Quantifying ocular inflammation in uveitis using optical coherence tomography

Inflammation is the key underlying physiological process in uveitis. It drives the onset of acute flares, causes permanent structural damage and can result in sight-threatening complications. Being able to accurately detect and measure changes in inflammatory activity is crucial for managing uveitic flares and rationalising therapeutic decisions. Unfortunately, many of the current methods for quantifying inflammation are imperfect, due to the fact that they are based on subjective and unreliable clinician estimates. In this thesis, I evaluated the potential for imaging-based technologies such as optical coherence tomography (OCT) to measure key markers of intraocular inflammation in uveitis. Whilst several key markers of inflammation are recognised, this thesis focuses on those with an existing clinical standard, which can be used as a comparator or reference test (anterior chamber cells, anterior chamber flare and vitreous haze). I conducted a series of systematic reviews evaluating potential instrument-based techniques for measuring anterior chamber cells, anterior chamber flare and vitreous inflammation, respectively. These identified OCT and laser flare photometry as potential instruments for measuring anterior chamber cell and flare, and OCT and retinal photography for measuring vitreous inflammation. However, the interpretation of results in each review was limited by relatively few studies and the inclusion of highly heterogenous uveitic patient populations, varying severities of disease, and lack of a standardised image acquisition protocol. Second, in the prospective study, OCTAVE (OCT-assisted vitreous evaluation), I found that our custom OCT-based vitreous analysis technique (EQUIP) demonstrated good repeatability in healthy and uveitic eyes, was able to detect vitreous inflammation and was associated with the current clinical vitreous haze grading. The EQUIP measurement was able to predict visual acuity whereas the current standard method (clinician grading 3 using the National Eye Institutevitreous haze scale) could not. Whilst these results were encouraging, there remains substantial overlap in the OCT measurement between NEI vitreous haze grades. It is not clear whether this is due to poor signal-to-noise ratio of the OCT technique, or a sign of poor reliability of the comparator (clinician-based grading using the NEI vitreous haze scale). Further investigation through longitudinal studies may be able to answer this question. In summary, OCT has demonstrated potential for quantifying inflammation for multiple key measures in uveitis. However, a key limitation for the validation of all instrument-based measures has been the lack of a reliable reference test

Visual Impairment and Blindness

Blindness and vision impairment affect at least 2.2 billion people worldwide with most individuals having a preventable vision impairment. The majority of people with vision impairment are older than 50 years, however, vision loss can affect people of all ages. Reduced eyesight can have major and long-lasting effects on all aspects of life, including daily personal activities, interacting with the community, school and work opportunities, and the ability to access public services. This book provides an overview of the effects of blindness and visual impairment in the context of the most common causes of blindness in older adults as well as children, including retinal disorders, cataracts, glaucoma, and macular or corneal degeneration

The Retina in Health and Disease

Vision is the most important sense in higher mammals. The retina is the first step in visual processing and the window to the brain. It is not surprising that problems arising in the retina lead to moderate to severe visual impairments. We offer here a collection of reviews as well as original papers dealing with various aspects of retinal function as well as dysfunction. New approaches in retinal research are described, such as the expression and localization of the endocannabinoid system in the normal retina and the role of cannabinoid receptors that could offer new avenues of research in the development of potential treatments for retinal diseases. Moreover, new insights are offered in advancing knowledge towards the prevention and cure of visual pathologies, mainly AMD, RP, and diabetic retinopathy

Neuroimaging - Clinical Applications

Modern neuroimaging tools allow unprecedented opportunities for understanding brain neuroanatomy and function in health and disease. Each available technique carries with it a particular balance of strengths and limitations, such that converging evidence based on multiple methods provides the most powerful approach for advancing our knowledge in the fields of clinical and cognitive neuroscience. The scope of this book is not to provide a comprehensive overview of methods and their clinical applications but to provide a "snapshot" of current approaches using well established and newly emerging techniques

Evaluation of PD-L1 expression in various formalin-fixed paraffin embedded tumour tissue samples using SP263, SP142 and QR1 antibody clones

Background & objectives: Cancer cells can avoid immune destruction through the inhibitory ligand PD-L1. PD-1 is a surface cell receptor, part of the immunoglobulin family. Its ligand PD-L1 is expressed by tumour cells and stromal tumour infltrating lymphocytes (TIL). Methods: Forty-four cancer cases were included in this study (24 triple-negative breast cancers (TNBC), 10 non-small cell lung cancer (NSCLC) and 10 malignant melanoma cases). Three clones of monoclonal primary antibodies were compared: QR1 (Quartett), SP 142 and SP263 (Ventana). For visualization, ultraView Universal DAB Detection Kit from Ventana was used on an automated platform for immunohistochemical staining Ventana BenchMark GX. Results: Comparing the sensitivity of two different clones on same tissue samples from TNBC, we found that the QR1 clone gave higher percentage of positive cells than clone SP142, but there was no statistically significant difference. Comparing the sensitivity of two different clones on same tissue samples from malignant melanoma, the SP263 clone gave higher percentage of positive cells than the QR1 clone, but again the difference was not statistically significant. Comparing the sensitivity of two different clones on same tissue samples from NSCLC, we found higher percentage of positive cells using the QR1 clone in comparison with the SP142 clone, but once again, the difference was not statistically significant. Conclusion: The three different antibody clones from two manufacturers Ventana and Quartett, gave comparable results with no statistically significant difference in staining intensity/ percentage of positive tumour and/or immune cells. Therefore, different PD-L1 clones from different manufacturers can potentially be used to evaluate the PD- L1 status in different tumour tissues. Due to the serious implications of the PD-L1 analysis in further treatment decisions for cancer patients, every antibody clone, staining protocol and evaluation process should be carefully and meticulously validated

Abstracts from the 50th European Society of Human Genetics Conference: Posters

International audienc

The Shared Genetic Architecture of Modifiable Risk for Dementia and its Influence on Brain Health

Targeting modifiable risk factors for dementia may prevent or delay dementia. However, the mechanisms by which risk factors influence dementia remain unclear and current research often ignores commonality between risk factors. Therefore, my thesis aimed to model the shared genetic architecture of modifiable risk for dementia and explored how these shared pathways may influence dementia and brain health. I used linkage disequilibrium score regression and genomic structural equation modelling (SEM) to create a multivariate model of the shared genetics between Alzheimer’s disease (AD) and its modifiable risk factors. Although AD was genetically distinct, there was widespread genetic overlap between most of its risk factors. This genetic overlap formed an overarching Common Factor of general modifiable dementia risk, in addition to 3 subclusters of distinct sets of risk factors. Next, I performed two multivariate genome-wide association studies (GWASs) to identify the risk variants that underpinned the Common Factor and the 3 subclusters of risk factors. Together, these uncovered 590 genome-wide significant loci for the four latent factors, 34 of which were novel findings. Using post-GWAS analyses I found evidence that the shared genetics between risk factors influence a range of neuronal functions, which were highly expressed in brain regions that degenerate in dementia. Pathway analysis indicated that shared genetics between risk factors may impact dementia pathogenesis directly at specific loci. Finally, I used Mendelian randomisation to test whether the shared genetic pathways between modifiable dementia risk factors were causal for AD. I found evidence of a causal effect of the Common Factor on AD risk. Taken together, my thesis provides new insights into how modifiable risk factors for dementia interrelate on a genetic level. Although the shared genetics between modifiable risk factors for dementia seem to be distinct from dementia pathways on a genome-wide level, I provide evidence that they influence general brain health, and so they may increase dementia risk indirectly by altering cognitive reserve. However, I also found that shared genetics risk between risk factors in certain genomic regions may directly influence dementia pathogenesis, which should be explored in future work to determine whether these regions represent targets to prevent dementia