Defining the Ischemic Penumbra Using Magnetic Resonance Oxygen Metabolic Index

Abstract

Background and Purpose Penumbral biomarkers promise to individualize treatment windows in acute ischemic stroke. We used a novel MRI approach which measures oxygen metabolic index (OMI), a parameter closely related to PET-derived cerebral metabolic rate of oxygen utilization, to derive a pair of ischemic thresholds: (1) an irreversible-injury threshold which differentiates ischemic core from penumbra and (2) a reversible-injury threshold which differentiates penumbra from tissue not-at-risk for infarction. Methods Forty acute ischemic stroke patients underwent MRI at three time-points after stroke onset: < 4.5 hours (for OMI threshold derivation), 6 hours (to determine reperfusion status), and 1 month (for infarct probability determination). A dynamic susceptibility contrast method measured CBF, and an asymmetric spin echo sequence measured OEF, to derive OMI (OMI=CBF*OEF). Putative ischemic threshold pairs were iteratively tested using a computation-intensive method to derive infarct probabilities in three tissue groups defined by the thresholds (core, penumbra, and not-at-risk tissue). An optimal threshold pair was chosen based on its ability to predict: infarction in the core, reperfusion-dependent survival in the penumbra, and survival in not-at-risk tissue. The predictive abilities of the thresholds were then tested within the same cohort using a 10-fold cross-validation method. Results The optimal OMI ischemic thresholds were found to be 0.28 and 0.42 of normal values in the contralateral hemisphere. Using the 10-fold cross-validation method, median infarct probabilities were 90.6% for core, 89.7% for non-reperfused penumbra, 9.95% for reperfused penumbra, and 6.28% for not-at-risk tissue. Conclusions OMI thresholds, derived using voxel-based, reperfusion-dependent infarct probabilities, delineated the ischemic penumbra with high predictive ability. These thresholds will require confirmation in an independent patient sample.

Mapping of cerebral metabolic rate of oxygen using dynamic susceptibility contrast and blood oxygen level dependent MR imaging in acute ischemic stroke

“…Our findings are in line with PET studies [5], revealing stable CMRO 2 caused by perfusion impairment and elevated OEF [11]. Moreover, the finding that rCMRO 2 values were significantly decreased within the infarct core compared to perfusion-restricted tissue and healthy tissue is consistent with PET imaging [11,17] as well as with a previous study analyzing MR-derived CMRO 2 [2]. The latter found ischemic thresholds based on their ability to predict infarction or survival of tissue within the ischemic core, penumbra, and tissue at risk for infarction.…”

“…Yet, because first imaging occurred on average 46 min after treatment in this previous study, falsely decreased thresholds may have been estimated due to tissue that was reperfused immediately after rtPA administration and therefore not detected with the initial MR scan. Comparable mean rCMRO 2 ratios of perfusion-impaired tissue appear to be higher than the calculated threshold for penumbral tissue [2]. This effect is most likely caused by the fact that perfusion-impaired VOI contains large amounts of tissue which is not at risk of infarction and not yet reperfused regularly, since treatment was administered after the initial MR scan in our study.…”

“…However, this modality is practically inapplicable in acute stroke diagnosis due to the long examination duration (in total >40 min) [4,10,38]. In contrast, MR imaging has been shown to detect elevated rCMRO 2 indirectly through elevated deoxyhemoglobin in tissue at risk of infarction based on BOLD and DSC PWI in previous studies [2]. rCMRO 2 maps as used in our study and previously are corrected for the influence of CBV and CBF, which varies significantly in supply territories of occluded vessels, and therefore, the local metabolic impairment, visualized indirectly through accumulation of deoxyhemoglobin and corrected for perfusion impairment, is reflected more precisely than with uncorrected T2′-measurements alone.…”

“…However, transverse relaxation times T2 and T2* alone are not valid indicators of blood oxygenat i o n b e c a u s e t h e y a r e i n f l u e n c e d b y t h e t o t a l deoxyhemoglobin content within a voxel, i.e., the blood volume, blood flow, and a number of additional influences [25]. Because of this, more sophisticated methods have been developed to estimate CMRO 2 [2,26,48], which are based on an acceptably fast semi-quantitative measurements of the relative oxygen extraction fraction (rOEF) with a reasonable volume coverage [25]. This new BOLD-based method for rOEF mapping has been applied in glioma patients [25,43], yielding promising results [43], and was multiplied by the standard dynamic DSC voxel-by-voxel-derived CBF in order to calculate the relative CMRO 2 (rCMRO 2 ).…”

pH-sensitive MRI demarcates graded tissue acidification during acute stroke ― pH specificity enhancement with magnetization transfer and relaxation-normalized amide proton transfer (APT) MRI

“…In comparison, despite the fluctuation of cerebral perfusion and oxygen saturation, tissue pH is well regulated under the normal physiological conditions. Tissue pH shift is associated with glucose/oxygen delivery and consumption imbalance during the acute stroke (An et al, 2015; Shen et al, 2016; Shu et al, 2016; Zhu et al, 2013). Because tissue acidification is exacerbated by the reduced buffering capacity of bicarbonate and hypoperfusion, often leading to cell death and tissue damage (Siesjo, 1992), pH imaging can serve as an important surrogate metabolic imaging biomarker during acute ischemic stroke.…”