Bandula, S; (2017) Equilibrium Contrast Imaging for Extracellular Volume Quantification. Doctoral thesis , UCL (University College London).

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Abstract

In disease and senescence, the balance between cells and the surrounding interstitium is altered. Cell injury and inflammation induce fibrosis, with collagen deposition leading to expansion of the interstitium. When diffuse, this expansion can affect the structure and function of the whole organ. Examples of diffuse fibrosis include liver cirrhosis and myocardial fibrosis, which are becoming more prevalent as the population ages. Traditional assessment of such diseases involves invasive biopsy, but for many tissues, biopsy is poorly tolerated and carries a significant complication risk. Recently our group has developed a new technique (equilibrium imaging) that utilises the extracellular contrast agents employed widely in MRI and CT to quantify tissue fractional extracellular volume (ECV). Early work demonstrated a significant elevation in myocardial ECV in hypertrophic cardiomyopathy and aortic stenosis. Equilibrium contrast imaging potentially offers a powerful new non-invasive tissue biomarker for ‘extracellular disease’, and promises new insights into the biology of these conditions. In this thesis I develop the equilibrium imaging technique, beginning with an evaluation of the basic principles of extracellular volume estimation by EQ-MRI - using a 3-dimensional engineered tissue model. I show an association between ECV quantified during construction of six engineered models with ECV measured using EQ-MRI (R2=0.77, p=0.02). I then explore the use of equilibrium imaging in quantifying two disease processes that alter the extracellular volume – diffuse fibrosis and amyloidosis. EQ-MRI is used in systemic amyloidosis to demonstrate significant elevation in ECV within the liver (0.32) and spleen (0.39) compared with healthy volunteers (p<0.01). I then translate the basic EQ method to a new modality – computed tomography, a potentially simpler and more widely available imaging platform. EQ-CT is used to show an association between ECV and a histological comparator in cardiac valve disease (r=0.71); and in liver cirrhosis (r=0.64). EQ-MRI is also used as a reference test to investigate diffuse 99mTc-DPD skeletal muscle uptake in systemic ATTR amyloidosis. Using a novel scoring system to quantify uptake, I show that skeletal muscle ECV increases with 99mTc-DPD soft tissue score (R2=0.34) - suggesting that skeletal muscle is a significant target organ for amyloid deposition. Technical development of the CT technique required the optimisation of image acquisition and processing for quantitative attenuation measurement within tissues, and advancement of the contrast protocol to allow rapid ECV estimation using a bolus only dynamic equilibrium technique. In summary, this research thesis presents methological development and validation of EQ imaging for tissue extracellular volume fraction quantification.

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