Introduction

The blood brain barrier (BBB) provides a robust physical and biochemical border for molecular exchange between intra- and extravascular compartments. BBB disruptions are well known in high-grade brain tumours. As a result, permeability of blood vessels in pathological tissue is increased, allowing blood constituents and other potentially harmful substances to leak from the vessels into brain tissue.^1-3 In clinical routine, BBB disruptions are currently assessed by contrast-enhanced T1w-MRI. Better quantification of BBB integrity would be of high clinical interest, but available contrast agent (CA) based methods are limited. Dynamic contrast-enhanced (DCE) MRI, based on the T1 shortening effect of gadolinium (Gd), is limited to the detection of major BBB disruptions, due to the size and chemical structure of Gd-compounds.⁴ In addition, Gd is not applicable in patients with renal malfunctions. Previously proposed non-invasive alternatives lack quantitative measures of BBB integrity.^5,6 In contrast, Mahroo et al. proposed non-invasive and quantitative BBB-mapping based on time-encoded arterial spin labelling (ASL) MRI,⁷ which uses blood water as an endogenous freely-diffusible tracer. Due to its small size, water is an ideal candidate for detecting even subtle changes in BBB permeability and has shown promising results.^8-10 The proposed extended model⁷ is based on a two-compartment model of intra- and extravascular space.¹¹ It accounts for inta-voxel transit by considering cerebral blood flow (CBF) and arterial transit time (ATT) and yields an estimate for the exchange time (Texch) for water across the BBB. Here we present first results of an ongoing clinical translation study of ASL-based BBB-mapping in patients with high-grade intra-axial glioma and metastases.
We hypothesized, that ASL-based BBB mapping may be sensitive to impaired BBB-integrity. This may result in faster water exchange, which could be reflected by decrease in measured Texch.

Methods

Seventeen subjects underwent MRI on a 3T Ingenia Elition X (Philips, Best, Netherlands). Six patients with intra-axial, high-grade glioma and metastases (age (55.1±13.4)y, 3 female) were compared to eleven healthy controls (HC, age (25.25±2.7)y, 7 female). The imaging protocol included structural MRI (pre- and post-CA T1w-MPR, T2w-FLAIR), ASL-based BBB-mapping by combining two time-encoded Hadamard sequences,¹² and PDw data for CBF quantification (Fig.1).
Anatomical images were co-registered, skull-stripped and segmented into masks of tumorous tissue (CA-enhancing regions and edema) using an ensemble classifier (BraTS Toolkit).¹³ Based on T1w images, segments of normal-appearing (na) GM, WM, and CSF were calculated using ANTs Atropos,¹⁴ excluding tumorous areas. Moreover, na-whole brain regions were used to account for tumour locations at border-zones between tissues. Texch was calculated from the extended two-compartment model,⁷ as implemented in FSL’s fabber toolbox.^15-17 Quantitative analyses used custom-built MATLAB (v2020a, TheMathWorksInc., Natick, USA) programs and SPM12,¹⁸ for segmenting HCs’ tissue maps and co-registration. Regional statistical analyses of Texch included tumour and normal-appearing tissues as well as group comparisons between patients and HCs. Finally, Texch in tumour vs. normal-appearing brain tissue was correlated.

Results

Exemplary data showed reduced Texch (Fig.2C,G) in CA-enhancing (Fig.2A,E) and FLAIR hyperintense (Fig.2B,F) tissue. In line, statistical analyses on group level yielded reduced group-average Texch in tumorous tissue compared to naGM (Texch_tumour=(0.123±0.023)s vs. Texch_GM=(0.153±0.042)s, Fig.3A). Similarly, there was a strong trend for lower Texch compared to na-whole brain (Fig.3B). Exchange times were lower in naWM, both for patients (Fig.3C) and HC (not shown). Compared to HCs, Texch was not only reduced in tumorous tissue but in all brain regions, with significant reductions in naGM and na-whole brain (Fig.4). In patients, a strong correlation was found between Texch in tumour regions and naGM (Fig.5A) as well as na-brain (Fig.5B). Interestingly, Texch maps of the metastasis patients (Fig.2C) did in naGM rather resemble HCs.

Discussion

As hypothesized, water exchange times were decreased within brain tumours which accords with well-known BBB disruptions¹ and increased volume transfer constants (Ktrans) from DCE studies.^2,3,19-21 Moreover, our consistently lower Texch in naWM, both for patients and HCs, agrees well with increased WM-Ktrans as reported by DCE studies² . Similarly, HCs’ Texch values agree well with the literature.^7,8 However, future investigation is needed to disentangle effects in WM from regionally lowered SNR using ASL.²² Interestingly, Texch was not only reduced in tumorous tissue, but also in naGM and whole brain compared to HCs. This might be explained by subtle disease-related BBB impairments. However, previously reported age-related BBB-impairments^23,24 may also contribute as our HCs were younger than the patients. Nevertheless, these findings may be interesting for chemotherapy planning.^25,26 Correlation between Texch in tumorous tissue vs. naGM and na-whole brain, suggests reduced BBB integrity even in seemingly unaffected brain areas. This ongoing study finally aims to discern between glioma and metastases to better characterize different underlying patho-mechanisms resulting in BBB impairment.⁴

Conclusion

We successfully demonstrated the sensitivity of ASL-based BBB mapping to patho-physiologically driven decreases of BBB-integrity. Texch may be a promising proxy for BBB impairments. Texch appeard to be sensitive to even subtle changes in normal appearing tissue, which may yield additional insights to brain tumour patho-physiology. In a broader context, clinical applications of ASL-based BBB mapping appear auspicious in numerous other pathologies with (subtle) BBB dysfunctions,^10,27,28 such as Alzheimer’s and small vessel disease.

Acknowledgements

We acknowledge the support by Ev. Studienwerk Villigst e.V (personal grant to GH) and the German research Foundation (DFG, grant PR 1039/6-3)

References

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