Brain Perfusion & Permeability Imaging
Tadashi Nariai1

1Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan

Synopsis

Educational Lecture to discuss on the clinical usefulness of combined use of PET and physiological imaging with MRI. Focus is set on chronic occlusive cerebrovascular diseases and malignant brain tumor.

Introduction

With the advent of PET/MR imaging, it has become vital to interpret the multiple physiological parameters that can be obtained by PET and physiological MR imaging. The presenter has long been using both of these imaging modalities for the treatment of occlusive cerebrovascular disease and malignant brain tumor. In this lecture, correlation of multiple PET/MR parameters among these disease will be demonstrated mainly by using presenter’s clinical data together with literature review. Clinical significance of these parameters will also be discussed.

Physiological parameters of cerebrovascular occlusive disease measured with PET and MRI.

In order to estimate natural risk and to determine the optimal treatment of occlusive cerebrovascular disease, it is vital to clarify the degree of hemodynamic compromise in each patient. Patients at high risk of ischemic stroke generally exhibit abnormally high oxygen extraction fraction (OEF) and elevated cerebral blood volume, a combination of states described as misery perfusion or Grade 2 hemodynamic stress (Grubb et al. 1998, Derdeyn et al. 2002). The concurrent measurement of cerebral blood flow, metabolism, and blood volume by positron emission tomography (PET) serves as the optimal method for evaluating hemodynamics in patients. PET is usually unavailable in daily clinical practice, however, and it provides only poor information on the structural integrity of hypo-perfused tissue. Perfusion-weighted magnetic resonance imaging (PWI) provides various parameters on cerebral hemodynamics non-invasively and in less time than PET. In the past, we conducted a study to compare the parameters obtained with DSC-MRI and PET in moyamoya patients (Tanaka et al. 2006). In this paper, we demonstrate that mean transit time (MTT) and cerebral blood volume (CBV) that was measured with DSC-MRI are reliable parameter to estimate Grade 2 hemodynamic stress. By using DSC-MRI for the treatment of moyamoya disease, we showed that DSC-MRI can be used with the same reliability as more invasive measure such as PET or acetazolamide challenge test to determine the surgical indication and to foresee the surgical result (Nariai et al. 1994, Ishii et al. 2014). Recently, we have completed another comparative study in moyamoya disease to compare the reliability of cerebral blood flow (CBF) value obtained with ASL-MRI (Hara et al. submitted). In this, we compared the parameters among ASL-MRI, PET and DSC-MRI. Once we obtain CBF map using 2 post-labeling delays (PLDs) (shorter ASL: sASL = 1525 ms, delayed ASL: dASL = 2525 ms), sASL-CBF values had a moderate correlation with the PET-CBF values (r = 0.46) and the correlation was greater (r = 0.50) in areas with MTT delay (delay of MTT in comparison to control lesion (cerebellum) ) ≤1.5 s, while sASL underestimated the PET-CBF in regions with MTT delay>1.5 s. The dASL-CBF overestimated the PET-CBF regardless of MTT delay. (Figure 1) More interesting finding was obtained by comparing ASL-CBF using two different PLD with DSC-MRI measured time parameters. Ratio of dASL-CBF to sASL-CBF (dASL-CBF/sASL-CBF) was significantly correlated with the time parameters measured by DSC-MRI (Tmax, TTP, and MTT (r = 0.68, 0.55, 0.53, respectively)). (Figure 2) Although further trial is necessary to find optimum combination of PLD, this result may lead to the development of new imaging strategy to measure perfusion delay non-invasively using multiple PLD in ASL-MRI. As MTT reflect the reciprocal of cerebral perfusion pressure (Powers et al. 1984), this strategy may be a sensitive imaging method to evaluate impaired perfusion pressure in totally non-invasive manner.

Physiological parameters of malignant brain tumor measured with PET and MRI.

It has now been well recognized that morphological imaging is not enough to characterize the pathophysiology of malignant brain tumor for the purpose of intensive treatment of them. Instead, imaging of tumor biomarker using physiological imaging of PET and MRI (Waldman et al. 2009). The reasons why physiological imaging is inevitable in malignant brain tumor treatment are summarized into two points;1)glioma invades into brain parenchyma without disruption of blood brain barrier (BBB) and, therefore, area harboring tumor cells cannot be identified neither with Gd-enhanced T1 images nor FLAIR images by MRI. 2) morphological imaging never be able to distinguish between the active malignant tumor and the treatment induced necrosis. PET imaging using amino acid probes, such as 11C methionine, is now recognized as useful tool to solve these two problems (Nariai et al. 2005). We reported that , with use of 11C methionine PET, surgical removal of glioma based on PET guided navigation and gamma knife treatment against recurrent metastatic brain tumor by differentiating tumor and necrotic tissue led to the prolongation of patients’ survival after the treatment (Tanaka et al. 2009, Momose et al. 2014). As these indicate, use of PET amino acid imaging has high potential to improve the treatment of malignant brain tumor. PET tumor imaging other than fluoro-deoxy-glucose, however, is now in the stage of clinical trial, and accessibility is highly limited. Therefore, establishment of physiological imaging with MRI (or X-ray CT) is awaited for practical clinical use. Our comparative study between 11C methionine PET and dynamic CT perfusion (Nambu et al. 2003) revealed that the tumor uptake of 11C methionine and dynamic CT measured tumor blood volume changes concordantly after gamma-knife treatment against malignant glioma, but increased permeability of tumor vessel that was induced by high dose irradiation did not caused increased uptake of methionine (Figure 3). Figure 4-A indicated the non-correspondence between PET measured methionine uptake and permeability of tumor vessels. Instead, in Figure 4-B, we demonstrated that significant correlation between tumor blood volume and methionine uptake. This result can be applied for physiological imaging with MRI. Presumably among various physiological tumor parameters, those indicating tumor vessel density may be usable parameters to imitate PET tumor imaging. As indicated in Figure 5, recurrent glioblastoma in the are without Gd enhancement could be detected by 11C methionine PET imaging and ASL-MRI. Biological status of of treatment induced tumor effect can be imaged by 11C methionine PET and vessel density parameters depicted by DSC-MRI and ASL-MRI (Figure 6). Result of both the ASL and the DSC study, however, could be influenced by permeability of tumor vessels (Tanaka et al. 2011). Contribution of permeability change on ASL and DSC measured parameters must be examined as we denied the contribution of permeability change on the uptake of 11C methionine using CT perfusion (Figure 3 and 4). To do this, we started clinical study using DCE-MRI to examine tumor vessel permeability together with ASL, DSC, and 11C methionine. Preliminary result may be introduced in the lecture.

Conclusions

For the intensive treatment of cerebrovascular occlusive disease and malignant brain tumor, PET can provide valuable parameters that are supported by many clinical research evidence. Application of such research result for routine clinical setting, development of physiological MR study that can provide alternative parameters supported by comparative study must be necessary . By now, we presented the reliability of DSC-MRI measured MTT as alternative to PET-measured OEF, and the reliability of ASL or DSC MRI based tumor vessel parameters as alternative to 11C methionine PET. Further study to compare PET and physiological MRI parameters may lead to the establishment of another good alternative for routine clinical use.

Acknowledgements

This study was partially supported by research grant from SENSHI Medical Research Foundation.

References

Derdeyn, C. P., et al. (2002). Variability of cerebral blood volume and oxygen extraction: stages of cerebral haemodynamic impairment revisited. Brain 125(Pt 3): 595-607.

Grubb, R. L., Jr., et al. (1998). Importance of hemodynamic factors in the prognosis of symptomatic carotid occlusion. JAMA 280(12): 1055-1060.

Hara, S., et al. (submitted). Non-invasive evaluation of CBF and perfusion delay of moyamoya disease using arterial spin-labeling MRI with multiple post-labeling delays: comparison with 15O gas -PET and with DSC-MRI . Am J Neuroradiol.

Ishii, Y., et al. (2014). Practical clinical use of dynamic susceptibility contrast magnetic resonance imaging for the surgical treatment of moyamoya disease. Neurosurgery 74(3): 302-309.

Momose, T., et al. (2014). Clinical benefit of 11C methionine PET imaging as a planning modality for radiosurgery of previously irradiated recurrent brain metastases. Clin Nucl Med 39(11): 939-943.

Nambu, K., et al. (2003). Quantitative evaluation of cerebral vascular permeability using multi-slice dynamic CT. Acta Neurochir Suppl 86: 53-55.

Nariai, T., et al. (1994). Surgically induced angiogenesis to compensate for hemodynamic cerebral ischemia. Stroke 25(5): 1014-1021.

Nariai, T., et al. (2005). Usefulness of L-[methyl-11C] methionine-positron emission tomography as a biological monitoring tool in the treatment of glioma. J Neurosurg 103(3): 498-507.

Powers, W. J., et al. (1984). Physiological responses to focal cerebral ischemia in humans. Ann Neurol 16(5): 546-552.

Tanaka, Y., et al. (2011). Arterial spin labeling and dynamic susceptibility contrast CBF MRI in postischemic hyperperfusion, hypercapnia, and after mannitol injection. J Cereb Blood Flow Metab 31(6): 1403-1411.

Tanaka, Y., et al. (2009). Glioma surgery using a multimodal navigation system with integrated metabolic images. J Neurosurg 110(1): 163-172.

Tanaka, Y., et al. (2006). Quantitative evaluation of cerebral hemodynamics in patients with moyamoya disease by dynamic susceptibility contrast magnetic resonance imaging--comparison with positron emission tomography. J Cereb Blood Flow Metab 26(2): 291-300.

Waldman, A. D., et al. (2009). Quantitative imaging biomarkers in neuro-oncology." Nat Rev Clin Oncol 6(8): 445-454.

Figures

All plots between regional values of PET-CBF and those of sASL-CBF or dASL-CBF are divided by MTT delay cutoff of 1.5 s. A virtual straight line of PET-CBF equal to sASL-CBF was drawn in panel A, B, D and E. The mean ratio of dASL-CBF/PET-CBF is 1.26 (95% CI: 1.21-1.30) in the areas with MTT delay ≤1.5 s and 1.12 (95% CI: 1.03-1.21) in the areas with MTT delay >1.5 s (F).

The correlations between the ratio of dASL-CBF/sASL-CBF and the DSC time-based parameters. Tmax, MTT and TTP are well correlated with dASL-CBF/sASL-CBF (from A, B and C: r=0.68, 0.55, 0.53 respectively and p<0.0001 for all).

Follow up of malignant glioma after gamma knife treatment using 11C methionine and dynamic CT. Reduction of 11C methionine uptake and CBV corresponded well. On the other hand, increase of Ki (BBB transport constant) after treatment did not cause increase in 11C methionine uptake.

Plots to examine the correlation between 11C methionine uptake (PET) and Ki (BBB transport constant) (dynamic CT) (A) and cerebral blood volume (dynamic CT) (B). 11C methionine uptake and CBV are significantly correlated, but Ki (BBB transport constant) did not have any influence on 11C methionine uptake.

PET and MRI follow-up during bevacizumub treatment against glioblastoma. Although Gd T1 and T2 MRI did not indicate any change, 11C-Methionine PET (MET-PET) depicted recurrent tumor in the area without Gd enhancement. ASL MRI that was obtained at the same time also depicted area with elevated blood flow by indicating recurrent tumor.

PET and MRI follow-up monitoring the effectiveness of bevacizumub treatment agains glioblastoma. A) After GK treatment, area with Gd enhancement enlarge and edema worsened. Uptake of methionine, however, decreased. B) Although the area with Gd enhancement did not change after the initiation of bevacizumub, all physiological MR factors dramatically decreased as early as 1 week after the initiation of treatment.



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