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Background: Lewy body dementia (LBD), consisting of Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), is known to make up more than 15% of dementia cases at autopsy, however the clinical prevalence rate is reported to be much lower at around 5-6%. Difficulties with diagnosis and/or lack of specific treatments may contribute to this difference. This study investigated the diagnosis and management pathways of LBD and whether inflammation could play a role in the pathophysiology and hence provide a route for future diagnostic and treatment pathways. Methods: Clinical diagnostic rates of LBD in clinics across several NHS trusts in East Anglia were reviewed, followed by an in-depth notes review of patients identified with LBD together with age and gender matched controls. A literature review of the current evidence for inflammation in LBD, preceded a case control study to investigate further. Nineteen DLB patients together with 16 age and gender matched healthy controls underwent [11C]PK11195 PET imaging, and the same cohorts, plus an additional 10 matched control subjects underwent peripheral cytokine analysis. Results: The clinical prevalence rate of LBD was low compared to the known pathology rates, with delays identified in the diagnosis of DLB compared to other dementia subtypes. Delays were also seen between the onset of dementia symptoms and the clinical diagnosis of dementia in Parkinson's disease (PD). The literature review identified studies providing evidence of inflammation in PD but few studies had been carried out in DLB. PET imaging revealed microglial activation negatively correlated with disease severity in DLB, suggesting inflammation occurs early in the disease. DLB patients also showed evidence of differences in cytokine levels compared to healthy controls. Conclusion: The study showed evidence of inflammatory changes in DLB, providing a potential target for treatment and/or biomarkers, that could assist in increasing clinical diagnostic rates.

The protein alpha-synuclein (α-synuclein) accumulates in the brain in disorders such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). It is believed that the monomeric form of α-synuclein can adopt a partially folded structure and start to aggregate and form intermediately sized oligomers or protofibrils. The aggregation process can continue with the formation of insoluble fibrils, which are deposited as Lewy bodies. The oligomers/protofibrils have been shown to be toxic to neurons and are therefore believed to be involved in the pathogenesis of the actual diseases.       The overall aims of this thesis were to investigate the properties of α-synuclein oligomers and to generate and characterize antibodies against these species. In addition, the potential for immunotherapy of the α-synuclein oligomer-selective antibodies were evaluated in a transgenic mouse model with α-synuclein pathology. Stable, β-sheet rich α-synuclein oligomers were induced by incubation with either one of the reactive aldehydes 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE). The oligomers exhibited distinct morphological properties, although both types were toxic when added to a neuroblastoma cell line. The seeding effects of ONE-induced oligomers were studied in vitro and in vivo. The oligomers induced seeding of monomeric α-synuclein in a fibrillization assay but not in a cell model or when injected intracerebrally in transgenic mice. It seemed, however, as if the oligomers affected α-synuclein turnover in the cell model. By immunizing mice with HNE-induced oligomers antibody producing hybridomas were generated. Three monoclonal antibodies were found to have strong selectivity for α-synuclein oligomers. These antibodies recognized Lewy body pathology in brains from patients with PD and DLB as well as inclusions in the brain from young α-synuclein transgenic mice, but did not bind to other amyloidogenic proteins. Finally, immunotherapy with one of the oligomer/protofibril selective antibodies resulted in lower levels of such α-synuclein species in the spinal cord of α-synuclein transgenic mice. To conclude, this thesis has focused on characterizing properties of α-synuclein oligomers. In particular, antibodies selectively targeting such neurotoxic forms were generated and evaluated for passive immunization in a transgenic mouse model. Such immunotherapy may represent a future treatment strategy against Lewy body disorders.

Made available in DSpace on 2014-07-29T15:29:10Z (GMT). No. of bitstreams: 1 Dissert_EbersonSRN.pdf: 1230800 bytes, checksum: 70200ae7fcfb893a1baed80412086408 (MD5) Previous issue date: 2011-04-29 / Dementia is a neurodegenerative syndrome by impressive and also by the high occurrence rates of morbidity in caregivers. Dementia with Lewy bodies is a complex neuropsychiatric frame member, considered the second cause of degenerative dementia in the elderly, and resulting impact on quality of life in caregivers. The objectives of this study were to identify in the literature, the impact of caregiving on the quality of life for caregivers of a patient with dementia to describe the strategies used by health professionals and researchers in Brazil or to mitigate the negative impacts of caring for the patient dementia and assessing quality of life for families living with and caring for patients with dementia with Lewy bodies. It was initially performed an integrative review the electronic databases of the National Library of Medicine (PubMed) and Latin American Health Sciences (LILACS), the interval from 1999 to 2010. Then a cross-sectional study evaluated 90 caregivers of patients with dementia with Lewy bodies, responding to a sociodemographic questionnaire and the instrument for assessing the quality of life, WHOQOL-BREF. The integrative review included 19 articles, showing that despite high rates of stress, anxiety and physical and mental burden of home caregivers of patients with dementia, there is little national scientific output in this regard. Strategies were listed health professionals in two papers, with proof of the applicability and effectiveness of these interventions help the needs of caregivers. The field study showed that caregivers were mostly men, with two primary school education, married, average age 47.4 years ± 13.8 years and average time as a caregiver of 13.9 ± 9.3 months. The highest average scores for quality of life was in the Physical Domain and the lowest in the psychological and Environment. Variables associated with quality of life were age and duration of caregiver. Caregivers aged 60-75 years had the lowest scores in the Physical Domain. Those who care for less time had the greatest impact in the psychological environment and quality of life. We conclude that it is necessary to support the emotional aspects of the professional caregiver, allowing for better management of the situation. Knowledge and understanding of the specific symptoms of the disease helps the adequacy of personal resources to deal with behavioral changes, identified as the factor most impacting on the caregiver's life. Special attention should be given to changes in the caregiver's health, so it does not become a "hidden patient" and unable to cope with the demands of patients with dementia with Lewy bodies. / A demência é uma síndrome neurodegenerativa impactante pela grande ocorrência e também pelos índices de morbidade nos cuidadores. A demência com corpos de Lewy é um quadro neuropsiquiátrico complexo associado, considerado como segunda causa de demência degenerativa em idosos, e que provoca impacto na qualidade de vida nos cuidadores. Os objetivos deste estudo foram identificar na literatura, o impacto do cuidado na qualidade de vida de quem cuida de um portador de demência; descrever as estratégias utilizadas por profissionais de saúde e ou pesquisadores brasileiros para amenizar os impactos negativos decorrentes do ato de cuidar do portador de demência e avaliar a qualidade de vida de familiares que convivem e cuidam de portadores de demência com corpos de Lewy. Inicialmente foi realizada uma revisão integrativa nas bases eletrônicas da National Library of Medicine (PubMed) e Literatura Latino Americana de Ciências da Saúde (LILACS), no intervalo de 1999 a 2010. Em seguida foi realizado estudo transversal que avaliou 90 cuidadores de pacientes com demência com corpos de Lewy, respondendo a um questionário sociodemográfico e ao instrumento de avaliação da qualidade de vida, WHOQOL-BREF. A revisão integrativa incluiu 19 artigos, evidenciando que, apesar de altos os índices de estresse, ansiedade e desgaste físico e mental dos cuidadores domiciliares de pacientes com demência, é escassa a produção cientifica nacional a esse respeito. Foram apontadas estratégias dos profissionais de saúde em dois artigos, com aplicabilidade e comprovação da eficácia dessas intervenções no auxilio às necessidades dos cuidadores. O perfilsociodemográfico do estudo de campo evidenciou que os cuidadores entrevistados eram na maioria homens, com 2º grau de escolaridade, casados, de idade média 47,4 ± 13,8 anos anos e média de tempo como cuidador de 13,9 ± 9,3 meses. A maior média dos domínios de qualidade de vida foi no Domínio Físico e a menor nos Domínios Psicológico e Meio Ambiente. As variáveis associadas à qualidade de vida foram a idade e o tempo de cuidador. Os cuidadores com idade entre 60 - 75 anos apresentaram piores escores no Domínio Físico. Aqueles que cuidam há menos tempo tiveram maior impacto nos Domínios Psicológico e Meio Ambiente da qualidade de vida. Conclui-se que é necessário suporte profissional aos aspectos emocionais do cuidador, permitindo melhor gerenciamento da situação. O conhecimento das especificidades e compreensão dos sintomas da patologia auxiliam na adequação dos recursos pessoais para enfrentar as alterações comportamentais, apontadas como o fator mais impactante na vida do cuidador. Atenção especial deve ser dada às alterações na saúde do cuidador, para que ele não se torne um paciente oculto e incapaz de lidar com as demandas do portador de demência com corpos de Lewy.

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This master’s thesis deals with diagnostics of prodromal stage of Lewy body disease using microstate analysis. First part of the thesis includes theoretical background which is needed for understanding discussed topics and presented results. This part consists of description of the disease, diagnostic options, electroencephalography, pre-processing of the EEG record and the microstate analysis process. Theoretical background is followed by a practical part of the thesis. In the beginning, there is a chapter about a dataset, used EEG device, and own solution of the pre-processing. Microstate analysis is discussed next, its output parameters were compared between groups with statistical methods. Comparison of the subjects in prodromal stage of Lewy body disease and healthy controls brought significant differences in three parameters of microstates, in rate of unlabelled time frames and also for some counts of transitions between each map or unlabelled sections. Comparison of the subjects in prodromal stage of Lewy body disease and healthy controls brought significant differences in three parameters of microstates, in rate of unlabelled time frames and also for some counts of transitions between each map or unlabelled sections.

The theme of this dissertation is to improve the exploration of patient subgroups with a precision medicine lens, specifically using repeated measures data to evaluate longitudinal trajectories of clinical, biological, and lifestyle measures. Our proposed methodological contributions fall into two branches of statistical methodology: undirected graphical models and functional data analysis. In the first part of this dissertation, our goal was to study longitudinal networks of brain imaging biomarkers and clinical symptoms during the time leading up to manifest Huntington's disease diagnosis among patients with known genetic risk of disease. Understanding the interrelationships between measures may improve our ability to identify patients who are nearing disease onset and who therefore might be ideal patients for clinical trial recruitment. Gaussian graphical models are a powerful approach for network modeling, and several extensions to these models have been developed to estimate time-varying networks. We propose a time-varying Gaussian graphical model specifically for a time scale that is centered on an anchoring event such as disease diagnosis. Our method contains several novel components intended to 1) reduce bias known to stem from 𝑙₁ penalization, and 2) improve temporal smoothness in network edge strength and structure. These novel components include time-varying adaptive lasso weights, as well as a combination of 𝑙₁, 𝑙₂, and 𝑙₀ penalization. We demonstrated via simulation studies that our proposed approach, as well as more computationally efficient subsets of our full proposed approach, have superior performance compared to existing methods. We applied our proposed approach to the PREDICT-HD study and found that the network edges did change with time leading up to and beyond diagnosis, with change points occurring at different times for different edges. For clinical symptoms, bradykinesia became well-connected with symptoms from several other domains. For imaging measures, we observed a loss of connection over time among gray matter regions, white matter regions, and the hippocampus. In the second part of this dissertation, we consider time-varying network models for settings in which data are not all Gaussian. We sought to compare longitudinal clinical symptom networks between patients with neuropathologically-defined Alzheimer's disease (AD) vs. neuropathologically-defined Lewy body dementia (LBD), two common types of dementia which can often be clinically misdiagnosed. Given that the clinical measures of interest were largely non-Gaussian, we examined the literature for undirected graphical models for mixed data types. We then proposed an extension to the existing time-varying mixed graphical model by adding time-varying adaptive lasso weights, modeling time in reverse in order to treat neuropathological diagnoses as baseline covariates. The proposed adaptive lasso extension serves a two-fold purpose: they alleviate well-known bias of 𝑙₁ penalization and they encourage temporal smoothness in edge estimation. We demonstrated the improved performance of our extension in simulations studies. Applying our method to the National Alzheimer's Coordinating Center database, we found that the edge structure surrounding the Wechsler Memory Scale Revised (WMS-R) Logical Memory parts IA (immediate recall) and IIA (delayed recall) may contain important markers for discriminant analysis of AD and LBD populations. In the third part of this dissertation, we explored a methodologically distinct area of research from the first two parts, moving from graphical models to functional data analysis. Our goal was to extract meaningful chronotypes, or phenotypes of circadian rhythms, from activity count data collected from accelerometers. Existing approaches for analyzing diurnal patterns using these data, including the cosinor model and functional principal components analysis, have revealed and quantified population-level diurnal patterns, but considerable subject-level variability remained uncaptured in features such as wake/sleep times and activity intensity. This remaining informative variability could provide a better understanding of chronotypes, or behavioral manifestations of one’s underlying 24-hour rhythm. Curve registration, or alignment, is a technique in functional data analysis that separates "vertical" variability in activity intensity from "horizontal" variability in time-dependent markers like wake and sleep times. We developed a parametric registration framework for 24-hour accelerometric rest-activity profiles that are represented as dichotomized into epoch-level states of activity or rest. Specifically, we estimated subject-specific piecewise linear time-warping functions parametrized with a small set of parameters. We applied this method to data from the Baltimore Longitudinal Study of Aging and illustrated how estimated parameters can give a more flexible quantification of chronotypes compared to traditional approaches.

Pesticides have been suggested to play a role in the development of many neurodegerative diseases including Parkinson's disease and Alzheimer's disease. Additionally, it has been suggested that exposure to pesticides and other environmental chemicals during the early stages of life could result in an increased vulnerability to such substances that could lead to neurotoxicity and degeneration late in life. We hypothesized that exposure to mixtures of certain pesticides could change neurotransmitter levels and cellular oxidative stress and that this would be greater in mice exposed early and later in life than mice exposed only as adults. We studied the effects of permethrin (PR) (a pyrethroid type I) and endosulfan (EN) (an organochlorine) on the levels of catecholamines, indolamines, acetylcholinesterase, lipid peroxidation and α-synuclein in the brain of mice. These pesticides have different structures but both are known to modify the kinetics of voltage-sensitive ion channels and calcium ion flux/homeostasis that could affect the release of several neurotransmitters. The study consisted of two experiments: In the first experiment, adult C57Bl/6 mice (7-9 months old) were injected, intraperitoneally, with the following treatments: EN 4.3, 2.15 mg/kg; PR 150, 15 mg/kg and their mixtures EN 4.3 + PR 150 and EN 2.15 + PR 15 mg/kg. Mice were sacrificed 24 hrs after the last injection. In the second experiment, doses consisted of EN 0.7, 1.4 mg/kg, PR 1.5, 15 mg/kg and their mixtures EN 0.7 + PR 1.5 mg/kg and EN 1.4 + PR 15 mg/kg were given to juvenile mice intraperitoneally daily during a period of two weeks from postnatal day 5 to 19. Mice were then, left undisturbed with their dams. Re-challenge was performed when mice were 7-9 months old and dosages of EN 4.3, 2.15 mg/kg, PR 150, 15 mg/kg and their mixtures, EN 4.3 + PR 150 and EN 2.15 + PR 15 mg/kg were given intraperitoneally every other day during a period of two weeks to match the treatments when pesticide exposure was only as adults. Mice were sacrificed 24 hrs after the last injection. The corpora striatum was extracted and analyzed by HPLC for catecholamines (dopamine, DOPAC, homovalinic acid and norepinephrine) and indolamines (serotonin and 5-HIAA). In general low doses of permethrin and endosulfan alone and in combination (EN 2.15 + PR 15 mg/kg) altered the levels of catecholamines and indolamines in both studies with adult mice and mice dosed as juveniles and re-challenged as adults. Catecholamine and indolamines levels were affected to a greater extent in the adult mice than in mice dosed as juveniles and re-challenged as adults, when compared to controls. Acetylcholinesterase was increased under both exposure situations but again adult mice seemed to be more affected than mice dosed as juveniles and re-challenged as adults. Because reactive oxygen species have been implicated in the development of Parkinson's disease, and are known to cause degradation of certain neurotransmitters, we monitored the levels of lipid peroxides in brain cortex as an indicator of free radical tissue damage. The peroxide levels were measured by thiobarbituric acid reactive products (TBARS). Increased levels of lipid peroxides were significant in the low dose treatment groups of the adult study. However, there seemed to be a pattern between the levels of dopamine and DOPAC in the striatum and the levels of peroxidation in cortex. The presence of dopamine metabolites appeared to be related to high levels of peroxidation within the basal ganglia and up-regulation of proteins such as α-synuclein. Western blots of α-synuclein in both experiments of the study showed intense double and triple bands that corresponded to aggregated α-synuclein. In general, when compared with controls, mice dosed as juveniles and re-challenged as adults did not alter the above parameters as much as mice dosed only as adults. Instead, the mice first dosed as juveniles seemed to develop an adaptation response to the later exposure of these pesticides. Taking all these results into account, early exposure and re-challenge with permethrin and endosulfan in this study appeared to induce a protective response against neurochemical changes in the brain of these mice. In addition, low doses of these pesticides and the low dose combination mixture seem to exert an effect on the parameters studied. Therefore, exposure to pesticides such as endosulfan and permethrin and their combinations could make a contribution towards the initiation or aggravation of biochemical neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. / Master of Science

Charles Bonnet syndrome (CBS) is defined as complex persistent visual hallucinations in the absence of mental disorder. It is associated with advanced age and poor vision. It is common, with prevalence estimates of up to 63% among older people with significant visual impairment. CBS would not be diagnosed in the presence of dementia, but its relationship to milder cognitive impairment is unclear. The few studies that have examined this are underpowered and provide contradictory results. There are 16 case reports of dementia emerging in people with a diagnosis of CBS. These cases raise the possibility of an association between impaired insight at diagnosis of CBS and the subsequent development of dementia. This thesis reports the findings of a prospective cohort study which describes changes in cognitive functioning over one year in patients with CBS and age-matched controls. Participants were recruited from low vision and glaucoma assessment clinics. A clinical assessment was carried out by an old age psychiatrist, and participants had a detailed assessment of visual functioning. This thesis also describes the findings of the first study to use voxel-based morphometry (VBM) to investigate changes in volume of grey and white matter in CBS. Participants were recruited from the same clinics as the cohort study, and underwent MRI scanning on a 1.5T scanner, to a protocol designed to produce 1mm3 voxels. Twelve participants with CBS and ten controls were followed up. Two people in the CBS group developed dementia, while none did in the control group. The CBS group showed a mean change in the score on the Addenbrooke’s cognitive examination (ACE-R) of -3.7 points, compared to a change of +1.4 in the control group. This difference was not statistically significant. The CBS participants performed worse on the verbal fluency item of the ACE-R, a difference which was statistically significant. The VBM analysis was conducted on 11 CBS participants and 11 controls. The CBS group showed an increase in grey matter volume in the right cerebellar hemisphere. This difference retained significance after family-wise error correction, non-stationary correction, and ANCOVA to control for the effects of possible confounders. As far as the author is aware, these are the most methodologically robust studies to date to have investigated cognition and morphological brain changes in CBS. The findings of the cohort study were inconclusive. However, the two cases of dementia in CBS patients add weight to the suspicion that this is a clinically important outcome in the condition, and the finding of abnormalities in frontal lobe testing in participants with CBS fits with a theoretical model of visual hallucination generation. Moreover, this type of research appears to be acceptable to a frail and visually disabled population, and studies powered to investigate this issue more fully would be feasible. The VBM findings report the presence of underlying structural brain abnormalities in CBS, in a region not usually associated with visual hallucinations. Possible links with Lewy body dementia, and implications for theories of visual hallucinations, are discussed.

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