger A T-inflow (36 [29, 40] mm 2 ) compared to age-matched controls (29 [26, 31] mm 2 , p=0.01). CBF and OEF were higher (p=0.001, p=0.002), and CaO 2 was lower (pT-inflow positively correlated with CBF (p=0.002) and OEF (p2 (p=0.02; Figure ). Conclusion: Increased cross sectional area of large cerebral arteries may provide an additional compensatory mechanism in SCA to augment CBF and aid in meeting cerebral oxygen demand. Further work is needed to determine if MRA measurements provide a non-invasive precursor to increased cerebral metabolic stress and stroke risk.

Introduction: The role of increased CBF after endovascular thrombectomy in post-ischemic hyperperfusion has not been studied in detail. We aimed to investigate the timing of CBF increases on PWI after thrombectomy in association with hemorrhagic transformation. Methods: We analyzed prospectively collected data in consecutive patients treated with endovascular thrombectomy. Inclusion criteria were: (1) patients with ICA or M1 occlusion, and (2) PWI and GRE obtained within 12 hours and 12-48 hours after thrombectomy. We compared each rCBF with early hemorrhage (within 12 hours after thrombectomy), late hemorrhage (12-48 hour) and non-hemorrhage in basal ganglia (BG) and MCA cortical or subcortical (CS) region. In each PWI dataset, ROIs were placed in two slice levels of the BG and three slice levels of the CS region. Results: Fifty-three patients met inclusion criteria. Early BG hemorrhages were noted in 13 patients, with 4 late BG hemorrhage, 8 early CS hemorrhage and 3 late CS hemorrhage. There were no significant differences on rCBF in PWI within 12 hours after thrombectomy between early hemorrhage, late hemorrhage and non-hemorrhage groups. In contrast, rCBF on 12-48 hours PWI in the BG region was significantly higher in the early BG hemorrhage than non-BG hemorrhage (lower BG slice 1.36 vs 1.01, p Conclusions: Most intracerebral hemorrhages after thrombectomy were seen within 12 hours after intervention. A rCBF increase in hemorrhage cases was not seen on PWI within 12 hours after thrombectomy. rCBF increases on PWI 12-48 hours after thrombectomy, however, was associated with post-thrombectomy hemorrhage within 12 hours.

Background and Purpose— Estimation of infarction based on computed tomographic perfusion (CTP) has been challenging, mainly because of noise associated with CTP data. The Bayesian method is a robust probabilistic method that minimizes effects of oscillation, tracer delay, and noise during residue function estimation compared with other deconvolution methods. This study compares CTP-estimated ischemic core volume calculated by the Bayesian method and by the commonly used block-circulant singular value deconvolution technique. Methods— Patients were included if they had (1) anterior circulation ischemic stroke, (2) baseline CTP, (3) successful recanalization defined by thrombolysis in cerebral infarction ≥IIb, and (4) minimum infarction volume of >5 mL on follow-up magnetic resonance imaging (MRI). CTP data were processed with circulant singular value deconvolution and Bayesian methods. Two established CTP methods for estimation of ischemic core volume were applied: cerebral blood flow (CBF) method (relative CBF, 2 seconds) and cerebral blood volume method (145%). Final infarct volume was determined on MRI (fluid-attenuated inversion recovery images). CTP and MRI-derived ischemic core volumes were compared by univariate and Bland-Altman analysis. Results— Among 35 patients included, the mean/median (mL) difference for CTP-estimated ischemic core volume against MRI was −4/−7 for Bayesian CBF ( P =0.770), 20/12 for Bayesian cerebral blood volume ( P =0.041), 21/10 for circulant singular value deconvolution CBF ( P =0.006), and 35/18 for circulant singular value deconvolution cerebral blood volume ( P Conclusions— Despite existing variabilities between CTP postprocessing methods, Bayesian postprocessing increases accuracy and limits variability in CTP estimation of ischemic core.

Background and Purpose— Ipsilateral thalamic diaschisis (ITD) describes the reduction of thalamic function, metabolism, and perfusion resulting from a distant lesion of the ipsilateral hemisphere. Our aim was to evaluate the perfusion characteristics and clinical impact of ITD in acute middle cerebral artery stroke, which does not directly affect the thalamus. Methods— One hundred twenty-four patients with middle cerebral artery infarction were selected from a prospectively acquired cohort of 1644 patients who underwent multiparametric computed tomography (CT), including CT perfusion for suspected stroke. Two blinded readers evaluated the occurrence of ITD, defined as ipsilateral thalamic hypoperfusion present on ≥2 CT perfusion maps. Perfusion alterations were defined according to the Alberta Stroke Program Early CT Score regions. Final infarction volume and subacute complications were assessed on follow-up imaging. Clinical outcome was quantified using the modified Rankin Scale. Multivariable linear and ordinal logistic regression analysis were applied to identify independent associations. Results— ITD was present in 25/124 subjects (20.2%, ITD+). In ITD+ subjects, perfusion of the caudate nucleus, internal capsule, and lentiform nucleus was more frequently affected than in ITD− patients (each with P P =0.002) and cerebral blood volume ( P P =0.021) were observed. There was no independent association of ITD with final infarction volume or clinical outcome at discharge in treatment subgroups (each with P >0.05). ITD had no influence on the development of subacute stroke complications. Conclusions— ITD in the form of thalamic hypoperfusion is a frequent CT perfusion finding in the acute phase in middle cerebral artery stroke patients with marked involvement of subcortical areas. ITD does not result in thalamic infarction and had no independent impact on patient outcome. Notably, ITD was misclassified as part of the ischemic core by automated software, which might affect patient selection in CT perfusion–based trials.

Background and Purpose— This study aimed to assess how the ischemic core measured by perfusion computed tomography (CTP) was affected by the delay and dispersion effect. Methods— Ischemic stroke patients having CTP performed within 6 hours of onset were included. The CTP data were processed twice, generating standard cerebral blood flow (sCBF) and delay- and dispersion-corrected CBF (ddCBF), respectively. Ischemic core measured by the sCBF and ddCBF was then compared at the relative threshold U test and limits of agreement. Patients were also classified into favorable and unfavorable CTP patterns. The imaging pattern classification by sCBF and ddCBF was compared by the χ 2 test; their respective ability to predict good clinical outcome (3-month modified Rankin Scale score) was tested in logistic regression. Results— Fifty-five patients were included in this study. Median sCBF ischemic core volume was 38.5 mL (12.4–61.9 mL), much larger than the median core volume of 17.2 mL measured by ddCBF (interquartile range, 5.5–38.8; P P =0.97) and 16.7 mL (95% limits of agreement, −21.7 to 55.2; P P Conclusions— Delay and dispersion correction increases the accuracy of ischemic core measurement on CTP.

Background and Purpose— Increased stroke risk correlates with hemodynamic failure, which can be assessed with ( 15 O-)H 2 O positron emission tomography (PET) cerebral blood flow (CBF) measurements. This gold standard technique, however, is not established for routine clinical imaging. Standardized blood oxygen-level–dependent (BOLD) functional magnetic resonance imaging+CO 2 is a noninvasive and potentially widely applicable tool to assess whole-brain quantitative cerebrovascular reactivity (CVR). We examined the agreement between the 2 imaging modalities and hypothesized that quantitative CVR can be a surrogate imaging marker to assess hemodynamic failure. Methods— Nineteen data sets of subjects with chronic cerebrovascular steno-occlusive disease (age, 60±11 years; 4 women) and unilaterally impaired perfusion reserve on Diamox-challenged ( 15 O-)H 2 O PET were studied and compared with a standardized BOLD functional magnetic resonance imaging+CO 2 examination within 6 weeks (8±19 days). Agreement between quantitative CBF- and CVR-based perfusion reserve was assessed. Hemodynamic failure was staged according to PET findings: stage 0: normal CBF, normal perfusion reserve; stage I: normal CBF, decreased perfusion reserve; and stage II: decreased CBF, decreased perfusion reserve. The BOLD CVR data set of the same subjects was then matched to the corresponding stage of hemodynamic failure. Results— PET-based stage I versus stage II could also be clearly separated with BOLD CVR measurements (CVR for stage I 0.11 versus CVR for stage II −0.03; P P R 2 =0.47 and P =0.02, R 2 = 0.25, respectively). Conclusions— BOLD CVR corresponded well to CBF perfusion reserve measurements obtained with ( 15 O-)H 2 O-PET, especially for detecting hemodynamic failure in the affected hemisphere and middle cerebral artery territory and for identifying hemodynamic failure stage II. BOLD CVR may, therefore, be considered for prospective studies assessing stroke risk in patients with chronic cerebrovascular steno-occlusive disease, in particular because it can potentially be implemented in routine clinical imaging.

Approximately 40% of acute ischemic strokes are caused by proximal intracranial large vessel occlusion (LVO) and are associated with the worst clinical outcomes.1 Early reperfusion with IV tPA (tissue-type plasminogen activator) and intra-arterial thrombectomy leads to reduced final infarct volumes, lower disability rates, and improved cognitive function after anterior circulation LVO.2–6 However, most stroke patients with LVO remain untreated because they present beyond the conventional time windows for acute reperfusion therapies.7,8 Therefore, a growing paradigm has been to transition to a therapeutic window that is tailored to each patient’s individual pathophysiology or brain tissue window rather than a standardized time window.9,10 The principle of pathophysiology-based reperfusion therapy is built on the fundamental concept of a dynamic interrelation between the ischemic core (tissue that is already infarcted) and the ischemic penumbra (physiologically impaired but potentially salvageable tissue).11–13 After arterial occlusion, there can be temporal growth of the ischemic core into the penumbral area that is modulated by collateral blood flow, the key element setting the pace of the ischemic process.14 Infarct growth is thought to progress at different speeds across individuals because patients with occlusion of the proximal middle cerebral artery (MCA) or internal carotid artery (ICA) terminus present with widely variable stroke volumes independently of time after symptom onset.15–18 We refer to patients with LVO who experience rapid infarct growth as fast progressors. These patients have failing collaterals and a large ischemic core despite presenting early within 6 hours of stroke onset. Conversely, a significant number of patients maintain a small ischemic core and significant salvageable tissue beyond 6 hours and up to several days after persistent LVO.17,19 The latter patients are slow progressors because they maintain good collaterals and …

A 55-year-old man presents within 2 hours of acute left-sided weakness. Head computed tomography reveals a 60 mL right thalamic hemorrhage. Blood pressure (BP) on presentation is 150/95 mm Hg. Should BP be lowered? If yes, what is the target BP and which antihypertensive agents should be used? Intensive BP Lowering in Intracerebral Hemorrhage ### Craig Anderson As the on-call stroke neurologist, I would treat this patient according to an approved management of intracerebral hemorrhage (ICH) protocol readily available on the hospital intranet and my decision support tool. The patient is at high risk for poor outcome—early presentation, large hematoma, deep location—and early, rapid and sustained control of elevated systolic BP (SBP, target

Background and Purpose— Identification of salvageable penumbra tissue by dynamic susceptibility contrast magnetic resonance imaging is a valuable tool for acute stroke patient stratification for treatment. However, prior studies have not attempted to combine the different perfusion maps into a predictive model. In this study, we established a multiparametric perfusion imaging model and cross-validated it using positron emission tomography perfusion for detection of penumbral flow. Methods— In a retrospective analysis of 17 subacute stroke patients with consecutive magnetic resonance imaging and H2O15 positron emission tomography scans, perfusion maps of cerebral blood flow, cerebral blood volume, mean transit time, time-to-maximum, and time-to-peak were constructed and combined using a generalized linear model (GLM). Both the GLM maps and the single perfusion maps alone were cross-validated with positron emission tomography-cerebral blood flow scans to predict penumbral flow on a voxel-wise level. Performance was tested by receiver-operating characteristics curve analysis, that is, the area under the curve, and the models’ fits were compared using the likelihood ratio test. Results— The GLM demonstrated significantly improved model fit compared with each of the single perfusion maps ( P Conclusions— Our results support a dynamic susceptibility contrast magnetic resonance imaging–based GLM as an improved model for penumbral flow prediction in stroke patients. With given perfusion maps, this model is a straightforward and observer-independent alternative for therapy stratification.

Background and Purpose— Computed tomography perfusion imaging can estimate the size of the ischemic core, which can be used for the selection of patients for endovascular therapy. The relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF) thresholds chosen to identify ischemic core influence the accuracy of prediction. We aimed to analyze the accuracy of various rCBV and rCBF thresholds for predicting the 27-hour infarct volume using RAPID automated analysis software from the SWIFT PRIME trial (Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment) data. Methods— Patients from the SWIFT PRIME study who achieved complete reperfusion based on time until the residue function reached its peak >6 s perfusion maps obtained at 27 hours were included. Patients from both the intravenous tissue-type plasminogen activator only and endovascular groups were included in analysis. Final infarct volume was determined on magnetic resonance imaging (fluid-attenuated inversion recovery images) or computed tomography scans obtained 27 hours after symptom onset. The predicted ischemic core volumes on rCBV and rCBF maps using thresholds ranging between 0.2 and 0.8 were compared with the actual infarct volume to determine the most accurate thresholds. Results— Among the 47 subjects, the following baseline computed tomography perfusion thresholds most accurately predicted the actual 27-hour infarct volume: rCBV=0.32, median absolute error (MAE)=9 mL; rCBV=0.34, MAE=9 mL; rCBF=0.30, MAE=8.8 mL; rCBF=0.32, MAE=7 mL; and rCBF=0.34, MAE=7.3. Conclusions— Brain regions with rCBF 0.30 to 0.34 or rCBV 0.32 to 0.34 thresholds provided the most accurate prediction of infarct volume in patients who achieved complete reperfusion with MAEs of ≤9 mL. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01657461.

Background and Purpose— Renal denervation (RD) may protect against cardiovascular diseases regardless of blood pressure (BP)–lowering effect. We hypothesized that RD can improve the outcome of acute ischemic stroke (AIS) in hypertensive rats. Methods— An AIS model of spontaneously hypertensive stroke-prone rats (SHRSPs) was prepared by 90-minute middle cerebral artery occlusion followed by reperfusion. At 30 minutes poststroke, the SHRSPs were subjected to (1) sham operation or (2) RD to determine the beneficial effects of RD posttreatment. In addition, we evaluated the neuroprotective effects of RD posttreatment in Wistar Kyoto rats and RD pretreatment in SHRSPs with AIS. Results— RD significantly ameliorated neurological deficit and infarct volume at 1 and 7 days after middle cerebral artery occlusion. RD immediately and continuously normalized elevated BP during 24 hours. This normalization of BP by RD was associated with the reduction of cerebral blood flow during both middle cerebral artery occlusion and reperfusion periods. Thus, RD-induced BP normalization seems to ameliorate cerebrovascular overperfusion in SHRSPs with AIS. On the contrary, RD did not affect cerebral vascular resistance or cerebral vasoreactivity and did not increase Akt and endothelial NO synthase phosphorylation, thereby indicating no apparent change of cerebrovascular function. RD significantly attenuated cerebral oxidative stress as estimated by dihydroethidium staining and gp91 phox expression. The beneficial effects were not seen in Wistar Kyoto rats, whereas RD pretreatment improved neurological function in SHRSPs. Conclusions— RD posttreatment improved outcome in the hypertensive AIS rat model. Therefore, we suggest that BP normalization by RD may be a promising therapeutic strategy for AIS.

Background and Purpose— Cerebral small vessel disease (SVD) is associated with cognitive impairment. This may be because of decreased microstructural integrity and microvascular perfusion, but data on these relationships are scarce. We determined the relationship between cognition and microvascular perfusion and microstructural integrity in SVD patients, using intravoxel incoherent motion imaging—a diffusion-weighted magnetic resonance imaging technique designed to determine microvascular perfusion and microstructural integrity simultaneously. Methods— Seventy-three patients with SVD and 39 controls underwent intravoxel incoherent motion imaging and neuropsychological assessment. Parenchymal diffusivity D (a surrogate measure of microstructural integrity) and perfusion-related measure fD* were calculated for the normal appearing white matter, white matter hyperintensities, and cortical gray matter. The associations between cognitive performance and D and fD* were determined. Results— In SVD patients, multivariable analysis showed that lower fD* in the normal appearing white matter and cortical gray matter was associated with lower overall cognition ( P =0.03 and P =0.002, respectively), lower executive function ( P =0.04 and P =0.01, respectively), and lower information-processing speed ( P =0.04 and P =0.01, respectively). D was not associated with cognitive function. In controls, no association was found between D , fD* , and cognition. Conclusions— In SVD patients, lower cognitive performance is associated with lower microvascular perfusion in the normal appearing white matter and cortical gray matter. Our results support recent findings that both cortical gray matter and normal appearing white matter perfusion may play a role in the pathophysiology of cognitive dysfunction in SVD. Clinical Trial Registration— URL: http://www.trialregister.nl . Unique identifier: NTR3786.

Background and Purpose— Cerebral venous thrombosis (CVT) affects venous hemodynamics and can provoke severe stroke and chronic intracranial hypertension. We sought to comprehensively analyze 3-dimensional blood flow and hemodynamic alterations during acute CVT including collateral recruitment and at follow-up. Methods— Twenty-two consecutive patients with acute CVT were prospectively included and underwent routine brain magnetic resonance imaging (MRI) and 4-dimensional flow MRI at 3 T for the in vivo assessment of cerebral blood flow. Neurological and MRI follow-up at 6 months was performed in 18 patients. Results— Three-dimensional blood flow visualization and quantification of large dural venous sinuses and deep cerebral veins was successfully performed in all patients. During acute CVT, we observed abnormal flow patterns including stagnant flow, flow acceleration in stenoses, and change of flow directions. In patients with complete recanalization, flow trajectories resembled those known from previously published 4-dimensional flow MRI data in healthy adults. There was a trend toward a relationship between occluded segments and cerebral lesions (not significant). Furthermore, patients with versus without cerebral lesions showed increased mean (0.08±0.09 versus 0.005±0.014 m/s) and peak velocities (0.18±0.21 versus 0.006±0.02 m/s) within partially thrombosed left and right transverse sinuses ( P Conclusions— Four-dimensional flow MRI was successfully applied for the 3-dimensional visualization and quantification of venous hemodynamics in patients with CVT and provided new dynamic information regarding vessel recanalization. This technique seems promising to investigate the contribution of hemodynamic parameters and collaterals in a larger cohort to identify those at risk of stroke.

Background and Purpose— The aim of this study is to determine the spatial and volumetric accuracy of infarct core estimates from relative cerebral blood flow (rCBF) by comparison with near-contemporaneous diffusion-weighted imaging (DWI), and evaluate whether it is sufficient for patient triage to reperfusion therapies. Methods— One hundred ninety-three patients enrolled in the DEFUSE 2 (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution) and SENSE 3 (Sensitivity Encoding) stroke studies were screened, and 119 who underwent acute magnetic resonance imaging with DWI and perfusion imaging within 24 hours of onset were included. Infarct core was estimated using reduced rCBF at 12 thresholds (−6 mm2/s). For each threshold, volumetric agreement between the rCBF and DWI core estimates was assessed using Bland-Altman, correlation, and linear regression analyses; spatial agreement was assessed using receiver operating characteristic analysis. Results— An rCBF threshold of 0.32 yielded the smallest mean absolute volume difference (14.7 mL), best linear regression fit (R 2 =0.84), and best spatial agreement (Youden index, 0.38; 95% CI, 0.34–0.41) between rCBF and DWI, with high correlation ( r =0.91, P P 70 mL) than small infarcts (≤70 mL), with Youden indices of 0.53 (95% CI, 0.49–0.56) and 0.34 (95% CI, 0.30–0.37), respectively. Conclusions— Strong correlation and agreement with near-contemporaneous DWI indicate that infarct core estimates obtained using rCBF are sufficiently accurate for patient triage to reperfusion therapies. The identified optimal rCBF threshold of 0.32 closely approximates the threshold currently used in clinical practice.

InIntroduction: Cerebral blood flow (CBF) autoregulation is impaired after acute cerebral infarction (AIS). Although previous studies revealed that changes in cerebral oxygenation occurred when head-of-bed raised from flat to head-up position within 72hr after onset, chronological changes of this phenomenon had never been evaluated. Hypothesis: We hypothesized that the impairment of CBF autoregulation improved within 7-10 days after onset of AIS. We aimed to evaluated the chronological changes in oxygenated- (ΔHbO 2 ), deoxygenated- (ΔHb) and total-hemoglobin (ΔtHb) concentration in response to passive sitting between Method: We repeatedly measured forehead ΔHbO2, ΔHb and ΔtHb in response to raise the head-of-bed to 30 degrees from spine within 72hr (1 st measurement) and 7-10 days (2 nd measurement) after onset of AIS by using time-resolved near-infrared spectroscopy. Difference in the ΔHbO2, ΔHb and ΔtHb values between two measurements were compared. We also evaluated Spearman Rank Correlation Coefficient of those values between affected and unaffected side in each measurement. Results: A total of 37 participants (mean age, 70.4±12.5 years; 13 females) with a first AIS hospitalization in the Seirei Mikatahara General Hospital, Hamamatsu, Japan, were enrolled. No significant differences of ΔHbO 2, ΔHb or ΔtHb in either affected or unaffected side were observed between two measurements. The ΔHbO 2, ΔHb or ΔtHb of the affected side did not correlate with those in the unaffected side at the first measurement (ΔHbO 2 ; r=0.197, p=0.282, ΔHb; r=0.065, p=0.695. and ΔtHb; r=0.193, p=0.245, respectively). Interestingly, the correlation coefficients of the ΔHbO 2, ΔHb and ΔtHb between affected and unaffected side at the 2 nd measurement were statistically significant (ΔHbO 2 ; r=0.420, p=0.011, ΔHb; r=0.398, p=0.017. and ΔtHb; r=0.490, p=0.003, respectively). Conclusion: Although cerebral oxygenation changes in relation to posture change did not correlate between affected or unaffected side within 72hr after onset, this difference was improved in 7-10 days after onset. Our result suggested that the impairment of CBF autoregulation improved, at least partially, within 7-10 days after onset of AIS.

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 (p2 =[0.1701-0.2013], p2 =[0.2429-0.2864], p, 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.

Introduction: Endovascular Therapy(EVT) has been shown to be efficacious for treatment of large artery occlusion (LAO) acute ischemic stroke (AIS). The 2018 American Heart Association Guidelines for Management of Acute Ischemic Stroke recommend EVT for patients with anterior circulation LAO AIS with ASPECTS ≥6 and groin puncture within 6 hours of symptom onset. CT Perfusion (CTP) pattern with CBF < 30% of ≥ 70cc is a predictor of a large core infarction. Patients within 6 hours of symptom onset with LAO AIS with favorable ASPECTS on non-contrast head CT and large core infarct measurements on CTP may present a decision-making challenge. Hypothesis: CTP CBF < 30% of ≥ 70cc predicts poor functional outcome in anterior circulation LAO AIS with ASPECTS ≥6 with groin puncture for EVT within 6 hours of symptom onset. Methods: From a large healthcare system’s stroke network database, we conducted a retrospective analysis of functional outcomes (90 day mRS) of patients who presented with LAO AIS with ASPECTS ≥6 with CBF < 30% of ≥ 70cc who underwent EVT with groin puncture within 6 hours from symptom onset between July 2016 and March 2018. Results: Over a 21-month period, 12 cases were identified with CBF < 30% ≥ 70cc and ASPECTS ≥ 6 who underwent EVT within 6 hours of symptom onset. Mean and median CBF < 30% were 119.8 cc and 99 cc, while mean and median ASPECTS scores were 9.3 and 10. TICI 3 revascularization was achieved in 6 patients, and TICI 2B was achieved in 3 patients, within one patient each achieving TICI 2A, TICI 1 and TICI 0. Mean and median mRS at discharge were 4.2 and 4, while mean and median 90 day mRS were 4 and 3. Of the five patients who died, none sustained parenchymal type 2 hemorrhages, and two had TICI 2B, two had TICI 3, one had TICI 0 revascularization. Conclusions: In our experience, most patients presenting within 6 hours of symptom onset with a CBF < 30% of ≥ 70cc and an ASPECTS ≥6 achieved poor functional outcomes (mRS of >2) despite overall good rates of revascularization.

Introduction: Most of patients with mild neurological symptoms despite the carotid or middle cerebral artery occlusion (CO or MCAO) are treated without thrombectomy because of no its evidence.However, among them, some patients’ neurological symptoms deteriorate during hospitalization. Methods: We included in our retrospective study acute ischemic stroke patients 1) who were admitted to our institution between April 2011 and January 2018, 2) who could walk before stroke, 3) who underwent MR angiography(MRA), displaying occlusion of the internal carotid artery(ICA) or the M1 segment of the middle cerebral artery(MCA), 4) who presented low NIHSS scores of 4 or less and didn’t undergo thrombectomy.We evaluated patients’ baseline features, NIHSS scores on arrival and at discharge, and time-intensity curve (TIC)-cerebral blood flow (CBF) grade. TICs were generated on region of interests set at symmetrical positions of the bilateral MCA territories. According to the time to peak (TP) and the peak signal (PS) comparing the affected side(a) with the contralateral side(c), we defined (TPa/TPa) divided by (TPc/TPc) as CBF% and grade 1 as CBF% of less than 0.2, grade 2 as CBF% of 0.2 or more and CBF% less than 0.7 and grade 3 as CBF% of 0.7 or more. We defined patients with NIHSS at discharge higher than NIHSS on admission as Group Worse and defined others as Group Non-Worse. Result: Thirty-six patients met our inclusion criteria and were analyzed. The median age was 76.5 years, and 24 patients were men. Median NIHSS score on arrival and at discharge was 2 and 1. There were no patients with CBF grade 1, 8 patients with CBF grade 2 and 28 with CBF grade 3. There were 7 patients in Group Worse and 29 in Group Non-Worse.In Group Worse and Non-Worse, median age was 64 and 78 (ns), median NIHSS score at admission was 2 and 2 (ns), 4 patients and 4 patients in CBF grade 2 and 3 patients and 25 patients in CBF grade 3 (p Conclusion: CBF grade based on dMRi is the significant predictor of neurological deterioration. In cases of CBF grade 2 due to the ICA or MCA occlusion, neurological symptoms probably deteriorate in 50% of patients during hospitalization without thrombectomy.

Background and Objectives: External counterpulsation (ECP) is a non-invasive method used to augment cerebral blood flow of patients with ischaemic stroke via induced hypertension. We aimed to investigate whether the cerebral augmentation index (CAI) evaluated by ECP can predict clinical outcomes after acute ischemic stroke. Methods: We enrolled acute ischemic stroke patients within 7 days after stroke onset. Bilateral middle cerebral arteries of patients were monitored using transcranial Doppler (TCD). Flow velocity changes before, during and after ECP were, respectively, recorded for 3 mins. The cerebral augmentation index (CAI) was the increase in percentage of the middle cerebral artery mean flow velocity during ECP compared with baseline. TCD data were analysed based on the side ipsilateral or contralateral to the infarct. The modified Rankin Scale (mRS) (good outcome: mRS 0∼2; poor outcome: mRS 3∼6) was evaluated 3 months after the index stroke. Results: 200 patients were included (mean age, 64.5±8.9 years; 86.5% males). At month 3 after stroke onset, univariate analysis showed that the National Institutes of Health Stroke Scale at recruitment was significantly higher in the poor outcome group, while the bilateral CAIs were significantly lower in the good outcome group than those in the poor outcome group (ipsilateral 3.72±2.94 vs 7.92±6.25, p=0.032; contralateral 4.04±3.82 vs 6.98±6.05, p=0.048). Multivariate logistic regression showed that bilateral CAIs were independently correlated with an unfavorable functional outcome after adjusting for confounding factors. Conclusions: The higher degree of cerebral blood flow velocity augmentation on the both sides ipsilateral and contralateral to the infarct induced by ECP is independently correlated with an unfavorable functional outcome after acute ischemic stroke.

Background and Purpose— Both intracerebral hemorrhage (ICH) and brain edema have been attributed to reperfusion after intravenous thrombolysis. We explored the interaction of recanalization and core size for imaging outcomes (ICH and vasogenic brain edema). Methods— In patients with anterior circulation occlusion given intravenous thrombolysis 2 s and relative cerebral blood flow 2 s). CT and CT angiography at 24 hours were reviewed for ICH (European Cooperative Acute Stroke Study [ECASS]-2 definition), early vasogenic edema (third International Stroke Trial [IST-3] criteria), and recanalization (thrombolysis in myocardial infarction 2–3). Independent effects of recanalization, core volume and potential interactions on edema, ICH and day 90 outcomes were estimated by logistic regression. Results— In 123 patients, there was a trend for recanalization to be associated with H1/2 ICH (odds ratio [OR], 2.3 [0.97–5.5]; P =0.06) but not with PH1/2 ICH (OR, 1.7 [0.33–8.8]; P =0.5), any edema, or significant brain edema (OR, 1.45 [0.4–4.9]; P =0.55). Ischemic core (>50 mL) was associated with any ICH (OR, 4.0 [1.6–9.5]; P =0.003), edema (OR, 5.4 [2–14]; P P P =0.8), after controlling for recanalization. There was no significant interaction of recanalization and large core for any adverse outcomes. Conclusions— Large ischemic core was associated with poorer outcomes and both early vasogenic brain edema and ICH, but recanalization on 24-hour CT angiography was associated with clinically favorable outcome. There was no significant interaction of recanalization and large core volume for any outcomes. The association of hemorrhage or brain edema with post-thrombolysis reperfusion is unclear.

Background and Purpose— Cross-sectional studies suggest that chronic hemodynamic impairment may cause selective cortical neuronal damage in patients with atherosclerotic internal carotid artery or middle cerebral artery occlusive disease. The purpose of this longitudinal study was to determine whether the progression of cortical neuronal damage, evaluated as a decrease in central benzodiazepine receptors (BZRs), is associated with hemodynamic impairment at baseline or hemodynamic deterioration during follow-up. Methods— We evaluated the distribution of BZRs twice using positron emission tomography and 11 C-flumazenil over time in 80 medically treated patients with atherosclerotic internal carotid artery or middle cerebral artery occlusive disease that had no ischemic episodes during follow-up. Using 3D stereotactic surface projections, we quantified abnormal decreases in the BZRs in the cerebral cortex within the middle cerebral artery distribution and correlated changes in the BZR index with the mean hemispheric values of hemodynamic parameters obtained from 15 O gas positron emission tomography. Results— In the hemisphere affected by arterial disease, the BZR index in 40 patients (50%) was increased during follow-up (mean 26±20 months). In multivariable logistic regression analyses, increases in the BZR index were associated with the decreased cerebral blood flow at baseline and an increased oxygen extraction fraction during follow-up. Increases in the oxygen extraction fraction during follow-up were associated with a lack of statin use. Conclusions— In patients with atherosclerotic internal carotid artery or middle cerebral artery disease, the progression of cortical neuronal damage was associated with hemodynamic impairment at baseline and hemodynamic deterioration during follow-up. Statin use may be beneficial against hemodynamic deterioration and therefore neuroprotective.

Ischemic stroke results from occlusion of a cerebral artery, and it is the leading cause of disability and the fifth leading cause of death in the United States.1 Cerebral artery occlusion results in irreversible death of a component of cerebral tissue, which is referred to as the core infarction. There is an additional component of brain tissue that is ischemic, but viable, which is commonly referred to as the penumbra. The penumbra is at risk of irreversible infarction if timely restoration of blood flow is not achieved, and the preservation of the penumbra by restoration of arterial blood flow is the target of reperfusion therapy in the treatment of ischemic stroke. Increasingly, perfusion computed tomography CT (PCT) is performed for physiological evaluation of the brain parenchyma in the setting of cerebral ischemia, and this technique may be used to determine volume of core infarction and of the penumbra. The physiological data derived from PCT is typically displayed in perfusion maps, including cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT; Figure 1). Regions of brain with severely reduced CBV or CBF correspond to the region of core infarction.2 Regions of brain with prolongation of the MTT or its derivatives, the time-to-peak and time-to-maximum (Tmax) of the residue function, have been shown to accurately measure the penumbra in patients with acute ischemic stroke.2 Figure 1. Matched and Mismatched perfusion computed tomography (PCT) imaging in a patient with middle cerebral artery (MCA) occlusions. Noncontrast head CT (NCCT) and PCT images in a patient with a matched core and penumbra (patient 1) and in a patient with a mismatch between the core and penumbra (patient 2). Patient 1: NCCT images demonstrate evidence of acute ischemia within the left MCA territory, including loss of the left insular ribbon (NCCT, …

Background and Purpose— Here, we describe the clinical, angiographic characteristics, and long-term surgical outcome of hemorrhagic moyamoya disease in children. Methods— We retrospectively collected 374 consecutive children with moyamoya disease (hemorrhagic 30 and ischemic 344) between 2004 and 2012 in our hospital. The clinical and radiological characteristics of the hemorrhagic patients were retrospectively described and analyzed. All the hemorrhagic patients underwent encephalo-duro-arterio-synangiosis procedure. Digital subtraction angiography was performed to evaluate the efficacy of vascularization. Clinical follow-up outcomes were obtained through clinical visits, telephone, or letter interview. Results— In our study, the ratio of female to male patients in the hemorrhagic group was significantly higher than the ischemic group (2:1 versus 0.9:1; P P Conclusions— The presence of anterior choroidal artery and posterior communicating artery dilation may be associated with the bleeding episode in the children with hemorrhagic moyamoya disease. The encephalo-duro-arterio-synangiosis surgery can effectively increase the cerebral blood flow in children, which may decrease the incidence of recurrent hemorrhage.