Vascular imaging in brain metastasis

Perfusion MRI is an important technique in the imaging of brain tumours, since tumour blood flow can differentiate between primary brain tumours and metastases and can also inform treatment planning and outcome. Currently, clinical perfusion MRI techniques are most commonly performed using gadolinium-based contrast agents, which carry a risk of toxicity from gadolinium deposition in tissues and from nephrogenic systemic fibrosis.
Arterial spin labelling (ASL) MRI is a contrast agent-free MRI technique to obtain measurements of blood flow in organs such as the brain but has, thus far, mainly been limited to preclinical and clinical research studies. Recommendations for the standardisation of this technique in the clinic have been proposed, to facilitate its incorporation into routine clinical practice. Such recommendations have yet to be proposed for the preclinical use of ASL MRI. The work presented here encompasses, firstly, an optimisation of the ASL MRI technique for use in rats through the use of a multiphase pseudo-continuous labelling approach (MP-pCASL MRI). This sequence and its output cerebral blood flow (CBF) measurements were validated with gold-standard autoradiography and, subsequently, applied to a rat breast cancer brain metastasis model. CBF was monitored during tumour progression and compared to clinically- relevant MRI techniques. MP-pCASL MRI CBF measurements demonstrated a decrease in metastasis blood flow over time, correlating with a decreased microvessel density and increased levels of hypoxia histologically.
Subsequently, vascular normalisation treatment, using either bevacizumab or cediranib, was performed in this rat model of brain metastasis and MP-pCASL MRI was assessed as a contrast-free detection technique for vascular normalisation. Although, vascular normalisation was not established upon bevacizumab treatment of brain metastases, cediranib treatment led to a decrease in the permeability factor, Ktrans, from dynamic contrast-enhanced (DCE) MRI, the current detection method for this treatment. Furthermore, metastasis blood flow obtained with MP-pCASL MRI was maintained during cediranib treatment, compared to a significant decrease in brain metastasis blood flow in vehicle-treated rats. Thus, MP-pCASL MRI could be used as a novel detection method for the onset of vascular normalisation in brain metastases, particularly in circumstances where the injection of contrast-agents, required for DCE MRI, is contraindicated and/or in situations where multiple MRI sessions may be needed.
In conclusion, the proposed, rat-optimised, MP-pCASL MRI technique can provide accurate and reproducible CBF measurements in rats and successfully identify brain regions with dysregulated blood, such as brain metastases. Finally, MP-pCASL MRI can detect vascular normalisation in brain metastases. It is hoped that the findings presented in this thesis can lead to a standardisation of preclinical ASL MRI and to the incorporation of ASL MRI for the imaging of brain tumours and their response to vascular normalisation treatments in both preclinical and clinical settings.

Keywords: Arterial spin labelling
Brain metastasis
Vascular normalisation
Magnetic resonance imaging
Advisor: Sibson, N
Chappell, M