Visual function in aging and age-related macular degeneration including subretinal drusenoid deposits

Age-related macular degeneration (AMD) is the leading cause of visual impairment in the developed world among people over 50 years of age. Although AMD is clinically characterised by the presence of drusen, subretinal drusenoid deposits (SDD) have also been recognized as a distinct morphological feature that confers increased risk of developing advanced AMD. To date, there has been a lack of validated biomarkers that can capture early changes in visual function that strongly correlate to the anatomical alterations which also include SDD phenotype. This thesis aimed to explore functional and structural markers to differentiate between healthy eyes (n=11) and intermediate AMD (iAMD) with SDD (n=11) and without SDD (n=17) and non-foveal atrophic AMD (n=11). Firstly, I assessed scotopic thresholds using a novel dark-adapted chromatic (DAC) perimeter, in healthy aging and in varying AMD disease. Individuals with SDD had depressed retinal sensitivity centrally, particularly inferiorly and nasally. Functionally, eyes with SDD were comparable to eyes with non-foveal atrophy, but structurally differed in outer nuclear layer (ONL) and total retinal volumes and thicknesses. Importantly, only rod-mediated tests were able to distinguish iAMD with and without SDD. Another aim of this thesis was to explore the efficacy of 670nm light on aging and AMD. Although an improvement in scotopic thresholds was observed in healthy aged eyes (n=4) compared to younger eyes (n=5), a pilot study conducted in 40 participants over the age 55 years (12 control, 28 with intermediate AMD) refuted any clinical benefit. In conclusion, this thesis supports the need to re-classify the AMD severity scale by incorporating eyes with SDD as a separate group. This phenotype should be sub-analysed in clinical trials evaluating potential prophylactic agents to delay the progression. Scotopic sensitivity offers diagnostic value, but rod intercept time offers both prognostic and diagnostic value as candidate biomarkers

Investigation of pathophysiological mechanisms in clinically isolated syndrome using advanced imaging techniques

This thesis concerns an observational study of patients recruited after their first episode of neurological symptoms suggestive of demyelination in the central nervous system and diagnosed either with clinically isolated syndrome or relapsing-remitting multiple sclerosis. In multiple sclerosis, brain tissues can exhibit extensive neuroaxonal microstructural and metabolic abnormalities, but little is known about their presence and significance at the time of the first demyelinating episode. I used a novel multi-parametric quantitative MRI approach, combining neurite orientation dispersion and density imaging (NODDI), which gives information about tissue microstructure, and 23Na MRI, which estimates total sodium concentration, a marker of metabolic dysfunction, in the brains of clinically isolated syndrome patients. I found microstructural and sodium homeostasis alterations in cortical areas of patients that showed clinical relevance. Within the diffuse axonal dispersion found in the normal-appearing white matter, the corpus callosum shared with lesions, signs of axonal damage and metabolic dysfunction, thus emerging as a possible target for early neuroprotective interventions. Structural cortical networks (SCNs) represent patterns of coordinated morphological modifications in cortical areas and they have shown pathophysiological changes in many brain disorders, including multiple sclerosis. I investigated alterations of SCNs at the individual level in this early cohort. Patients showed altered small-world topology, an efficient network organization combining dense local clustering with relatively few long-distance connections. These disruptions were worse for patients with higher lesion load and worse cognitive processing speed indicating that pathophysiological changes in the cortical morphology can influence clinical outcomes. Finally, I hypothesised that the patients in the cohort presenting with optic neuritis may have disturbances in neuropsychological functions related to visual processes. I found that cognitive visuospatial processing is affected after unilateral optic neuritis and improves over time with visual recovery, independently of the structural damage in the visual and central nervous system

Optic pathway glioma in type 1 neurofibromatosis: Review of its pathogenesis, diagnostic assessment, and treatment recommendations

Type 1 neurofibromatosis (NF1) is a dominantly inherited condition predisposing to tumor development. Optic pathway glioma (OPG) is the most frequent central nervous system tumor in children with NF1, affecting approximately 15-20% of patients. The lack of well-established prognostic markers and the wide clinical variability with respect to tumor progression and visual outcome make the clinical management of these tumors challenging, with significant differences among distinct centers. We reviewed published articles on OPG diagnostic protocol, follow-up and treatment in NF1. Cohorts of NF1 children with OPG reported in the literature and patients prospectively collected in our center were analyzed with regard to clinical data, tumor anatomical site, diagnostic workflow, treatment and outcome. In addition, we discussed the recent findings on the pathophysiology of OPG development in NF1. This review provides a comprehensive overview about the clinical management of NF1-associated OPG, focusing on the most recent advances from preclinical studies with genetically engineered models and the ongoing clinical trials

Investigating neuroinflammatory disease through retinal imaging and biomarkers

Neuroinflammatory diseases, in particular multiple sclerosis (MS) and neuromyelitis optica spectrum disorder, often affect the anterior visual pathways. This can occur through direct inflammatory insult in the form of optic neuritis or through retrograde degeneration, but progressive neurodegenerative processes related to axonal loss and atrophy also play a role. Energy failure has been postulated as an important factor mediating factor in these neurodegenerative processes, but its exact role is poorly understood. The advent of optical coherence tomography (OCT) enables high resolution imaging of the retina with relative ease. In neurology research, OCT has mostly been used to quantify retinal layer thicknesses. This thesis focuses on the largely unexplored potential of OCT as a functional biomarker. The primary aim is to develop indirect non-invasive in-vivo biomarkers informing on metabolic function, taking into account the high energy demand of the retina, particularly during dark-adaptation. First, two novel functional OCT measures are presented; the dynamic dark-adaptation related thickening of the outer retinal layers and the relative reflectivity of the ellipsoid zone (EZ), which comprises the majority of retinal mitochondria. Both measures appeared to be reduced in acute optic neuritis, and also in chronic neuroinflammatory disease in the case of EZ reflectivity. Furthermore, pilot OCT-angiography (OCTA) data indicated that vascular density was reduced in acute optic neuritis. As reduced EZ reflectivity and lower vascular density were present to a similar degree in both eyes of acute optic neuritis patients suggest that a background level of mitochondrial dysfunction and hypoperfusion may occur in neuroinflammatory disease, independent from acute inflammatory activity. The work presented in this thesis illustrates that OCT has the potential to provide valuable information on retinal function in neuroinflammatory disease. In the future, artificial intelligence and big data analysis may enable the development of a holistic analysis method for raw OCT data, providing a summary report on both qualitative, such as presence of microcystic macular oedema (MMO), and quantitative scan features, such as layer thickness, vascular density and reflectivity. Comprehensive analysis of both functional and structural OCT data may facilitate diagnosis, inform on prognosis and provide important insight into the role of metabolic failure in the pathophysiology of neuroinflammatory disease

Neuroimaging of Sudden Unexpected Death in Epilepsy (SUDEP)

BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of premature death among people with epilepsy. The precise mechanisms underlying SUDEP remain elusive, though work so far demonstrates a potential centrally mediated event in which autonomic, respiratory and/or arousal processes fail to recover following a significant seizure. Neuroimaging enables non-invasive assessment of the structural and functional architecture among sites and networks involved in regulating such processes; damage or alterations may indicate a central predisposition in those at high-risk and who suffer SUDEP, and provide non-invasive biomarkers. // METHODS: In this thesis, structural and functional imaging techniques were employed to address this possibility. Both retrospective investigations of those who succumbed to SUDEP, and prospective studies of those at high-risk, were performed. Voxel-based morphometry, volumetry and resting-state functional magnetic resonance imaging (RS-fMRI) network analysis techniques were utilised to identify and characterise brain structural and functional alterations relative to low-risk subjects and controls. // RESULTS: Brain morphometric and volumetric alterations among sites involved in cardiorespiratory regulation and recovery were found in those who later suffered SUDEP and in matched, living individuals at high risk. Prospective work revealed similar, and additional, structural alterations in those at high-risk which were associated with the extent of seizure-related hypoxemia; notably among the thalamus, periaqueductal grey (PAG), medulla, vermis and hippocampus. Network analysis of functional imaging data revealed disturbed patterns of connectivity in high-risk temporal lobe epilepsy (TLE) patients, and altered functional organisation in confirmed cases of SUDEP, among regulatory brain sites as well as the whole brain. // CONCLUSIONS: Structural and resting state functional connectivity disturbances were found in patients who suffered SUDEP, and those at elevated risk. Injury and connectivity disturbances may indicate damage or dysfunction within sites and networks involved central regulatory processes, which could facilitate SUDEP. However, further work is required to elucidate the precise mechanisms of volume and functional connectivity alterations, and to provide firm links between centrally mediated autonomic and respiratory dysfunction, SUDEP and related imaging findings. A more immediate use for the imaging outcomes revealed here may rest with the development of non-invasive biomarkers, which may one day assist in identifying those at risk and evaluating individual risk for SUDEP based on injury to brain sites or altered functional networks

Disrupted Spontaneous Neural Activity in Patients With Thyroid-Associated Ophthalmopathy: A Resting-State fMRI Study Using Amplitude of Low-Frequency Fluctuation

PurposeThe purpose of the study was to investigate the brain functional alteration in patients with thyroid-associated ophthalmopathy (TAO) by evaluating the spontaneous neural activity changes using resting-state functional magnetic resonance imaging (rs-fMRI) with the amplitude of low-frequency fluctuation (ALFF) method.Materials and MethodsThe rs-fMRI data of 30 TAO patients (15 active and 15 inactive) and 15 healthy controls (HCs) were included for analyses. The ALFF values were calculated and compared among groups. Correlations between ALFF values and clinical metrics were assessed.ResultsCompared with HCs, active TAOs showed significantly decreased ALFF values in the left middle occipital gyrus, superior occipital gyrus, and cuneus. Compared with inactive TAOs, active TAOs showed significantly increased ALFF values in the bilateral precuneus. Additionally, inactive TAOs showed significantly decreased ALFF values in the left middle occipital gyrus, superior occipital gyrus, cuneus, and bilateral precuneus than HCs. The ALFF value in the right precuneus of TAOs was positively correlated with clinical activity score (r = 0.583, P < 0.001) and Mini-Mental State Examination (MMSE) score (r = 0.377, P = 0.040), and negatively correlated with disease duration (r = −0.382, P = 0.037). Moreover, the ALFF value in the left middle occipital gyrus of TAOs was positively correlated with visual acuity (r = 0.441, P = 0.015).ConclusionTAO patients had altered spontaneous brain activities in the left occipital lobe and bilateral precuneus. The neuropsychological aspect of the disease should be noticed during clinical diagnosis and treatment