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Comparing non-invasive blood-brain barrier mapping with dynamic susceptibility contrast MRI in patients with high-grade glioma and metastasis1School of Medicine and Health, Department of Neuroradiology, Technical University of Munich, Munich, Germany, 2School of Medicine and Health, TUM-Neuroimaging Center, Technical University of Munich, Munich, Germany, 3School of Medicine and Health, Clinic of Neurology, Technical University of Munich, Munich, Germany, 4MR Physics, Fraunhofer Institute for Digital Medicine MEVIS, Bremen, Germany, 5MR-Imaging and Spectroscopy, University of Bremen, Bremen, Germany, 6mediri GmbH, Heidelberg, Germany, 7C.J. Gorter MRI Center, Department of Radiology, Leiden University Medical Center, Leiden, Netherlands, 8Leiden Institute of Brain and Cognition, Leiden University, Leiden, Netherlands, 9Philips GmbH Market DACH, Hamburg, Germany
Synopsis
Keywords: Tumors (Post-Treatment), Permeability, Blood Brain Barrier
Motivation: Glioma-induced blood-brain barrier (BBB) disruptions can be characterized by dynamic susceptibility contrast MRI via the leakage parameter K2. However, it may lack sensitivity to subtle impairments. Recently, non-invasive ASL-based water-exchange measurements (Tex) were proposed to measure even subtle BBB-impairments.
Goal(s): We hypothesized correlations of Tex with K2 in contrast-enhancing tissue (CET).
Approach: K2 & Tex were compared in 22 patients with brain tumors and 19 healthy controls.
Results: Tex agreed well with K2 in CET and was sensitive to pathophysiologically impaired BBB. Moreover, results indicate superior sensitivity to subtle impairments, which may improve therapy planning and progress monitoring.
Impact: ASL-based Tex allows non-invasive detection of the pathophysiologically impaired blood-brain barrier in tumors. Whereas its sensitivity to subtle impairments may improve treatment planning in tumors, it could also impact diagnosis of neurodegenerative diseases such as Alzheimer's or Parkinson’s.
Introduction
The blood-brain barrier (BBB) is a robust barrier hindering potentially harmful substances from leaking into the brain. Severe BBB damage in high-grade brain tumors is well-known.1-3 Clinically used contrast agent (CA) enhanced T1-weighted MRI allows qualitative analyses, but suffers from limited sensitivity due to comparably large Gadolinium (Gd) compounds. Quantitative information can be obtained by the dynamic susceptibility contrast (DSC) MRI-based leakage parameter K2.4-6 Generally K2 describes two effects: K2>0 represents a dominant T1-shortening and K2<0 relates to T2*-effects from susceptibility differences between intra- and extravascular space. Higher |K2| is associated with increased leakage.6,7 While correlations of K2 with ktrans from dynamic contrast enhanced (DCE) MRI and tumor grade were reported,7-10 sensitivity to subtle impairments is debated.11 Gd is also contraindicated in subjects with renal malfunction.12-15Using water as a freely diffusible tracer, we16 recently proposed non-invasive BBB mapping, which is expected to be sensitive to even subtle impairments.17-19 Based on Hadamard-encoded20,21 multi-echo (multi-TE) arterial spin labeling (ASL) data, an extended T2-based two-compartment model is applied and water exchange times Tex are calculated.16,22 Hypothesizing that reduced Tex indicates BBB impairment, we recently reported shorter Tex in tumorous tissue.23 However, validation with an independent measure is lacking.
The aim of this work is therefore to evaluate correlations between CA-based K2 and ASL-based Tex in tumors. We hypothesize that in areas with impaired BBB, reduced Tex correlates with increased K2. Additionally, we evaluated normal-appearing (NA) tissue for potential impairments.
Methods
MRI-data of 24 patients (68.5±12.8y,10f) with relapsed intra-axial, high-grade glioma (n=12) and metastases (n=12) were compared with 19 age-matched healthy controls (HCs,64±14.8y,14f). A 3T Elition Ingenia X was used (Philips,Best,Netherlands). Three subjects were excluded due to incomplete data acquisition or incidental findings. The imaging protocol included standard diagnostic imaging (CA-enhanced T1w&FLAIR), DSC for K2,4,6 and ASL-BBB for Tex16 (Fig.1). Anatomical images were co-registered, skull-stripped, and segmented into masks of CA-enhancing tissue (CET) and edema using an ensemble classifier (BraTS Toolkit).24 Segments of normal-appearing grey matter (NAGM) and NAWM, were calculated using ANTs Atropos.25 Analyses used Matlab (v2021b,TheMathWorksInc.,Natick,USA) and SPM12.26 For CET, VOIs larger than 3cm³ were evaluated (n=7). Pearson-Correlations of Tex with K2>0, K2<0 and |K2| were calculated. |K2| was used for regional investigations of combined T1 and T2*-effects. Lastly, Tex and |K2| were compared between patients and HCs (unpaired t-tests, p<0.05).Results
Data from a representative Glioma patient (Fig.2, 1a-e) show rim-like CA uptake (1a) and extensive edema (1b). This visually agrees with hypointense regions in Tex (1d) and increased K2 (1e), dominated by K2>0. Similar effects are seen in a metastasis patient (2a-e), however, K2-maps were dominated by K2<0 in CET (2e).On group-level, Tex correlated well with K2>0 (r=-0.36), K2<0 (r=0.77), and |K2| (r=-0.37) in CET (Fig.3,top), while correlations in NAGM were low (Fig.3, bottom). In CET, Tex was significantly reduced compared to NAGM (Fig.4,top), similar to increased |K2| in CET compared to NAGM and NAWM (Fig.4,bottom). In edema, Tex was likewise reduced, while K2 was not increased (Fig.5A). Compared to HCs, Tex was significantly reduced in (NA)GM (p=0.008) and (NA)WM (p=0.041), while |K2| was just marginally increased in patients (Fig.5B).
Discussion
As hypothesized, our results indicate that reduced Tex correlates with increased K2 in CET with impaired BBB. This agreement was found for both K2 domains (K2>0 and K<0) and |K2|. In NAGM, weak correlations of Tex with K2 reflect expectations, as very subtle CA-leakage largely reduces K2-sensitivity. Lowered Tex in CET agrees well with increased |K2| and can be interpreted as increased leakage which concords with several reports from DCE2,27 and DSC6-8 studies. Similar Tex in CET and NAWM may be due to comparably low ASL signal in NAWM, limiting Tex accuracy. Low Tex in edema may, however, indicate BBB impairments preceding CA-leakage 28,29 that are not yet detectable using |K2|. Interestingly, Tex was significantly decreased in NAGM and NAWM of patients compared to HCs, while |K2| differed just slightly between groups. This may indicate subtle BBB impairment in NA-tissue without CA-leakage, which is not detectable with K2. This agrees with expected Tex sensitivity for subtle impairments using water as an endogenous tracer.16-19 This finding might be especially relevant in tumor progression monitoring and therapy planning.30-32Conclusion
In conclusion, ASL-based Tex is sensitive to pathophysiological changes in BBB-integrity and agrees well with DSC-based K2. Moreover, decreased Tex in NAGM and NAWM points to sufficient sensitivity to subtle impairments in normal appearing tissue, which may open pathways for advanced tumor therapy management. Consequently, non-invasive Tex could also contribute to understanding of BBB dysfunction in various other pathologies such as Alzheimer’s disease.33-35Acknowledgements
We would like to acknowledge support by the Ev. Studienwerk Villigst (personal grant to GH) and by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – project number 395030489. AM and MG received funding from the European Union's Horizon 2020 Research and Innovation Programme under grant agreement No. 825664.
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Figure 2: Exemplary data of two patients. T1w post contrast agent (CA, a), FLAIR (b), tissue masks (c), Tex (d) and K2 (e) maps are shown. The glioma patients’ rim-like CA uptake (1a) and pronounced edema (1b) are segmented into masks of contrast enhancing tissue (CET) and edema (1c). Tex (1d) is visibly reduced in the tumorous region, resembling areas of increased K2, dominated by K2>0. The metastasis patient similarly shows a rim like CA uptake (2a) with edema (2b). Here, hypointense Tex regions (2d) concord with areas where K2 < 0 (2e). Arrows indicate tumorous regions.
