Capillary Transit Time Heterogeneity Research Articles

Macro- and microvascular contributions to cerebral structural alterations in patients with asymptomatic carotid artery stenosis.

Atherosclerosis can underly internal carotid artery stenosis (ICAS), a major risk factor for ischemic stroke, as well as small vessel disease (SVD). This study aimed to investigate hemodynamics and structural alterations associated with SVD in ICAS patients. 28 patients with unilateral asymptomatic ICAS and 30 age-matched controls underwent structural (T1-/T2-weighted and diffusion tensor imaging [DTI]) and hemodynamic (pseudo-continuous arterial spin labeling and dynamic susceptibility contrast) magnetic resonance imaging. SVD-related alterations were assessed using free water (FW), FW-corrected DTI, and peak-width of skeletonized mean diffusivity (PSMD). Furthermore, cortical thickness, cerebral blood flow (CBF), and capillary transit time heterogeneity (CTH) were analyzed. Ipsilateral to the stenosis, cortical thickness was significantly decreased in the posterior dorsal cingulate cortex (p = 0.024) and temporal pole (p = 0.028). ICAS patients exhibited elevated PSMD (p = 0.005), FW (p < 0.001), and contralateral alterations in FW-corrected DTI metrics. We found significantly lateralized CBF (p = 0.011) and a tendency for lateralized CTH (p = 0.067) in the white matter (WM) related to ICAS. Elevated PSMD and FW may indicate a link between SVD and WM changes. Contralateral alterations were seen in FW-corrected DTI, whereas hemodynamic and cortical changes were mainly ipsilateral, suggesting SVD might influence global brain changes concurrent with ICAS-related hemodynamic alterations.

Clinical, qualitative imaging biomarkers, and tumor oxygenation imaging biomarkers for differentiation of midline-located IDH wild-type glioblastomas and H3 K27-altered diffuse midline gliomas in adults

PurposeTo compare the clinical, qualitative and quantitative imaging phenotypes, including tumor oxygenation characteristics of midline-located IDH-wildtype glioblastomas (GBMs) and H3 K27-altered diffuse midline gliomas (DMGs) in adults. MethodsPreoperative MRI data of 55 adult patients with midline-located IDH-wildtype GBM or H3 K27-altered DMG (32 IDH-wildtype GBM and 23 H3 K27-altered DMG patients) were included. Qualitative imaging assessment was performed. Quantitative imaging assessment including the tumor volume, normalized cerebral blood volume, capillary transit time heterogeneity (CTH), oxygen extraction fraction (OEF), relative cerebral metabolic rate of oxygen values, and mean ADC value were performed from the tumor mask via automatic segmentation. Univariable and multivariable logistic analyses were performed. ResultsOn multivariable analysis, age (odds ratio [OR] = 0.92, P = 0.015), thalamus or medulla location (OR = 10.48, P = 0.013), presence of necrosis (OR = 0.15, P = 0.038), and OEF (OR = 0.01, P = 0.042) were independent predictors to differentiate H3 K27-altered DMG from midline-located IDH-wildtype GBM. The area under the curve, accuracy, sensitivity, and specificity of the multivariable model were 0.88 (95 % confidence interval: 0.77–0.95), 81.8 %, 82.6 %, and 81.3 %, respectively. ConclusionsAlong with younger age, tumor location, less frequent necrosis, and lower OEF may be useful imaging biomarkers to differentiate H3 K27-altered DMG from midline-located IDH-wildtype GBM. Tumor oxygenation imaging biomarkers may reflect the less hypoxic nature of H3 K27-altered DMG than IDH-wildtype GBM and may contribute to differentiation.

Blood-brain Barrier Permeability May Influence Vasopressor Effects in Anesthetized Patients With Brain Tumor: An Analysis of Magnetic Resonance Imaging Data

Objective: This is a secondary analysis of data from a previous study of anesthetized brain tumor patients receiving ephedrine or phenylephrine infusions. 18 patients with magnetic imaging verified tumor contrast enhancement were included. We hypothesized that vasopressors induce microcirculatory flow changes, characterized by increased capillary transit time heterogeneity (CTH) and decreased mean transit time (MTT), in brain regions exhibiting BBB leakage. Methods: This is a secondary analysis of data from a previous study of anesthetized brain tumor patients receiving ephedrine or phenylephrine infusions. 18 patients with magnetic imaging verified tumor contrast enhancement were included. Postvasopressor to prevasopressor ratios of CTH, MTT, relative transit time heterogeneity (RTH), cerebral blood flow (CBF), cerebral blood volume, and oxygen extraction fraction (OEF) were calculated in tumor, peritumoral, hippocampal, and contralateral grey matter regions. Comparisons were made between brain regions and vasopressors. Results: During phenylephrine infusion, ratios of CTH, RTH, and CBF were greater, and ratios of MTT and OEF were lower, in the tumor region with contrast leakage compared with corresponding contralateral grey matter ratios. During ephedrine infusion, ratios of CTH, MTT, RTH, CBF, and cerebral blood volume were higher in the tumor region with leakage compared with contralateral grey matter ratios. In addition, the ratio of CBF was higher in all regions, the ratio of RTH was lower in the leaking tumor region, and the ratio of OEF was lower in peritumoral, hippocampal, and grey matter regions with ephedrine compared with phenylephrine. Conclusions: Vasopressors can induce distinct microcirculatory flow alterations in regions with compromised brain tumor barrier or BBB. Ephedrine, a combined α and β-adrenergic agonist, appears to result in fewer flow alterations and less impact on tissue oxygenation compared with phenylephrine, a pure α-adrenergic agonist.

Prediction of pseudoprogression in post-treatment glioblastoma using dynamic susceptibility contrast-derived oxygenation and microvascular transit time heterogeneity measures.

To evaluate the added value of MR dynamic susceptibility contrast (DSC)-perfusion-weighted imaging (PWI)-derived tumour microvascular and oxygenation information with cerebral blood volume (CBV) to distinguish pseudoprogression from true progression (TP) in post-treatment glioblastoma. This retrospective single-institution study included patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma and a newly developed or enlarging measurable contrast-enhancing mass within 12 weeks after concurrent chemoradiotherapy. CBV, capillary transit time heterogeneity (CTH), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) were obtained from DSC-PWI. Predictors were selected using univariable logistic regression, and performance was measured with adjusted diagnostic odds with tumour volume and area under the curve (AUC) of receiver operating characteristics analysis. A total of 103 patients were included (mean age, 59.6 years; 59 women), with 67 cases of TP and 36 cases of pseudoprogression. Pseudoprogression exhibited higher CTH (4.0 vs. 3.4, p= .019) and higher OEF (12.7 vs. 10.7, p= .014) than TP, but a similar CBV (1.48 vs. 1.53, p= .13) and CMRO2 (7.7 vs. 7.3s, p= .598). Independent of tumour volume, both high CTH (adjusted odds ratio [OR] 1.52; 95% confidence interval [CI]: 1.11-2.09, p= .009) and high OEF (adjusted OR 1.17; 95% CI:1.03-1.33, p= .016) were predictors of pseudoprogression. The combination of CTH, OEF, and CBV yielded higher diagnostic performance (AUC 0.71) than CBV alone (AUC 0.65). High intratumoural capillary transit heterogeneity and high oxygen extraction fraction derived from DSC-PWI have enhanced the diagnostic value of CBV in pseudoprogression of post-treatment IDH-wild type glioblastoma. In the early post-treatment stage of glioblastoma, pseudoprogression exhibited both high oxygen extraction fraction and high capillary transit heterogeneity and these dynamic susceptibility contrast-perfusion weighted imaging derived parameters have added value in cerebral blood volume-based noninvasive differentiation of pseudoprogression from true progression. • Capillary transit time heterogeneity and oxygen extraction fraction can be measured noninvasively through processing of dynamic susceptibility contrast imaging. • Pseudoprogression exhibited higher capillary transit time heterogeneity and higher oxygen extraction fraction than true progression. • A combination of cerebral blood volume, capillary transit time heterogeneity, and oxygen extraction fraction yielded the highest diagnostic performance (area under the curve 0.71).

Stronger influence of systemic than local hemodynamic-vascular factors on resting-state BOLD functional connectivity

Correlated fluctuations in the blood oxygenation level dependent (BOLD) signal of resting-state functional MRI (i.e., BOLD-functional connectivity, BOLD-FC) reflect a spectrum of neuronal and non-neuronal processes. In particular, there are multiple hemodynamic-vascular influences on BOLD-FC on both systemic (e.g., perfusion delay) and local levels (e.g., neurovascular coupling). While the influence of individual factors has been studied extensively, combined and comparative studies of systemic and local hemodynamic-vascular factors on BOLD-FC are scarce, notably in humans. We employed a multi-modal MRI approach to investigate and compare distinct hemodynamic-vascular processes and their impact on homotopic BOLD-FC in healthy controls and patients with unilateral asymptomatic internal carotid artery stenosis (ICAS). Asymptomatic ICAS is a cerebrovascular disorder, in which neuronal functioning is largely preserved but hemodynamic-vascular processes are impaired, mostly on the side of stenosis. Investigated indicators for local hemodynamic-vascular processes comprise capillary transit time heterogeneity (CTH) and cerebral blood volume (CBV) from dynamic susceptibility contrast (DSC) MRI, and cerebral blood flow (CBF) from pseudo-continuous arterial spin labeling (pCASL). Indicators for systemic processes are time-to-peak (TTP) from DSC MRI and BOLD lags from functional MRI. For each of these parameters, their influence on BOLD-FC was estimated by a comprehensive linear mixed model. Equally across groups, we found that individual mean BOLD-FC, local (CTH, CBV, and CBF) and systemic (TTP and BOLD lag) hemodynamic-vascular factors together explain 40.7% of BOLD-FC variance, with 20% of BOLD-FC variance explained by hemodynamic-vascular factors, with an about two-times larger contribution of systemic versus local factors. We conclude that regional differences in blood supply, i.e., systemic perfusion delays, exert a stronger influence on BOLD-FC than impairments in local neurovascular coupling.

Modeling transit time distributions in microvascular networks

The time a red blood cell (RBC) spends in the microvasculature is of prime importance for a number of physiological processes. In this work, we present a methodology for computing an approximation of the so-called transit time distribution (TTD), i.e., the probabilistic description of how long a RBC will reside within the network. As a proof of concept, we apply this methodology to three flavors of the mesh networks. We show that each network type supports multiple distinct steady-state configurations and we present tools for analyzing the associated collection of TTDs, ranging from standard measures like mean capillary transit time (MCTT) and capillary transit time heterogeneity (CTTH) to novel metrics.

Capillary transit time heterogeneity inhibits cerebral oxygen metabolism in patients with reduced cerebrovascular reserve capacity from steno-occlusive disease

The healthy cerebral perfusion demonstrates a homogenous distribution of capillary transit times. A disruption of this homogeneity may inhibit the extraction of oxygen. A high degree of capillary transit time heterogeneity (CTH) describes that some capillaries have very low blood flows, while others have excessively high blood flows and consequently short transit times. Very short transit times could hinder the oxygen extraction due to insufficient time for diffusion of oxygen into the tissue. CTH could be a consequence of cerebral vessel disease. We examined whether patients with cerebral steno-occlusive vessel disease demonstrate high CTH and if elevation of cerebral blood flow (CBF) by administration of acetazolamide (ACZ) increases the cerebral metabolic rate of oxygen (CMRO2), or if some patients demonstrate reduced CMRO2 related to detrimental CTH. Thirty-four patients and thirty-one healthy controls participated. Global CBF and CMRO2 were acquired using phase-contrast MRI. Regional brain maps of CTH were acquired using dynamic contrast-enhanced MRI. Patients with impaired cerebrovascular reserve capacity demonstrated elevated CTH and a significant reduction of CMRO2 after administration of ACZ, which could be related to high CTH. Impaired oxygen extraction from CTH could be a contributing part of the declining brain health observed in patients with cerebral vessel disease.

Resting-state BOLD functional connectivity depends on the heterogeneity of capillary transit times in the human brain A combined lesion and simulation study about the influence of blood flow response timing

Functional connectivity (FC) derived from blood oxygenation level dependent (BOLD) functional magnetic resonance imaging at rest (rs-fMRI), is commonly interpreted as indicator of neuronal connectivity. In a number of brain disorders, however, metabolic, vascular, and hemodynamic impairments can be expected to alter BOLD-FC independently from neuronal activity. By means of a neurovascular coupling (NVC) model of BOLD-FC, we recently demonstrated that aberrant timing of cerebral blood flow (CBF) responses may influence BOLD-FC. In the current work, we support and extend this finding by empirically linking BOLD-FC with capillary transit time heterogeneity (CTH), which we consider as an indicator of delayed and broadened CBF responses. We assessed 28 asymptomatic patients with unilateral high-grade internal carotid artery stenosis (ICAS) as a hemodynamic lesion model with largely preserved neurocognitive functioning and 27 age-matched healthy controls. For each participant, we obtained rs-fMRI, arterial spin labeling, and dynamic susceptibility contrast MRI to study the dependence of left-right homotopic BOLD-FC on local perfusion parameters. Additionally, we investigated the dependency of BOLD-FC on CBF response timing by detailed simulations. Homotopic BOLD-FC was negatively associated with increasing CTH differences between homotopic brain areas. This relation was more pronounced in asymptomatic ICAS patients even after controlling for baseline CBF and relative cerebral blood volume influences. These findings match simulation results that predict an influence of delayed and broadened CBF responses on BOLD-FC. Results demonstrate that increasing CTH differences between homotopic brain areas lead to BOLD-FC reductions. Simulations suggest that CTH increases correspond to broadened and delayed CBF responses to fluctuations in ongoing neuronal activity.

This Month in Anesthesiology

This Month in Anesthesiology

Anesthesiology

Phenylephrine, a pure α-adrenergic agonist, and ephedrine, an indirectly acting α- and β-adrenergic agonist, are commonly administered during neurosurgical procedures to treat anesthesia-related hypotension and maintain cerebral perfusion pressure. In this issue of Anesthesiology, Koch et al. compared ephedrine and phenylephrine treatment on cerebral macro- and microcirculation, measured by cerebral blood flow, and capillary transit time heterogeneity, in anesthetized brain tumor patients. In an accompanying editorial, García and Brown discuss the current limitations of intraoperative brain monitoring and the implications of these new findings. Cover Illustration: A. Johnson, Vivo Visuals Studio.

Comprehensive Evaluation of Cerebral Hemodynamics and Oxygen Metabolism in Revascularization of Asymptomatic High-Grade Carotid Stenosis

IntroductionRevascularization procedures in carotid artery stenosis have shown a positive effect in the restoration of cerebral oxygen metabolism as assessed by T2’ (T2 prime) imaging as well as capillary homeostasis by measurement of capillary transit time heterogeneity (CTH); however, data in patients with asymptomatic carotid stenosis without manifest brain lesions are scarce.Patients and MethodsThe effect of revascularization on the hemodynamic profile and capillary homeostasis was evaluated in 13 patients with asymptomatic high-grade carotid stenosis without ischemic brain lesions using dynamic susceptibility contrast perfusion imaging and oxygenation-sensitive T2’ mapping before and 6–8 weeks after revascularization by endarterectomy or stenting. The cognitive performance at both timepoints was further assessed.ResultsPerfusion impairment at baseline was accompanied by an increased CTH (p = 0.008) in areas with a time to peak delay ≥ 2 s in the affected hemisphere compared to contralateral regions. Carotid intervention improved the overall moderate hemodynamic impairment at baseline by leading to an increase in normalized cerebral blood flow (p = 0.017) and a decrease in mean transit time (p = 0.027), oxygen extraction capacity (OEC) (p = 0.033) and CTH (p = 0.048). The T2’ values remained unchanged.ConclusionThis study presents novel evidence of a state of altered microvascular function in patients with high-grade carotid artery stenosis in the absence of ischemic brain lesions, which shows sustained normalization after revascularization procedures.

MTT Heterogeneity in Perfusion CT Imaging as a Predictor of Outcome after Aneurysmal SAH.

Impairment of tissue oxygenation caused by inhomogeneous microscopic blood flow distribution, the so-called capillary transit time heterogeneity, is thought to contribute to delayed cerebral ischemia after aneurysmal SAH but has so far not been systematically evaluated in patients. We hypothesized that heterogeneity of the MTT, derived from CTP parameters, would give insight into the clinical course of patients with aneurysmal SAH and may identify patients at risk of poor outcome. We retrospectively analyzed the heterogeneity of the MTT using the coefficient of variation in CTP scans from 132 patients. A multivariable logistic regression model was used to model the dichotomized mRS outcome. Linear regression was used to eliminate variables with high linear dependence. T tests were used to compare the means of 2 groups. Furthermore, the time of the maximum coefficient of variation for MTT after bleeding was evaluated for correlation with the mRS after 6 months. On average, each patient underwent 5.3 CTP scans during his or her stay. Patients with high coefficient of variation for MTT presented more often with higher modified Fisher (P = .011) and World Federation of Neurosurgical Societies grades (P = .014). A high coefficient of variation for MTT at days 3-21 after aneurysmal SAH correlated significantly with a worse mRS score after 6 months (P = .016). We found no correlation between the time of the maximum coefficient of variation for MTT after bleeding and the patients' outcomes after 6 months (P = .203). Heterogeneity of MTT in CTP after aneurysmal SAH correlates with the patients' outcomes. Because the findings are in line with the pathophysiologic concept of the capillary transit time heterogeneity, future studies should seek to verify the coefficient of variation for MTT as a potential imaging biomarker for outcome.

Dynamics of cerebral perfusion and oxygenation parameters following endovascular treatment of acute ischemic stroke

BackgroundWe studied the effects of endovascular treatment (EVT) and the impact of the extent of recanalization on cerebral perfusion and oxygenation parameters in patients with acute ischemic stroke (AIS) and...

Blood flow, capillary transit times, and tissue oxygenation: the centennial of capillary recruitment.

The transport of oxygen between blood and tissue is limited by blood's capillary transit time, understood as the time available for diffusion exchange before blood returns to the heart. If all capillaries contribute equally to tissue oxygenation at all times, this physical limitation would render vasodilation and increased blood flow insufficient means to meet increased metabolic demands in the heart, muscle, and other organs. In 1920, Danish physiologist August Krogh was awarded the Nobel Prize in Physiology or Medicine for his mathematical and quantitative, experimental demonstration of a solution to this conceptual problem: capillary recruitment, the active opening of previously closed capillaries to meet metabolic demands. Today, capillary recruitment is still mentioned in textbooks. When we suspect symptoms might represent hypoxia of a vascular origin, however, we search for relevant, flow-limiting conditions in our patients and rarely ascribe hypoxia or hypoxemia to short capillary transit times. This review describes how natural changes in capillary transit-time heterogeneity (CTH) and capillary hematocrit (HCT) across open capillaries during blood flow increases can account for a match of oxygen availability to metabolic demands in normal tissue. CTH and HCT depend on a number of factors: on blood properties, including plasma viscosity, the number, size, and deformability of blood cells, and blood cell interactions with capillary endothelium; on anatomical factors including glycocalyx, endothelial cells, basement membrane, and pericytes that affect the capillary diameter; and on any external compression. The review describes how risk factor- and disease-related changes in CTH and HCT interfere with flow-metabolism coupling and tissue oxygenation and discusses whether such capillary dysfunction contributes to vascular disease pathology.

Hemodynamic impairments within individual watershed areas in asymptomatic carotid artery stenosis by multimodal MRI

Improved understanding of complex hemodynamic impairments in asymptomatic internal carotid artery stenosis (ICAS) is crucial to better assess stroke risks. Multimodal MRI is ideal for measuring brain hemodynamics and has the potential to improve diagnostics and treatment selections. We applied MRI-based perfusion and oxygenation-sensitive imaging in ICAS with the hypothesis that the sensitivity to hemodynamic impairments will improve within individual watershed areas (iWSA). We studied cerebral blood flow (CBF), cerebrovascular reactivity (CVR), relative cerebral blood volume (rCBV), relative oxygen extraction fraction (rOEF), oxygen extraction capacity (OEC) and capillary transit-time heterogeneity (CTH) in 29 patients with asymptomatic, unilateral ICAS (age 70.3 ± 7.0 y) and 30 age-matched healthy controls. In ICAS, we found significant impairments of CBF, CVR, rCBV, OEC, and CTH (strongest lateralization ΔCVR = –24%), but not of rOEF. Although the spatial overlap of compromised hemodynamic parameters within each patient varied in a complex manner, most pronounced changes of CBF, CVR and rCBV were detected within iWSAs (strongest effect ΔCVR = +117%). At the same time, CTH impairments were iWSA independent, indicating widespread dysfunction of capillary-level oxygen diffusivity. In summary, complementary MRI-based perfusion and oxygenation parameters offer deeper perspectives on complex microvascular impairments in individual patients. Furthermore, knowledge about iWSAs improves the sensitivity to hemodynamic impairments.

Abstract WP326: Cortical Border Zones Are More Vulnerable to Spreading Depression-Induced Capillary Flow Disturbances

Cortical spreading depression (SD) is a major metabolic challenge to the brain and is followed by a unique hemodynamic response. It has been suggested that the oligemic phase of this response is accompanied by a mild to moderate capillary dysfunction. To test this hypothesis, we directly investigated microcirculatory flow changes during and after SD at the territory of major arteries as well as their hemodynamically vulnerable watershed zones. Swiss mice (n=6) under isoflurane anesthesia were tracheotomized, mechanically ventilated, and imaged under two-photon microscopy through a closed cranial window. Mean transit time (MTT), capillary transit time heterogeneity (CTH) and relative transit time heterogeneity (RTH) were calculated based on an indicator-dilution method using intravenous boluses of Texas-red dextran fluorescent dye (70,000 MW; 0.5%). Boluses were performed at the steady-state and 1 min, 5 min and 30 minutes after potassium chloride-induced SD. MTT, CTH, and RTH were estimated within the territory and border zone of major arteries to reveal any regional differences. Physiological parameters were monitored and kept within normal limits throughout the experiments. Both MTT and CTH increased following SD in the territorial zone from 1.07±0.03 to 1.67±0.15 s (mean±SEM;p&lt;0.01) and from 0.51±0.03 to 0.94±0.07 s (mean±SEM;p&lt;0.01), respectively. However, RTH was only mildly increased in this region from 0.49±0.04 to 0.59±0.06 (p=0.03). In the watershed area, all three parameters showed a more prominent increase following SD and RTH rose from 0.64±0.06 to 1.25±0.22 at 30 minutes (p=0.04). These findings provide direct experimental evidence for prolonged capillary flow disturbances induced by cortical SD, which may account for some lasting neurological symptoms after aura. The particular vulnerability of border zones to SD-induced flow disturbances may be involved in the pathogenesis of some of the white matter MRI lesions observed in migraineurs.

Impaired perfusion and capillary dysfunction in prodromal Alzheimer's disease.

IntroductionCardiovascular disease increases the risk of developing Alzheimer's disease (AD), and growing evidence suggests an involvement of cerebrovascular pathology in AD. Capillary dysfunction, a condition in which capillary flow disturbances rather than arterial blood supply limit brain oxygen extraction, could represent an overlooked vascular contributor to neurodegeneration. We examined whether cortical capillary transit‐time heterogeneity (CTH), an index of capillary dysfunction, is elevated in amyloid‐positive patients with mild cognitive impairment (prodromal AD [pAD]).MethodsWe performed structural and perfusion weighted MRI in 22 pAD patients and 21 healthy controls.ResultsWe found hypoperfusion, reduced blood volume, and elevated CTH in the parietal and frontal cortices of pAD‐patients compared to controls, while only the precuneus showed focal cortical atrophy.DiscussionWe propose that microvascular flow disturbances antedate cortical atrophy and may limit local tissue oxygenation in pAD. We speculate that capillary dysfunction contributes to the development of neurodegeneration in AD.

Increased volumes of mildly elevated capillary transit time heterogeneity positively predict favorable outcome and negatively predict intracranial hemorrhage in acute ischemic stroke with large vessel occlusion.

In patients with acute ischemic stroke, we aimed to investigate whether microvascular changes, as indexed by capillary transit time heterogeneity (CTH), contribute to the decline of the chance for favorable outcome over time and whether they are a predictor of an intracranial hemorrhage (ICH). We retrospectively calculated CTH maps for 131 consecutive patients with acute ischemic stroke due to large vessel occlusion of the anterior circulation who had a relevant MRI PWI-DWI mismatch and were treated with endovascular thrombectomy (ET). Multivariable logistic regressions were conducted with favorable outcome (mRS ≤ 2 after 3months) and occurrence of an ICH as dependent variables and the volume of mildly elevated CTH as independent variable adjusted for age, successful recanalization, hypertension, diabetes, atrial fibrillation, NIHSS score on admission, DWI lesion volume, and symptom-onset-to-treatment time (OTT). A larger volume of mildly elevated CTH was a positive predictor of favorable outcome (OR 1.17; 1.03-1.33; p = 0.019) and a negative predictor of ICH (OR 0.83; 0.73-0.96; p = 0.009). As expected, successful recanalization (OR 5.54; 1.8-17; p = 0.003), low NIHSS on admission (OR 0.9; 0.82-1.00; p = 0.045), short OTT (OR 0.96; 0.94-0.99; p = 0.006), and low DWI volume (OR 0.68; 0.49-0.94; p = 0.021) were also predictors of favorable outcome, whereas other negative predictors of ICH were atrial fibrillation (OR 2.69; 1.10-6.57; p = 0.030), high NIHSS score on admission (OR 1.10 (1.01-1.19); p = 0.030), and large DWI volume (OR 1.51; 1.17-1.19; p = 0.002). An increased volume of mildly elevated CTH is a positive predictor of favorable outcome and a negative predictor for ICH in patients with acute ischemic stroke and mismatch undergoing ET. • The classification of potentially salvageable tissue and infarct core based on traditional net perfusion parameters (as Tmax or CBF) does not account for the microvascular distribution of blood. • However, the microvascular distribution of blood, as indexed by the capillary transit time heterogeneity (CTH), directly affects the availability of oxygen within the hypoperfused tissue and should therefore be respected in acute ischemic stroke imaging. • In our study, mildly elevated CTH is found to be a positive predictor for a favorable clinical outcome and a negative predictor for the occurrence of an intracranial hemorrhage in patients with acute ischemic stroke and homogenous mismatch who underwent ET.

Abstract WP338: Penetrating Arteriole Flow Dynamics and Capillary Transient Time Heterogeneity Following Experimental Stroke in Two Mouse Strains With Distinct Pial Collateral Circulation

Introduction: In the pathophysiology of ischemic stroke, Leptomeningeal collateral circulation plays a key role on the severity of infarction. Balb/C mice have impaired leptomeningeal collateral due to variants of Rabep2 on chromosome 7 ( Candq1 ), causing sever stroke compared to C57BL/6 mice with rich collateral anastomosis. However, it still remains unclear whether and how poor collateral circulation specifically affects hemodynamic adaptation of microvessels during cerebral ischemia. Method: Male C57BL/6 and Balb/C mice were subjected to distal middle cerebral artery occlusion (dMCAO) combined with 90 minutes-occlusion of the ipsilateral common carotid artery. A 4x4 mm 2 cranial window was created on the parietal cortex 2 mm lateral and 1 mm posterior from the bregma 3 weeks prior to imaging. Spatial and temporal changes of the total flow and axial velocity of the penetrating arterioles (PA), as well as mean transit time (MTT) and capillary transit time heterogeneity (CTTH) in the capillaries bordering the distal MCA and ACA branches were determined by optical coherent tomography-based microangiography and capillary velocimetry at baseline, during dMCAO, 1 hour, 1 day and 7 days after reperfusion in each strain. Results: Stroke-induced increase in CTTH in the region of middle cerebral artery was significantly greater in Balb/C compared to C57BL/6 mice, leading to significantly increased microvascular resistance and reduced oxygen extraction during MCAO and 1 hour after reperfusion in the former (P&lt;0.05). The total blood flow in PA reduced immediately after dMCAO in both strains of mice but it remained reduced in Balb/C mice after reperfusion in contrast to a sustainable recovery at 50% of prestroke level 7 days after stroke. Conclusion: Poor collateral anastomosis and impaired flow of penetrating arterioles is an additional risk factor for hemodynamic compromise during cerebral ischemia caused by reduced oxygen extraction, which may increase the severity of stroke.

Compromised microvascular oxygen delivery increases brain tissue vulnerability with age

Despite the possible role of impaired cerebral tissue oxygenation in age-related cognition decline, much is still unknown about the changes in brain tissue pO2 with age. Using a detailed investigation of the age-related changes in cerebral tissue oxygenation in the barrel cortex of healthy, awake aged mice, we demonstrate decreased arteriolar and tissue pO2 with age. These changes are exacerbated after middle-age. We further uncovered evidence of the presence of hypoxic micro-pockets in the cortex of awake old mice. Our data suggests that from young to middle-age, a well-regulated capillary oxygen supply maintains the oxygen availability in cerebral tissue, despite decreased tissue pO2 next to arterioles. After middle-age, due to decreased hematocrit, reduced capillary density and higher capillary transit time heterogeneity, the capillary network fails to compensate for larger decreases in arterial pO2. The substantial decrease in brain tissue pO2, and the presence of hypoxic micro-pockets after middle-age are of significant importance, as these factors may be related to cognitive decline in elderly people.