QSM in canine model of acute cerebral ischemia: A pilot study.

PURPOSE: In the present study, we investigated the potential of QSM to assess the physiological state of cortical tissue in the middle cerebral artery occlusion canine model of a cerebral ischemia. METHODS: Experiments were performed in 8 anesthetized canines. Gradient echo, perfusion, and DWI data of brains at normal and ischemic states were acquired. In the postprocessed susceptibility and quantitative cerebral blood flow maps, changes in values within the middle cerebral artery-fed cortical territories were quantified both on the ischemic and normal contralateral hemisphere side. RESULTS: QSM values in critically ischemic tissue were significantly different from contralateral values-namely, susceptibility increase was observed in the cases in which cerebral perfusion was maintained above the threshold of neuronal death. Furthermore, the data indicates presence of a significant correlation between the changes in susceptibility values, cerebral perfusion, and the infarct volume and pial collateral scores. Additionally, our data suggests that difference in cortical susceptibility is prospectively indicative of the infarct growth rate. CONCLUSION: In an experimental permanent middle cerebral artery occlusion model, QSM was shown to correlate with the functional parameters characterizing viability of ischemic tissue, thus warranting further research on its ability to provide complementary information during acute stroke MRI examinations in humans.

Mechanical Thrombectomy for Patients with In-Hospital Ischemic Stroke: A Case-Control Study.

BACKGROUND AND AIM: Patients with in-hospital acute ischemic stroke (AIS) have, in general, worse outcomes compared to those presenting from the community, partly attributed to the numerous contraindications to intravenous thrombolysis. We aimed to identify and analyze a group of patients with in-hospital AIS who remain suitable candidates for acute endovascular therapies. METHODS: A retrospective 6-year data analysis was conducted in patients evaluated through the in-hospital stroke alert protocol in a single tertiary care university hospital to identify those with in-hospital AIS due to acute intracranial large vessel occlusion (ILVO). Feasibility and safety of mechanical thrombectomy for in-hospital AIS was assessed in a case-control study comparing inpatients to those presenting from the community. RESULTS: From 1460 in-hospital stroke alert activations, 11% had a final diagnosis of AIS (n = 167). One hundred and two patients with in-hospital AIS had emergent intracranial vessel imaging and were included in our cohort. Acute ILVO was identified in 27 patients within this cohort. Patients were younger in the ILVO group and had more severe neurologic deficit on presentation. Compared to a matched (1:2) control group of patients presenting from the community, inpatients who underwent mechanical thrombectomy achieved equivalent technical success, safety, and clinical outcomes. CONCLUSIONS: The incidence of acute ILVO in patients with in-hospital AIS who underwent emergent vessel imaging is similar to the reported incidence of ILVO in patients presenting with community-onset AIS. Among patients with in-hospital AIS secondary to ILVO, mechanical thrombectomy is a feasible and safe therapy associated with favorable outcomes.

Absolute quantitative MR perfusion and comparison against stable-isotope microspheres.

PURPOSE: This work sought to compare a quantitative T1 bookend dynamic susceptibility contrast MRI based perfusion protocol for absolute cerebral blood flow (qCBF) against CBF measured by the stable-isotope neutron capture microsphere method, a recognized reference standard for measuring tissue blood flow, at normocapnia, hypercapnia, and in acute stroke. METHODS: CBF was measured in anesthetized female canines by MRI and microspheres over 2 consecutive days for each case. On day 1, 5 canines were measured before and during a physiological challenge induced by carbogen inhalation; on day 2, 4 canines were measured following permanent occlusion of the middle cerebral artery. CBF and cerebrovascular reactivity measured by MRI and microsphere deposition were compared. RESULTS: MRI correlated strongly with microspheres at the hemispheric level for CBF during normo- and hypercapnic states (r2 = 0.96), for individual cerebrovascular reactivity (r2 = 0.84), and for postocclusion CBF (r2 = 0.82). Correction for the delay and dispersion of the contrast bolus resulted in a significant improvement in the correlation between MRI and microsphere deposition in the ischemic state (r2 = 0.96). In all comparisons, moderate correlations were found at the regional level. CONCLUSION: In an experimental canine model with and without permanent occlusion of the middle cerebral artery, MRI-based qCBF yielded moderate to strong correlations for absolute quantitative CBF and cerebrovascular reactivity measurements during normocapnia and hypercapnia. Correction for delay and dispersion greatly improved the quantitation during occlusion of the middle cerebral artery, underscoring the importance for this correction under focal ischemic condition.

Quantitative susceptibility mapping as a monitoring biomarker in cerebral cavernous malformations with recent hemorrhage.

BACKGROUND: Quantitative Susceptibility Mapping (QSM) MRI allows accurate assessment of iron content in cerebral cavernous malformations (CCM), and a threshold increase by 6% in QSM has been shown to reflect new symptomatic hemorrhage (SH) in previously stable lesions. PURPOSE/HYPOTHESIS: It is unclear how lesional QSM evolves in CCMs after recent SH, and whether this could serve as a monitoring biomarker in clinical trials aimed at preventing rebleeding in these lesions. STUDY TYPE: This is a prospective observational cohort study. POPULATION: 16 CCM patients who experienced a SH within the past year, whose lesion was not resected or irradiated. FIELD STRENGTH/SEQUENCE: The data acquisition was performed using QSM sequence implemented on a 3T MRI system ASSESSMENT: The lesional QSM assessments at baseline and yearly during 22 patient-years of follow-up were performed by a trained research staff including imaging scientists. STATISTICAL TESTS: Biomarker changes were assessed in relation to clinical events. Clinical trial modeling was performed using two-tailed tests of time-averaged difference (assuming within-patient correlation of 0.8, power = 0.9 and alpha = 0.1) to detect 20%, 30% or 50% effects of intervention on clinical and biomarkers event rates during two years of follow-up. RESULTS: The change in mean lesional QSM of index hemorrhagic lesions was +7.93% per patient-year in the whole cohort. There were 5 cases (31%) of recurrent SH or lesional growth, and twice as many instances (62%) with a threshold (6%) increase in QSM. There were no instances of SH hemorrhage or lesional growth without an associated threshold increase in QSM during the same epoch. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2018;47:1133-1138.

Comparison between whole-body and head and neck neurovascular coils for 3-T magnetic resonance proton resonance frequency shift thermography guidance in the head and neck region.

The purpose of this study is to compare the image quality of magnetic resonance (MR) treatment planning images and proton resonance frequency (PRF) shift thermography images and inform coil selection for MR-guided laser ablation of tumors in the head and neck region. Laser ablation was performed on an agar phantom and monitored via MR PRF shift thermography on a 3-T scanner, following acquisition of T1-weighted (T1W) planning images. PRF shift thermography images and T2-weighted (T2W) planning images were also performed in the neck region of five normal human volunteers. Signal-to-noise ratios (SNR) and temperature uncertainty were calculated and compared between scans acquired with the quadrature mode body integrated coil and a head and neck neurovascular coil. T1W planning images of the agar phantom produced SNRs of 4.0 and 12.2 for the quadrature mode body integrated coil and head and neck neurovascular coil, respectively. The SNR of the phantom MR thermography magnitude images obtained using the quadrature mode body integrated coil was 14.4 versus 59.6 using the head and neck coil. The average temperature uncertainty for MR thermography performed on the phantom with the quadrature mode body integrated coil was 1.1 versus 0.3 °C with the head and neck coil. T2W planning images of the neck in five human volunteers produced SNRs of 28.3 and 91.0 for the quadrature mode body integrated coil and head and neck coil, respectively. MR thermography magnitude images of the neck in the volunteers obtained using the quadrature mode body integrated coil had a signal-to-noise ratio of 8.3, while the SNR using the head and neck coil was 16.1. The average temperature uncertainty for MR thermography performed on the volunteers with the body coil was 2.5 versus 1.6 °C with the head and neck neurovascular coil. The quadrature mode body integrated coil provides inferior image quality for both basic treatment planning sequences and MR PRF shift thermography compared with a neurovascular coil, but may nevertheless be adequate for clinical purposes.

Adenoma localization for recurrent or persistent primary hyperparathyroidism using dynamic four-dimensional CT and venous sampling.

PURPOSE: To determine if parathyroid venous sampling (PVS) combined with four-dimensional (4D) computed tomography (CT) improves sensitivity and accuracy of identification of parathyroid adenoma in patients with recurrent or persistent primary hyperparathyroidism (pHPT) and negative technetium-99m methoxyisobutyl isonitrile ((99m)Tc-MIBI) and ultrasound (US) scans. MATERIALS AND METHODS: Both PVS and 4D CT were performed in 28 patients with recurrent or persistent pHPT and negative (99m)Tc-MIBI and US examinations. Localization by 4D CT alone and in combination with PVS and lateralization by PVS alone were retrospectively assessed for correlation with surgical results. Suspected adenomas on 4D CT were said to correlate with PVS if venous drainage identified on CT corresponded to sites of elevated parathyroid hormone concentration on PVS. Lesions difficult to identify on 4D CT were lesions < 1 cm in longest dimension. Results of 4D CT were classified as positive, negative, or equivocal. RESULTS: Surgery was performed in 22 of 28 patients. Surgery identified 23 parathyroid adenomas, 1 carcinoma, and 2 hyperplastic glands in 20 patients. 4D-CT alone localized 11 lesions in 10 patients. PVS helped localize 13 additional lesions in nine more patients and clarified two lesions that were equivocal on 4D CT. Comparing 4D CT alone with 4D CT plus PVS, the sensitivity increased from 50% to 95% (P = .004), and accuracy increased from 55% to 91% (P = .022). PVS lateralization had a sensitivity of 93.3%, positive predictive value of 66.7%, and accuracy of 63.6%. CONCLUSIONS: PVS significantly improves 4D CT localization of parathyroid adenomas in patients undergoing repeat surgery for pHPT with negative (99m)Tc-MIBI and US.

Dynamic permeability and quantitative susceptibility: related imaging biomarkers in cerebral cavernous malformations.

BACKGROUND AND PURPOSE: Hyperpermeability and iron deposition are 2 central pathophysiological phenomena in human cerebral cavernous malformation (CCM) disease. Here, we used 2 novel MRI techniques to establish a relationship between these phenomena. METHODS: Subjects with CCM disease (4 sporadic and 17 familial) underwent MRI imaging using the dynamic contrast-enhanced quantitative perfusion and quantitative susceptibility mapping techniques that measure hemodynamic factors of vessel leak and iron deposition, respectively, previously demonstrated in CCM disease. Regions of interest encompassing the CCM lesions were analyzed using these techniques. RESULTS: Susceptibility measured by quantitative susceptibility mapping was positively correlated with permeability of lesions measured using dynamic contrast-enhanced quantitative perfusion (r=0.49; P≤0.0001). The correlation was not affected by factors, including lesion volume, contrast agent, and the use of statin medication. Susceptibility was correlated with lesional blood volume (r=0.4; P=0.0001) but not with lesional blood flow. CONCLUSIONS: The correlation between quantitative susceptibility mapping and dynamic contrast-enhanced quantitative perfusion suggests that the phenomena of permeability and iron deposition are related in CCM; hence, more leaky lesions also manifest a more cumulative iron burden. These techniques might be used as biomarkers to monitor the course of this disease and the effect of therapy.

Flow augmentation therapies preserve brain network integrity and hemodynamics in a canine permanent occlusion model.

The acute phase of ischemic stroke presents a critical window for therapeutic intervention, where novel approaches such as hyper-acute cerebral flow augmentation offer promising avenues for neuroprotection. In this study, we investigated the effects of two such therapies, NEH (a combination of norepinephrine and hydralazine) and Sanguinate (pegylated bovine carboxyhemoglobin), on resting-state functional connectivity, global mean signal (GMS), and blood oxygen level-dependent (BOLD) time lag in a pre-clinical canine model of stroke via permanent occlusion of the middle cerebral artery (total of n = 40 IACUC-approved mongrel canines randomly split into control/natural history and two treatment groups). Utilizing group independent component analysis (ICA), we identified and examined the integrity of sensorimotor and visual networks both pre- and post-occlusion, across treatment and control groups. Our results demonstrated that while the control group exhibited significant disruptions in these networks following stroke, the treatment groups showed remarkable preservation of network integrity. Voxel-wise functional connectivity analysis revealed less pronounced alterations in the treatment groups, suggesting maintained neural connections. Notably, the treatments stabilized GMS, with only minimal reductions observed post-occlusion compared to significant decreases in the control group. Furthermore, BOLD time-lag unity plots indicated that NEH and Sanguinate maintained consistent hemodynamic response timing, as evidenced by tighter clustering around the line of unity, suggesting a potential neuroprotective effect. These findings were underscored by robust statistical analyses, including paired T-tests and Mann-Whitney U tests, which confirmed the significance of the connectivity changes observed. The correlation of BOLD time-lag variations with neuroimaging functional biomarkers highlighted the impact of stroke and the efficacy of early therapeutic interventions. Our study supports the further study of flow augmentation therapies such as NEH and Sanguinate in stroke treatment protocols and suggests flow augmentation therapies should be further explored in an effort to improve patient outcomes.

Efficacy Assessment of Cerebral Perfusion Augmentation Through Functional Connectivity in an Acute Canine Stroke Model.

BACKGROUND AND PURPOSE: Ischemic stroke disrupts functional connectivity within the brain's resting-state networks (RSNs), impacting recovery. This study evaluates the effects of NEH (Norepinephrine and Hydralazine), a cerebral perfusion augmentation therapy, on RSN integrity in a hyper-acute canine stroke model. MATERIALS AND METHODS: Fifteen adult purpose-bred mongrel canines, divided into treatment and control (natural history) groups, underwent endovascular induction of acute middle cerebral artery occlusion (MCAO). Post-occlusion, the treatment group received intra-arterial Norepinephrine (0.1-1.52 µg/kg/min, adjusted for 25-45 mmHg above baseline mean arterial pressure) and Hydralazine (20mg). Resting-state fMRI data were acquired with a 3.0 T scanner using a BOLD-sensitive EPI sequence (TR/TE=1400 ms/20ms, 2.5 mm slices, 300 temporal positions). Preprocessing included motion correction, spatial smoothing (2.5 mm FWHM), and high-pass filtering (0.01 Hz cutoff). Functional connectivity within RSNs were analyzed through group-level independent component analysis (ICA) and weighted whole-brain ROI-to-ROI connectome, pre-and post-MCAO. RESULTS: NEH therapy significantly maintained connectivity post-MCAO in the Higher-order Visual and Parietal RSNs, as evidenced by thresholded statistical mapping (TFCE p-corr > 0.95). However, this preservation was network-dependent, with no significant changes in the Primary Visual and Sensorimotor networks. CONCLUSIONS: NEH demonstrates potential as a proof-of-concept therapy for maintaining RSN functional connectivity following ischemic stroke, emphasizing the therapeutic promise of perfusion augmentation. These insights reinforce the role of functional connectivity as a measurable endpoint for stroke intervention efficacy, suggesting clinical translatability for patients with insufficient collateral circulation. ABBREVIATIONS: NEH＝ Norepinephrine and Hydralazine; RSN＝ Resting-State Network; ICA = Independent Component Analysis; rsfMRI = resting-state Functional Magnetic Resonance Imaging; MCAO = Middle Cerebral Artery Occlusion; TFCE = Threshold-Free Cluster Enhancement.

Quantification of Collateral Supply with Local-AIF Dynamic Susceptibility Contrast MRI Predicts Infarct Growth.

Background and purpose: In ischemic stroke, leptomeningeal collaterals can provide compensatory blood flow to tissue at risk despite an occlusion, and impact treatment response and infarct growth. The purpose of this work is to test the hypothesis that local perfusion with an appropriate Local Arterial Input Function (AIF) is needed to quantify the degree of collateral blood supply in tissue distal to an occlusion. Materials and methods: Seven experiments were conducted in a pre-clinical middle cerebral artery occlusion model. Magnetic resonance dynamic susceptibility contrast (DSC) was imaged and post-processed as cerebral blood flow maps with both a traditionally chosen single arterial input function (AIF) applied globally to the whole brain (i.e. "Global-AIF") and a novel automatic delay and dispersion corrected AIF (i.e. "Local AIF") that is sensitive to retrograde flow. Pial collateral recruitment was assessed from x-ray angiograms and infarct growth via serially acquired diffusion weighted MRI scans both blinded to DSC. Results: The degree of collateralization at x-ray correlated strongly with quantitative perfusion determined using the Local AIF in the ischemic penumbra (R2=0.81) compared to a traditionally chosen Global-AIF (R2=0.05). Quantitative perfusion calculated using a Local-AIF was negatively correlated (less infarct progression as local perfusion increased) with infarct growth (R2 = 0.79) compared to Global-AIF (R2=0.02). Conclusions: Local DSC perfusion with a Local-AIF is more accurate for assessing tissue status and degree of leptomeningeal collateralization than traditionally chosen AIFs. These findings support use of a Local-AIF in determining quantitative tissue perfusion with collateral supply in occlusive disease.

Utility of head CT in the evaluation of vertigo/dizziness in the emergency department.

Acute dizziness (including vertigo) is a common reason to visit the emergency room, and imaging with head CT is often performed initially to exclude a central cause. In this study, consecutive patients presenting with dizziness and undergoing head CT were retrospectively reviewed to determine diagnostic yield. Four hundred forty-eight consecutive head CTs in a representative sample of dizzy emergency room (ER) patients, including patients with other neurological symptoms, were reviewed to identify an acute or subacute cause for acute dizziness along with the frequency and modalities used in follow-up imaging. The diagnostic yield for head CT ordered in the ER for acute dizziness is low (2.2 %; 1.6 % for emergent findings), but MRI changes the diagnosis up to 16 % of the time, acutely in 8 % of cases. Consistent with the American College of Radiology appropriateness criteria and the literature, this study suggests a low diagnostic yield for CT in the evaluation of acute dizziness but an important role for MRI in appropriately selected cases.

Augmentation of perfusion with simultaneous vasodilator and inotropic agents in experimental acute middle cerebral artery occlusion: a pilot study.

BACKGROUND: This study tests the hypothesis that simultaneous cerebral blood pressure elevation and potent vasodilation augments perfusion to ischemic tissue in acute ischemic stroke and it varies by degree of pial collateral recruitment. METHODS: Fifteen mongrel canines were included. Subjects underwent permanent middle cerebral artery occlusion; pial collateral recruitment was scored before treatment. Seven treatment subjects received a continuous infusion of norepinephrine (0.1-1.52 µg/kg/min; titrated 25-45 mmHg above baseline mean arterial pressure while keeping systolic blood pressure below 180 mmHg) and hydralazine (20 mg) starting 30 min post-occlusion. Perfusion (cerebral blood flow-CBF) was evaluated with quantitative dynamic susceptibility contrast MRI 2.5 hours post-occlusion to produce images in mL/100 g/min, and relative CBF measured as ratios. Mean region of interest (ROI) values were reported, and compared and subject to regression analysis to elucidate trends. RESULTS: Differences in quantitative CBF (qCBF) between treatment and control group varied by degree of pial collateral recruitment, based on Wilcoxon rank sum scores and regression model fit. For poorly collateralized subjects, ipsilateral anatomic, core infarct, and penumbra regions showed treatment with higher qCBF, raised above the ischemic threshold, compared with the control, while well collateralized subjects showed a paradoxical decrease maintained above the ischemic threshold for neuronal death. qCBF on the contralateral side increased regardless of collateralization. CONCLUSION: Results suggest that perfusion can be augmented in ischemic stroke with norepinephrine and hydralazine. Perfusion augmentation depends on degree of collateralization and territory in question, with some evidence of vascular steal.

Quantitative perfusion and water transport time model from multi b-value diffusion magnetic resonance imaging validated against neutron capture microspheres.

Purpose: Quantification of perfusion in ml/100 g/min, rather than comparing relative values side-to-side, is critical at the clinical and research levels for large longitudinal and multi-center trials. Intravoxel incoherent motion (IVIM) is a non-contrast magnetic resonance imaging diffusion-based scan that uses a multitude of b-values to measure various speeds of molecular perfusion and diffusion, sidestepping inaccuracy of arterial input functions or bolus kinetics. Questions remain as to the original of the signal and whether IVIM returns quantitative and accurate perfusion in a pathology setting. This study tests a novel method of IVIM perfusion quantification compared with neutron capture microspheres. Approach: We derive an expression for the quantification of capillary blood flow in ml/100 g/min by solving the three-dimensional Gaussian probability distribution and defining water transport time (WTT) as when 50% of the original water remains in the tissue of interest. Calculations were verified in a six-subject pre-clinical canine model of normocapnia, CO2 induced hypercapnia, and middle cerebral artery occlusion (ischemic stroke) and compared with quantitative microsphere perfusion. Results: Linear regression analysis of IVIM and microsphere perfusion showed agreement (slope = 0.55, intercept = 52.5, R2=0.64) with a Bland-Altman mean difference of -11.8 [-78,54] ml/100 g/min. Linear regression between dynamic susceptibility contrast mean transit time and IVIM WTT asymmetry in infarcted tissue was excellent (slope=0.59, intercept = 0.3, R2=0.93). Strong linear agreement was found between IVIM and reference standard infarct volume (slope = 1.01, R2=0.79). The simulation of cerebrospinal fluid (CSF) suppression via inversion recovery returned a blood signal reduced by 82% from combined T1 and T2 effects. Conclusions: The accuracy and sensitivity of IVIM provides evidence that observed signal changes reflect cytotoxic edema and tissue perfusion and can be quantified with WTT. Partial volume contamination of CSF may be better removed during post-processing rather than with inversion recovery.

"Tumoral pseudoblush" identified within gliomas at high-spatial-resolution ultrahigh-field-strength gradient-echo MR imaging corresponds to microvascularity at stereotactic biopsy.

PURPOSE: To use directed biopsy sampling to determine whether microvascular assessment within gliomas, by means of ultrahigh-field-strength high-spatial-resolution gradient-echo (GRE) magnetic resonance (MR) imaging at 8 T, correlates with histopathologic assessment of microvascularity. MATERIALS AND METHODS: The study was institutional review board approved and HIPAA compliant. Informed consent was obtained. Thirty-five subjects with gliomas underwent 8-T and 80-cm MR imaging by using a GRE sequence (repetition time, 600-750 msec; echo time, 10 msec; in-plane resolution, 196 mm). Haphazardly arranged serpentine low-signal-intensity structures, often associated with areas of low signal intensity within the tumor bed ("tumoral pseudoblush") at MR imaging, were presumed to be related to tumoral microvascularity. Microvessel density (MVD) and microvessel size (MVS) ranked with a semiquantitative three-tier scale (high, medium, and low) relative to cortical penetrating veins were assessed from regions of interest identified at MR imaging and were compared with a similar assessment of stereotactic biopsy specimens by using Kendall τb. Tumor grade (high vs low) was compared with ultrahigh-field-strength high-resolution GRE MR analysis by using Pearson χ2. Discrepancies between 8-T and histopathologic assessment were identified and analyzed. RESULTS: Ultrahigh-field-strength high-resolution GRE MR imaging and histopathologic assessment concurred for MVS (P<.0001) and MVD (P<.0001). World Health Organization classification tumor grade was associated with number (P<.0005) and size (P<.0005) of foci of microvascularity within the tumor bed at 8-T MR imaging. Radiation-induced microvessel hyalinosis mimicked tumor microvascularity at 8-T MR imaging. Potential confounders could result from radiofrequency inhomogeneity and displaced normal microvasculature. CONCLUSION: Microvascularity identified as a tumoral pseudoblush at ultrahigh-field-strength high-resolution GRE MR imaging without contrast material shows promise as a marker for increased tumoral microvascularity.

Effect of early Sanguinate (PEGylated carboxyhemoglobin bovine) infusion on cerebral blood flow to the ischemic core in experimental middle cerebral artery occlusion.

BACKGROUND: Sanguinate, a bovine PEGylated carboxyhemoglobin-based oxygen carrier with vasodilatory, oncotic and anti-inflammatory properties designed to release oxygen in hypoxic tissue, was tested to determine if it improves infarct volume, collateral recruitment and blood flow to the ischemic core in hyperacute middle cerebral artery occlusion (MCAO). METHODS: Under an IACUC approved protocol, 14 mongrel dogs underwent endovascular permanent MCAO. Seven received Sanguinate (8 mL/kg) intravenously over 10 min starting 30 min following MCAO and seven received a similar volume of normal saline. Relative cerebral blood flow (rCBF) was assessed using neutron-activated microspheres prior to MCAO, 30 min following MCAO and 30 min following intervention. Pial collateral recruitment was scored and measured by arterial arrival time (AAT) immediately prior to post-MCAO microsphere injection. Diffusion-weighted 3T MRI was used to assess infarct volume approximately 2 hours after MCAO. RESULTS: Mean infarct volumes for control and Sanguinate-treated subjects were 4739 mm3 and 2585 mm3 (p=0.0443; r2=0.687), respectively. Following intervention, rCBF values were 0.340 for controls and 0.715 in the Sanguinate group (r2=0.536; p=0.0064). Pial collateral scores improved only in Sanguinate-treated subjects and AAT decreased by a mean of 0.314 s in treated subjects and increased by a mean of 0.438 s in controls (p<0.0276). CONCLUSION: Preliminary results indicate that topload bolus administration of Sanguinate in hyperacute ischemic stroke significantly improves infarct volume, pial collateral recruitment and CBF in experimental MCAO immediately following its administration.

Influence of simultaneous pressor and vasodilatory agents on the evolution of infarct growth in experimental acute middle cerebral artery occlusion.

BACKGROUND: This study sought to test the hypothesis that simultaneous central blood pressure elevation and potent vasodilation can mitigate pial collateral-dependent infarct growth in acute ischemic stroke. METHODS: Twenty mongrel canines (20-30 kg) underwent permanent middle cerebral artery occlusion (MCAO). Eight subjects received continuous infusion of norepinephrine (0.1-1.5200 µg/kg/min; titrated to a median of 34 mmHg above baseline mean arterial pressure) and hydralazine (20 mg) starting 30 min following MCAO. Pial collateral recruitment was scored prior to treatment and used to predict infarct volume based on a previously reported parameterization. Serial diffusion magnetic resonance imaging (MRI) acquisitions tracked infarct volumes over a 4-hour time frame. Infarct volumes and infarct volume growth between treatment and control groups were compared with each other and to predicted values. Fluid-attenuated inversion recovery (FLAIR) MRI, susceptibility weighted imaging (SWI), and necropsy findings were included in the evaluation. RESULTS: Differences between treatment and control group varied by pial collateral recruitment based on indicator-variable regression effects analysis with interaction confirmed by regression model fit. Benefit in treatment group was only in subjects with poor collaterals which had 35.7% less infarct volume growth (P=0.0008; ANOVA) relative to controls. Measured infarct growth was significantly lower than predicted by the model (linear regression partial F-test, slope P<0.001, intercept=0.003). There was no evidence for cerebral hemorrhage or posterior reversible encephalopathy syndrome. CONCLUSION: Our results indicate that a combination of norepinephrine and hydralazine administered in the acute phase of ischemic stroke mitigates infarct evolution in subjects with poor but not good collateral recruitment.

A Roadmap for Developing Plasma Diagnostic and Prognostic Biomarkers of Cerebral Cavernous Angioma With Symptomatic Hemorrhage (CASH).

BACKGROUND: Cerebral cavernous angioma (CA) is a capillary microangiopathy predisposing more than a million Americans to premature risk of brain hemorrhage. CA with recent symptomatic hemorrhage (SH), most likely to re-bleed with serious clinical sequelae, is the primary focus of therapeutic development. Signaling aberrations in CA include proliferative dysangiogenesis, blood-brain barrier hyperpermeability, inflammatory/immune processes, and anticoagulant vascular domain. Plasma levels of molecules reflecting these mechanisms and measures of vascular permeability and iron deposition on magnetic resonance imaging are biomarkers that have been correlated with CA hemorrhage. OBJECTIVE: To optimize these biomarkers to accurately diagnose cavernous angioma with symptomatic hemorrhage (CASH), prognosticate the risk of future SH, and monitor cases after a bleed and in response to therapy. METHODS: Additional candidate biomarkers, emerging from ongoing mechanistic and differential transcriptome studies, would further enhance the sensitivity and specificity of diagnosis and prediction of CASH. Integrative combinations of levels of plasma proteins and characteristic micro-ribonucleic acids may further strengthen biomarker associations. We will deploy advanced statistical and machine learning approaches for the integration of novel candidate biomarkers, rejecting noncorrelated candidates, and determining the best clustering and weighing of combined biomarker contributions. EXPECTED OUTCOMES: With the expertise of leading CA researchers, this project anticipates the development of future blood tests for the diagnosis and prediction of CASH to clinically advance towards precision medicine. DISCUSSION: The project tests a novel integrational approach of biomarker development in a mechanistically defined cerebrovascular disease with a relevant context of use, with an approach applicable to other neurological diseases with similar pathobiologic features.

Predictors for the extent of pial collateral recruitment in acute ischemic stroke.

BACKGROUND: Pial arterioles can provide a variable degree of collateral flow to ischemic vascular territories during acute ischemic stroke. This study sought to identify predictive factors of the degree of pial collateral recruitment in acute ischemic stroke. METHODS: Clinical information and arteriograms from 62 consecutive patients with stroke due to either middle cerebral artery (MCA) M1 segment or internal carotid artery (ICA) terminus occlusion within 6 h following symptom onset were retrospectively reviewed. Pial collaterals were defined based on the extent of reconstitution of the MCA territory. Patients with slow antegrade flow distal to the occlusion site were excluded and no anesthetics were used prior or during angiography. Results were analyzed using multivariate nominal logistic regression. RESULTS: Better pial collateral recruitment was associated with proximal MCA versus ICA terminus occlusion (p = 0.005; odds ratio (OR) = 9.3; 95% confidence interval (CI), 2.16-53.3), lower presenting National Institutes of Health Stroke Scale Score (NIHSSS) (p = 0.023; OR = 6.51; 95% CI, 1.49-41.7), and lower diastolic blood pressure (p = 0.0411; OR = 5.05; 95% CI, 1.20-29.2). Age, gender, symptom duration, diabetes, laterality, systolic blood pressure, glucose level, hematocrit, platelet level, and white blood cell count at presentation were not found to have a statistically significant association with pial collateral recruitment. CONCLUSIONS: Extent of pial collateral recruitment is strongly associated with the occlusion site (MCA M1 segment versus ICA terminus) and less strongly associated with presenting NIHSSS and diastolic blood pressure.

Common transcriptome, plasma molecules, and imaging signatures in the aging brain and a Mendelian neurovascular disease, cerebral cavernous malformation.

Brain senescence is associated with impaired endothelial barrier function, angiogenic and inflammatory activity, and propensity to brain hemorrhage. The same pathological changes occur in cerebral cavernous malformations (CCM), a genetic neurovascular anomaly. We hypothesized common transcriptomic and plasma cytokine signatures in the aging brain and CCM. We identified 320 genes [fold change ≥1.5; p < 0.05; false discovery rate (FDR) corrected] commonly dysregulated in the aging brain and CCM. Ontology and pathway analyses of the common differentially expressed genes were related to inflammation and extracellular matrix organization. Plasma levels of C-reactive protein and angiopoietin-2 were significantly greater in older compared to younger healthy non-CCM subjects and were also greater in CCM (Sporadic and Familial) subjects regardless of age (all: p < 0.05; FDR corrected). Plasma levels of vascular endothelial growth factor were significantly greater in older compared to younger subjects, in both healthy non-CCM and Sporadic-CCM groups (all: padj < 0.05). Plasma levels of vascular endothelial growth factor were also significantly greater in Familial-CCM cases with germ line mutations regardless of age (all: padj < 0.05) compared to both healthy non-CCM and Sporadic-CCM subjects. Brain white matter vascular permeability assessed by MRI followed the same pattern as vascular endothelial growth factor across all groups. In addition, quantitative susceptibility mapping of brain white matter, a measure of iron deposition, was increased in older compared to younger healthy non-CCM subjects. Genetic aberrations, plasma molecules, and imaging biomarkers in a well characterized Mendelian neurovascular disease may also be applicable in the aging brain. Graphical abstract.

High-Resolution MRI Microscopy Coil Assessment of Parotid Masses.

The goal of this study was to determine whether high-resolution magnetic resonance imaging (MRI) microscopy coil imaging can improve the depiction parotid masses. A total of 14 parotid masses, including 7 salivary neoplasms, 2 abnormal lymph nodes, and 5 benign cystic lesions were imaged with T2-weighted and fat-suppressed postcontrast T1-weighted sequences using a 47-mm diameter microscopy coil in addition to conventional MRI sequences acquired with a conventional head and neck neurovascular coil. Compared to conventional parotid MRI sequences, microscopy coil images provided better definition of the margins of neoplasms, provide more detailed definition of lymph node morphology, and better depict certain cyst contents in the superficial portions of the parotid gland. The microscopy coil images provided significantly better definition of lesions and surrounding tissues within the superficial parotid gland with resptect to the deep parotid gland structures due to loss of signal. Furthermore, the fat-suppressed postcontrast T1-weighted microscopy coil images were significantly better than the corresponding T2-weighted images for delineating the superficial parotid gland. Ultimately, the microscopy coil sequences added over 10 minutes to the examination time.