Magnetic Resonance Imaging (MRI) is increasingly used to assess damage and disease in articular joints. This Thesis describes improvements in hardware and pulse sequences, to facilitate the visualization and quantitation of articular cartilage in human and rabbit knees, and in interphalangeal (IP) finger joints. Work on the human knee focused on the acquisition of localised 3D data-sets from each compartment individually, using a surface coil in transmit/receive mode. The advantage of the increase spatial resolution from localised MRI, was illustrated by comparison of the resulting patella articular cartilage thickness measurements, with equivalent measurements based on 3D volume scans. Those results clearly demonstrated that low spatial resolution images can over-estimate articular cartilage thickness. Rabbit knees with induced 'Quinoline Arthropathy' (QA) and 'Rheumatoid Arthritis' (RA) were also imaged and by optimising the RF probe configuration, it was possible to improve the spatial resolution, as compared with literature reports. Articular cartilage visualisation of the normal and QA joints was optimum for MTC-subtraction images; edge detection maps of those joints clearly showed the articular cartilage boundaries for normal as well as the swollen articular cartilage. The late stage pathology of the RA joints when imaged prevented some contrast regimes from being fully assessed for articular cartilage visualisation. However, the high spatial resolution 3D acquisitions of these rabbit knees clearly demonstrated the full extent of the joint damage, and in particular the severity of bone erosions. Initially the finger work optimised the MRI acquisition and data processing protocols for simultaneously measuring the joint space thickness in 3 DIP and 3 PIP joints in one hand. The results illustrated both the sensitivity of the different statistical measurements and the potential for further evaluation. This work demonstrates the scope of MRI for quantitative analysis of articular cartilage. It also illustrates the benefits of optimising RF probes for the required region-of-interest (ROI) and pulse sequences for articular cartilage visualisation.

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In this thesis, we investigate how to achieve an accurate reliable and rapid probe calibration. Our first step is to improve the reliability of an accurate calibration technique from the literature. The Cambridge phantom, a variant of plane-based calibration, has been shown to be one of the most accurate calibration techniques. Unfortunately, calibrations performed using plane-based techniques are often unreliable. We show how it is possible to provide feedback on the reliability of the calibration. This allows the user to rectify an unreliable calibration. Having achieved an accurate and reliable calibration, we now search for a fast and easy calibration technique. We study a class of two-dimensional alignment phantoms – the Z-fiducial phantom. Probe calibration using such a phantom only requires a single image of the phantom. However, calibration speed using this phantom is impeded by the necessity of segmenting isolated points on the phantom reliably, which requires human intervention. We solve this problem by mounting a thin rubber membrane on top of the phantom. The membrane is segmented automatically and the phantom features can be easily located. This enables us to segment isolated points automatically at the full PAL frame rate of 25Hz, enabling calibration to be completed in a few seconds. In addition, to improve the existing calibration techniques, we present two novel phantoms – the cone phantom and the Cambridge stylus. They are both simple in design, easy to use and produce accurate calibrations. The cone phantom produces calibrations with accuracies matching the Cambridge phantom. The Cambridge stylus is small in size and can be carried around conveniently. These phantoms offer alternatives to the Cambridge phantom and the Z-phantom, ensuring calibration reliability and simplicity, while producing accurate calibrations.

The ability to visualize the development of stroke-related brain damage in each individual is essential to gain a more complete understanding of the underlying mechanisms, which contribute to dysfunction, and potentially to aid clinical diagnosis. Previous positron emission tomography (PET) studies suggest the radioligands ¹¹C-Flumazenil and ¹¹C-PK11195 may be useful for <i>in vivo</i> investigation of selective neuronal loss and microglia activation. However, histological validation is lacking, while the time-course and inter-relationship between ¹¹C-Flumazenil and ¹¹C-PK11195 imaging are not fully understood. The ability to dynamically image stroke-related brain damage <i>in vivo</i> using these radioligands cannot be fully exploited in man. Consequently, this thesis describes the sequential use of both ¹¹C-Flumazenil and ¹¹C-PK11195, in combination with histopathological assessment, in a rodent temporary middle cerebral artery occlusion (tMCAo) model. Each subject was imaged at three time-points (1 hour, 48 hours and 14 days) after tMCAo. The model selected was characterised further and generated extensive cortical selective neuronal loss and microglial activation with very limited pan-necrosis. This is the first study to utilize a longitudinal MicroPET protocol to investigate ischaemia-induced cellular changes in a rodent model of stroke. The results indicate biphasic changes in ¹¹C-Flumazenil binding in the occluded cortex following tMCAo, which challenge the current understanding of ¹¹C-Flumazenil binding following ischaemia. Relationships with selective neuronal loss and pan-necrosis were complex, suggesting additional factors such as receptor plasticity may be contributing to the observed changes in ¹¹C-Flumazenil binding; representing several temporally evolving pathosphysiological mechanisms in the ischaemic penumbra. The results presented also validate ¹¹C-PK11195 as an <i>in vivo</i> marker of microglial activation in the reperfused penumbra, corroborating its usefulness to image inflammation after stroke <i>in vivo.</i>

Corneal confocal microscopy (GCM) is a novel non-invasive in vivo imaging clinical technique for the study of corneal cellular structure. It provides images of all layers of the cornea which are comparable to in-vitro histochemical techniques. In the series of studies presented in this thesis we have evaluated the considerable potential of GGM to quantify corneal nerve morphology in a range of clinical conditions characterised by small fibre damage. The results indicate that the widest application of GCM may well be in the field of peripheral metabolic (diabetes, Fabry disease) and other causes of neuropathies. Thus CCM may provide a means to identify patients at risk, follow progression and measure therapeutic response in not only diabetic neuropathy but also a range of other neuropathies.

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