505 research outputs found

    Analysis of the retina and visual pathway by OCT, OCTA and psychophysical tests in asymptomatic subjects at high genetic risk for the development of Alzheimer's disease

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    Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, leída el 15-07-2022La Enfermedad de Alzheimer (EA) es una enfermedad neurodegenerativa progresiva que se caracteriza: por una atrofia cortical difusa, declive de las funciones cognitivas, así como la agregación anormal de proteínas como la beta amiloide fibrilar (Aß) y tau hiperfosforilada (p-Tau).El factor de riesgo prevalente es la edad avanzada, tras el cual destaca la herencia genética. Elmayor factor de riesgo genético conocido es ser portador de al menos un alelo 4 del gen de la apoliproteina E (ApoE). Otro de los factores que incrementa el riesgo para desarrollar la EA, es la historia familiar de primer grado. Los signos cerebrales de la EA aparecen décadas antes del inicio clínico de la enfermedad. Dado que la relación entre cerebro y retina se establece ya desde la etapa embrionaria, los cambios retinianos detectados con técnicas de diagnóstico oftalmológico en sujetos con alto riesgo genético para el desarrollo de EA posibilitan la identificación de potenciales pacientes de EA en etapas muy tempranas...Alzheimer's disease (AD) is a progressive neurodegenerative disease characterised by: diffuse cortical atrophy, decline in cognitive functions, as well as abnormal aggregation of proteins such as fibrillar amyloid Beta (Aβ) and hyperphosphorylated tau(p-Tau).The prevalent risk factor is older age, after which genetic inheritance is the most important. The major known genetic risk factor is carrying at least one 4 allele of the apoliprotein E (ApoE 4)gene. Another factor that increases the risk of developing AD is a first-degree family history. Brain signs of AD appear decades before clinical onset of the disease. Since the relationship between brain and retina is established as early as the embryonic stage, retinal changes detected with ophthalmological diagnostic techniques in subjects at high genetic risk for developing AD make it possible to identify potential AD patients at very early stages..Fac. de MedicinaTRUEunpu

    Elesclomol Alleviates Menkes Pathology in Mice by Delivering Cu to Brain Cytochrome c Oxidase

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    Copper is an essential micronutrient required for the proper biological function of numerous enzymes. Absorption, transportation, and elimination of copper is highly regulated due to potential pathological effects of copper overload or deficiency. Menkes Disease is an X-linked inherited defect in active, directional copper transport caused by mutations in the ATP7A gene that results in profound copper deficiency and subsequent neurodegeneration in hemizygous male infants. The prognosis for those diagnosed with Menkes Disease is poor with death resulting before three years of age. Current therapeutic strategies involve parental replacement of systemic copper using histidine as the ionophoric carrier, but clinical trials have failed to significantly alter disease progression in most patients. Poor tissue penetrance and low restoration of cuproenzyme function explain the failure of histidine-based therapy in Menkes patients. Elesclomol is a chemotherapeutic agent with highly specific copper coordinating properties. The copper (II)-elesclomol complex is highly lipophilic, penetrates the blood-brain barrier, and has demonstrated the ability to restore cuproenzyme function in copper-deficient yeast strains at very low exposure levels. To assess the efficacy of an elesclomol-based copper replacement therapy, an intervention protocol in mottled-brindled mice was developed resulting in greater than 80% survival of affected male mice. Of these mice, average lifespan within the treatment group approximated wildtype length with multiple individuals surviving greater than 250 days. Phenotypic characterization of rescued Menkes-affected males reveals subtle deficiencies in neurologic and motor performance. Quantification of tissue copper levels and cuproenzyme function demonstrate partial restoration of copper levels and function of the key cuproenzyme cytochrome c oxidase. Pharmacokinetics and acute toxicity of the intervention regime were assessed. The complex exhibits biphasic distribution with slow elimination from peripheral tissues, moderate systemic exposure, and is well tolerated at low exposure levels. Based on these results, the copper (II)-elesclomol complex shows promise as a potential therapeutic agent for the treatment of Menkes Disease

    Hyperbaric Medicine

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    Hyperbaric oxygen is a known therapeutic agent, and treatments using this agent remain a matter of discussion and research. This Special Issue collection will add new knowledge and also offer some not so usual approaches to foster contemporary understanding and potential benefit for patients and scholars

    Characterising Changes in Visual Attention Following Traumatic Brain Injury (TBI)

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    Purpose: Traumatic Brain Injury (TBI) is a major worldwide public health concern, with approximately 69 million individuals sustaining some form of brain injury annually. Though this figure is likely to be underreported as many do not seek medical treatment. Long-term changes in cognition and memory are sequelae of all brain injury severities and, most commonly as deficits in attention. Attentional processes are heterogenous and have been proposed to comprise different functional aspects or components that operate to deploy attention in different ways. For example, attention can be selective, divided, sustained and spatially allocated. However, it remains to be established whether TBI leads to a general deficit in attention or whether certain components are more affected. The thesis addresses this research question by focusing on visual attention using two approaches. First, behaviourally using two novel tasks (Motion tracking and a variant of Posner cueing) in which their stimulus conditions (such as duration and search efficiency) were systematically varied to assess different components of attention. And secondly, by observing changes in the allocation of visual attention through eye movement measurements and pupil responses (which are effective markers of attention) while performing these attentional tasks. Method: A systematic review and meta-analysis was initially conducted (Chapter 2) to provide an indication of the impact of TBI on visual attention and its components from the published literature. Drawing on the limitations and gaps in knowledge observed from this review, a series of cross-sectional studies were conducted that compared the performance of patients with mild TBI and normal participants on multiple conditions in which each task condition was used to assess a specific component of visual attention. Particularly, in Chapters 3 and 4, selective, divided and sustained attention was investigated using a multiple object tracking (MOT) task and varying stimulus parameters such as the number of targets to be tracked, the number of distractors and tracking duration. In Chapters 5 and 6, we investigated the allocation of attention using a modified Posner cueing task for conditions in which search efficiency and cue validity were systematically varied. Behavioural measures include sensitivity and reaction time and response-independent measures, including the pupillary response and eye movements. Results: Meta-analysis of previous works showed that the combined effect size of an attentional deficit following TBI is large but characterised by high heterogeneity. The latter finding highlights the potential impact of different dependent and independent variables on study outcomes. Additionally, there was a paucity of knowledge in understanding changes in divided and sustained visual attention following TBI. Chapters 3 and 5 contribute to knowledge by showing that patients with mild TBI exhibit a poor ability to orient visual attention (endogenously and exogenously) and in tracking multiple targets, particularly when the tracking duration was long and the number of to-be-tracked targets and the number of distractors was high. Chapters 4 and 6 showed that deficits in attention following mild TBI are also associated with deficits in eye movement measures (number of fixation and duration and tracking strategy) and pupillometry measures (latency and pupil amplitude), which is broadly indicative of a lack of attentional resources. Conclusion: Collectively, the results of this thesis showed a generalised visual attention deficit after TBI, which was not selective to a specific component of visual attention. Deficits in visual attention manifested in all outcome measures (including performance accuracy and reaction time), which suggests the importance of considering them in the assessment of visual attention. The cognitively driven pupillary response and eye movement patterns differentiated patients with mild TBI and might be considered an alternative measure of visual attention, particularly in the clinical population

    Social attention in young children with autism spectrum disorder: Investigating cross-contextual gaze behaviours, and their relationship to autism severity, cognitive skills and social functioning

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    Social communication and interaction challenges are characteristic of autism spectrum disorder (ASD). Social attention has emerged to be an important behavioural phenotype in ASD, with accumulating evidence suggesting associations with social functioning and developmental outcomes. However, research gaps remain concerning the nature of social attention, the variability demonstrated across different experimental tasks and social contexts, and the ecologically validity of research methods. This thesis aimed to address these substantive and methodological issues by examining social attention patterns in a young cohort of autistic children, and their age-matched neurotypical peers, across three experimental contexts: 1) a traditional, eye-tracking task with static stimuli, 2) a novel, dynamic eye-tracking task incorporating shared book reading (SBR), and 3) an evaluation of the association in social attention across the two eye-tracking tasks and a play-based social interaction task. In Chapter 2, the influence of circumscribed interests (CI) on social attention patterns was investigated. The results of this study suggested there to be a reduced role for CIs and atypical attention patterns in both social and non-social domains. In Chapter 3, a novel SBR task was developed as a dynamic, ecologically relevant eye-tracking task designed to assess social and joint attention behaviours. Results indicated reduced social and joint attention behaviours, in conjunction with increased attention to non-salient background objects in autistic children. Associations between reduced social attention and poorer social functioning and cognitive skills were also evident in this cohort. In Chapter 4, the social attention patterns of the autistic cohort as measured by the two previous eye tracking tasks were correlated with these patterns in a live, play-based social interaction task between a researcher and the autistic child. Cross-contextual associations in social attention between the social interaction and dynamic tasks, and the dynamic and static tasks were observed. In contrast, there was no significant association in social attention patterns between the social interaction and static tasks. These outcomes contribute new insights into the social attention behaviours of autistic children, and evidence in favor of examining these behaviours in ecologically relevant contexts. They also contribute to evidence associating social attention with autism symptomatology and cognitive functioning. Ultimately, the outcomes of this research may improve our understanding of the needs of autistic children across social, cognitive and adaptive functioning domains

    Automating the eye examination using optical coherence tomography

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    Optical coherence tomography (OCT) devices are becoming ubiquitous in eye clinics worldwide to aid the diagnosis and monitoring of eye disease. Much of this uptake relates to the ability to non-invasively capture micron-resolution images, enabling objective and quantitative data to be obtained from ocular structures. Although safe and reasonably quick to perform, the costs involved with operating OCT devices are not trivial, and the requirement for OCT and other imaging in addition to other clinical measures is placing increasing demand on ophthalmology clinics, contributing to fragmented patient pathways and often extended waiting times. In this thesis, a novel “binocular optical coherence tomography” system that seeks to overcome some of the limitations of current commercial OCT systems, is clinically evaluated. This device incorporates many aspects of the eye examination into a single patient-operated instrument, and aims to improve the efficiency and quality of eye care while reducing the overall labour and equipment costs. A progressive framework of testing is followed that includes human factors and usability testing, followed by early stage diagnostic studies to assess the agreement, repeatability, and reproducibility of individual diagnostic features. Health economics analysis of the retinal therapy clinic is used to model cost effectiveness of current practice and with binocular OCT implementation. The binocular OCT and development of other low-cost OCT systems may improve accessibility, however there remains a relative shortage of experts to interpret the images. Artificial intelligence (AI) is likely to play a role in rapid and automated image classification. This thesis explores the application of AI within retinal therapy clinics to predict the onset of exudative age-related macular degeneration in fellow eyes of patients undergoing treatment in their first eye. Together with automated and simultaneous imaging of both eyes with binocular OCT and the potential for low-cost patient-facing systems, AI is likely to have a role in personalising management plans, especially in a future where preventive treatments are available
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