Perfusion MRI

Wu O, Ostergaard L, Sorensen GA. Technical aspects of perfusion-weighted imaging. Neuroimaging Clin N Am 2005;15(3):623-37, xi.Abstract
There is increasing interest in using diffusion-weighted (DWI) MR imaging and perfusion-weighted MR imaging (PWI) to assist clinical decision-making in the management of acute stroke patients. Larger PWI than DWI lesions have been speculated to represent potentially salvageable tissue that is at risk of infarction unless nutritive flow is restored and presence of these mismatches have been proposed as inclusion criteria for identifying patients most likely to benefit from therapeutic intervention. Understanding the technical aspects of PWI may improve comprehension of the capabilities and limitations of this technique.
Kwong KK, Wu O, Chan S-T, Nelissen K, Kholodov M, Chesler DA. Early time points perfusion imaging: relative time of arrival, maximum derivatives and fractional derivatives. Neuroimage 2011;57(3):979-90.Abstract
Time of arrival (TOA) of a bolus of contrast agent to the tissue voxel is a reference time point critical for the Early Time Points Perfusion Imaging Method (ET) to make relative cerebral blood flow (rCBF) maps. Due to the low contrast to noise (CNR) condition at TOA, other useful reference time points known as relative time of arrival data points (rTOA) are investigated. Candidate rTOA's include the time to reach the maximum derivative, the maximum second derivative, and the maximum fractional derivative. Each rTOA retains the same relative time distance from TOA for all tissue flow levels provided that ET's basic assumption is met, namely, no contrast agent has a chance to leave the tissue before the time of rTOA. The ET's framework insures that rCBF estimates by different orders of the derivative are theoretically equivalent to each other and monkey perfusion imaging results supported the theory. In rCBF estimation, maximum values of higher order fractional derivatives may be used to replace the maximum derivative which runs a higher risk of violating ET's assumption. Using the maximum values of the derivative of orders ranging from 1 to 1.5 to 2, estimated rCBF results were found to demonstrate a gray-white matter ratio of approximately 3, a number consistent with flow ratio reported in the literature.
Nelson S, Edlow BL, Wu O, Rosenthal ES, Westover BM, Rordorf G. Default Mode Network Perfusion in Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care 2016;25(2):237-42.Abstract
BACKGROUND: The etiology of altered consciousness in patients with high-grade aneurysmal subarachnoid hemorrhage (SAH) is not thoroughly understood. We hypothesized that decreased cerebral blood flow (CBF) in brain regions critical to consciousness may contribute. METHODS: We retrospectively evaluated arterial-spin labeled (ASL) perfusion magnetic resonance imaging (MRI) measurements of CBF in 12 patients with aneurysmal SAH admitted to our neurocritical care unit. CBF values were analyzed within gray matter nodes of the default mode network (DMN), whose functional integrity has been shown to be necessary for consciousness. DMN nodes studied were the bilateral medial prefrontal cortices, thalami, and posterior cingulate cortices. Correlations between nodal CBF and admission Glasgow Coma Scale (GCS) score, admission Hunt and Hess (HH) class, and GCS score at the time of MRI (MRI GCS) were tested. RESULTS: Spearman's correlation coefficients were not significant when comparing admission GCS, admission HH, and MRI GCS versus nodal CBF (p > 0.05). However, inter-rater reliability for nodal CBF was high (r = 0.71, p = 0.01). CONCLUSIONS: In this retrospective pilot study, we did not identify significant correlations between CBF and admission GCS, admission HH class, or MRI GCS for any DMN node. Potential explanations for these findings include small sample size, ASL data acquisition at variable times after SAH onset, and CBF analysis in DMN nodes that may not reflect the functional integrity of the entire network. High inter-rater reliability suggests ASL measurements of CBF within DMN nodes are reproducible. Larger prospective studies are needed to elucidate whether decreased cerebral perfusion contributes to altered consciousness in SAH.
Emmer BJ, van Osch MJ, Wu O, Steup-Beekman GM, Steens SC, Huizinga TW, van Buchem MA, van der Grond J. Perfusion MRI in neuro-psychiatric systemic lupus erthemathosus. J Magn Reson Imaging 2010;32(2):283-8.Abstract
PURPOSE: To use perfusion weighted MR to quantify any perfusion abnormalities and to determine their contribution to neuropsychiatric (NP) involvement in systemic lupus erythematosus (SLE). MATERIALS AND METHODS: We applied dynamic susceptibility contrast (DSC) perfusion MRI in 15 active NPSLE, 26 inactive NPSLE patients, and 11 control subjects. Cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) maps were reconstructed and regions of interest were compared between groups. In addition, the effect of SLE criteria, NPSLE syndromes, immunological coagulation disorder, and medication on CBF, CBV, and MTT was investigated. RESULTS: No significant differences were found between the groups in CBF, CBV, and MTT. No significant influence of SLE criteria or NPSLE syndromes on CBF, CBV, or MTT was found. No significant influence of anti-cardiolipin antibodies, lupus anti-coagulant, the presence of anti-phospholipid syndrome (APS), or medication on CBF, CBV, or MTT was found. CONCLUSION: Our findings suggest CBF, CBV, and MTT in the white and the gray matter in SLE patients is not significantly different from healthy controls or between patients with and without specific symptoms or with and without immunological disorder involving coagulation.
Copen WA, Deipolyi AR, Schaefer PW, Schwamm LH, González RG, Wu O. Exposing hidden truncation-related errors in acute stroke perfusion imaging. AJNR Am J Neuroradiol 2015;36(4):638-45.Abstract
BACKGROUND AND PURPOSE: The durations of acute ischemic stroke patients' CT or MR perfusion scans may be too short to fully sample the passage of the injected contrast agent through the brain. We tested the potential magnitude of hidden errors related to the truncation of data by short perfusion scans. MATERIALS AND METHODS: Fifty-seven patients with acute ischemic stroke underwent perfusion MR imaging within 12 hours of symptom onset, using a relatively long scan duration (110 seconds). Shorter scan durations (39.5-108.5 seconds) were simulated by progressively deleting the last-acquired images. CBV, CBF, MTT, and time to response function maximum (Tmax) were measured within DWI-identified acute infarcts, with commonly used postprocessing algorithms. All measurements except Tmax were normalized by dividing by the contralateral hemisphere values. The effects of the scan duration on these hemodynamic measurements and on the volumes of lesions with Tmax of >6 seconds were tested using regression. RESULTS: Decreasing scan duration from 110 seconds to 40 seconds falsely reduced perfusion estimates by 47.6%-64.2% of normal for CBV, 1.96%-4.10% for CBF, 133%-205% for MTT, and 6.2-8.0 seconds for Tmax, depending on the postprocessing method. This truncation falsely reduced estimated Tmax lesion volume by 71.5 or 93.8 mL, depending on the deconvolution method. "Lesion reversal" (ie, change from above-normal to apparently normal, or from >6 seconds to ≤6 seconds for the time to response function maximum) with increasing truncation occurred in 37%-46% of lesions for CBV, 2%-4% for CBF, 28%-54% for MTT, and 42%-44% for Tmax, depending on the postprocessing method. CONCLUSIONS: Hidden truncation-related errors in perfusion images may be large enough to alter patient management or affect outcomes of clinical trials.
Wu O, Benner T, Roccatagliata L, Zhu M, Schaefer PW, Sorensen AG, Singhal AB. Evaluating effects of normobaric oxygen therapy in acute stroke with MRI-based predictive models. Med Gas Res 2012;2(1):5.Abstract
BACKGROUND: Voxel-based algorithms using acute multiparametric-MRI data have been shown to accurately predict tissue outcome after stroke. We explored the potential of MRI-based predictive algorithms to objectively assess the effects of normobaric oxygen therapy (NBO), an investigational stroke treatment, using data from a pilot study of NBO in acute stroke. METHODS: The pilot study of NBO enrolled 11 patients randomized to NBO administered for 8 hours, and 8 Control patients who received room-air. Serial MRIs were obtained at admission, during gas therapy, post-therapy, and pre-discharge. Diffusion/perfusion MRI data acquired at admission (pre-therapy) was used in generalized linear models to predict the risk of lesion growth at subsequent time points for both treatment scenarios: NBO or Control. RESULTS: Lesion volume sizes 'during NBO therapy' predicted by Control-models were significantly larger (P = 0.007) than those predicted by NBO models, suggesting that ischemic lesion growth is attenuated during NBO treatment. No significant difference was found between the predicted lesion volumes at later time-points. NBO-treated patients, despite showing larger lesion volumes on Control-models than NBO-models, tended to have reduced lesion growth. CONCLUSIONS: This study shows that NBO has therapeutic potential in acute ischemic stroke, and demonstrates the feasibility of using MRI-based algorithms to evaluate novel treatments in early-phase clinical trials.
Wu O, Sumii T, Asahi M, Sasamata M, Ostergaard L, Rosen BR, Lo EH, Dijkhuizen RM. Infarct prediction and treatment assessment with MRI-based algorithms in experimental stroke models. J Cereb Blood Flow Metab 2007;27(1):196-204.Abstract
There is increasing interest in using algorithms combining multiple magnetic resonance imaging (MRI) modalities to predict tissue infarction in acute human stroke. We developed and tested a voxel-based generalized linear model (GLM) algorithm to predict tissue infarction in an animal stroke model in order to directly compare predicted outcome with the tissue's histologic outcome, and to evaluate the potential for assessing therapeutic efficacy using these multiparametric algorithms. With acute MRI acquired after unilateral embolic stroke in rats (n=8), a GLM was developed and used to predict infarction on a voxel-wise basis for saline (n=6) and recombinant tissue plasminogen activator (rt-PA) treatment (n=7) arms of a trial of delayed thrombolytic therapy in rats. Pretreatment predicted outcome compared with post-treatment histology was highly accurate in saline-treated rats (0.92+/-0.05). Accuracy was significantly reduced (P=0.04) in rt-PA-treated animals (0.86+/-0.08), although no significant difference was detected when comparing histologic lesion volumes. Animals that reperfused had significantly lower (P<0.01) GLM-predicted infarction risk (0.73+/-0.03) than nonreperfused animals (0.81+/-0.05), possibly reflecting less severe initial ischemic injury and therefore tissue likely more amenable to therapy. Our results show that acute MRI-based algorithms can predict tissue infarction with high accuracy in animals not receiving thrombolytic therapy. Furthermore, alterations in disease progression due to treatment were more sensitively monitored with our voxel-based analysis techniques than with volumetric approaches. Our study shows that predictive algorithms are promising metrics for diagnosis, prognosis and therapeutic evaluation after acute stroke that can translate readily from preclinical to clinical settings.
Copen WA, Schaefer PW, Wu O. MR perfusion imaging in acute ischemic stroke. Neuroimaging Clin N Am 2011;21(2):259-83, x.Abstract
Magnetic resonance (MR) perfusion imaging offers the potential for measuring brain perfusion in acute stroke patients, at a time when treatment decisions based on these measurements may affect outcomes dramatically. Rapid advancements in both acute stroke therapy and perfusion imaging techniques have resulted in continuing redefinition of the role that perfusion imaging should play in patient management. This review discusses the basic pathophysiology of acute stroke, the utility of different kinds of perfusion images, and research on the continually evolving role of MR perfusion imaging in acute stroke care.
Kwong KK, Reese TG, Nelissen K, Wu O, Chan S-T, Benner T, Mandeville JB, Foley M, Vanduffel W, Chesler DA. Early time points perfusion imaging. Neuroimage 2011;54(2):1070-82.Abstract
The aim was to investigate the feasibility of making relative cerebral blood flow (rCBF) maps from MR images acquired with short TR by measuring the initial arrival amount of Gd-DTPA evaluated within a time window before any contrast agent has a chance to leave the tissue. We named this rCBF measurement technique utilizing the early data points of the Gd-DTPA bolus the "early time points" method (ET), based on the hypothesis that early time point signals were proportional to rCBF. Simulation data were used successfully to examine the ideal behavior of ET while monkey's MRI results offered encouraging support to the utility of ET for rCBF calculation. A better brain coverage for ET could be obtained by applying the Simultaneous Echo Refocusing (SER) EPI technique. A recipe to run ET was presented, with attention paid to the noise problem around the time of arrival (TOA) of the contrast agent.
Jafari-Khouzani K, Emblem KE, Kalpathy-Cramer J, Bjørnerud A, Vangel MG, Gerstner ER, Schmainda KM, Paynabar K, Wu O, Wen PY, Batchelor T, Rosen B, Stufflebeam SM. Repeatability of Cerebral Perfusion Using Dynamic Susceptibility Contrast MRI in Glioblastoma Patients. Transl Oncol 2015;8(3):137-46.Abstract
OBJECTIVES: This study evaluates the repeatability of brain perfusion using dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) with a variety of post-processing methods. METHODS: Thirty-two patients with newly diagnosed glioblastoma were recruited. On a 3-T MRI using a dual-echo, gradient-echo spin-echo DSC-MRI protocol, the patients were scanned twice 1 to 5 days apart. Perfusion maps including cerebral blood volume (CBV) and cerebral blood flow (CBF) were generated using two contrast agent leakage correction methods, along with testing normalization to reference tissue, and application of arterial input function (AIF). Repeatability of CBV and CBF within tumor regions and healthy tissues, identified by structural images, was assessed with intra-class correlation coefficients (ICCs) and repeatability coefficients (RCs). Coefficients of variation (CVs) were reported for selected methods. RESULTS: CBV and CBF were highly repeatable within tumor with ICC values up to 0.97. However, both CBV and CBF showed lower ICCs for healthy cortical tissues (up to 0.83), healthy gray matter (up to 0.95), and healthy white matter (WM; up to 0.93). The values of CV ranged from 6% to 10% in tumor and 3% to 11% in healthy tissues. The values of RC relative to the mean value of measurement within healthy WM ranged from 22% to 42% in tumor and 7% to 43% in healthy tissues. These percentages show how much variation in perfusion parameter, relative to that in healthy WM, we expect to observe to consider it statistically significant. We also found that normalization improved repeatability, but AIF deconvolution did not. CONCLUSIONS: DSC-MRI is highly repeatable in high-grade glioma patients.
Christensen S, Mouridsen K, Wu O, Hjort N, Karstoft H, Thomalla G, Röther J, Fiehler J, Kucinski T, Østergaard L. Comparison of 10 perfusion MRI parameters in 97 sub-6-hour stroke patients using voxel-based receiver operating characteristics analysis. Stroke 2009;40(6):2055-61.Abstract
BACKGROUND AND PURPOSE: Perfusion-weighted imaging can predict infarct growth in acute stroke and potentially be used to select patients with tissue at risk for reperfusion therapies. However, the lack of consensus and evidence on how to best create PWI maps that reflect tissue at risk challenges comparisons of results and acute decision-making in trials. Deconvolution using an arterial input function has been hypothesized to generate maps of a more quantitative nature and with better prognostic value than simpler summary measures such as time-to-peak or the first moment of the concentration time curve. We sought to compare 10 different perfusion parameters by their ability to predict tissue infarction in acute ischemic stroke. METHODS: In a retrospective analysis of 97 patients with acute stroke studied within 6 hours from symptom onset, we used receiver operating characteristics in a voxel-based analysis to compare 10 perfusion parameters: time-to-peak, first moment, cerebral blood volume and flow, and 6 variants of time to peak of the residue function and mean transit time maps. Subanalysis assessed the effect of reperfusion on outcome prediction. RESULTS: The most predictive maps were the summary measures first moment and time-to-peak. First moment was significantly more predictive than time to peak of the residue function and local arterial input function-based methods (P<0.05), but not significantly better than conventional mean transit time maps. CONCLUSIONS: Results indicated that if a single map type was to be used to predict infarction, first moment maps performed at least as well as deconvolved measures. Deconvolution decouples delay from tissue perfusion; we speculate this negatively impacts infarct prediction.
Deipolyi AR, Wu O, Macklin EA, Schaefer PW, Schwamm LH, Gilberto Gonzalez R, Copen WA. Reliability of cerebral blood volume maps as a substitute for diffusion-weighted imaging in acute ischemic stroke. J Magn Reson Imaging 2012;36(5):1083-7.Abstract
PURPOSE: To assess the reliability of cerebral blood volume (CBV) maps as a substitute for diffusion-weighted MRI (DWI) in acute ischemic stroke. In acute stroke, DWI is often used to identify irreversibly injured "core" tissue. Some propose using perfusion imaging, specifically CBV maps, in place of DWI. We examined whether CBV maps can reliably subsitute for DWI, and assessed the effect of scan duration on calculated CBV. MATERIALS AND METHODS: We retrospectively identified 58 patients who underwent DWI and MR perfusion imaging within 12 h of stroke onset. CBV in each DWI lesion's center was divided by CBV in the normal-appearing contralateral hemisphere to yield relative regional CBV (rrCBV). The proportion of lesions with decreased rrCBV was calculated. After using the full scan duration (110 s after contrast injection), rrCBV was recalculated using simulated shorter scans. The effect of scan duration on rrCBV was tested with linear regression. RESULTS: Using the full scan duration (110 s), rrCBV was increased in most DWI lesions (62%; 95% confidence interval, 48-74%). rrCBV increased with increasing scan duration (P < 0.001). Even with the shortest duration (39.5 s) rrCBV was increased in 33% of lesions. CONCLUSION: Because DWI lesions may have elevated or decreased CBV, CBV maps cannot reliably substitute for DWI in identifying the infarct core.
Lorenzano S, Rost NS, Khan M, Li H, Lima FO, Maas MB, Green RE, Thankachan TK, Dipietro AJ, Arai K, Som AT, Pham L-DD, Wu O, Harris GJ, Lo EH, Blumberg JB, Milbury PE, Feske SK, Furie KL. Oxidative Stress Biomarkers of Brain Damage: Hyperacute Plasma F2-Isoprostane Predicts Infarct Growth in Stroke. Stroke 2018;Abstract
BACKGROUND AND PURPOSE: Oxidative stress is an early response to cerebral ischemia and is likely to play an important role in the pathogenesis of cerebral ischemic injury. We sought to evaluate whether hyperacute plasma concentrations of biomarkers of oxidative stress, inflammation, and tissue damage predict infarct growth (IG). METHODS: We prospectively measured plasma F2-isoprostane (F2-isoP), urinary 8-oxo-7,8-dihydro-2'-deoxyguoanosine, plasma oxygen radical absorbance capacity assay, high sensitivity C reactive protein, and matrix metalloproteinase 2 and 9 in consecutive patients with acute ischemic stroke presenting within 9 hours of symptom onset. Patients with baseline diffusion-weighted magnetic resonance imaging and follow-up diffusion-weighted imaging or computed tomographic scan were included to evaluate the final infarct volume. Baseline diffusion-weighted imaging volume and final infarct volume were analyzed using semiautomated volumetric method. IG volume was defined as the difference between final infarct volume and baseline diffusion-weighted imaging volume. RESULTS: A total of 220 acute ischemic stroke subjects were included in the final analysis. One hundred seventy of these had IG. Baseline F2-isoP significantly correlated with IG volume (Spearman ρ=0.20; P=0.005) and final infarct volume (Spearman ρ=0.19; P=0.009). In a multivariate binary logistic regression model, baseline F2-isoP emerged as an independent predictor of the occurrence of IG (odds ratio, 2.57; 95% confidence interval, 1.37-4.83; P=0.007). In a multivariate linear regression model, baseline F2-isoP was independently associated with IG volume (B, 0.38; 95% confidence interval, 0.04-0.72; P=0.03). CONCLUSIONS: Elevated hyperacute plasma F2-isoP concentrations independently predict the occurrence of IG and IG volume in patients with acute ischemic stroke. If validated in future studies, measuring plasma F2-isoP might be helpful in the acute setting to stratify patients with acute ischemic stroke for relative severity of ischemic injury and expected progression.
Rost NS, Cougo P, Lorenzano S, Li H, Cloonan L, Bouts MJRJ, Lauer A, Etherton MR, Karadeli HH, Musolino PL, Copen WA, Arai K, Lo EH, Feske SK, Furie KL, Wu O. Diffuse microvascular dysfunction and loss of white matter integrity predict poor outcomes in patients with acute ischemic stroke. J Cereb Blood Flow Metab 2018;38(1):75-86.Abstract
We sought to investigate the relationship between blood-brain barrier (BBB) permeability and microstructural white matter integrity, and their potential impact on long-term functional outcomes in patients with acute ischemic stroke (AIS). We studied 184 AIS subjects with perfusion-weighted MRI (PWI) performed <9 h from last known well time. White matter hyperintensity (WMH), acute infarct, and PWI-derived mean transit time lesion volumes were calculated. Mean BBB leakage rates (K2 coefficient) and mean diffusivity values were measured in contralesional normal-appearing white matter (NAWM). Plasma matrix metalloproteinase-2 (MMP-2) levels were studied at baseline and 48 h. Admission stroke severity was evaluated using the NIH Stroke Scale (NIHSS). Modified Rankin Scale (mRS) was obtained at 90-days post-stroke. We found that higher mean K2 and diffusivity values correlated with age, elevated baseline MMP-2 levels, greater NIHSS and worse 90-day mRS (all p < 0.05). In multivariable analysis, WMH volume was associated with mean K2 ( p = 0.0007) and diffusivity ( p = 0.006) values in contralesional NAWM. In summary, WMH severity measured on brain MRI of AIS patients is associated with metrics of increased BBB permeability and abnormal white matter microstructural integrity. In future studies, these MRI markers of diffuse cerebral microvascular dysfunction may improve prediction of cerebral tissue infarction and functional post-stroke outcomes.

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