Evaluation of perfusion and hypoxia parameters in healthy subjects and patients with high-grade carotid artery stenosis
Stephan Kaczmarz1, Jens Göttler1, Anne Kluge1, Dimitrios C. Karampinos2, Claus Zimmer1, and Christine Preibisch1,3

1Department of Neuroradiology, Technische Universität München, Munich, Germany, 2Department of Radiology, Technische Universität München, Munich, Germany, 3Clinic for Neurology, Technische Universität München, Munich, Germany


Severe intracranial arterial stenosis (SIAS) is a major health issue as it often accounts for strokes. Here, we present preliminary data from a clinical study in patients with SIAS compared to healthy controls. The major aim was to evaluate the reliability of perfusion and oxygenation related measures by analyzing their hemispheric symmetry to assess their potential diagnostic capabilities. Preliminary results imply symmetry of all measures between hemispheres of healthy controls. Regarding patients, only pCASL-based CBF implies a reduced perfusion on the side of carotid artery stenosis which is in accordance to recent literature and is currently under further investigation.


Severe intracranial arterial stenosis (SIAS) is a major public health issue and accounts for approximately 20% of all strokes1. High oxygen extraction fraction (OEF) is a risk factor for developing an ischemic stroke in patients with SIAS and is usually measured by 15O2-PET 2,3. To increase availability and patient comfort, a non-invasive MR method for estimation of cerebral oxygen metabolism would be highly appreciated. A fast and robust measure of vascular deoxygenation, namely the relative OEF (rOEF) has been recently developed4 and successfully applied in patients with glioma5 and acute stroke6. However, in patients with subtle impairments, motion and other instabilities might impair results4. Here, we present preliminary data from a clinical study in patients with SIAS compared to healthy controls. The major aim was to evaluate the reliability of rOEF as well as Dynamic Susceptibility Contrast (DSC) and pseudo-Continuous Arterial Spin Labeling (pCASL) based perfusion measures by analyzing their hemispheric symmetry in gray matter (GM) in order to assess their potential diagnostic capabilities.


In the ongoing clinical study, 15 subjects (9 healthy, 6 patients with unilateral SIAS >75%, age 70.6y±5.2y, 11 males) underwent MRI on a clinical Philips 3T Ingenia MR-Scanner (Philips Healthcare, Hamburg, Germany), using a 16ch head/neck-coil for clinical and 32ch head-coil for pCASL imaging. The protocol comprised rOEF-mapping (voxel size 2x2x3mm3, 112x92 matrix, 30 slices) by separate acquisition of a multi-echo GRASE (8 echoes, TE1=ΔTE=16ms, TR=8971ms, acq.time 2:24min) and a multi-GE sequence (12 echoes, TE1=ΔTE=5ms, TR=1950ms, α=30°, rapid flyback, acq.time 6:08min) for T2 and T2* mapping6. DSC data were obtained during a bolus injection of 15ml Gd-DTPA using single-shot GE EPI (TR=1516ms, TE=30ms, α=60°, 80 dynamics) after an carotid artery angiography with 17ml Gd-DTPA. Non-invasive perfusion mapping was performed by a single-shot pCASL sequence with a 2D EPI-readout (voxel size 3x3.1x5mm3, matrix 64x62, 16 slices, TE/TR=11ms/4396ms, label duration τ=1800ms, post labeling delay PLD=2000ms, background-suppression, 30 dynamics, acq.time 5:02min; including proton-density-weighted M0 for normalization). Data coregistration, evaluation and calculation of rOEF ($$$rOEF\propto\frac{R2'}{rCBV}$$$ with $$$R2'=\frac{1}{T2*}-\frac{1}{T2}$$$) following Hirsch et al.6 and Cerebral Blood Flow (CBF) following the perfusion study group of ISMRM7 $$CBF=\frac{6000\cdot\lambda\cdot\Delta M\cdot e^{\frac{PLD}{T_{1}(Blood)}}}{2\cdot\alpha\cdot T_{1}(Blood)\cdot M_{0}\cdot\left(1-e^{-\frac{\tau}{T_{1}(Blood)}}\right)}$$ with brain-blood coefficient λ=0.9ml/g, label-control-difference ∆M, T1 of arterial blood at 3T T1(Blood)=1650ms and labeling efficiency α=0.85 were performed with SPM128 and custom Matlab programs9. All images were normalized to standard MNI brain and patient data were flipped so that the affected hemisphere was on the left side in each case. For each hemisphere, 9 VOI’s were defined (Fig.1), masked by GM (pGM≥0.75) and mean values of the evaluated parameters calculated. Corresponding VOI averages of both hemispheres were compared by means of 2-sample T-tests and Bland-Altman plots12.


All modalities showed good image quality and appeared reasonably symmetric on visual inspection (Fig.2). pCASL and DSC-based CBF maps looked similar but are not absolutely congruent. A closer, more quantitative analysis by means of Bland-Altman plots revealed that only pCASL-based CBF maps showed a detectable asymmetry for patients with SIAS with slightly decreased CBF on the affected hemisphere but not for healthy controls (Fig.3). DSC-based CBF and rCBV tended to be slightly asymmetric for both groups, whereas rOEF and DSC-based MTT are symmetric for both groups (Table 1). However, it has to be considered that the variances for all modalities are relatively high compared to the differences.


In healthy controls, our results point to a general symmetry of perfusion and oxygenation related measures between hemispheres (Table 1). Regarding patients, pCASL-based CBF implies a reduced perfusion on the side of carotid artery stenosis as expected (Fig.3). In contrast, qualitative DSC-based CBF does not show differences between both groups, which can be explained by general methodological shortcomings of DSC to estimate CBF14. Therefore, pCASL-based CBF maps are valued more reliable compared to DSC. Missing rOEF asymmetry in patients fits nicely with recent results of Bouvier et al. who found a decreased Cerebral Metabolic Rate for Oxygen ($$$CMRO_2\propto CBF\cdot OEF$$$), but symmetric tissular oxygen saturation in patients with arterial occlusion15. They assumed that decreased CMRO2 was mainly caused by reduced CBF while OEF was unaffected which is in accordance with our preliminary results. Nevertheless, the presented method has to be further characterized with increasing the sample size.


These preliminary results are promising and show the expected behavior for healthy controls. In addition, pCASL CBF seems capable to detect perfusion impairments for patients with SIAS which is in accordance with recent literature. However, further measurements in a larger group of patients are required to increase statistical power and thereby proof the first findings.


The authors acknowledge the help of the Friedrich Ebert Stiftung for their support.


1: Petty GW, Brown RD, Whisnant JP, Sicks JD, O'Fallon WM & Wiebers DO. Ischemic stroke subtypes: a population-based study of incidence and risk factors. Stroke, 30 (1999) 2513-2516.

2: Derdeyn CP, Videen TO, Grubb RL, Powers WJ. Comparison of PET oxygen extraction fraction methods for the prediction of stroke risk. J Nucl Med, 42 (2001) 1195-1197.

3: Yamauchi H, Fukuyama H, Nagahama Y, Nabatame H, Ueno M, Nishizawa S, Konishi J & Shio H. Significance of increased oxygen extraction fraction in five-year prognosis of major cerebral arterial occlusive diseases. J Nucl Med, 40 (1999) 1992-1998.

4: Hirsch NM, Toth V, Forschler A, Kooijman H, Zimmer C & Preibisch C. Technical considerations on the validity of blood oxygenation level-dependent-based MR assessment of vascular deoxygenation. NMR Biomed, 27 (2014) 853-862.

5: Toth V, Forschler A, Hirsch NM, den Hollander J, Kooijman H, Gempt J, Ringel F, Schlegel J, Zimmer C & Preibisch C. MR-based hypoxia measures in human glioma. J Neurooncol, 115 (2013) 197-207.

6: Gersing A, Ankenbrank M, Schwaiger B, Kooijman H, Wunderlich S, Zimmer C, Preibisch C. BOLD-based MRI hypoxia measurements in stroke patients. submitted.

7: Alsop DC, Detre JA, Golay X, et al. Recommended implementation of arterial spin-labeled perfusion MRI for clinical applications: A consensus of the ISMRM perfusion study group and the European consortium for ASL in dementia. Magnetic Resonance in Medicine 73(1) (2015): 102-116.

8: Statistical Parametric Mapping software (SPM12): www.fil.ion.ucl.ac.uk/spm, [09.Nov 2015].

9: MATLAB and Statistics Toolbox Release 2013a, The MathWorks, Inc., Natick, Massachusetts, United States.

10: Maldjian JA, Laurienti PJ, Burdette JB, Kraft RA. An Automated Method for Neuroanatomic and Cytoarchitectonic Atlas-based Interrogation of fMRI Data Sets. NeuroImage (2003) 19:1233-1239.

11: Maldjian JA, Laurienti PJ, Burdette JH. Precentral Gyrus Discrepancy in Electronic Versions of the Talairach Atlas. Neuroimage 21(1) (2004) 450-455.

12: Bland-Altman and Correlation Plot software, Ran Klein 2010: http://www.mathworks.com/matlabcentral/fileexchange/45049-bland-altman-and-correlation-plot [09.Nov 2015].

13: Vinci software, Max-Planck-Institut für neurologische Forschung, Cologne, Germany: http://www.nf.mpg.de/vinci3/ , [09.Nov 2015].

14: Buxton RB, editor. Introduction to functional magnetic resonance imaging: Principles and techniques. 2 ed. Volume Chapter 12. Cambridge: Cambridge University Press; 2009.

15: Bouvier J, Detante O, Tahon F, et al. Reduced CMRO2 and cerebrovascular reserve in patients with severe intracranial arterial stenosis: A combined multiparametric qBOLD oxygenation and BOLD fMRI study. Human Brain Mapping 36(2) (2015) 695-706.


Figure 1: Volumes of interest (VOI) for statistical data analysis were manually selected with the WFU PickAtlas10,11. 12 inferior (A1-A3) and 6 superior VOI’s (B1-B3) are overlaid in color on coronal, sagittal and axial views of a smoothed MNI brain template for illustration. Corresponding VOI’s in the left and right hemisphere are depicted in equal colors.

Figure 2: Overview of relevant modalities: rOEF, R2', DSC-based rCBV and different perfusion measures (DSC-based MTT and CBF; pCASL based CBF) for a selected slice of a healthy male volunteer (65y). Images were depicted by Vinci13.

Figure 3: Comparison of pCASL-based CBF values between corresponding left and right hemispheric VOI’s in GM by Bland Altman plots. Patient’s images were aligned with the stenosis on the left hemisphere. Each data point corresponds to a mean VOI value. The Bland Altman plot of pCASL-based CBF values of healthy controls imply symmetric CBF in both hemispheres (A), whereas patients tend to show decreased CBF within the affected left hemisphere while deviations are slightly increased (B).

Table 1: GM-mean values of rOEF, MTT, CBV and DSC- and pCASL-based CBF and their comparison in symmetric left and right hemispheric VOI’s for healthy subjects and patients with SIAS by Bland Altman parameters (right - left differences and standard deviations) and two-sample T-tests. pCASL-based CBF asymmetry for patients is marked by asterisks. Please note that comparably low pCASL-based CBF means might be caused by partial volume effects due to the GM-mask definition at 75% probability level.

Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)