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Transit time homogenization in ischemic stroke - A novel biomarker of penumbral microvascular failure?

ABSTRACT: Cerebral ischemia causes widespread capillary no-flow in animal studies. The extent of microvascular impairment in human stroke, however, is unclear. We examined how acute intra-voxel transit time characteristics and subsequent recanalization affect tissue outcome on follow-up MRI in a historic cohort of 126 acute ischemic stroke patients. Based on perfusion-weighted MRI data, we characterized voxel-wise transit times in terms of their mean transit time (MTT), standard deviation (capillary transit time heterogeneity - CTH), and the CTH:MTT ratio (relative transit time heterogeneity), which is expected to remain constant during changes in perfusion pressure in a microvasculature consisting of passive, compliant vessels. To aid data interpretation, we also developed a computational model that relates graded microvascular failure to changes in these parameters. In perfusion-diffusion mismatch tissue, prolonged mean transit time (>5 seconds) and very low cerebral blood flow (?6?mL/100?mL/min) was associated with high risk of infarction, largely independent of recanalization status. In the remaining mismatch region, low relative transit time heterogeneity predicted subsequent infarction if recanalization was not achieved. Our model suggested that transit time homogenization represents capillary no-flow. Consistent with this notion, low relative transit time heterogeneity values were associated with lower cerebral blood volume. We speculate that low RTH may represent a novel biomarker of penumbral microvascular failure.

SUBMITTER: Engedal TS

PROVIDER: S-EPMC6259320 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Transit time homogenization in ischemic stroke - A novel biomarker of penumbral microvascular failure?

Engedal Thorbjørn S TS Hjort Niels N Hougaard Kristina D KD Simonsen Claus Z CZ Andersen Grethe G Mikkelsen Irene Klærke IK Boldsen Jens K JK Eskildsen Simon F SF Hansen Mikkel B MB Angleys Hugo H Jespersen Sune N SN Pedraza Salvador S Cho Tae H TH Serena Joaquín J Siemonsen Susanne S Thomalla Götz G Nighoghossian Norbert N Fiehler Jens J Mouridsen Kim K Østergaard Leif L

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20170731 11

Cerebral ischemia causes widespread capillary no-flow in animal studies. The extent of microvascular impairment in human stroke, however, is unclear. We examined how acute intra-voxel transit time characteristics and subsequent recanalization affect tissue outcome on follow-up MRI in a historic cohort of 126 acute ischemic stroke patients. Based on perfusion-weighted MRI data, we characterized voxel-wise transit times in terms of their mean transit time (MTT), standard deviation (capillary trans ...[more]

PMID: 28758524

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Project description:Background: To discover novel metabolic biomarkers of ischemic stroke (IS), we carried out a two-stage metabolomic profiling of IS patients and healthy controls using untargeted and targeted metabolomic approaches. Methods: We applied untargeted liquid chromatography-mass spectrometry (LC-MS) to detect the plasma metabolomic profiles of 150 acute IS patients and 50 healthy controls. The candidate differential microbiota-derived metabolite phenylacetylglutamine (PAGln) was validated in 751 patients with IS and 200 healthy controls. We evaluated the associations between PAGln levels and the severity and functional outcomes of patients with IS. Clinical mild stroke was defined as the National Institutes of Health Stroke Scale (NIHSS) score 0-5, and moderate-severe stroke as NIHSS score >5. A favorable outcome at 3 months after IS was defined as the modified Rankin Scale (mRS) score 0-2, and unfavorable outcome as mRS score 3-6. Results: In untargeted metabolomic analysis, we detected 120 differential metabolites between patients with IS and healthy controls. Significantly altered metabolic pathways were purine metabolism, TCA cycle, steroid hormone biosynthesis, and pantothenate and CoA biosynthesis. Elevated plasma PAGln levels in IS patients, compared with healthy controls, were observed in untargeted LC-MS analysis and confirmed by targeted quantification (median 2.0 vs. 1.0 μmol/L; p < 0.001). Patients with moderate-severe stroke symptoms and unfavorable short-term outcomes also had higher levels of PAGln both in discovery and validation stage. After adjusting for potential confounders, high PAGln levels were independently associated with IS (OR = 3.183, 95% CI 1.671-6.066 for the middle tertile and OR = 9.362, 95% CI 3.797-23.083 for the highest tertile, compared with the lowest tertile) and the risk of unfavorable short-term outcomes (OR = 2.286, 95% CI 1.188-4.401 for the highest tertile). Conclusions: IS patients had higher plasma levels of PAGln than healthy controls. PAGln might be a potential biomarker for IS and unfavorable functional outcomes in patients with IS.

Project description:Background and objectiveInflammation has emerged as a prominent risk factor for cerebral small vessel disease (CSVD). However, the specific association between various inflammatory biomarkers and the development of CSVD remains unclear. Serine proteinase inhibitor A3 (SERPINA3), Matrix metalloproteinase-9 (MMP-9), Tissue inhibitor metalloproteinase-1 (TIMP-1), Monocyte Chemoattractant Protein-1 (MCP-1) are several inflammatory biomarkers that are potentially involved in the development of CSVD. In this present study, we aimed to investigate the relationship between candidate molecules and CSVD features.MethodThe concentration of each biomarker was measured in 79 acute ischemic stroke patients admitted within 72 h after symptom onset. The associations between blood levels of inflammatory markers and CSVD score were investigated, as well as each CSVD feature, including white matter hyperintensities (WMH), lacunes, and enlarged perivascular spaces (EPVS).ResultsThe mean age was 69.0 ± 11.8 years, and 65.8% of participants were male. Higher SERPINA3 level (>78.90 ng/mL) was significantly associated with larger WMH volume and higher scores on Fazekas's scale in all three models. Multiple regression analyses revealed the linear association between absolute WMH burden and SERPINA3 level, especially in model 3 (β = 0.14; 95% confidence interval [CI], 0.04-0.24 ; p =0.008 ). Restricted cubic spline regression demonstrated a dose-response relationship between SERPINA3 level and larger WMH volume (p nonlineariy = 0.0366 and 0.0378 in model 2 and mode 3, respectively). Using a receiving operating characteristic (ROC) curve, plasma SERPINA3 level of 64.15 ng/mL distinguished WMH >7.8 mL with the highest sensitivity and specificity (75.92% and 60%, respectively, area under curve [AUC] = 0.668, p = 0.0102). No statistically significant relationship has been found between other candidate biomarkers and CSVD features.ConclusionIn summary, among four inflammatory biomarkers that we investigated, SERPINA3 level at baseline was associated with WMH severity, which revealed a novel biomarker for CSVD and validated its relationship with inflammation and endothelial dysfunction.

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Transit time homogenization in ischemic stroke - A novel biomarker of penumbral microvascular failure?

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Transit time homogenization in ischemic stroke - A novel biomarker of penumbral microvascular failure?

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