Дисертації: "Biomarkers of neurodegenerative disease"

1

Rittman, Timothy. "Connectivity biomarkers in neurodegenerative tauopathies." Thesis, University of Cambridge, 2015. https://www.repository.cam.ac.uk/handle/1810/248866.

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The primary tauopathies are a group of neurodegenerative diseases affecting movement and cognition. In this thesis I study Progressive Supranuclear Palsy (PSP) and the Corticobasal Syndrome (CBS), two parkinsonian disorders associated with accumulation of hyperphos- phorylated and abnormally folded tau protein. I contrast these two disorders with Parkinson’s disease (PD), which is associated with the accumulation of alpha-synuclein but has a genetic association with the MAPT gene encoding tau. Understanding the tauopathies to develop effective treatments will require a better grasp of the relationships between clinical syndromes and cognitive measures and how the anatomical and neurochemical networks that underlie clinical features might be altered by disease. I investigate simple clinical biomarkers, showing that a two-minute test of verbal fluency is a potential diagnostic biomarker to distinguish between PD and PSP and that the ACE-R and its subscores could play a role in monitoring cognition over time in PD, PSP and CBS. I assess the implementation of network analysis in Functional Mag- netic Resonance Imaging (fMRI) data, introduce Maybrain software for graphical network analysis and visualisation. I go on to show an overlap between graph theory network measures and I identify three main factors underlying graph network measures of: efficiency and distance, hub characteristics, network community measures. I apply these measures in PD, PSP and the CBS. All three diseases caused a loss of functional connectivity in com- parison to the control group that was concentrated in more highly connected brain regions and in longer distance connections. In ad- dition, widely localised cognitive function of verbal fluency co-varied with the connection strength in highly connected regions across PD, PSP and CBS. To take this further, I investigated specific functional covariance networks. All three disease groups showed reduced connectivity between the basal ganglia network and other networks, and between the anterior salience network and other networks. Localised areas of increased co- variance suggest a breakdown of network boundaries which correlated with motor severity in PSP and CBS, and duration of disease in CBS. I explore the link between gene expression of the tau gene MAPT and its effects on functional connectivity showing that the expression of MAPT correlated with connection strength in highly connected hub regions that were more susceptible to a loss of connection strength in PD and PSP. I conclude by discussing how tau protein aggregates and soluble tau oligomers may explain the changes in functional brain networks. The primary tauopathies are a group of neurodegenerative diseases affecting movement and cognition. In this thesis I study Progressive Supranuclear Palsy (PSP) and the Corticobasal Syndrome (CBS), two parkinsonian disorders associated with accumulation of hyperphos- phorylated and abnormally folded tau protein. I contrast these two disorders with Parkinson’s disease (PD), which is associated with the accumulation of alpha-synuclein but has a genetic association with the MAPT gene encoding tau. Understanding the tauopathies to develop effective treatments will require a better grasp of the relationships between clinical syndromes and cognitive measures and how the anatomical and neurochemical networks that underlie clinical features might be altered by disease. I investigate simple clinical biomarkers, showing that a two-minute test of verbal fluency is a potential diagnostic biomarker to distinguish between PD and PSP and that the ACE-R and its subscores could play a role in monitoring cognition over time in PD, PSP and CBS. I assess the implementation of network analysis in Functional Mag- netic Resonance Imaging (fMRI) data, introduce Maybrain software for graphical network analysis and visualisation. I go on to show an overlap between graph theory network measures and I identify three main factors underlying graph network measures of: efficiency and distance, hub characteristics, network community measures. I apply these measures in PD, PSP and the CBS. All three diseases caused a loss of functional connectivity in com- parison to the control group that was concentrated in more highly connected brain regions and in longer distance connections. In ad- dition, widely localised cognitive function of verbal fluency co-varied with the connection strength in highly connected regions across PD, PSP and CBS. To take this further, I investigated specific functional covariance networks. All three disease groups showed reduced connectivity between the basal ganglia network and other networks, and between the anterior salience network and other networks. Localised areas of increased co- variance suggest a breakdown of network boundaries which correlated with motor severity in PSP and CBS, and duration of disease in CBS. I explore the link between gene expression of the tau gene MAPT and its effects on functional connectivity showing that the expression of MAPT correlated with connection strength in highly connected hub regions that were more susceptible to a loss of connection strength in PD and PSP. I conclude by discussing how tau protein aggregates and soluble tau oligomers may explain the changes in functional brain networks.

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2

Boman, Andrea. "Lysosomal network proteins as biomarkers and therapeutic targets in neurodegenerative disease." Doctoral thesis, Linköpings universitet, Avdelningen för cellbiologi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-122347.

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The pre-symptomatic stage of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) occurs several decades before the clinical onset. Changes in the lysosomal network, i.e. the autophagosomal, endosomal and lysosomal vesicular system, are among the first alterations observed. There are currently no treatments to slow or cure neurodegenerative diseases, and there is a great need for discovery of treatment targets in cellular pathways where pathology pre-dates the neuronal death. It is also crucial to be able to diagnose neurodegenerative diseases earlier, both to enable early intervention treatment and aid in selecting clinical trial populations before the patient has widespread pathology. This thesis aims at investigating the potential of lysosomal network proteins as biomarkers and therapeutic targets in neurodegenerative disease. A targeted search for lysosomal network proteins was performed in cerebrospinal fluid (CSF) from AD patients, and seven proteins: early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), lysozyme, microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were elevated. The levels of EEA1, LAMP-1, LAMP-2, LC3, lysozyme and Rab3 were also measured in CSF from parkinsonian syndrome patients: PD, clinically diagnosed 4-repeat tauopathy, pathologically confirmed corticobasal degeneration (CBD) and pathologically confirmed progressive supranuclear palsy (PSP) patients. LAMP-1 and LAMP-2 were decreased in PD. LC3 and lysozyme levels were increased in 4-repeat tauopathy patients. EEA1 was decreased and lysozyme increased in PSP, and LAMP-1, LAMP-2, LC3 and lysozyme were increased in CBD. The lysosomal network proteins had different CSF protein profiles in all the parkinsonian syndromes, as well as in AD. It should be emphasized that only a select few of the lysosomal network proteins were observed to be changed, rather than a general change in lysosomal network proteins, which implicates the involvement of these seven proteins in specific pathological processes. The most interesting candidates, LAMP-2 and lysozyme, were selected for further study for their involvement in the pathology of AD. Lysozyme was found to co-localise with Aβ plaques in AD patients and overexpression prolonged survival and improved the activity in a Drosophila model of AD. Lysozyme was found to alter the aggregation pathway of Aβ1-42, to counteract the formation of toxic Aβ species and to protect from Aβ1-42 induced cell toxicity. Aβ1-42 in turn was found to increase the expression of lysozyme in both neuronal and glial cells. These data suggest that lysozyme levels rise in AD as a compensatory response which is protective against Aβ associated toxicity. LAMP-2 mRNA and protein were found increased in brain areas relevant for AD pathology and various cellular models showed complex involvement of LAMP-2 in Aβ related pathology, with extensive crosstalk between LAMP-2 and Aβ. Exposure to oligomeric Aβ1-42 caused an upregulation of LAMP-2 and in turn, overexpression of LAMP-2 caused a reduction in secreted levels of Aβ1-42, as well as changing the generation pattern of Aβ and affecting clearance and secretion of Aβ1-42. These data indicate that the increased levels of LAMP-2 in AD could be an attempt to regulate Aβ generation and secretion. In summary, this thesis reports that utilising lysosomal network proteins as biomarkers and novel therapeutic targets for neurodegenerative diseases holds great promise.

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3

Raby, Samantha Jade. "The development of biomarkers for neurodegenerative diseases." Thesis, Lancaster University, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.734440.

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The accumulation of misfolded proteins to form inclusion bodies and other protein aggregates outside of cells is a pathological hallmark of neurodegenerative diseases. These aggregating proteins represent potential biomarkers of disease that may facilitate disease diagnosis and the development of therapeutic treatments. Currently neurodegenerative diseases are diagnosed clinically using physical, behavioural and memory based tests along with brain imaging techniques. These methods are associated with variable sensitivity and specificity, and at the point of development of physical symptoms a large amount of neuronal damage has already occurred. Protein biomarkers in easily accessible fluids such as plasma and CSF, can provide additional information to aid in earlier diagnosis, therefore allowing treatments to have a better chance of not only alleviating symptoms but slowing disease progression or perhaps halting disease development.

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Marková, Veronika. "Potential Neurophysiological Biomarkers for the Diagnosis of Age-related Neurodegenerative Diseases." Thesis, Högskolan i Skövde, Institutionen för biovetenskap, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-18839.

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The global population with dementia is rapidly increasing around the world.The major risk factor for dementia is aging. There is currently no treatmentavailable and the cost of symptomatic treatment is high. There is a growinginterest in possible clinical applications of non-invasive methods that are safeand easy-to-perform in diagnosis of dementia. The purpose of this paper is toinvestigate the usage of transcranial magnetic stimulation (TMS) withelectroencephalography (EEG) to diagnose dementia in early stages of thedisease. Early diagnosis is needed to reduce the costs of symptomatic care.When investigating the usage of TMS-EEG technology, we will look at how wecan distinguish dementia in different neurodegenerative diseases between eachother. More research is needed to suggest an accurate parameters fordiagnosis of dementia with this type of technology.

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5

Yousef, Jamil. "Development of Sandwich Assays for Potential Protein Biomarkers in Neurodegenerative Diseases." Thesis, KTH, Skolan för kemi, bioteknologi och hälsa (CBH), 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-278727.

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As the aging population is increasing worldwide, so is the prevalence of neurodegenerativediseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia(FTD) and amyotrophic lateral sclerosis (ALS). Reliable biomarkers able to aid the diagnosis anddifferentiation of these diseases are needed in order to start the right treatment as early as possible.Due to its representative state of the central nervous system, cerebrospinal fluid (CSF) is afavorable sample material for biomarker discovery within neurodegenerative diseases. Alteredprotein levels of this body fluid might serve as a biomarker, but further validation of earlierfindings is needed. The aim of this project was to validate earlier studies suggesting potentialprotein biomarkers in CSF. From a list of 80 potential biomarkers in the CSF of patient samples,eight were chosen to be included in this validation effort. By utilizing a suspension bead array ina sandwich assay setup, 21 antibodies were tested in an initial screening. Antibody pairs that couldmeasure the protein levels in a dilution dependent manner was further optimized before individualpatient samples were analyzed. Sandwich assays targeting the three proteins Amphiphysin(AMPH), Chitotriosidase-1 (CHIT1) and Beta-synuclein (SNCB) were successfully developed andcorrelated to earlier generated data using a suspension bead array with a single binder setup.Therefore, the earlier findings of elevated levels of AMPH and SNCB in AD patients and CHIT1in ALS patients were successfully validated.
Prevalensen av neurodegenerativa sjukdomar såsom Alzheimers sjukdom (AD), Parkinsonssjukdom (PD), frontallobsdemens (FTD) och amyotrofisk lateralskleros (ALS) ökar i takt med denåldrande populationen. Pålitliga biomarkörer som kan hjälpa till vid diagnostiseringen av dessasjukdomar behövs för att starta rätt behandling så tidigt som möjligt. Ryggmärgsvätska, enkroppsvätska tillhörande det centrala nervsystemet, kan ge en inblick i det centrala nervsystemetstillstånd. Förändrade proteinnivåer i denna kroppsvätska skulle därför kunna fungera sombiomarkörer. Målet i detta projekt var att validera tidigare föreslagna proteinbiomarkörer iryggmärgsvätska. Utifrån en lista av 80 tidigare analyserade proteiner i ryggmärgsvätska hospatienter, inkluderades åtta proteiner i detta valideringsförsök. En antikroppsbaserad så kalladsandwich assay användes i en suspension bead array för att testa 21 stycken antikroppar i ett initialtscreeningsförsök. Antikroppspar som kunde mäta proteinnivåer på ett spädningsberoende vis i detinitiala screeningsförsöket optimerades vidare innan den utvecklade sandwich assayn användes föratt analysera proteinnivåer i individuella prover. Sandwich assays gentemot Amphiphysin(AMPH), Chitotriosidase-1 (CHIT1) och Beta-synuclein (SNCB) kunde bli framtagna ochkorrelerade gentemot tidigare genererat data från en single binder assay på ett framgångsrikt sätt.Projektet kunde därmed validera tidigare fynd som indikerat förhöjda nivåer av AMPH och SNCBi AD patienter, samt förhöjda nivåer av CHIT1 i ALS patienter.

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6

Farajipour, Parisa. "In Vitro Biomarker Detection for Early Diagnosis of Neurodegenerative Diseases via the Ocular Fluid." University of Akron / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=akron1259778648.

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Cameron, James R. "Eye as a window to the brain : investigating the clinical utility of retinal imaging derived biomarkers in the phenotyping of neurodegenerative disease." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31379.

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Background: Neurodegenerative diseases, like multiple sclerosis, dementia and motor neurone disease, represent one of the major public health threats of our time. There is a clear persistent need for novel, affordable, and patient-acceptable biomarkers of these diseases, to assist with diagnosis, prognosis and impact of interventions. And these biomarkers need to be sensitive, specific and precise. The retina is an attractive site for exploring this potential, as it is easily accessible to non-invasive imaging. Remarkable technology revolutions in retinal imaging are enabling us to see the retina in microscopic level detail, and measure neuronal and vascular integrity. Aims and objectives: I therefore propose that retinal imaging could provide reliable and accurate markers of these neurological diseases. In this project, I aimed to explore the clinical utility of retinal imaging derived measures of retinal neuronal and vessel size and morphology, and determine their candidacy for being reliable biomarkers in these diseases. I also aimed to detail the methods of retinal imaging acquisition, and processing, and the principles underlying all these stages, in relation to understanding of retinal structure and function. This provides an essential foundation to the application of retinal imaging analysis, highlighting both the strengths and potential weaknesses of retinal biomarkers and how they are interpreted. Methods: After performing detailed systematic reviews and meta-analyses of the existing work on retinal biomarkers of neurodegenerative disease, I carried out a prospective, controlled, cross-sectional study of retinal image analysis, in patients with MS, dementia, and ALS. This involved developing new software for vessel analysis, to add value and maximise the data available from patient imaging episodes. Results: From the systematic reviews, I identified key unanswered questions relating to the detailed analysis and utility of neuroretinal markers, and diseases with no studies yet performed of retinal biomarkers, such as non-AD dementias. I recruited and imaged 961 participants over a two-year period, and found clear patterns of significance in the phenotyping of MS, dementia and ALS. Detailed analysis has provided new insights into how the retina may yield important disease information for the individual patient, and also generate new hypotheses with relation to the disease pathophysiology itself. Conclusions: Overall, the results show that retinal imaging derived biomarkers have an important and specific role in the phenotyping of neurodegenerative diseases, and support the hypothesis that the eye is an important window to neurological brain disease.

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8

Ismail, Kurimun. "Development and utilization of Luminex biomarker assays for diagnosis and monitoring of neurodegenerative disease." Thesis, Lancaster University, 2016. http://eprints.lancs.ac.uk/82998/.

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A common pathological feature of various neurodegenerative disorders is the accumulation of misfolded proteins in the brain. Neurodegenerative disorders associated with protein misfolding include Alzheimer’s disease (AD), Parkinson’s disease (PD), dementia with Lewy bodies (DLB), fronto-temporal lobar degeneration (FTLD), motor neuron disease (MND), Huntington’s disease and the prion diseases. The incidence and prevalence of most of these diseases is rising, especially those that cause dementia, due to an increase in the average human life span. The diagnosis of neurodegenerative disorders is heavily reliant on physical examinations and assessment of clinical symptoms. The clinical symptoms of many of these neurodegenerative diseases overlap, which poses a huge difficulty for accurate diagnosis, especially in the early stages. This has led to an interest in identifying reliable and robust discriminatory molecular biomarkers. A successful biomarker test will not only provide a more accurate means of diagnosis, but will allow efficient tracking of disease progression, benefitting the process of developing therapeutic strategies. In this project, the development and validation of a bead based assay system that has multiplexing capabilities (simultaneously measure multiple analytes in a single sample via a single assay) has been described. This assay system uses the Luminex technology and has been developed to quantitatively measure phosphorylated α-synuclein, total α-synuclein, total DJ-1 and LRRK2 in human CSF and plasma. These proteins are predominantly implicated in diseases collectively termed α-synucleinopathies. The initial aim of the project was to develop assays for proteins that span a range of neurodegenerative disorders, however, for reasons discussed in the final chapter of this thesis, this was not possible. This project provides evidence on how the use of plasma as a possible matrix for potential markers associated with brain diseases can be justified, since levels of phosphorylated α-synuclein in matched plasma and CSF samples positively correlated with each other. Plasma would be an ideal sample source for biomarker studies, since it is less invasive than obtaining CSF, thus allowing longitudinal studies to be performed. It was also shown how the DJ-1 protein in plasma may carry diagnostic potential by allowing differentiation between PD patients and healthy controls (p=0.004) as well as between PD and MSA patients (p=0.005). The discrimination between PD and MSA is vital since the two diseases are symptomatically very similar, thus posing a greater issue with accurate diagnosis. There has been minimal research discussing the presence of LRRK2 in human biological fluids such as plasma and CSF. This thesis presents the use of western blotting, high performance liquid chromatography (HPLC) and the Luminex technology as a means of detecting this protein in human CSF and plasma. The data related to LRRK2 in this thesis, opens up avenues for further research into this protein; to definitively show whether it can be detected in such biological fluids and whether it has any value as a biomarker.

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Gavidia, Bovadilla Giovana. "Study of longitudinal neurodegeneration biomarkers to support the early diagnosis of Alzheimer’s disease." Doctoral thesis, Universitat Politècnica de Catalunya, 2018. http://hdl.handle.net/10803/666067.

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Alzheimer’s Disease (AD) is a progressive and neurodegenerative disorder characterized by pathological brain changes starting several years before clinical symptoms appear. Earlier and accurate identification of those brain structures changes can help to improve diagnosis and monitoring, allowing that future treatments target the disease in its earliest stages, before irreversible brain damage or mental decline takes place. The brain of AD subjects shrinks significantly as the disease progress. Furthermore, ageing is the major risk factor for sporadic AD, older brains being more susceptible than young or middle-aged ones. However, seemingly healthy elderly brains lose matter in regions related to AD. Likewise, similar changes can also be found in subjects having mild cognitive impairment (MCI), which is a symptomatic pre-dementia phase of AD. This work proposes two methods based on statistical learning methods, which are focused on characterising the ageing-related changes in brain structures of healthy elderly controls (HC), MCI and AD subjects, and addressing the estimation of the current diagnosis (ECD) of HC, MCI and AD, as well as the prediction of future diagnosis (PFD) of these groups mainly focused on the early diagnosis of conversion from MCI to AD. Data correspond to longitudinal neurodegeneration measurements from Magnetic Resonance Imaging (MRI) images. These biomarkers were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Open Access Series of Imaging Studies (OASIS). ADNI data includes MRI biomarkers available at a 5-year follow up on HC, MCI and AD subjects, while OASIS data only includes biomarkers measured at baseline on HC and AD. In the first method, called M-res, variant (vr) and quasi-variant (qvr) biomarkers were identified on HC subjects by using a Linear Mixed Effects (LME) approach on males and females, separately. Then, we built an ageing-based null model, which would characterise the normal atrophy and growth patterns of vr and qvr biomarkers, as well as the correlation between them. By using the null model on those subjects who had been clinically diagnosed as HC, MCI or AD, normal age-related changes were estimated, and then, their deviation scores (residuals) from the observed MRI-based biomarkers were computed. In contrast to M-res, the second method, called M-raw, is focused on directly analyzing the raw MRI-based biomarkers values stratified by five-year age groups. M-raw includes a differential diagnosis-specific feature selection (FS) method, which is applied before classification. In both methods, the differential diagnosis problem was addressed by building Support Vector Machines (SVM) models to carry out three main experiments—AD vs. HC, MCI vs. HC, and AD vs. MCI. In M-res, the SVM models were trained by using as input the residuals computed for the vr biomarkers plus the age, whereas in M-raw, we used the pool of selected features plus age, gender and years of education. The advancement of early disease prediction was calculated as the average number of years advanced in the PFD of the subjects concerning the last known clinical diagnosis. Finally, the ability of both methods to correctly discriminate AD vs. HC subjects was evaluated and compared by testing them on OASIS subjects observed at baseline. Results confirm accelerated or reduced estimates of decline in all cortical biomarkers with increasing age and a frontotemporal pattern of atrophy in HC subjects, as well as in MCI and AD. Regarding the ECD problem, all SVM models obtained better results than comparable methods in the literature for most classification quality indicators, especially on AD vs. HC. Both methods also improve the PFD given the current clinical tests, both in prediction quality indicators and the amount of time by which the diagnosis is advanced.
La enfermedad de Alzheimer (AD) es un trastorno progresivo y neurodegenerativo caracterizado por cambios patológicos en el cerebro que comienzan varios años antes de aparecer los primeros síntomas clínicos. La identificación temprana y precisa de estos cambios ayuda a mejorar el diagnóstico y la monitorización, permitiendo que la enfermedad sea abordada en sus primeras etapas, antes de producirse un deterioro morfológico y mental irreversible. El cerebro de los sujetos con AD se reduce significativamente a medida que avanza la enfermedad, siendo el envejecimiento el principal factor de riesgo para la AD esporádica, donde los cerebros de la gente mayor son más susceptibles que los más jóvenes. Sin embargo, ha sido observado que los cerebros de los adultos mayores y de los sujetos en una fase anterior con deterioro cognitivo leve (MCI) pierden materia en regiones relacionadas con AD. Esta tesis propone dos métodos basados en métodos de aprendizaje estadísticos, que se centran en caracterizar los cambios relacionados con el envejecimiento en estructuras cerebrales de controles sanos de edad avanzada (HC), MCI y AD, y en abordar la estimación del diagnóstico actual (ECD) de estos grupos, así como la predicción de su diagnóstico futuro (PFD), principalmente en el diagnóstico precoz de la conversión de MCI a AD. Los datos utilizados corresponden a biomarcadores de neurodegeneración longitudinal obtenidas de imágenes de Resonancia Magnética (MRI). Estos biomarcadores se obtuvieron a partir de los estudios Alzheimer?s Disease Neuroimaging Initiative (ADNI) y Open Access Series of Imaging Studies (OASIS). Los datos de ADNI incluyeron biomarcadores de MRI disponibles en un seguimiento de 5 años en sujetos HC, MCI y AD, mientras que los datos de OASIS solo incluyeron biomarcadores medidos al inicio del estudio en HC y AD. En el primer método, denominado M-res, los biomarcadores que cambiaron significativamente (vr) y los que cambiaron en una reducida escala (qvr) fueron identificados en sujetos HC utilizando modelos lineales de efectos mixtos (LME). Asimismo, modelos nulos basados en el normal envejecimiento del cerebro fueron construidos para cada género. A través de estos ellos se buscó caracterizar la atrofia normal y los patrones de crecimiento de los biomarcadores vr y qvr, así como la correlación entre ellos. Estos modelos fueron utilizados en los sujetos HC, MCI y AD restantes para inferir los valores normales de los biomarcadores vr y luego calcular sus desviaciones (residuos) respecto a los biomarcadores observados. A diferencia de M-res, el segundo método denominado M-raw, se centra en el análisis de los valores directos de los biomarcadores MRI, estratificados por grupos de edad de cinco años. M-raw incluye un método de selección de características específicas del diagnóstico diferencial aplicado antes de la clasificación. En ambos métodos, se entrenaron máquinas soporte vectorial (SVM) para abordar tres experimentos: AD vs. HC, MCI vs. HC y AD vs. MCI. En M-res, los modelos SVM fueron entrenados a partir de los residuos calculados para los biomarcadores vr más la edad, mientras que en M-raw, se utilizó el grupo de características seleccionadas más la edad, el sexo y los años de educación. El avance de la predicción temprana de la enfermedad fue calculada como el promedio de años avanzados en el PFD con respecto al último diagnóstico clínico conocido. Los resultados confirman una reducción en todos los biomarcadores corticales a medida que la edad avanza, siendo el cambio de algunas regiones más acelerados que otras. Asimismo, se observó un patrón de atrofia frontotemporal en los tres grupos de sujetos. Con respecto al problema ECD, todos los modelos SVM obtuvieron mejor desempeño en la clasificación que los métodos comparables en la literatura, especialmente en AD vs. HC. Ambos métodos también mejoraron la PFD, tanto en los indicadores de calidad de predicción como en el tiempo de avance en el diagnóstico (hasta 1.87 años antes en sujetos de 80-84 años).

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Chaney, Aisling. "Investigating imaging biomarkers of neuroinflammation and neurodegeneration in rodent models of Alzheimer's disease." Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/investigating-imaging-biomarkers-of-neuroinflammation-and-neurodegeneration-in-rodent-models-of-alzheimers-disease(16750cf1-eb30-49c5-b9eb-9f01d4a0560f).html.

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease resulting in alterations in memory, language, executive function and emotional behaviour. Although it can be characterised by symptoms, by the time they arise significant pathological alterations have already emerged in the central nervous system, namely increased amyloid plaques, neurofibrillary tangles and neuronal loss. Despite known pathological hallmarks the exact aetiology of AD is poorly understood and no current treatments are available. However, there is growing interest in the role of neuroinflammation in AD, with increases observed in the early stages of disease and with disease progression. Moreover, it has been suggested that peripheral inflammation can influence neuroinflammation and worsen neurodegeneration. Using Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRS) we can non-invasively measure biomarkers of neuroinflammation and degeneration allowing multi-modal investigation of its role in normal aging and AD. Considering this the objectives of this study were to (i) Use PET and MRS to investigate neuroinflammatory and metabolite alterations in transgenic (TG) models of AD and their wildtype (WT) animals. (ii) Assess rates of cognitive decline in these models using memory based tests. (iii) Investigate relatively new TgF344AD rat as an AD model by characterising younger time-points than previously reported. (iv) Investigate the contribution of peripheral inflammation on AD progression. PET and MRS imaging was carried out longitudinally in the APPswe×PS1de9 mouse. Neuroinflammation was confirmed ex vivo and cognitive ability was assessed by behavioural tests. Results revealed significantly increase hippocampal and thalamic neuoinflammation in old TG mice as assessed by [18F]DPA-714 PET and supported by immunohistochemistry. Reduced neuronal marker N-acetlyaspartate was seen with age and was exacerbated in the TG mice. Accelerated cognitive decline was also seen in TG mice. PET and MRS imaging was carried out at 6 and 12 months in the TgF344AD model, which expresses amyloid and tau pathology as well as neuronal loss. No cognitive decline was observed in TG rats; however increased anxiety behaviour was seen. Increased [18F]DPA-714 PET was observed as an effect of gene in the thalamus at 6 months and the hypothalamus at 12 months. Increases in glutamate were seen with age in the TG rats but not the WTs. Increased inflammation and metabolite alterations were seen with aging. The effect of peripheral urinary tract infection (UTI) on cognition and imaging out was assessed. Imaging was carried out prior to and after re-current UTI. Infection induced cognitive decline in infected TG but not WT rats. Infection had an increasing effect on hypothalamic neuroinflammation in WT rats but a decreasing effect on TG rats, which masked the original gene differences. This thesis is set out in the alternative format with each experimental study represented as a chapter. Results in this thesis implicate neuroinflammation in AD development and progression. In addition, we report systemic infection-CNS interactions accelerating cognitive decline in AD and highlight the importance of understanding the effects of comorbidities in disease.

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11

Omar, Jama Sukri. "Tau phosphorylation on threonine 217 as a potential biomarker for neurodegenerative diseases." Thesis, Högskolan i Borås, Akademin för textil, teknik och ekonomi, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:hb:diva-21321.

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Hyperfosforylering av biomarkörproteinet Tau förekommer i flera neurodegenerativa sjukdomar som kallas Taupathies. Proteinets huvudfunktion i människokroppen är att modulera flexibilitet och stabilitet för axonal-mikrotubulin. I Taupathies utlöser hyperfosforyleringen av Tau instabilitet och neurodegenerationen. I dagens läge kan hyperfosforylering av treonin 217 (P217) endast mätas i hjärnan. I den här studien undersöks hyperfosforyleringen av treonin 217 (P217). I syfte att se om nivåerna av P217 är mätbara i cerebrospinalvätska (CSV) och i blodet. Samt för att evaluera hur nivåer av P217 förändras i olika Taupathies, genom att testa hjärnprover från friska kontroller och olika Taupathies. Studien görs för att öka kunskapen om effekten av hyperfosforylering av treonin 217 i Taupathies och för att bidra med en ny provtagningsmetod för P217. Simoa HD-1 Analyzer var instrumentet som användes för analyserna av P217. Det är ett instrument som kan upptäcka onormala nivåer av biomarkörer genom kvantifiering, med hjälp av antikroppar och ett enzym. Enzymet kallas Streptavidin β-galaktosidas och omvandlar en befintlig P217-molekyl i proven till en fluorescerande produkt. Genom Simoa HD-1 Analyzer utvecklades en ultrasensitiv analys med antikropparna P217 och Tau 12, som kunde upptäcka mycket låga nivåer av P217 i hjärnan, CSF och i blod. Förändring av P217-nivåer hittades även i olika Taupathies. De Taupathies med de högsta nivåerna av P217 var Progressiv supranukleär pares, Corticobasal degeneration och Globular glial Taupathies.
Hyperphosphorylation of the biomarker protein Tau occurs in many neurodegenerative diseases called Taupathies. The proteins main function in the human body is to modulate flexibility and stability for axonal microtubules. In Taupathies the hyperphosphorylation of the Tau triggers instability and neurodegeneration. Nowdays hyperphoshorylation on threonine 217 (P217) can only be measured in the brain. In this study the hyperphoshorylation on the phosphorylation site of threonine 217 (P217) is examined. In aim to see if levels of P217 is measurable in cerebrospinal fluid (CSF) and in blood. As well to evaluate how P217 variate in different Taupathies, through the use of brain samples from healthy controls and different Taupathies. The study is made for the purpose of enhancing the pure knowledge about the effect of hyperphosphorylation on threonine 217 in Taupathies and to contribute with a new sampling method for P217. Simoa HD-1 Analyzer was the key instrument of the analyses of P217. It’s an instrument which can detect abnormal levels of biomarkers through quantification, with help of antibodies and an enzyme. The enzyme is called Streptavidin β-galactosidase and converts an existing P217 molecule in the samples to a fluoresce product. Through the use of Simoa HD-1 Analyzer an ultrasensitive assay with antibodies P217 and Tau 12 was developed which could detect very low levels of P217 in brain, CSF and in blood. Variation of P217 levels was also found in different Taupathies. The Taupathies with the highest levels of P217 was Progressive supranuclear palsy, Corticobasal Degeneration and Globular glial Taupathies.

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12

Hiscox, Lucy Victoria. "Early characterisation of neurodegeneration with high-resolution magnetic resonance elastography." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31198.

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This thesis contributes to recent interest within medical imaging regarding the development and clinical application of magnetic resonance elastography (MRE) to the human brain. MRE is a non-invasive phase-contrast MRI technique for measurement of brain mechanical properties in vivo, shown to reflect the composition and organisation of the complex tissue microstructure. MRE is a promising imaging biomarker for the early characterisation of neurodegeneration due to its exquisite sensitivity to variation among healthy and pathological tissue. Neurodegenerative diseases are debilitating conditions of the human nervous system for which there is currently no cure. Novel biomarkers are required to improve early detection, differential diagnosis and monitoring of disease progression, and could also ultimately improve our understanding of the pathophysiological mechanisms underlying degenerative processes. This thesis begins with a theoretical background of brain MRE and a description of the experimental considerations. A systematic review of the literature is then performed to summarise brain MRE quantitative measurements in healthy participants and to determine the success of MRE to characterise neurological disorders. This review further identified the most promising acquisition and analysis methods within the field. As such, subsequent visits to three brain MRE research centres, within the USA and Germany, enabled the acquisition of exemplar phantom and brain data to assist in discussions to refine an experimental protocol for installation at the Edinburgh Imaging Facility, QMRI (EIF-QMRI). Through collaborations with world-leading brain MRE centres, two high-resolution - yet fundamentally different - MRE pipelines were installed at the EIF-QMRI. Several optimisations were implemented to improve MRE image quality, while the clinical utility of MRE was enhanced by the novel development of a Graphical User Interface (GUI) for the optimised and automatic MRE-toanatomical coregistration and generation of MRE derived output measures. The first experimental study was performed in 6 young and 6 older healthy adults to compare the results from the two MRE pipelines to investigate test-retest agreement of the whole brain and a brain structure of interest: the hippocampal formation. The MRE protocol shown to possess superior reproducibility was subsequently applied in a second experimental study of 12 young and 12 older cognitively healthy adults. Results include finding that the MRE imaging procedure is very well tolerated across the recruited population. Novel findings include significantly softer brains in older adults both across the global cerebrum and in the majority of subcortical grey matter structures including the pallidum, putamen, caudate, and thalamus. Changes in tissue stiffness likely reflect an alteration to the strength in the composition of the tissue network. All MRE effects persist after correcting for brain structure volume suggesting changes in volume alone were not reflective of the detected MRE age differences. Interestingly, no age-related differences to tissue stiffness were found for the amygdala or hippocampus. As for brain viscosity, no group differences were detected for either the brain globally or subcortical structures, suggesting a preservation of the organisation of the tissue network in older age. The third experiment performed in this thesis finds a direct structure-function relationship in older adults between hippocampal viscosity and episodic memory as measured with verbal-paired recall. The source of this association was located to the left hippocampus, thus complementing previous literature suggesting unilateral hippocampal specialisation. Additionally, a more significant relationship was found between left hippocampal viscosity and memory after a new procedure was developed to remove voxels containing cerebrospinal fluid from the MRE analysis. Collectively, these results support the transition of brain MRE into a clinically useful neuroimaging modality that could, in particular, be used in the early characterisation of memory specific disorders such as amnestic Mild Cognitive Impairment and Alzheimer's disease.

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13

Viodé, Arthur. "Quantification multiplexe de biomarqueurs d’intérêt clinique et de leurs protéoformes par spectrométrie de masse. Application à l’analyse de cohortes médicales." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS515.

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Les protéoformes désignent toutes les formes sous lesquelles une protéine peut être présente. Cela inclut les formes portant des modifications post-traductionnelles, les isoformes et les formes résultant d’épissages alternatifs. Ces modifications peuvent influer sur la fonction d’une protéine, d’où l’intérêt de développer des méthodes sensibles, spécifiques et robustes de quantification de protéoformes pour une meilleure compréhension de mécanismes pathologiques ou la recherche de biomarqueurs. L’objectif de ce travail a été d’exploiter les avantages de la spectrométrie de masse à haute résolution pour la caractérisation et la quantification de protéoformes de protéines associées à des maladies neurodégénératives. Nous nous sommes principalement intéressés à deux protéines, la C9ORF72 et l’alpha-synucléine. Dans un premier temps, une méthode de quantification des deux isoformes de la C9ORF72 a été développée et appliquée à une cohorte de 43 cerveaux humains comprenant des cas de démences fronto-temporale (DFT) avec ou sans mutation C9ORF72. Les résultats obtenus montrent pour la première fois par spectrométrie de masse une diminution d’environ 50% de l’isoforme longue de la C9ORF72 en présence de la mutation. Dans une seconde étape, nous avons élargi l’analyse à la quantification multiplexe de 49 protéines cérébrales potentiellement impliquées dans les DFT. En parallèle, nous nous sommes intéressés aux formes tronquées de l’alpha-synucléine. Leur quantification a été réalisée par une approche top-down dans des tissus cérébraux et une approche par bottom-up dans le liquide céphalorachidien (LCR). Enfin, l’analyse a été étendue à la quantification multiplexe de l’alpha-synucléine et de la protéine tau du LCR
Proteoforms describe the complexity of protein forms. This includes forms with post-translational modifications, isoforms and forms resulting from alternative splicing. These modifications can influence the function of a protein, hence the interest in developing sensitive, specific and robust methods for the quantification of proteoforms for a better understanding of pathological mechanisms or biomarkers discovery. The objective of this work was to take advantage of high-resolution mass spectrometry for the characterization and quantification of proteoforms associated with neurodegenerative diseases. We mainly focused on two proteins, C9ORF72 and alpha-synuclein. First, a method for quantifying the two C9ORF72 isoforms was developed and applied to a cohort of 43 human brains including cases of frontotemporal dementia (FTD) with or without C9ORF72 mutation. The results obtained show for the first time by mass spectrometry a decrease of about 50% of the long isoform of C9ORF72 in the presence of the mutation. Then, we extended the analysis to the multiplex quantification of 49 brain proteins potentially involved in FTD. In parallel, we focused on the truncated forms of alpha-synuclein. Their quantification was performed by a top-down approach in brain tissue and a bottom-up approach in cerebrospinal fluid (CSF). Finally, the analysis was extended to the multiplex quantification of alpha-synuclein and tau protein in CSF

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14

Rebbah, Sana. "Distance entre distributions : application à l'imagerie médicale et à l'aéronautique." Thesis, Toulouse 3, 2019. http://www.theses.fr/2019TOU30124.

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Dans le domaine médical, au cours des deux dernières décennies, un nombre croissant de méthodes d'analyse d'images quantitatives ont été développées dont l'analyse par régions d'intérêt, l'analyse voxel à voxel et l'analyse d'histogrammes. Cette dernière est largement utilisée dans la cadre de la recherche sur la sclérose en plaques afin de quantifier les changements pathologiques diffus particulièrement présents dans cette maladie. Un inconvénient de cette approche est que l'ensemble des informations incluses dans l'histogramme n'est pas exploité ; seules des mesures arbitraires sont choisies pour décrire l'histogramme ; incluant la moyenne, la médiane, les centiles... Ainsi dans un premier lieu, nous avons proposé d'intégrer dans un classifieur toute l'information incluse dans l'histogramme et non pas seulement quelques descripteurs locaux, dans le but d'améliorer les performances de classification des populations de sclérose en plaques (groupes dans un essai thérapeutique et in fine groupes de pronostics différents). Par la suite, étant donné que l'histogramme est une estimation trop simpliste d'une distribution de probabilité, nous présentons l'une des applications possibles de la géométrie de l'information sur les distributions de probabilité et démontrons l'intérêt de l'utilisation de la géométrie non-euclidienne dans le contexte de la classification des populations de la maladie d'Alzheimer. Nous avons notamment fait l'analogie avec le domaine de l'aéronautique, plus précisément dans l'étude des retards aéroportuaires. En effet, l'analyse actuellement réalisée se situe au niveau macroscopique et fournit un indicateur de retard moyen, sans tenir compte des mécanismes intermédiaires pouvant conduire au retard final. Ainsi, dans le cadre de la classification des retards aéroportuaires, tout comme dans les applications médicales, nous avons remplacé l'indicateur moyen par un modèle statistique paramétrique plus complet : les distributions de probabilité
In the medical field, over the past two decades, a growing number of quantitative image analysis have been developed including regions of interest analysis, voxel-by-voxel analysis and histogram analysis. The latter is widely use in Multiple Sclerosis research to quantify the diffuse pathological prominent in this disease. A disadvantage of this approach is that all the information included in the histogram is not exploited; only arbitrary measures are chosen to describe the histogram; including the average, the median, the percentiles... Thus, first, we proposed to integrate in a classifier all the information included in the histogram and not just some local descriptors, in order to improve the classification performance of the Multiple Sclerosis populations (i.e. groups in therapeutic trials and in fine groups at different prognosis). Thereafter, given that the histogram is an overly simplistic estimate of a probability distribution, we present one of the possible applications of information geometry on probability distributions and we demonstrate the interest of using non-Euclidean geometry in the context of the Alzheimer's disease population classification. Furthermore, we have made the analogy with the field of aeronautics, specifically in the study of flight delays. Indeed, the analysis currently carried out is at a macroscopic level and provides an indicator of average delay, without considering the intermediate mechanisms that may lead to the final delays. Thus, in the clustering of airport delays, we have replaced the average indicator with a more complete parametric statistical model: Distributions

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15

Sleven, Hannah. "Models of neurodegenerative mitochondrial disease." Thesis, University of Oxford, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.598048.

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Mitochondrial diseases affect the core energy generating pathways and can result in significant cognitive impairment and neurodegeneration. The mechanisms underlying the neurological and pathological consequences of mitochondrial disease are not understood and current treatment of mitochondrial diseases is limited in scope and efficacy. pyruvate dehydrogenase (PDH) and Complex I are key mitochondrial enzymes pivotal for cellular energy metabolism, and mutations in genes coding for PDH and Complex I proteins are common causes of mitochondrial disease. This thesis describes the use oftwo techniques, gene targeting, and RNA interference, to generate in vitro models of Complex I and PDH deficiency in pluripotent cell lines. Gene targeting of the ndufal gene was unsuccessful, however, a number of cell lines were isolated with significant reductions in PDH activity mediated by RNAi targeted against the Pdhal transcript. These cells lines were neurodifferentiated in vitro and used to characterise the developmental and degenerative consequences of PDH deficiency on neural cultures. The cultures were found to successfully differentiate into neural cells, but were developmentally abnormal with defective neuronal migration and neurite extension, and neuritic varicosities, an indication of neuritic degeneration in many neurological disease models. These features were activity-dependent with the most severe phenotype found in the cell line with the least residual PDH activity. These cultures were used to explore the nature of energy metabolism in PDH deficient neurons, and therapeutic strategies were successfully tested. This research has successfully established a reproducible and practical model to assess neurodegeneration in PDH deficiency, to test t reatments and to model theories of disease mechanisms. As such it provides promise for the improvement of the understanding of and treatment of disorders of brain energy metabolism in the future.

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16

Biro, Andrew J. "Specific aspects of neurodegenerative disease." Thesis, University of British Columbia, 1989. http://hdl.handle.net/2429/28919.

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This thesis is broken into four chapters. The first two chapters summarize two separate lines of investigation into the role of a putative neurotoxin in the pathogenesis of Huntington's Disease (HD). The third chapter outlines an investigation of the putative role of beta-N-methylamino-L-alanine (BMAA) in the pathogenesis of amyotrophic lateral sclerosis (ALS), while the final chapter details a post-mortem investigation of the contents of biogenic amines and amino acids in the brain of a man who died of a familial form of parkinsonism. Chapter I is a description of a chromatographic technique developed to isolate quinolinic acid (QA), an endogenous compound implicated in the pathogenesis of HD, from deproteinized human sera. A cation exchange column was used to selectively isolate QA, which was eluted with 10 mM HCl. The eluted fractions were analyzed by UV spectrometry to isolate and quantify QA. Once the fractions corresponding the elution of authentic QA were isolated, concentrated and the excess HCl removed, the fractions were added to growing fetal rat striatal explant cultures as an assay of neurotoxicity. Since HD involves the selective degeneration of GABAergic neurons in the striatum, the activity of glutamic acid decarboxylase, the final enzyme in the synthesis of GABA, was used to determine the viability of the cultures. Unfortunately, the method was confounded by the contamination of all effluents by compounds originating from the cation exchange resin, which were discovered to be neurotoxic to the striatal cultures, and as a result the investigation had to be abandoned. Chapter II describes an investigation designed to further characterize the nature of neurotoxicity observed in the sera obtained from patients with HD (Perry et al. 1987). Compounds with the capacity to selectively stimulate neurons at the N-methyl-D-aspartate (NMDA) receptor have been implicated in a variety of neurodegenerative disorders, including HD. Selective antagonists at the NMDA receptor have been shown to protect neurons from the degenerative effects of such "excitotoxins". The investigation described used MK-801, a potent noncompetitive NMDA antagonist, in an attempt to protect fetal rat striatal cultures from the neurodegenerative effects of the sera obtained from HD patients. The results obtained were equivocal. No evidence was obtained to support a role of the NMDA receptor in the mediation of the neurotoxicity, and in addition the neurodegenerative effects of HD sera were not reproduced in the present investigation. A variety of possible explanations for the apparent discrepancy are suggested. Chapter III describes an experiment intended to produce an animal model of ALS based on the observations by Spencer et al. 1987 that chronic oral administration of BMAA in monkeys produced the histological and behavioural characteristics of this disease. In the present investigation synthetic D,L-BMAA was given by gavage to mice over an eleven week period. Since BMAA is known to act at the NMDA receptor, a subset of the mice were also given MK-801 in an effort to protect them from any deleterious effects based on the action of BMAA at this receptor. The animals were sacrificed at the end of the experiment, and biochemical analyses were performed on the striata and cortices of the animals. In addition, neuropathological studies were performed on the spinal cords, basal ganglia and related structures. The results indicated no biochemical or neuropathological abnormality as a result of BMAA administration. Chapter IV describes a post-mortem investigation of a man who was a member of a well described pedigree which carries an autosomal dominant form of parkinsonism. The object of the investigation was to determine post-mortem levels of dopamine, noradrenaline, serotonin and their metabolites, in addition to amino acids in various regions of brain. Although conflicting evidence was obtained during life, neuropathological findings and the present neurochemical analyses confirm the degeneration of the nigrostriatal dopaminergic tract, characteristic of parkinsonism, in this man.
Medicine, Faculty of
Anesthesiology, Pharmacology and Therapeutics, Department of
Graduate

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17

Radakovic, Ratko. "Multidimensional apathy in neurodegenerative disease." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/25959.

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Apathy is characterised by a lack of motivation towards goal directed behaviour and is a symptom of various neurodegenerative diseases. There are various tools that can be used to assess apathy but a caveat of these is that they usually assess it as a unidimensional concept. Apathy has been recognised to have a multidimensional substructure. The Dimensional Apathy Scale is the only comprehensive measure designed to quantify neurobiologically-based subtypes, called Executive, Emotional and Initiation apathy. The first aim of this study was to explore multidimensional apathy, and its associations with demographic variables, in healthy, community dwelling adults. Secondly, multidimensional apathy was explored in neurodegenerative diseases, specifically Amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and Alzheimer’s disease (AD). For each disease group, the validity and reliability of both the self rated and carer rated DAS were also determined. Finally, the association between specific apathy subtype impairments and executive dysfunction was explored in ALS patients. Four hundred healthy community dwelling adults, eighty-three ALS patients (seventy-five carers), thirty-four PD patients (thirty carers) and forty-nine AD patients (eighty-nine carers) were recruited for the questionnaire study. In the healthy community dwelling adults, Executive apathy decreased with age, whereas Emotional increased with age. Gender differences were also shown with higher apathy in males on Emotional apathy. There were also employment differences, in that Executive apathy was higher in unemployed individuals compared to those who were employed. Emotional apathy showed difference in type of employment, where full time employed individuals were significantly more apathetic than those employed part time. These findings were taken into account in selecting the appropriate control samples to match our patient groups. In the patient groups, ALS patients were found to be significantly more impaired on the Initiation subscale when compared to controls. Furthermore, Initiation apathy was found to be the most frequent impairment above abnormality cut-off on the carer rated DAS. PD patients were significantly more impaired on Executive and Initiation apathy when compared to controls. These two subscales were most frequently above abnormality cut-off in the carer rated DAS. Finally, AD patients were significantly more impaired on all subscales when compared to controls and, on the carer rated DAS, global impairment over all subscales was most often reported as above abnormality cut-off. Additionally in AD, there was a significant disparity between carer and patient ratings on Executive and Initiation apathy, indicating patients’ impaired awareness. When comparing patient groups, there was a significant difference between carer rated apathy subtype impairments for each patient group. Validity and reliability of the DAS was found to be robust when compared to standard measures of apathy and depression. In the experimental study, a sample of ALS patients (and their carers) and healthy controls (and their informants) were recruited to complete a battery of neuropsychological tests, the DAS, other apathy and depression measures. ALS patients were impaired on tasks of executive functioning when compared to controls. Furthermore, apathy subtype deficits were associated with executive dysfunction in ALS. In conclusion, apathy is a multidimensional concept that manifests in different subtype profiles dependent on neurodegenerative disease. This has further implications for understanding and assessment of cognitive dysfunction and neuropsychiatric symptoms, such as apathy, in ALS and other neurodegenerative disease patient groups.

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18

Dury, R. J. "Understanding haemodynamics in neurodegenerative disease." Thesis, University of Nottingham, 2018. http://eprints.nottingham.ac.uk/50380/.

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In this thesis, the haemodynamic, functional and structural changes in Alzheimer's Disease, Huntington's Disease and Multiple Sclerosis are assessed at 7T. Across all chapters, there is a focus on the use of Arterial Spin Labelling (ASL) to provide haemodynamic measures of perfusion (or cerebral blood flow) and transit time (TT) to provide a useful marker of disease. Arterial Spin Labelling (ASL) has the advantage that it is a non-invasive method to measure perfusion using magnetic resonance imaging (MRI). Clinically, perfusion is assessed using contrast-enhanced techniques which requires the intravenous administration of an exogenous gadolinium-based contrast agent, such as Prohance-TM and Gadovist-TM. Contrast-enhanced techniques typically provide higher SNR than ASL methods, however the non-invasive nature of ASL makes it a safe method suited for repeated measures in any subjects, including those with poor renal clearance. Additionally, gadolinium contrast agents have been shown to accumulate in neuronal tissue, and until the clinical significance of this is determined, contrast-enhanced scans should be performed with caution. In Chapter 5, arterial spin labelling is used to assess cerebral perfusion in a patient group with Alzheimer's Disease (AD) and compared with an age-matched healthy control group (HC). Functional MRI (fMRI) is used to assess functional connectivity within the default mode network (DMN) and measures compared between the AD and HC group. In addition, high resolution structural data is acquired to assess the effects of atrophy in AD. Results demonstrate a significant decrease in grey matter perfusion and a significant increase in grey matter transit time in the AD group compared the HC group. A trend showing a decrease in functional connectivity in the DMN was found in the AD group as compared to the HC group. As expected, significant grey matter loss and cortical thinning were observed in the AD group compared to the HC group. Secondly, haemodynamic and vascular changes in a Huntington's Disease (HD) patient group are assessed and compared with healthy age matched controls (HC). Phase contrast angiography is used to assess vessel density and vessel radius distributions between the two groups. Structural data was also acquired to assess grey matter volume and cortical thickness differences between the two groups. A significant reduction in perfusion was found in grey matter, putamen and the caudate in the HD group compared to the HC group. The ASL transit time was found to be significantly increased in the caudate and putamen in the HD group compared to the HC group. Phase contrast angiography data showed an increase in the frequency of smaller vessels (0.15-0.35mm) in the HD group compared to the HC group, whereas larger vessels appeared more frequently in the HC group. A significant reduction in grey matter volume was also observed in the HD group compared to the HC group, which manifested as thinning of the cortical ribbon. In the final study of this thesis, high spatial resolution arterial spin labelling is used to assess perfusion inside cortical lesions and compare with perfusion in surrounding normal appearing grey matter in a Multiple Sclerosis (MS) patient group. Grey matter perfusion as a function of distance from the cortical lesions was also assessed. It was found that cortical lesions have reduced perfusion compared to surrounding normal appearing grey matter. Perfusion increased and stabilised immediately outside of the cortical lesion itself, suggesting that the perfusion deficit observed is highly spatially localised.

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19

Vadnal, Jonathan. "Epigenetic Mechanisms in Neurodegenerative Disease." Kent State University / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=kent1353955013.

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20

Blundell, James Michael. "Cognitive assessment of paediatric neurodegenerative disease." Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/6042/.

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Inherited metabolic diseases (IMD’s) are a large class of heterogeneous genetic disorders caused by dysfunction within a single pathway of intermediary metabolism. In many of these diseases, the dysfunction of metabolic enzymes leads to the accumulation of toxic metabolites which disrupts the normal development of the central nervous system. With the advent of treatments that positively influence neuropsychological outcomes, there is a need for sensitive and objective neuropsychological measures that allow patients to be systematically tracked in order to understand the efficacy of existing treatments. In this thesis, a neuropsychological test battery consisting of attention, language and oculomotor measures was developed to accurately describe individual and developmental differences between IMD patients and healthy developing controls. The functioning of five diseases was examined: Morquio syndrome (\(N\) = 12), Hurler syndrome (\(N\) = 3), Maroteux-Lamy syndrome (\(N\) = 2), Tyrosinemia type I (\(N\) = 13) and Tyrosinemia type III (\(N\) = 5). Findings indicated that disease effects were not homogeneous across tasks, and that performance on the same tasks was not uniform across diseases. The obtained data offers a promising basis for understanding how biological factors influence the severity and timecourse of developmental effects in future research.

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21

Wiberg, Henning. "Analytical Approaches to Neurodegenerative Disease Protein Aggregation." Licentiate thesis, KTH, Analytisk kemi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-34027.

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22

Guest, William Clay. "Template-directed protein misfolding in neurodegenerative disease." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/41990.

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Protein misfolding diseases represent a large burden to human health for which only symptomatic treatment is generally available. These diseases, such as Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis, and the systemic amyloidoses, are characterized by conversion of globular, nativelyfolded proteins into pathologic β-sheet rich protein aggregates deposited in affected tissues. Understanding the thermodynamic and kinetic details of protein misfolding on a molecular level depends on accurately appraising the free energies of the folded, partially unfolded intermediate, and misfolded protein conformers. There are multiple energetic and entropic contributions to the total free energy, including nonpolar, electrostatic, solvation, and configurational terms. To accurately assess the electrostatic contribution, a method to calculate the spatially-varying dielectric constant in a protein/water system was developed using a generalization of Kirkwood Frohlich theory along with brief all-atom molecular dynamics simulations. This method was combined with previously validated models for nonpolar solvation and configurational entropy in an algorithm to calculate the free energy change on partial unfolding of contiguous protein subsequences. Results were compared with those from a minimal, topologically-based Gō model and direct calculation of free energies by steered all-atom molecular dynamics simulations. This algorithm was applied to understand the early steps in the misfolding mechanism for β₂-microglobulin, prion protein, and superoxide dismutase 1 (SOD1). It was hypothesized that SOD1 misfolding may follow a template-directed mechanism like that discovered previously for prion protein, so misfolding of SOD1 was induced in cell culture by transfection with mutant SOD1 constructs and observed to stably propagate intracellularly and intercellularly much like an infectious prion. A defined minimal assay with recombinant SOD protein demonstrated the sufficiency of mutant SOD1 alone to trigger wtSOD1 misfolding, reminiscent of the “protein-only” hypothesis of prion spread. Finally, protein misfolding as a feature of disease may extend beyond neurodegeneration and amyloid formation to cancer, in which derangement of protein folding quality control may lead to antibodyrecognizable misfolded protein present selectively on cancer cell surfaces. The evidence for this hypothesis and possible therapeutic targets are discussed as a future direction.

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23

Yates, Alexandra Caroline. "Stress-activated protein kinases and neurodegenerative disease." Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.287325.

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24

Sassi, Mohammed M. "Apolipoprotein-E genotype in major neurodegenerative diseases." Thesis, University of Nottingham, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.339716.

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25

Chandrasekaran, Sreedevi. "A Network View on Neurodegenerative Disorders." VCU Scholars Compass, 2013. http://scholarscompass.vcu.edu/etd/3083.

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Neurodegeneration is a chronic, progressive and debilitating condition that affects majority of the World's elderly population who are at greater risk. Numerous scientific studies suggest that there could be a common underlying molecular mechanism that promotes the degeneration and the subsequent neuronal loss, however so far the progress in this direction is rather limited. Abnormal protein misfoldings, as well as protein plaque formations in the brain, are some of the hallmark characteristic features of neurodegenerative disorders (NDDs). Genetic and environmental factors, oxidative stress, excessive reactive oxygen species formation, mitochondrial dysfunction, energy depletion and autophagy disruption etc. are some of the widely suspected mechanisms that manifest the cognitive, motor and emotional symptoms of these NDDs. Motivated by some molecular traits found in common in several NDDs, network-based systems biology tools and techniques were used in this study to identify critical molecular players and underlying biological processes that are common for Parkinson's, Alzheimer's and Huntington's disease. Utilizing multiple microarray gene expression datasets, several biomolecular networks such as direct interaction, shortest path, and microRNA regulatory networks were constructed and analyzed for each of the disease conditions. The network-based analysis revealed 26 genes of potential interest in Parkinson's, 16 in Alzheimer's and 30 in Huntington's disease. Many new microRNA-target regulatory interactions were identified. For each disorder, several routes for possible disease initiation and protection scenarios were uncovered. A unified neurodegeneration mechanism network was constructed by utilizing the significantly differentially expressed genes found in common in Parkinson's, Alzheimer's and Huntington's microarray datasets. In this integrated network many key molecular partakers and several biological processes that were significantly affected in all three NDDs were uncovered. The integrated network also revealed complex dual-level interactions that occur between disease contributing and protecting entities. Possibilities of microRNA-target interactions were explored and many such pairs of potential interest in NDDs were suggested. Investigating the integrated network mechanism, we have identified several routes for disease initiating, as well as alleviating ones that could be utilized in common for Parkinson's, Alzheimer's and Huntington's disease. Finding such crucial and universal molecular players in addition to maintaining a delicate balance between neurodegeneration promoters and protectors is vital for restoring the homeostasis in the three NDDs.

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26

Abuaisha, Karim Belkais Faraj. "Prognostic biomarkers of periodontal disease." Thesis, King's College London (University of London), 2016. https://kclpure.kcl.ac.uk/portal/en/theses/prognostic-biomarkers-of-periodontal-disease(77882787-a695-42a3-b7e4-7caa8e9c4bde).html.

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Objectives: Previous studies in our laboratory have identified the antimicrobial proteins Human Neutrophil Protein 1 – 3 (HNP1-3), Myeloid Related Protein 8 (S100A8/MRP8) and LL-37 as putative periodontal salivary biomarkers. The aims of the studies reported in this thesis were to investigate the diagnostic and prognostic potential of these markers, together with Matrix Metalloproteinase- 8 (MMP-8), serum markers C - reactive protein (CRP) and Interleukin-6 (IL-6), on the initial outcome of nonsurgical periodontal treatment. Material & Methods: We carried out a cross sectional study which aimed to verify and establish a diagnostic threshold for a group of salivary biomarkers (MMP-8, HNP1-3, S100A8 and LL-37) and to test the validity of the diagnostic utility of these biomarkers. A total of 133 unstimulated saliva samples (46 with chronic periodontitis, 38 with aggressive periodontitis and 49 with gingivitis) were analysed by ELISA. In addition multiple markers were combined to give a single combined cut off point by normalising each biomarker to percentage of cut-off point value, (such that x + y = combined cut off point). These pre-determined cut-off points were applied to salivary AMPs levels in an independent cohort originally collected to investigate the effects of diabetes on periodontitis. To investigate prognostic potential a total of 66 participants were recruited to a longitudinal intervention study of patients with moderate–severe Chronic Periodontitis. 53 subjects completed the protocol and were included in the final analysis. Subjects (28 male, 25 female) age range (23-65 years) with were recruited, with 14 smokers and 3 with type II diabetes, and saliva and serum samples were collected prior to periodontal examination. Patients were then given a course of non-surgical periodontal therapy over 2 visits. 8-10 weeks post-operatively saliva/serum sampling and clinical examination were repeated. Salivary MMP-8, S100A8 and HNP1-3 concentrations were all determined by ELISAs. In addition we measured serum levels of CRP and Interleukin 6. Results: In the cross-sectional study the HNP1-3 and S100A8 could differentiate between gingivitis and chronic periodontitis with high specificity (around 90%) and around 75% sensitivity compared to MMP-8 which was able to discriminate between gingivitis and periodontitis (chronic and aggressive) with both high 3 specificity and sensitivity. LL37 showed no significant diagnostic potential. Within the independent cohort the application of pre-determined thresholds, either individual or combined cut-offs, were able to detect periodontitis with specificity of between 75 – 85 % but with very low sensitivity. In addition diabetic status was found to result in significantly increased MMP-8 and S100A8 concentrations in subjects with periodontal disease. In the intervention study, treatment resulted in reductions in the mean: a) number of deep sites (>4mm) (33.57 ± 20.75 vs 18.51 ± 13.87; mean ± SD, p<0.0001); b) probing pocket depths (5.92 ± 0.47 mm vs 4.74 ± 0.76 mm, p<0.0001); c) bleeding index (0.32 ± 0.20 vs 0.21 ± 0.16, p<0.0001); d) plaque index (0.46 ± 0.20 vs 0.37 ± 0.18, p=0.0003). Only the mean concentrations of MMP-8 and S100A8 showed significant reductions post-treatment (MMP-8: 355.4 ± 319.9 ng/ml vs 216.6 ± 217.2 ng/ml, p<0.0001), (S100A8: 1182 ± 1095 ng/ml vs 693.9 ± 719.6 ng/ml, p=0.0007). Only the change in concentrations of MMP-8 were strongly associated with magnitude of treatment response (MMP-8: r2= 0.1, p=0.02). In addition, the baseline levels of MMP-8 & S100A8 were also associated with treatment response (MMP-8: r2= 0.1, p=0.03; S100A8: r2=0.1, p=0.02). Overall, there were 13 out of 53 participants who did not respond to the treatment (24.5% of cases). MMP-8 baseline concentrations were significantly higher in responders (419.3 ± 343.1 ng/ml) than non-responders (158.8 ± 73.3 ng/ml) (p=0.009). MMP-8 concentrations at baseline that were above the cut-off (<182.8 ng/ml) predicted a good response to periodontal treatment with 77% sensitivity and 70% specificity. There was no effect of the single round of non-surgical periodontal treatment on the levels of systemic markers CRP & IL-6, and also there was no correlation between local and systemic markers. Conclusion: These results of both studies suggest that MMP-8, HNP1-3 and S100A8 may be useful to identify cases of periodontitis with good specificity and moderate sensitivity and may give superior results when combined. In addition the salivary MMP-8 and S100A8 showed promising periodontal prognostic ability to detect the likelihood of a good response to treatment, with MMP-8 showed the best results with moderate sensitivity and specificity. However, further validation studies would be useful in larger, non-diabetic cohorts.

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27

Lim, Soojin. "Fluorescent Indicators for Disease Biomarkers." PDXScholar, 2012. https://pdxscholar.library.pdx.edu/open_access_etds/262.

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Xanthene dyes are common fluorophores which have been widely used as molecular probes. The xanthene fluorophores can be used as highly selective optical sensors to detect disease biomarkers. A new fluorogenic dye containing an alpha, beta-unsaturated aldehyde moiety exhibits selective fluorescent signal enhancement in the presence of cysteine or peptides containing N-terminal cysteine residues. The mechanism is based on synergistic covalent and supramolecular interactions. A unique rhodamine boronic acid indicator is used in an optimized data collection protocol for wavelength- and time-dependent selectivity of various saccharides and nucleosides. One indicator is thereby capable of selectively distinguishing structurally related analytes in mixtures. Moreover, the rhodamine-based boronic acid responds linearly to increasing riboside concentrations in urine samples, potentially enabling the screening for inborn purine metabolism disorders.

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28

Barra, Cátia Isabel de Almeida. "Inflammatory biomarkers in Alzheimer’s disease." Master's thesis, Universidade de Aveiro, 2014. http://hdl.handle.net/10773/13277.

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Mestrado em Biomedicina Molecular
Alzheimer’s disease (AD) is the most common form of dementia. Histopathologically it is characterized by the presence of two major hallmarks, the intracellular neurofibrillary tangles (NFT) and the extracellular senile plaques (SP), which are surrounded by activated astrocytes and microglia. Neuroinflammation has been associated with some neurodegenerative diseases. In AD the inflammatory process, prompted by increased Aβ production and aggregation, was reported to have a fundamental role in disease pathogenesis. In early stages the inflammation could have a beneficial role in the pathology, since it has been proposed that the microglia and astrocytes activated could be involved in (amyloid β) Aβ clearance. Nevertheless, the chronic activation of the microglia leads to excessive production of the inflammatory components, including cytokines. It promotes alterations in amyloid precursor protein (APP) expression and processing, stimulating the increase of Aβ accumulation, abnormal Tau phosphorylation and, consequently, neurotoxic effects, irreversible damage and loss of neurons. Since chronic neuroinflammation is a feature of AD, inflammatory proteins may constitute potential biomarkers candidates to assist clinical diagnosis of this dementia. Thus, the main aim of this study was to identify putative inflammatory biomarkers for AD by flow citometry analysis. For plasma samples of individuals examined by clinical dementia rating (CDR) and mini mental (MM) diagnostic tests were used. Subjects were subdivided in 3 distinct groups, a control group (CDR-/MM-) and two patient groups, CDR+/MM- and CRD+/MM+, the former may include mild cognitive impairment (MCI) patients and the latest group included 5 patients clinical diagnosed as AD. Data analysis revealed differences in the inflammatory proteins levels of both patients groups (CDR+/MM- and CDR+/MM+) in comparison to healthy individuals (CDR-/MM-). Interleukin-8 (IL-8) plasma levels were statistically different (P<0,05) from control group. Significant correlation between IL-8 concentrations and the CDR stages was also identified. Additionally, correlations of monocyte chemoattractant protein-1 (MCP-1) with both IL-8 and IL-6 were observed. Taken together these findings suggested that IL-8 could be a potential biomarker not only for AD but also for diagnosis of initial stages of dementia.
A doença de Alzheimer (DA) é o tipo de demência mais comum. Histopatologicamente é caracterizada pela presença de tranças neurofibrilares intracelulares (TNF) e de placas senis extracelulares (PS), as quais estão rodeadas pela microglia e por astrócitos. A neuroinflamação tem sido associada com várias doenças neurodegenerativas. Na DA o processo inflamatório, desencadeado pelo aumento da produção e agregação do péptido Aβ, desempenha um papel fundamental na patogénese da doença. Nas fases inicias, a inflamação possui um papel benéfico na patologia, uma vez que tem sido proposto que a microglia e os astrócitos quando ativados estão envolvidos na remoção de β-amilóide (Aβ). No entanto, a ativação crónica da microglia conduz à produção excessiva de componentes inflamatórios, incluindo citocinas. Isto provoca alterações na expressão e processamento da proteína percursora de amilóide (PPA), estimulando o aumento da produção e acumulação de Aβ, fosforilação anormal da proteína Tau e, consequentemente, efeitos neurotóxicos e perda de neurónios. Uma vez que a neuroinflamação crónica é uma característica da DA, proteínas inflamatórias poderão constituir potenciais candidatos a biomarcadores que auxiliem no diagnóstico clínico desta doença. Desta forma, o principal objectivo deste trabalho foi identificar biomarcadores inflamatórios para a DA através da técnica de citometria de fluxo. Para tal, foram analisadas amostras de plasma de doentes que foram, previamente, examinados por testes de avaliação cognitiva, clinical dementia rating (CDR) e mini mental (MM). Os sujeitos foram divididos em três grupos distintos, o grupo controlo (CDR-/MM-) e dois grupos de pacientes, CDR+/MM- e CDR+/MM+. O primeiro grupo de pacientes pode conter indivíduos com ligeiras alterações cognitivas (MCI) e o segundo inclui 5 pacientes clinicamente diagnosticados para DA. A análise dos dados revelou diferenças nos níveis de proteínas inflamatórias de ambos os grupos de doentes (CDR+/MM- e CDR+/MM+) em comparação com os indivíduos saudáveis (CDR-/MM-). Os níveis plasmáticos de interleucina-8 (IL-8) foram estatisticamente deferentes (p<0,05) do grupo controlo. Correlação significativa entre as concentrações de IL-8 e os estados de CDR foi identificada. Adicionalmente, foram observadas correlações entre MCP-1 e IL-8 e a IL-6. Em conjunto, estes resultados sugerem que a IL-8 poderá ser um potencial biomarcador não só para a DA mas também para o diagnóstico precoce de demência.

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29

Last, Victoria. "A role for phospholipase A2 in neurodegenerative disease." Thesis, Royal Veterinary College (University of London), 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558969.

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30

Mroczkowska, Stephanie. "Ocular and systemic vascular dysfunction in neurodegenerative disease." Thesis, Aston University, 2012. http://publications.aston.ac.uk/16525/.

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The important role played by vascular factors in the pathogenesis of neurodegenerative disease has been increasingly realised over recent years. The nature and impact of ocular and systemic vascular dysfunction in the pathogenesis of comparable neurodegenerative diseases such as glaucoma and Alzheimer’s disease (AD) has however never been fully explored. The aim of this thesis was therefore to investigate the presence of macro- and micro-vascular alterations in both glaucoma and AD and to explore the relationships between these two chronic, slowly progressive neurodegenerative diseases. The principle sections and findings of this work were: 1. Is the eye a window to the brain? Retinal vascular dysfunction in Alzheimer’s disease · Mild newly diagnosed AD patients demonstrated ocular vascular dysfunction, in the form of an altered retinal vascular response to flicker light, which correlated with their degree of cognitive impairment. 2. Ocular and systemic vascular abnormalities in newly diagnosed normal tension glaucoma (NTG) patients · NTG patients demonstrated an altered retinal arterial constriction response to flicker light along with an increased systemic arterial stiffness and carotid artery intima-media thickness (IMT). These findings were not replicated by healthy age matched controls. 3. Ocular vascular dysregulation in AD compares to both POAG and NTG · AD patients demonstrated altered retinal arterial reactivity to flicker light which was comparable to that of POAG patients and altered baseline venous reactivity which was comparable to that of NTG patients. Neither alteration was replicated by healthy controls. 4. POAG and NTG: two separate diseases or one continuous entity? The vascular perspective · POAG and NTG patients demonstrated comparable alterations in nocturnal systolic blood pressure (SBP) variability, ocular perfusion pressure, retinal vascular reactivity, systemic arterial stiffness and carotid IMT. · Nocturnal SBP variability was found to correlate with both retinal artery baseline diameter fluctuation and carotid IMT across the glaucoma groups.

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31

Keller, Margaux Finn. "HERITABILITY AND SEX-EFFECT ANALYSES OF NEURODEGENERATIVE DISEASE." Diss., Temple University Libraries, 2014. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/288134.

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Anthropology
Ph.D.
This work analyzes the genetic basis of three neurodegenerative diseases using several thousands of individuals of European descent to determine a range of phenotypic heritability outside of what has been identified by prior methods. By measuring additive genetic variance genome-wide, measures of its contribution to the phenotypic variance of these diseases were substantially increased, in some instances by a factor of 10 or more. Additionally, regional-mapping methods identified segments of the genome exhibiting significantly high heritability estimates associated with one of the neurodegenerative diseases, Amyotrophic lateral sclerosis. This resulted in the detection of novel candidate regions and provided conclusive evidence for the polygenic architecture of this disease. Lastly, novel risk variants associated with Parkinson's disease were identified on the X chromosome, a previously ignored genomic region. Overall, the employment of new analytic methods produced robust and novel results, adding substantial information to the neurodegenerative disease literature and connecting the anthropological perspective with growing informatics-based methods.
Temple University--Theses

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32

Mok, K. Y. B. "Genetics of neurodegenerative disease : a genome-wide approach." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1398391/.

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Neuro-degenerative diseases present an increasingly heavy burden in our ageing population. Genetic factors play an important role in the aetiology of the neuro-degenerative diseases. Dissecting the underlying genetic mechanism gives us vital clues to the pathophysiology, and ultimately helps us develop novel therapeutic interventions. Recent technological advances in genotyping genetic variants and bioinformatics have revolutionized the approach to the study of genetic diseases. The initial major advance was the accurate genotyping and data processing for hundreds of thousands single nucleotide polymorphisms simultaneously. Studies on the association between these polymorphisms, mostly common variants, and complex diseases became feasible. The association can shed light to the pathophysiology. My thesis rides on these developments, applying them to the study of genetics in neurodegenerative diseases. The first part of the thesis is a pilot study on genetics of cervical dystonia, using a genome-wide association approach. Given the small sample size, no statistically significant results were identified. A few potential loci were suggested after imputation. The second part is a study on amyotrophic lateral sclerosis. Meta-analysis was performed on five recently published genome-wide association studies. A follow-up haplotype analysis was carried out on these cohorts, comparing this with data available from familial studies. A single founding haplotype leading to amyotrophic lateral sclerosis was proposed. Subsequent identification of the causal gene, C9orf72, within the haplotype region by our collaborators led to further phenotyping studies. The third part describes a copy number variant analysis of idiopathic Parkinson’s disease. The study was based on the genome-wide association data in the UK cohort in comparison to other cohorts. Chromosome 22q11.2 heterozygous deletion was found to play an important role in the aetiology of Parkinson’s disease. This thesis demonstrates that utilization of emerging genetic technology has advanced our understanding of some of the genetic factors predisposing to these neurodegenerative diseases.

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33

Hesse, William R. (William Reichard). "Quantitative analysis of proteotoxicity associated with neurodegenerative disease." Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/112510.

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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2017.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 125-147).
Neurodegenerative diseases are a costly burden, both economically and in terms of human suffering. A common feature of neurodegenerative diseases is that they stem from problems with protein folding, but the underlying biology that leads to neuron death is not well understood. Due to this lack of mechanistic information there are currently no therapeutics that treat underlying mechanisms that lead to cell loss. This thesis explores the link between complications in protein folding and cell death. In the first part of this thesis, I combined modeling of the proteotoxicity of polyglutamine (as exemplified in Huntington's Disease) in Saccharomyces cerevisiae with microfluidics and automated microscopy. From these studies, I have found that glutamine-rich proteins suppress the toxicity of poly-glutamine expanded Huntingtin by physically interacting and sequestering the protein at the IPOD (insoluble protein deposit) quality control compartment. These studies have provided new insight into possible therapeutic strategies and how the proteomes of different cell types may protect or sensitize sells to specific proteotoxic stresses. In the second part of this thesis, I quantitatively and systematically studied the toxicity of a-synuclein, which is implicated in the synucleinopathy family of diseases, including Parkinson's Disease. To systematically study the effect of toxic levels of a-synuclein expression on cellular homeostasis, I constructed a library of fluorescent reporters and utilized automated, high-throughput microscopy to image changes in reporter localization and abundance in response to a-synuclein toxicity. The results from this study have illuminated a number of pathways that were not previously studied for a-synuclein toxicity and have tied together disparate findings from many other studies. Additionally, I have shown that our experimental strategy is generalizable and can be applied other yeast models of neurodegenerative toxicity, such as poly-glutamine and AO 1-42. In summary, the quantitative studies presented in this thesis have expanded our understanding of the mechanisms underlying a variety of toxicities related to neurodegeneration. The biological insights gained from these studies have helped illuminate new areas of inquiry that may be used to combat these diseases.
by William R. Hesse.
Ph. D.

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34

Hosp, Fabian. "A quantitative interaction screen for neurodegenerative disease proteins." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2013. http://dx.doi.org/10.18452/16669.

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Der erste Teil dieser Arbeit beschreibt die Durchführung eines quantitativen Ansatzes zur Detektion von Protein-Protein-Interaktionen (PPI) mit einem Schwerpunkt für Proteine, die in vier häufigen neurodegenerativen Krankheiten eine Rolle spielen: die Alzheimer-, Parkinson- und Huntington-Krankheit, sowie die spinozerebelläre Ataxie Typ 1 (SCA1). Die Interaktionsstudie kombiniert die stabile Isotopen-Markierung von Aminosäuren in der Zellkultur mit der Affinitätsaufreinigung von Proteinen und hochauflösender Massenspektrometrie. Dieser Ansatz zielt darauf ab, systematisch die Interaktionspartner von gesunden und krankheitsassoziierten Proteinvarianten zu identifizieren und zu quantifizieren. Darüber hinaus wurde das quantitative Interaktionsverfahren genutzt, um zu prüfen ob PPI durch krankheitsassoziierte Mutationen beeinträchtigt werden. Neben der Validierung möglicher Nebeneffekte, sowie dem Vergleich mit Informationen über PPI aus der Literatur, wurde ein Teil der identifizierten Interaktoren durch zusätzliche Koimmunopräzipitations-Experimente in zwei verschiedenen Zelllinien bestätigt. Mit Hilfe von Drosophila SCA1-Krankheitsmodellen und in Kombination mit RNAi-basierter Stummschaltung identifizierter Interaktoren wurde festgestellt, dass ein großer Teil der Kandidaten Neurodegeneration in vivo beeinflusst. Zusätzlich wurden die Alzheimer-spezifischen PPI-Daten auf genomweite Assoziationsstudien übertragen. Bemerkenswerterweise waren Polymorphismen in einzelnen Nukleotiden in den Genen zugehöriger Interaktoren wahrscheinlicher mit solchen Genen assoziiert, die eine Prädisposition für die Alzheimer-Krankheit haben, als mit zufällig ausgewählten Genen. Schlussendlich konnten Folgeexperimente für zwei ausgewählte Interaktionspartner den Nachweis für eine bislang unbekannte Rolle der N-Glykosylierung und einen neuen Zusammenhang zwischen dem RNA-bindenden Protein LRPPRC und mitochondrialer Dysfunktion in der Alzheimer-Krankheit vorlegen.
The first part of the present thesis describes the establishment of a quantitative protein-protein interaction (PPI) screen with a focus on proteins involved in four common neurodegenerative diseases (NDDs): Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and spinocerebellar ataxia type 1 (SCA1). The interaction screen combines stable-isotope labeling by amino acids in cell culture (SILAC) with protein affinity purification and high-resolution mass spectrometry. This approach aims to systematically identify and quantify interaction partners of normal and known disease-associated variants of proteins involved in NDDs. Moreover, the quantitative interaction screen was employed to study how PPIs are affected by disease-associated mutations. Along with validation of possible off-target effects and comparison of the data with literature-reported PPIs, a subset of identified interactors was validated by additional co-immunoprecipitation experiments in two different cell lines. Utilizing Drosophila models for SCA1 in combination with RNAi-mediated silencing of identified interactors, a large fraction of candidates was observed to also affect neurodegeneration in vivo. In addition, AD-specific PPI data was mapped to patient cohort data obtained from genome-wide associations studies. Notably, single-nucleotide polymorphisms in the genes of interactors of the disease-associated protein variants were more likely associated with susceptibility to AD than randomly selected genes. Finally, functional follow-ups for two selected interaction partners provided evidence for a yet unreported role of N-linked glycosylation in AD, and a novel link to mitochondrial dysfunction in AD by means of the RNA-binding protein LRPPRC.

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35

Yeh, Hsin-Hsien. "Utility and validation of the histone deacetylase (HDAC) substrate, [18F]FAHA, as a positron emission tomography (PET) imaging biomarker in non-human primates and HD transgenic mice for evaluation of neurodegenerative diseases and HDAC inhibitor treatment." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/utility-and-validation-of-the-histone-deacetylase-hdac-substrate-18ffaha-as-a-positron-emission-tomography-pet-imaging-biomarker-in-nonhuman-primates-and-hd-transgenic-mice-for-evaluation-of-neurodegenerative-diseases-and-hdac-inhibitor-treatment(69cbe9a1-aa64-45d6-947f-9368eabb071c).html.

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Histone deacetylase (HDAC) inhibitors (HDACIs) have long been studied and shown promises in the treatment of various neurodegenerative disorders including Huntington’s disease (HD). Based on many demonstrated potentials of HDACIs in mitigating various diseases, we evaluated the utility of [18F]FAHA, a radiolabeled derivative of suberoylanilide hydroxamic acid (SAHA), as a PET imaging agent for characterizing HDAC activity in a non-human primate model and a R6/2 transgenic mouse model of HD. We were aiming at HD as a potential first application, and therefore also examined the expression of HDAC and acetyl histone (AH) in brains of HD patients. This thesis describes that [18F]FAHA was metabolized rapidly to [18F]FACE in both blood plasma and brain. Kinetic analysis indicated that peripherally generated [18F]FACE contributed to the total brain activity. We therefore used a dual-input function model to analyze the kinetics of tracer accumulation and inhibition by SAHA in rhesus monkeys. Parametric images demonstrated the inhibition of HDAC activity in the brain by SAHA in a dose-dependent manner. Huntington’s mice (R6/2) showed a gradual increase of [18F]FAHA accumulation in all organs including the brain with age. In human tissue we found significant losses of acetyl histons expression from cells in the caudate nucleus and Purkinje cells of the cerebellum in HD, while the level of HDAC 5 was increased in these cells. The data obtained in rhesus monkeys indicated that PET imaging with [18F]FAHA could be used as a pharmacodynamic biomarker of the inhibition of class IIa HDACs by HDACIs in the brain and facilitate the development and clinical translation of novel class-IIa HDACIs.

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36

Cope, Keary Arthur. "Breath biomarkers of exposure and disease." Available to US Hopkins community, 2002. http://wwwlib.umi.com/dissertations/dlnow/3068135.

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37

Workman, Victoria. "Microfluidic encapsulation of cells for transplantation in neurodegenerative disease." Thesis, Cardiff University, 2009. http://orca.cf.ac.uk/55884/.

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Polymer encapsulation is now an accepted route into cellular therapies via implantation of therapeutically active allogeneic and xenogeneic cells. Although many methods are currently used for encapsulation of cells, no single method is capable of producing large volumes of mono-disperse beads, containing cells completely covered by the polymer of choice. The overall aim of this project was to develop a microfluidic method to encapsulate dopamine releasing cells in an alginate matrix, determine their viability in vitro and investigate implantation into a rodent model of Parkinson's disease. During the course of this study a novel microfluidic method was developed. Two cell types were encapsulated a human test line and a therapeutic cell line derived from rat brain tumour cells (PC 12). Cell viability, measured using an adapted trypan blue exclusion method, was observed to be minimally affected by the encapsulation process. Confocal images of cells encapsulated within alginate beads were collected in addition to long term viability data, up to 90 days post-encapsulation. Dopamine was still detected after PC 12 cell encapsulation through use of an ELISA. Modifications to the developed microfluidic method allowed beads of an appropriate size (<250microm in diameter) to be implantated into a rodent brain via a cannula. Upon implantation of alginate beads into rats' brains there was no evidence of beads after 7 days. Attempts were made to stabilise alginate beads further by addition of barium as a cross-linking agent and polycation secondary coating. Beads were observed to be more stable and remained visible within brain tissue for 14 days. Imaging of fluorescent alginate beads revealed that beads produced using the developed microfluidic method were homogeneous in nature. The work presented here represents the first microfluidic method to be developed which is capable of encapsulating viable cells. Moreover, the viability measurements carried out were the first such experiments to be performed on cells encapsulated using microfluidic methods. Although the structure of alginate beads produced using more commonplace methods has been shown, this has not previously been reported for beads produced using a microfluidic technique.

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38

Witter, Daniel Philip. "Aspects of cholesterol homeostasis : Biochemical role in neurodegenerative disease." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.531800.

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39

Charriez, Christina Margaret. "ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTOR REGULATION IN EXPERIMENTAL NEURODEGENERATIVE DISEASE." UKnowledge, 2010. http://uknowledge.uky.edu/gradschool_diss/19.

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The α7 nicotinic acetylcholine receptor (nAChR) is involved in learning and memory, synaptic plasticity, neuroprotection, inflammation, and presynaptic regulation of neurotransmitter release. Alzheimer’s disease (AD), a neurodegenerative disease characterized by diminished cognitive abilities, memory loss, and neuropsychiatric disturbances, is associated with a loss of nAChRs. Similarly, traumatic brain injury (TBI) may result in long term neurobehavioral changes exemplified by cognitive dysfunction. Deficits in α7 nAChR expression have previously been shown in experimental TBI and may be related to cognitive impairment experienced in patients following TBI. The purpose of this dissertation was to investigate changes in α7 nAChR expression in models of neurodegeneration and determine if allosteric modulation of the nAChR facilitates functional recovery following experimental TBI through changes in nAChRs. Experimental models employed include a transgenic mouse model of AD that overexpresses the amyloid precursor protein (APPswe mice) and the controlled cortical impact injury model of TBI in rats. Quantitative receptor autoradiography using α-[125I]-bungarotoxin and [125I]-epibatidine and in situ hybridization were used to investigate changes in nAChR density and mRNA expression, respectively. In the first study, the effects of aging and β-amyloid on α7 nAChR expression were evaluated in APPswe mice. Hippocampal α7 nAChR density was significantly upregulated in APPswe mice compared to wild-type mice. It is postulated that elevated Aβ levels bind to the α7 nAChR resulting in upregulation. In a second study, galantamine, a medication used in the treatment of AD, was administered subchronically following experimental TBI to determine if treatment could facilitate cognitive recovery and affect nAChR expression. Interestingly, the results indicate TBI interferes with agonist mediated upregulation of nAChRs, and galantamine did not improve function in a behavioral task of learning a memory. In a third study, the regulation of TBI related deficits in α7 nAChRs was examined 48 hours following injury. α7 nAChR deficits occurred with a reduction in α7 mRNA in several hippocampal regions and non-α7 nAChR deficits occurred with a reduction in α4 mRNA in the metathalamus. The results of these studies suggest AD and TBI may involve complex but parallel processes contributing to the regulation of α7 nAChRs.

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40

Gu, Mei. "Mitochondrial function in Parkinson's disease and other neurodegenerative diseases." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322371.

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41

Dyson, Sean Christopher. "Novel strategies for neurotrophic factor delivery in neurodegenerative disease." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608085.

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42

Vincenti, James Edward. "Role of activation of microglia in neurodegenerative prion disease." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/15928.

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Prion diseases are a group of fatal neurodegenerative protein-misfolding diseases. Microglia, the resident myeloid cells found within the brain, have been shown to demonstrate a reactive morphology during the disease process with conflicting evidence for both a neurotoxic and neuroprotective role. The studies presented here aimed to investigate the role of microglia activation using transcriptomic and morphological analysis of prion disease in mice. Initially, the host immune response to prion disease was explored using a publically available mouse prion disease dataset. Re-analysis of this dataset was performed using BioLayout Express3D; a novel software tool that supports the visualisation and clustering of correlation networks. Disease-associated genes up-regulated during the later stages of infection were present in two main clusters. The cellular origin of these genes was explored by examining their expression in a dataset comprised of pure populations of cells. This demonstrated that the primary cluster of up-regulated transcripts encompassed genes expressed mainly by microglia and to a lesser extent astrocytes and neurons. The secondary cluster comprised almost exclusively of interferon response genes. The conclusions of these analyses were different from those of the original study that suggested disease-associated genes were primarily neuronal in origin. Mouse models of prion disease were established by infecting a novel line of BALB/cJ inbred mice, expressing EGFP under control of a myeloid specific Csf1r promoter, with the 79A prion strain. Quantification of the morphological changes of EGFP expressing microglia suggested the cells accumulated in the medulla at sites of early misfolded protein deposition with minimal change in their overall appearance. An activated microglia morphology was not observed until protein deposition was extensive. Isolation of EGFP expressing microglia was performed for transcriptome analysis. The vast majority of disease associated genes demonstrated increased expression at the onset of clinical symptoms. The gene list was found to be highly enriched for genes associated with an innate immune response regulated by the NFκB signalling cascade. Also highly enriched were processes associated with protein translation, energy production and stress response. These data suggest a high metabolic load is burdened by proliferating microglia; and as part of a response which is strikingly more pro-inflammatory in nature than has previously been attributed to the microglia phenotype within prion disease. As an active contributor to normal homeostasis, microglia are more than just innate immune surveillance and are now considered an integral component in both the healthy and diseased brain. The ramifications of activation toward the microglia phenotype shown here will have direct and potentially cytotoxic influence on neighbouring microglia and other brain cell types implying microglia as major contributors to the neurotoxic environment found within the CNS during prion disease. Furthermore the identification of genes associated with metabolism offer many intriguing possibilities for manipulating the activity of microglia in pre-clinical therapeutic intervention.

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43

Wang, Wenjia. "Item Response Theory in the Neurodegenerative Disease Data Analysis." Thesis, Bordeaux, 2017. http://www.theses.fr/2017BORD0624/document.

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Les maladies neurodégénératives, telles que la maladie d'Alzheimer (AD) et Charcot Marie Tooth (CMT), sont des maladies complexes. Leurs mécanismes pathologiques ne sont toujours pas bien compris et les progrès dans la recherche et le développement de nouvelles thérapies potentielles modifiant la maladie sont lents. Les données catégorielles, comme les échelles de notation et les données sur les études d'association génomique (GWAS), sont largement utilisées dans les maladies neurodégénératives dans le diagnostic, la prédiction et le suivi de la progression. Il est important de comprendre et d'interpréter ces données correctement si nous voulons améliorer la recherche sur les maladies neurodégénératives. Le but de cette thèse est d'utiliser la théorie psychométrique moderne: théorie de la réponse d’item pour analyser ces données catégoriques afin de mieux comprendre les maladies neurodégénératives et de faciliter la recherche de médicaments correspondante. Tout d'abord, nous avons appliqué l'analyse de Rasch afin d'évaluer la validité du score de neuropathie Charcot-Marie-Tooth (CMTNS), un critère important d'évaluation principal pour les essais cliniques de la maladie de CMT. Nous avons ensuite adapté le modèle Rasch à l'analyse des associations génétiques pour identifier les gènes associés à la maladie d'Alzheimer. Cette méthode résume les génotypes catégoriques de plusieurs marqueurs génétiques tels que les polymorphisme nucléotidique (SNPs) en un seul score génétique. Enfin, nous avons calculé l'information mutuelle basée sur la théorie de réponse d’item pour sélectionner les items sensibles dans ADAS-cog, une mesure de fonctionnement cognitif la plus utilisées dans les études de la maladie d'Alzheimer, afin de mieux évaluer le progrès de la maladie
Neurodegenerative diseases, such as Alzheimer’s disease (AD) and Charcot Marie Tooth (CMT), are complex diseases. Their pathological mechanisms are still not well understood, and the progress in the research and development of new potential disease-modifying therapies is slow. Categorical data like rating scales and Genome-Wide Association Studies (GWAS) data are widely utilized in the neurodegenerative diseases in the diagnosis, prediction and progression monitor. It is important to understand and interpret these data correctly if we want to improve the disease research. The purpose of this thesis is to use the modern psychometric Item Response Theory to analyze these categorical data for better understanding the neurodegenerative diseases and facilitating the corresponding drug research. First, we applied the Rasch analysis in order to assess the validity of the Charcot-Marie-Tooth Neuropathy Score (CMTNS), a main endpoint for the CMT disease clinical trials. We then adapted the Rasch model to the analysis of genetic associations and used to identify genes associated with Alzheimer’s disease by summarizing the categorical genotypes of several genetic markers such as Single Nucleotide Polymorphisms (SNPs) into one genetic score. Finally, to select sensitive items in the most used psychometrical tests for Alzheimer’s disease, we calculated the mutual information based on the item response model to evaluate the sensitivity of each item on the ADAS-cog scale

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44

Grinbergs-Saull, Anna. "Patient representation and the research agenda in neurodegenerative disease." Thesis, University of Brighton, 2015. https://research.brighton.ac.uk/en/studentTheses/ab40bfb3-ce1a-4b42-9fbc-479034321619.

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Patient organisations are often characterised in sociological literature as patient representatives, speaking for people affected by an illness in medical, political and scientific spheres. Using Motor Neurone Disease and Parkinson’s organisations as case studies, I investigate the challenges faced by patient organisations attempting to fulfil this role, focusing in particular on the need to balance responsibilities associated with care and campaign functions and increasing engagement in research. The principal focus of this PhD is to examine different conceptualisations of representativeness that have been discussed overtly and implicitly by participants. I have examined the extent to which patient organisations represent their members’ needs and cultivate a sense of collective identity, the way in which the patient organisations represent their members during the setting of research agendas, and finally I have considered the extent to which representation coincides with the concept of patient involvement.

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45

Turnquist, Casmir. "The role of p53 and ASPP2 in neurodegenerative disease." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:e7d4cdfb-9ebe-4716-b3ca-d50b4b278d1a.

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Two cellular processes of central importance to cancer and neurodegeneration are apoptosis and cellular senescence. Both are a means of cellular suicide that are utilized in time- and context-dependent manners and have important evolutionary purposes. However, they are also the drivers of many deleterious processes underlying cancer and neurodegeneration. Many of the cellular responses to aging and age-related diseases, including apoptosis and senescence, converge on the tumor suppressor pathway, p53. Here I examine the molecular basis for loss of cell polarity and accelerated cell death mediated by apoptosis stimulating protein of p53 2 (ASPP2) in neurodegeneration. In this study we find that ASPP2 mediates STAT1Linduced apoptosis. Lipopolysaccharide (LPS) induces ASPP2 mRNA expression in vitro. Also, LPS induces nuclear ASPP2 in vivo at the blood-cerebral spinal fluid-barrier (BCSFB), the brain's barrier to inflammation. Consistent with ASPP2's role as a gatekeeper to inflammation, ASPP2 mutant mouse brains possess enhanced neuroinflammation. Elevated ASPP2 expression is also observed in mouse models and human neuroinflammatory disease tissue in astrocytes. The identification of ASPP2 as a novel transcriptional target of STAT1 and the observed increase in ASPP2 expression in both mouse and human neuroinflammatory disorders, suggests that the identified STAT1/ASPP2 pathway may connect tumor suppression and cell polarity to neuroinflammation. Additionally, I investigate the regulation of cellular senescence by p53 isoforms as a means to enhance neuroprotection of astrocytes in chronic neurodegenerative diseases, Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Here we report that p53 isoforms, Δ133p53 and p53β, are endogenous regulators of cellular senescence in the central nervous system (CNS). Δ133p53 functions as a dominant-negative regulator of full-length (FL)Lp53 and represses senescence, while p53β as a co-activator of FLLp53, promotes senescence. In neurodegenerative disease brain tissue, FLL53 and p53β are upregulated while Δ133p53 is downregulated. We demonstrate that Δ133p53 and p53β directly regulate astrocyte senescence, including the release of key neurotoxic proL inflammatory cytokines such as ILL6 and ILL1β. Also, we show that the p53 isoform switch that occurs during aging and neurodegeneration promotes neuronal toxicity using coL culture experiments with human iPSC-derived motor neurons and human astrocytes. We also demonstrate that astrocyte senescence can be rescued through overexpression of Δ133p53, revealing a promising therapeutic approach to delay or inhibit the progression of neurodegeneration.

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46

Vigbedor, Maa Ohui Shormeh. "Structure and regulation of G-substrate in neurodegenerative disease." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/8292.

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G-substrate is a 23 kDa protein named as a specific substrate of cGMP-dependent protein kinase and found predominantly in cerebellar Purkinje cells. As a component of the NO/cGMP/PKG pathway, G-substrate is potentially involved in several important cellular processes and has so far been associated with a number of disease conditions: a single point mutation in G-substrate has been linked to hypercholesterolaemia, while the potent inhibition of PP2A by phosphorylated Gsubstrate possibly influences Tau protein hyperphosphorylation and contributes to Alzheimer's disease pathology. Conversely, overexpression of G-substrate protein in dopaminergic neurons has been found to protect neurons from Parkinson's disease toxins, making G-substrate a possible target of interventions for mitigating the debilitating effects of Parkinson's disease on patients. A shorter splice variant, which only retains one of the phosphorylatable threonine motifs, has recently been described for G-substrate and given the importance of phosphorylation to its action as a phosphatase inhibitor, this study focuses on determining whether both variants of the protein exhibit similar levels of phosphatase inhibition and interact with the same/similar proteins in vivo. We were also interested in determining whether the 51 amino acid section absent from short G-substrate resulted in any significant differences in protein structure, which potentially has implications on functions in vivo. My results indicate the association of G-substrate with a wide range of proteins involved in processes including cell cycle regulation, endocytosis and signalling and the two variants do not always interact with the same proteins. Among these interactors is the PARK 7/ DJ-1 protease, which like G-substrate has been shown to be neuroprotective. I have found that G-substrate is proteolysed by DJ-1 in its active form and interactions between these two proteins is affected by the anti-vertigo drug Tanganil. Phosphatase inhibition studies suggest that the G-substrate variants affect phosphatase activity to different extents under similar conditions, while NMR and circular dichroism structural studies suggest that in solution, the full length Gsubstrate variant is slightly more compactly folded. Understanding the details of G-substrate action in the cell will lead to a better understanding of its roles including the protection of dopaminergic neurons from Parkinson's disease toxins and shed more light on the intricacies of the NO/cGMP/PKG signalling pathway as a whole, thus providing important information that might help improve strategies for dealing with conditions involving this pathway and help develop interventions for diseases such as Alzheimer's and Parkinson's.

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47

Davison, James Edward. "Multimodal magnetic resonance investigation of childhood metabolic neurodegenerative disease." Thesis, University of Birmingham, 2012. http://etheses.bham.ac.uk//id/eprint/3612/.

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Background: The central nervous system is frequently affected in children with inherited metabolic disorders (IMD). The causes of the brain insult are incompletely understood, and novel methods are required for disease diagnosis and monitoring response to novel therapies. Aims & Methods: The study aimed to improve understanding of the pathogenesis of IMD-related neurodegeneration, and to identify potential disease biomarkers in specific IMD, by directly investigating alterations in brain tissue metabolite profiles using non-invasive in vivo magnetic resonance spectroscopy (MRS) in conjunction with conventional MRI brain scans. Results: MRI/MRS studies were performed on over 300 children. Normal brain metabolite profiles were established from a standard comparator cohort. A detailed quality analysis enabled combination of data from different scanner systems. Non-standard brain metabolites were detected in 2.3% of children. Metabolite-based methods of disease progression monitoring were evaluated in Hunter Syndrome. Mechanisms leading to strokes in patients with propionic acidaemia and to learning difficulties and epilepsy in argininosuccinic aciduria were explored using brain tissue metabolite profiling. Conclusions: Non-invasive in vivo brain tissue metabolite profiling is achievable using quantitative magnetic resonance spectroscopy in the routine clinical paediatric setting, and has utility in disease diagnostics, in monitoring disease progression and in investigating disease pathogenesis.

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48

Messmer, Kirsten. "Studies relating to inflammatory neurotoxicity in neurodegenerative diseases." Thesis, University of Sheffield, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340182.

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49

Franco, Iborra Sandra. "Mitochondrial quality control in neurodegenerative diseases: focus on Parkinson’s disease and Huntington’s disease." Doctoral thesis, Universitat Autònoma de Barcelona, 2018. http://hdl.handle.net/10803/565668.

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Darrerament s’han produït avanços importants que han contribuït al coneixement dels mecanismes de disfunció cel·lular i mort en la malaltia de Parkinson (MP) i en la malaltia de Huntington (MH). Ambdues malalties són trastorns del moviment que es caracteritzen per la pèrdua específica de neurones dels ganglis basals, les neurones dopaminèrgiques de la substància nigra (SN), en el cas de la MP i les neurones espinoses de l’estriat, en el cas de la MH. Malgrat les diferències, ambdues comparteixen processos patològics comuns com la presència de proteïnes malplegades, l’estrés oxidatiu i disfunció mitocondrial. La mitocòndria és la font d’energia principal en les cèl·lules eucariotes, però també és un orgànul dinàmic relacionat amb una gran quantitat de processos cel·lulars. La disrupció de la homeòstasis mitocondrial i la subseqüent disfunció mitocondrial juguen un paper important en la patofisiologia de les malalties neurodegeneratives. El manteniment de la integritat mitocondrial a través de diferents mecanismes de control és crític per a la superviviència neuronal. Aquesta tesi es centra en l’estudi dels mecanismes de control de qualitat mitocondrial en la MP i la MH, per tal d’entendre millor els mecanismes que duen a la mort cel·lular. En el primer capítol, he estudiat el transport de proteïnes a la mitocòndria en models in vitro i in vivo de la MP. In vitro, la inhibició del complexe I produeix una alteració del transport de proteïnes a la mitocòndria així com una disminució dels nivells de proteïnes OXPHOS, acumulació de proteïnes agregades i disminució dels nivells de chaperones mitocondrials. Per tal de restablir el transport de proteïnes mitocondrials es van sobreexpressar dos components clau del sistema de translocases: la translocasa de la membrana externa 20 (TOM20) i la translocasa de la membrana interna 23 (TIM23). La sobreexpressió in vitro de TOM20 i TIM23 va restaurar el transport de proteïnes mitocondrials i va alleugerar la disfunció mitocondrial i la mort cel·lular. La inhibició del complexe I en ratolins també dóna lloc a una alteració del transport de proteïnes mitocondrials i produeix neurodegeneració del sistema dopaminèrgic. La sobreexpressió de TIM23 va restaurar parcialment el transport de proteïnes i va protegir lleugerament les neurones dopaminèrgiques de la SN. En canvi, la sobreexpressió de TOM20 va ser incapaç de millorar el transport de proteïnes mitocondrials i, fins i tot, va exacerbar la mort cel·lular. Aquests resultats posen de relleu el paper de la disfunció del transport de proteïnes mitocondrials, en particular de dos dels seus components, en la patogènesis de la MP i suggereixen la necessitat de futurs estudis es centrin en altres elements d’aquest sistema. En el segon capítol, he estudiat el paper de la proteïna huntingtina en la mitofàgia i com la seva mutació, que dóna lloc a una expansió de glutamines, pot afectar a aquesta funció. Per a tal fi, he treballat en un model in vitro de cèl·lules estriatals ST-Q7 (control) i ST-Q111 (mutant). En condicions fisiològiques, la mitofàgia induïda no es troba mitjançada pel reclutament de parkin als mitocondris despolaritzats. La huntingtina mutada afecta la mitofàgia induïda a través de l’alteració de la seva funció de scaffold en diferents passos del procés de mitofàgia: (i) activació d’ULK1 a través de l’alliberament de mTORC1, (ii) formació del complexe Beclin 1-Vps15,(iii) interacció dels adaptadors de mitofàgia OPTN i NDP52 amb huntingtina i, (iv) amb LC3. Com a resultat, els mitocondris de les cèl·lules ST-Q111 estan més danyats i tenen una respiració mitocondrial deficient. Aquests resultats demostren la presència d’una alteració en la mitofàgia com un mecanisme lligat a la MH. En conclusió, el descobriment de noves dianes mitocondrials en la MP i MH emfatitza el paper important que juga el control de qualitat mitocondrial en la neurodegeneració.
In the past years, several important advances have expanded our understanding of the pathways that lead to cell dysfunction and death in Parkinson’s disease (PD) and Huntington’s disease (HD). Both diseases are movement disorders characterized by the loss of a specific subset of neurons within the basal ganglia, dopaminergic neurons in the substantia nigra pars compacta (SNpc), in the case of PD, and medium spiny neurons in the striatum, in the case of HD,. Despite distinct clinical and pathological features, these two neurodegenerative disorders share critical underlying pathogenic mechanisms such as the presence of misfolded and/or aggregated proteins, oxidative stress and mitochondrial anomalies. Mitochondria are the prime energy source in most eukaryotic cells, but these highly dynamic organelles are also involved in a multitude of cellular events. Disruption of mitochondrial homeostasis and the subsequent mitochondrial dysfunction plays a key role in the pathophysiology of neurodegenerative diseases. Therefore, maintenance of mitochondrial integrity through different surveillance mechanisms is critical for neuronal survival. In this thesis I have studied in depth some mitochondrial quality control mechanisms in the context of PD and HD, in order to broaden the knowledge about the pathomechanisms leading to cell death. In the first chapter I have studied mitochondrial protein import in in vitro and in vivo models of PD. In vitro, complex I inhibition, a characteristic pathological hallmark in PD, impaired mitochondrial protein import. This was associated with OXPHOS protein downregulation, accumulation of aggregated proteins inside mitochondria and downregulation of mitochondrial chaperones. Therefore, we aimed to reestablish the mitochondrial protein import by overexpressing two key components of the system: translocase of the outer membrane 20 (TOM20) and translocase of the inner membrane 23 (TIM23). Overexpression of TOM20 and TIM23 in vitro restored protein import into mitochondria and ameliorated mitochondrial dysfunction and cell death. Complex I inhibition also impaired mitochondrial protein import and led to dopaminergic neurodegeneration in vivo. Overexpression of TIM23 partially rescued protein import into mitochondria and slightly protected dopaminergic neurons in the SNpc. On the contrary, TOM20 overexpression did not rescue protein import into mitochondria and exacerbated neurodegeneration in both SNpc and striatum. These results highlight mitochondrial protein import dysfunction and the distinct role of two of their components in the pathogenesis of PD and suggest the need for future studies to target other elements in the system. In the second chapter, I have studied the role of huntingtin in mitophagy and how the polyglutamine expansion present in mutant huntingtin can affect its function. For such, I worked with differentiated striatal ST-Q7 (as control) and ST-Q111 (as mutant) cells, expressing full length huntingtin. In these conditions, induced mitophagy was not mediated by Parkin recruitment into depolarized mitochondria. Mutant huntingtin impaired induced mitophagy by altering wildtype huntingtin scaffolding activity at different steps of mitophagy process: (i) ULK1 activation through its release from the mTORC1, (ii) Beclin1-Vps15 complex formation, (iii) interaction of the mitophagy adapters OPTN and NDP52 with huntingtin and (iv) with LC3. As a result, mitochondria from ST-Q111 cells exhibited increased damage and altered mitochondrial respiration. These results uncover impaired mitophagy as a potential pathological mechanism linked with HD. In conclusion, we have discovered new mitochondrial targets for PD and HD emphasizing the important role that mitochondrial quality control plays in neurodegeneration

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50

Nong, Rachel Yuan. "Proximity Ligation Assays for Disease Biomarkers Analysis." Doctoral thesis, Uppsala universitet, Molekylära verktyg, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-158634.

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One of the pressing needs in the field of disease biomarker discovery is new technologies that could allow high performance protein analysis in different types of clinical material, such as blood and solid tissues. This thesis includes four approaches that address important limitations of current technologies, thus enabling highly sensitive, specific and parallel protein measurements. Paper I describes a method for sensitive singleplex protein detection in complex biological samples, namely solid phase proximity ligation assay (SP-PLA). SP-PLA exhibited improved sensitivity compared to conventional sandwich immunoassays. We applied SP-PLA to validate the potential of GDF-15 as a biomarker for cardiovascular disease. Paper II describes ProteinSeq, a multiplexed immunoassay based on the principle of SP-PLA, for parallel detection of 36 proteins using next-generation sequencing as readout. ProteinSeq exhibited improved sensitivity compared to multiplexed sandwich immunoassays, and the potential to achieve even higher levels of multiplexing while preserving a high sensitivity and specificity. We applied ProteinSeq to analyze 36 proteins, including one internal control, in 5 μl of plasma samples in a cohort of patients with cardiovascular disease and healthy controls. Paper III describes PLA-DTM, a strategy for recording all possible interactions between sets of proteins in clinical samples. Individual proteins and their interactions are first encoded to dual barcoded DNA by PLA, and the barcodes are interrogated by a method named dual tag microarray (DTM). We applied the method for studying interactions among protein members of the NFκB signaling pathway. Paper IV describes a novel probing strategy for analyzing individual biomolecules in solution or in situ. The technique employs a new class of probes for unfolding proximity ligation assays - uPLA probes. The probes are designed so that each probe set is sufficient in forming and replicating circular DNA reporter, without interactions among themselves when incubated with the sample. The uPLA probing strategy provides ease in the design of multiple probe sets in parallelized assays while enhancing the specificity of detection. We used the uPLA probes to detect various targets, including synthetic DNA and cancer-related transcripts in situ.

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