Дисертації: "Parkinson's disease, biomarkers, treatment"

1

Luan, Hemi. "Mass spectrometry based metabolomics for biomarkers of Parkinson's disease." HKBU Institutional Repository, 2017. https://repository.hkbu.edu.hk/etd_oa/396.

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Increasing evidence has shown that abnormal metabolic phenotypes in body fluids reflect the pathogenesis and pathophysiology of Parkinson's disease (PD). However, the relationship between metabolic phenotypes and PD is not fully understood. Mass spectrometry (MS) based metabolomics is a powerful technique, which was frequently used for the sensitive and reproducible detection of hundreds to thousands of metabolites in biofluid samples.. Here we developed and performed MS-based metabolomics studies involving hundreds of human urine samples with data acquired from multiple analytical batches for surveying potential biomarkers of PD. A new software statTarget was developed and introduced. Protocols for liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) were developed, including sample preparation, data acquisition, quality controls, quality assurance and data analysis. Urinary metabolites from a total of 401 clinical urine samples collected from 106 idiopathic PD patients and 104 normal control subjects were profiled by using LC-MS. Quality control (QC) strategy has been performed in MS-based metabolomics for high reproducibility and accuracy of MS data. GC-MS with methyl chloroformate (MCF) derivatization was used for profiling highly polar metabolites in patients with early-, middle- and advanced-stage PD. Our study revealed the significant correlation between clinical phenotypes and urinary metabolite profiles. Comprehensive metabolomics was successfully developed with the goal of identifying urinary metabolite markers that can be used for evaluating the development of PD. A group of 18 metabolites have shown not only a high discriminating ability for the early-stage PD patients but also accurately distinguished the middle- and advanced- stages patients from control subjects. For the evaluation of PD, 18 metabolites showed good potential as metabolite markers with related metabolic pathway variations observed in branched chain amino acid metabolism, glycine derivation, steroid hormone biosynthesis, tryptophan metabolism, and phenylalanine metabolism.. We have further performed targeted analysis of potential biomarkers by using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and GC-MS. The UPLC-MS/MS method was developed and optimized for detecting the concentration variation of metabolites in tryptophan metabolism for alpha-synuclein over-expressed flies (Parkinson's disease model). The altered tryptophan metabolism was proved as one of the common metabolite signatures between PD patients and alpha-synuclein over-expressed fly model of PD, and thus may be used for developing potential markers of the disease and evaluating the efficacy of novel therapeutic agents. An asymmetric labeling strategy and positive chemical ionization gas chromatography-tandem mass spectrometry (PCI-GC-MS-MS) approach was developed for the determination of non-amino organic acids and amino acids, as well as short chain fatty acids. Carboxylic and amino groups could be selectively labelled by propyl and ethyl groups, respectively. The specific neutral losses of C3H8O (60 Da), C3H5O2 (74 Da) and C4H8O2 (88 Da) were useful in the selective identification for qualitative analysis of organic acids and amino acid derivatives. The developed PCI-GC-MS/MS method showed good reproducibility and linear range.. In summary, metabolomics study has its inherent advantage in the characterization of biomarkers for the development of PD and may bring new scientific knowledge as well as impact on the progression of PD and other related neurodegenerative diseases.

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2

Han, Brent. "Biomarkers of progression in mirroring models of Parkinson's disease." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2008. http://wwwlib.umi.com/cr/ucsd/fullcit?p1453005.

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Thesis (M.S.)--University of California, San Diego, 2008.
Title from first page of PDF file (viewed June 25, 2008). Available via ProQuest Digital Dissertations. Includes bibliographical references (p. 34-37).

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3

Tabatabaei, Ali Reza. "Parkinson's disease : etiology, prevention and treatment." Thesis, University of British Columbia, 1991. http://hdl.handle.net/2429/30382.

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This thesis consists of three chapters dealing with different aspects of Parkinson's disease (PD). 3-Acetylpyridine (3-AP), a naturally occurring neurotoxin, was studied for its neurodegenerative properties on the mesostriatal dopaminergic system in rats as a possible environmental cause of idiopathic PD. Chronic administration of this compound to rats caused a moderate but insignificant reduction of striatal dopamine (determined by HPLC measurement of striatal dopamine) and a more substantial degeneration of cerebellar neurons and their neurotransmitters (determined by amino acid analysis of cerebellum). Prophylactic use of a high dose of nicotinamide prevented the reduction of dopamine in the striatum as well as the severe behavioural manifestations induced by 3-AP in rats. The cerebellar damage, however, was not affected. Different mechanisms of damage by 3-AP in these structures were presumed based on the protective effects of nicotinamide in the substantia nigra but not in the cerebellum. Possible protective properties of MK-801 (a noncompetitive NMDA antagonist) and nicotinamide against MPTP neurotoxicity were also examined in mice. MK-801 treatment provided a substantial protection against MPTP-induced reduction of striatal dopamine. Nicotinamide on the other hand provided no such protection. Finally, a new controversial approach to the treatment of parkinsonism was evaluated. Nervous tissue from 13-15 day-old fetuses was transplanted into MPTP-treated mice. The transplanted material was harvested from different areas of the fetal brain and was prepared by various procedures to examine the possible bases of any improvement in the host animal. After two studies, we did not find a biochemical improvement in transplanted mice treated with MPTP regardless of the nature of the transplanted materials.
Medicine, Faculty of
Anesthesiology, Pharmacology and Therapeutics, Department of
Graduate

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4

Athauda, Dilan Sampath. "Exenatide and the treatment of Parkinson's disease." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10053514/.

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Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting approximately 1% of people over the age of 65. Despite the best available medical and surgical therapies, there are no known treatments that can slow or alter clinical disease progression or continued neurodegeneration, thus any novel intervention that could delay or slow progression of PD would provide much needed health and socio-economic benefits. The mechanisms underlying PD pathogenesis remain unclear but there is accumulating evidence to suggesting that Type 2 diabetes and PD, both age-related diseases, share similar dysfunctional pathways. Alterations in metabolism, inflammation and mitochondrial function occur in both diseases and growing evidence suggests these pathways may impact on various tissues’ ability to respond to insulin, leading to “insulin resistance” in peripheral tissues and neurones, promoting cell death pathways and leading ultimately to diabetes and neurodegeneration respectively. The common pathways between these two conditions has led some to speculate that “insulin sensitizing” treatments for patients with Type 2 diabetes may be useful as novel treatments in neurodegenerative diseases such as PD. Exenatide is a Glucagon-like peptide-1 (GLP-1) agonist, currently licensed for the treatment for Type 2 diabetes and acts on insulin signalling pathways. It has demonstrated neuroprotective effects across a variety of animal toxin models of PD and also in a proof of concept, open label trial of mid-stage PD patients, conferring persistent motor and cognitive benefits sustained past the period of drug exposure. In this thesis I will present the first data from a fully randomised, placebo-controlled trial of exenatide in PD patients and explore the effects of exenatide on disease progression in PD and its influence on motor and non-motor symptoms. Furthermore, I will explore the pharmacokinetics of exenatide in this population and, utilising data from serum extracellular vesicles (exosomes) enriched for neuronal origin from the Exenatide-PD trial participants, demonstrate that peripherally administered exenatide can engage with neuronal insulin signalling pathways, providing some mechanistic context for the trial results. Taken together, data presented here will provide compelling evidence supporting the links between insulin signalling and PD and that the role of exenatide and other GLP-1 agonists as a novel treatment for PD should be explored further.

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5

Aviles-Olmos, I. "Exenatide as a novel treatment for Parkinson's Disease." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1415695/.

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PD is a progressive neurodegenerative disease that results in intolerable disability for most patients despite the best current medical and surgical therapies. A treatment that slows, or stops clinical progression is the major therapeutic goal of current PD research. Multiple avenues of research including epidemiology, molecular genetics and cell biology have identified links between Parkinson’s disease (PD) and Type 2 diabetes mellitus (T2DM). Several recent discoveries have highlighted common cellular pathways that potentially relate neurodegenerative processes with abnormal mitochondrial function and abnormal glucose metabolism. In parallel with these advances, a treatment for insulin resistance (Exenatide) has been evaluated as a possible disease modifying drug in PD, which forms the core of my PhD. Exenatide is the synthetic version of Exendin-4, confirmed to be an agonist of the Glucagon-like-peptide-1 (GLP-1) receptor, and resistant to the normal GLP-1 enzymatic degradation processes. The aim of this thesis is the evaluation of Exenatide’s possible role as a potential neuroprotective/disease modifying agent in PD (with only preliminary insights regarding its mechanisms of action in neurodegeneration). This study presents the following data: 1. Methods used to obtained proof of concept data from patients with moderate PD treated with Exenatide to provide preliminary support for its further study. 2. An exploration of possible objective measures of differences resulting from Exenatide exposure in a PD biomarker- SPECT imaging, using statistical parametric mapping of a subgroup of patients treated with Exenatide. 3. Prolonged follow up of these patients to further try and help distinguish placebo effects from possible biological effects of Exenatide in PD. 4. An attempt to identify a possible mechanism of action of Exenatide in our cohort of patients. Glucose tolerance tests were performed as an indirect measure of insulin resistance.

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6

Wang, Michelle J. "Predictive ability of cerebrospinal fluid biomarkers in diagnosing and evaluating Parkinson's disease." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/92059.

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Thesis: M. Eng., Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science, 2014.
This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from student-submitted PDF version of thesis.
Includes bibliographical references (page 31).
Currently, there are a variety of clinical assessments and rating scales used in the research and treatment of Parkinson's disease (PD). Despite the widespread use and reliance on these scales, they do not offer a uniform, objective measure. Many previous studies have indicated promising relationships between various biomarkers and Parkinsonian symptoms that could lead to objective measures by using statistical methods and providing p-values. However, we could not find any literature that uses machine learning or directly tests predictive value. The goal of this thesis was to determine whether or not cerebrospinal fluid (CSF) biomarker data could predict incidence of Parkinson's with a high degree of accuracy and differentiate between patients with varying levels of severity. We used various supervised machine learning algorithms on the Parkinson's Progression Markers Initiative (PPMI) baseline data set provided by the Michael J. Fox Foundation, and reported the percentage of patients correctly diagnosed by each algorithm on an isolated test data set. The best classifier averaged 69% accuracy in distinguishing human controls from PD patients. While this does indicate the presence of some predictive power, it is not clinically useful and we tentatively conclude a negative result. The data pertain to the CSF biomarkers available from PPMI at the end of October 2013.
by Michelle J. Wang.
M. Eng.

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7

Antoniades, Chrystalina Andrea. "The development and optimization of biomarkers for Huntington's and Parkinson's disorders." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609075.

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8

Crocker, Stephen J. "Novel therapeutic strategies for the treatment of Parkinson's disease." Thesis, University of Ottawa (Canada), 2001. http://hdl.handle.net/10393/9053.

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Parkinson's disease (PD) is a common neurodegenerative disorder associated with the loss of dopamine neurons located in the substantia nigra pars compacta. Current pharmacological approaches for the treatment of PD are confounded by development of abnormal involuntary movements called dyskinesias, and offer limited long-term utility because they do not stop the disease progression. Accordingly, this thesis addressed two primary issues limiting the present treatments of Parkinson's disease: the molecular basis of dopamine receptor-related dyskinesias, and attenuation of dopamine neuron death. Administration of dopamine receptor agonists to rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway produce changes in the denervated striatum that enable subsequent exposure to dopamine agonists to elicit potentiated circling behaviour, a phenomenon called "priming". Priming is used as a model to study the molecular basis of dyskinesias. Here, I demonstrate that dopamine D1-receptor priming is associated with a profound elevation of the nuclear transcription factor FosB in the denervated striatum. Moreover, intrastriatal delivery of an antisense oligonucleotide to fosB effectively blocked the induction of striatal FosB by dopamine agonist administration and attenuated the circling response elicited by injection of a selective dopamine D1-receptor agonist 3 days later. These findings suggest that dopamine receptor mediated FosB expression in the striatum plays a role in priming. In addition, the results from this study suggest that fosB may be involved the intracellular events which are responsible for the development of dyskinesias following chronic dopamine replacement therapy. The molecular processes which mediate the loss of nigral dopamine neurons in Parkinson's disease are not known. Recently, a novel family of mammalian proteins, called Inhibitor of Apoptosis (IAP) proteins, were cloned and shown to prevent cell death induced by a variety of cytotoxic factors. In two separate studies, I demonstrate that enhanced neuronal expression of two of these IAP proteins, neuronal apoptosis inhibitor protein (NAIP) and X-linked IAP (XIAP), prevents the death of nigral dopamine neurons following exposure to the dopaminergic neurotoxins. In rats, intrastriatal administration of recombinant adenoviruses containing NAIP (Ad.NAIP) was shown to prevent both the cellular and behavioural deficits produced by intrastriatal administration of 6-OHDA when compared to adenovirus control (Ad.lacZ) lesioned animals. Secondly, I describe a novel strain of mice engineered to overexpress XIAP in neurons by using a neuron-specific enolase promoter (NSE-xiap). Moreover, I demonstrate that NSE-xiap mice were profoundly resistant to the deleterious effects of the dopaminergic neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Since administration of MPTP can produce behavioural and neuropathological deficits reminiscent of PD in humans, results from this study suggest that IAP proteins may have utility for the treatment and prevention of cell death in idiopathic PD. Taken together, these studies suggest that neuroprotective strategies based on enhanced neuronal expression of IAP proteins may have novel therapeutic potential for treating neurodegeneration associated with Parkinson's disease.

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9

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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10

Yarnall, Alison Jane. "Predicting cognitive impairment in Parkinson's disease using neurophysiology and biochemical parameters as biomarkers." Thesis, University of Newcastle upon Tyne, 2013. http://hdl.handle.net/10443/2278.

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Parkinson’s disease (PD) is a common neurodegenerative condition with multiple associated non-motor symptoms. Of these, dementia is a frequent debilitating complication of the disorder, with significant morbidity and mortality. Some forms of mild cognitive impairment in PD (PD-MCI) may represent a pre-dementia state and certain clinical, laboratory and neurophysiological parameters may increase the accuracy of prediction of cognitive decline. If validated, these markers would offer the opportunity for disease modification and therapeutic intervention at a critical early stage of the illness, when the viable neuronal population is greater. The key aim of this thesis was to characterise cognitive impairment in PD in a cohort of newly diagnosed cases, and evaluate how a panel of biomarkers correlated with cognitive phenotypes to predict risk of future cognitive decline. The main findings were that PD-MCI was common, and was associated with a distinct clinical phenotype. Memory impairment was the most common single domain affected, although the majority of those with PD-MCI were classified as nonamnestic single domain subtype. A significant correlation was found between pattern recognition memory, sensitive to temporal lobe impairments, and cerebrospinal amyloid-β 1-42 levels, thought to represent amyloid-β metabolism and deposition Both amyloid-β 1-42 and 1-40 levels were significantly lower in those with impaired cognition. In addition, short latency afferent inhibition, a neurophysiological in vivo non-invasive measurement of cholinergic function, was also reduced in participants with mild cognitive impairment. These findings suggest that cholinergic dysfunction and amyloid deposition may contribute to the underlying pathophysiology of early PD- MCI. The major conclusion from this thesis is that PD-MCI is heterogeneous and more frequent than previously reported in early disease. This is associated with abnormalities of amyloid processing and cholinergic dysfunction, and may highlight those at risk of developing dementia. Longitudinal assessment of these individuals will enable us to determine and better model those measures predictive of cognitive decline at an early disease stage.

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11

Cheung, Marcus Ting Hin. "Personalized stimuli as treatment for resting tremor in Parkinson's disease." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/62554.

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Resting tremor in Parkinson’s disease (PD) affects quality of life and individuals’ ability to complete activities of daily living. Resting tremor has been shown to respond to transcranial alternating current stimulation (tACS) when delivered out of phase with the tremor. The present work aimed to further investigate potential tACS-based treatment mechanisms by designing and delivering personalized stimuli and extend our understanding of Parkinsonian resting tremor. Nine participants with tremor dominant PD received fourteen unique tACS stimuli to Primary Motor Cortex (M1) and Supplementary Motor Area (SMA). Effect on tremor was measured before and during stimulation via a 9 degree of freedom (DoF) motion sensor. The first principal component score was obtained from Principal Component Analysis (PCA) of these measures and the power of the data was compared before and during stimulation using a two-sample t-test. Four custom stimuli were designed by weighted linear combination of the data with the greatest effect on tremor; two of which were designed to be suppressive and two were designed to be augmentative towards tremor. Average power was calculated following delivery of the personalized and non-personalized stimuli. Regardless of whether tACS was delivered as a personalized or non-personalized stimuli, results indicate an increased average power during stimulation compared to no stimulation and an overall trend towards augmentation of tremor across participants. Supporting analyses, including Multivariate Empirical Mode Decomposition (MEMD) reinforce this finding, showing no clear trend towards any specific frequencies contributing to tremor suppression. The present results suggest that a broad spectrum frequency-based approach is not an effective means of suppressing tremor in people with PD and a phase-based or more targeted frequency approach may have more promise as a treatment mechanism for resting tremor in PD.
Applied Science, Faculty of
Electrical and Computer Engineering, Department of
Graduate

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12

Chu, Man Tak. "Differential effects of neurokinins in models of Parkinson's disease." HKBU Institutional Repository, 2011. http://repository.hkbu.edu.hk/etd_ra/1252.

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13

Butterfield, London. "Apathy in Parkinson's Disease: A Behavioral Intervention Study." Scholar Commons, 2013. http://scholarcommons.usf.edu/etd/4873.

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Apathy, a symptom reflecting motivational and self-initiation impairment, is one of the most common neuropsychiatric symptoms in Parkinson's disease (PD), with an average estimated prevalence of 40-45%. Elevated apathy has been associated with a host of negative associates and consequences, including cognitive impairment, poor daily functioning, poor treatment compliance and illness outcome, reduced quality of life, and increased caregiver burden and distress. While some studies have evaluated pharmacologic approaches to the treatment of apathy, few studies have evaluated non-pharmacologic approaches and we have identified no studies that have evaluated the efficacy of non-pharmacologic treatments of apathy in Parkinson's patients despite the need for such research. The purpose of the present study was to develop and gather pilot data on the acceptability, feasibility, and estimated efficacy of a primarily telephone-based, 6-week activity scheduling and monitoring intervention that incorporates an external cueing component to target disease-related self-generational deficits, on reducing levels of apathy in non-demented, highly apathetic PD patients. The project included three phases: (1) development of protocol materials, (2) determine ease of training paraprofessional interventionists, and (3) to assess feasibility, acceptability, and estimated effect of treatment in a one-arm uncontrolled trial. Patient apathy, depression, and quality of life significantly improved post-treatment and improvements in apathy and depression were maintained at one-month follow-up. While enrollment proved challenging, feasibility, acceptability, and efficacy data were strong and promising. Larger, randomized controlled trials are needed to investigate the efficacy of the presented intervention.

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14

Zhou, He Feng. "Tetramethylpyrazine analogue T-006 exerts neuroprotective effects in the multiple experimental models of Parkinson’s disease." Thesis, University of Macau, 2018. http://umaclib3.umac.mo/record=b3953422.

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15

Fall, Per-Arne. "Aspects of Parkinson's disease. Epidemiology, risk factors and ECT in advanced disease." Doctoral thesis, Linköpings universitet, Geriatrik, 1999. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-5011.

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The purpose was to investigate some aspects of epidemiology, risk factors and treatment with ECT in advanced Parkinson’s disease (PD). In study I, we performed a descriptive epidemiologic population-based survey in the Central Health Care District in Östergötland in south-east Sweden, with a population of almost 150,000 inhabitants 1989. The case finding was accomplished in three ways: 1. Collection of all prescriptions for Parkinson’s disease. 2. Search in medical files. 3. Checking with all nursing homes in the area. The crude prevalence was found to be 115 per 100,000 inhabitants. When we used the European Standard Population as a tool for easy comparisons of PD prevalence between different areas and time periods 76 PD-cases per 100,000 inhabitants were found. The corresponding incidences were 11.0 (crude) and 7.9 (age standardised) per 100,000 person-years. Mean age at onset was 65.6. A low prevalence and a high age at onset suggested that e.g. environmental factors could influence the occurrence of PD, and the results implies that only few such factors were present in the investigated area. The findings led to study II, a case-control study which investigated the possible impact of nutritional and environmental risk factors for idiopathic Parkinson’s disease (IP), including 113 cases and 263 control subjects. Dietary, drinking, and smoking habits, as well as previous occupation, were requested in a structured questionnaire. No increased risk was found for any of the nutrients. A reduced risk was found for coffee, wine, and spirits but also for broiled meat, smoked ham or meat, eggs, French loaf or white bread, and tomatoes. These findings could indicate an antioxidant effect. Frequency of preceding and present smoking was reduced in IP patients. Possible mechanisms are discussed. Various occupational groups and exposures were analysed and increased risks of IP in men were found for agricultural work, pesticide exposure, male carpenters, and in female cleaners. In advanced PD there is a need for further therapeutic improvements, and electroconvulsive therapy (ECT) is one insufficiently explored and evaluated method. In study III ECT 16 non-depressed, nondemented PD patients with advanced disease were treated with ECT. In all patients an antiparkinsonian effect of ECT was seen, lasting between a few days and 18 months. Five patients, all with signs of blood brain barrier damage, developed transitory mental confusion after ECT. The results indicated that ECT could cause increased dopaminergic activity, which led us to study IV. Single photon emission computed tomography (SPECT) with the cocaine analogue [123I]-β-CIT was used in order to visualise dopaminergic neurones in the brain. Six patients with PD were examined before and after a series of ECT, and in three cases SPECT was also repeated after one year. The side-to-side difference in the radiotracer uptake was found to be significantly lower in striatum located contralaterally to the part of the body with most pronounced symptomatology. No significant change in uptake of [123I]-β-CIT was seen after ECT, although all patients improved and the most pronounced improvement was seen in patients with less advanced PD. Study V points at two new positive observations with maintenance ECT (MECT). i.e. repeated ECT treatment of PD. One patient had either severe mental side effects on higher L-dopa doses or intolerable parkinsonian symptoms on lower doses. MECT implied marked improvement in parkinsonian symptoms without mental side effects. Another PD patient, who also had a mental depression, showed slight improvement of motor symptoms on a series of ECT. When treated with MECT further antiparkinsonian effects were seen.
On the day of the public defence the status of the article IV was: Submitted; articel V was: Accepted for publication after revision.

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16

Eslamboli, Andisheh. "Lesion methods and treatment strategies in primate models of Parkinson's disease." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.615616.

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17

Carelli, S. "DEVELOPING A REGENERATIVE MEDICINE APPROACH FOR THE TREATMENT OF PARKINSON'S DISEASE." Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/230550.

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Parkinson’s disease (PD) is the second most common neurodegenerative disease, after Alzheimer’s disease, and the most common movement disorder. Drug treatment and deep brain stimulation can ameliorate symptoms, but the progressive degeneration of dopaminergic neurons in the substantia nigra eventually leads to severe motor dysfunction. While some effective treatments for patients with PD exist, these treatment strategies are mainly symptomatic and aimed at increasing dopamine levels in the degenerating nigrostriatal system. Existing drugs are limited in their relief and decrease in effectiveness as PD progresses.The transplantation of stem cells has emerged as a promising approach to replace lost neurons in order to restore dopamine levels in the striatum and reactivate functional circuits. Post mortem neural precursor cells (PM-NPCs) are a subclass of sub ventricular zone (SVZ)-derived neural progenitors, capable of surviving many hours (16 hours) after donor death. The in vitro differentiation yields more neurons (about 30-40%) compared to regular NPCs (Marfia et al., 2011). Recently from the SVZ of a transgenic mouse strain expressing green fluorescent protein (GFP) under the promoter C of the ubiquitin gene [(C57BL/6-Tg(UBC-GFP)30Scha/J)] we isolated GFP PM-NPCs, from mice at 6 hours after the donor death. These cells were characterized and their potential of in terms of replacement therapy was investigated in a mouse model of Parkinson disease. The degeneration of dopaminergic neurons was obtained through the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at the dosage of 36 mg/kg intraperiteoneally (i.p.). After 1 week the lesion was stabilized by a second administration (i.p.) of the neurotoxin at the dosage of 20 mg/kg. 1x 105 of PM-PCs-GFP were injected unilaterally into the striatum of C57/BL mice by using specific stereotaxic coordinates 3 days after the second MPTP administration. The effects of transplanted cells were determined by means of performance tests aimed at detecting behavioral improvements. Moreover, the neurochemical changes were also studied by high performance liquid chromatography (HPLC). In order to study the in vivo fate of grafted GFP PM-NPCs animals were perfused 2 weeks after transplantation and immunohistochemistry studies were performed. Our results show that animals grafted with GFP PM-NPCs determined a remarkable improvement of behavioral parameters measured by means of both horizontal and vertical grid tests (forepaw fault and time required to grab on the grids while turning and climbing down) since the third day after transplantation. These improvements were very significant and the average values were close to control animals. This was maintained during all the two weeks of experimental observation. By means of immunofluorescence staining we observed that the majority of transplanted GFP-PM-NPCs were vital and able to migrate ventrally and caudally from the injection site lengths as far as 1000 microns into the striatum, and could reach the ipsilateral and contralateral substantia nigra pars compacta. Moreover, morphological analyses revealed that transplanted cells in the striatum are able to differentiate into tyrosine hydroxylase (40%), cholinergic (40%), and gabaergic neurons (25%). This study provides new evidences that PM-NPCs will be useful for developing cellular PD therapies. Future studies should further explore the clinical potential role of the investigated post mortem neural precursors cells in order to provide new perspectives for PD treatment.

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18

Johansson, Anders. "Search for biomarkers in ALS and Parkinson's Disease positron emission tomography and cerebrospinal fluid studies /." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univeritetsbiblioteket [distributör], 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-102040.

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19

Fu, Jessie FangLu. "Investigation of Parkinson's disease related pattern and altered dopamine release pattern in treatment-induced complications and non-motor symptoms of Parkinson's disease." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/58816.

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Parkinson's Disease is the second most common neurodegenerative disorder. Apart from motor symptoms, cognitive deficits are also common. Treatments, mainly in the form of dopamine (DA) replacement therapy, although reduce motor symptoms at first, can lead to treatment-induced complications. Abnormal spatial covariance metabolic pattern linked to the motor and cognitive symptoms of Parkinson's Disease (PD) have previously been defined using Fludeoxyglucose (FDG) Positron Emission Tomography (PET). In contrast, little is known about the functional networks in the serotonergic system, which is known to be closely related to cognitive dysfunctions of the disease. In this thesis work, we want to investigate the interactions between the dopaminergic and serotonergic pathways in presymptomatic and early stages of the disease, and their contributions to treatment-induced complications and non-motor symptoms in PD subjects. In the first part of this project, we investigated the PD and LRRK2 mutation related patterns in the serotonergic system by studying 12 asymptomatic LRRK2 mutation carriers (LRRK2-AMC), 9 healthy controls (HC), and 18 PD subjects using [¹¹C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) PET and a principal component analysis (PCA) based regional covariance model with bootstrap resampling. The serotonergic PD-related pattern (SPDRP) significantly separated PD subjects from HC subjects (p<0.0001). A distinct asymptomatic LRRK2 mutation-related pattern (LRRK2-AMRP) significantly separated LRRK2-AMC with HC subjects (p<0.0001). In the second part of the project, we analyzed the medication-induced DA release pattern for 10 early PD subjects using double [¹¹C]-Raclopride scans. We found a significant negative correlation between DA release and age of onset in the striatum. These findings, although obtained with a small number of subjects, suggest that the serotonergic system may be affected by PD in a specific pattern and regions relatively preserved binding may contribute to cognitive dysfunctions related to PD. LRRK2-AMC subjects showed a distinct pattern, which indicates that either such increase is of compensatory nature or is a characteristic of this specific mutation. The combination of abnormal medication-induced DA release pattern and upregulation of the serotonergic system may be able to explain the occurrence of treatment-induced complications and non-motor symptoms in PD patients, and act as a potential early marker for the disease.
Science, Faculty of
Physics and Astronomy, Department of
Graduate

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20

Baker, B. J. "Vascularisation of grafts to the CNS." Thesis, University of Oxford, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.236280.

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21

Messiou, Christina. "Investigation of quantitative biomarkers of treatment response in malignant bone disease." Thesis, Institute of Cancer Research (University Of London), 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.538326.

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22

Flores, Joseph. "Human retinal pigment epithelial cell transplantation for the treatment of Parkinson's disease." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/36675.

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Cell replacement therapies have been thoroughly investigated in the hope of finding a long-term, continuous dopaminergic (DAergic) source to treat motor dysfunctions in Parkinson’s disease (PD). However, mixed clinical results, safety and logistical concerns, and ethical issues have led to the interruption of these therapies in the clinic. Human Retinal Pigment Epithelial (hRPE) cells from fetal or neonatal origin have been proposed as a tissue transplant alternative for PD. HRPE cells are of neuroectoderm origin and play an integral part in normal retinal survival and function by providing nutritive, trophic, and anti-inflammatory support. HRPE cells are a potential cell therapy source for PD because of their DAergic properties. In the RPE, dopa is an intermediate product in the melanin biosynthetic pathway, catalyzed by the tyrosine hydroxylase analog tyrosinase. Since tyrosinase-produced dopa can exit the cell through plasma membrane amino acid transporters, RPE implantation into the parkinsonian brain could provide a continuous source of dopa to striatal DA terminals. Previous reports have shown that hRPE cells attached to biocompatible gelatin microcarriers (hRPE-GM) can successfully ameliorate parkinsonian symptoms in PD patients. However, these observations are empirical in nature; indeed, little is known about long-term hRPE-GM survival or its underlying mechanism of action. The present thesis addresses the hypotheses that 1) hRPE-GM implants ameliorate behavioural deficits, 2) hRPE-GM survive long-term in the host striatum, and 3) the mechanism of action of hRPE-GM implants is not solely due to the in situ production of dopa and may involve alternate mechanisms of action, with an emphasis on anti-inflammatory factors. Using the rodent 6-OHDA model for PD, we investigated the qualitative survival and behavioural effects of hRPE-GM implants combining post mortem immunohistochemistry and non drug-induced behavioural paradigms. Next, we assessed the hypothesized reduction in inflammatory reactions to hRPE-GM implants (in the absence of immunosuppression) by quantifying the inflammatory response using stereological methods. Finally, we described a quantitative timeline of in vivo hRPE-GM survival using our recently developed superparamagnetic labeling techniques and MRI. These studies will provide further support for using hRPE cells as a therapeutic option for PD.

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23

Kafritsas, Jonathan G. "Development of Polymer-based Sol-Gel Therapeutics for Parkinson's Disease." Thesis, Griffith University, 2021. http://hdl.handle.net/10072/406509.

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Neurodegeneration in Parkinson’s disease is associated with the formation of neuronal cytoplasmic inclusion bodies, termed Lewy Bodies, which are comprised mainly of the pre-synaptic protein α-synuclein. Aggregation of α-synuclein and subsequent formation of Lewy Bodies is associated with raised intraneuronal Ca (II) and Cu (I/II) levels. In alignment with this notion, post-mortem studies of Parkinson’s disease brain tissue have demonstrated the sparing of neurons that express the Ca (II) buffering protein, Calbindin-D28k. As a result, the upregulation of endogenous metal binding proteins may serve as a potential target to inhibit α-synuclein aggregation. Recent in vitro studies displayed that the vitamin-D analogue Calcipotriol and glucocorticoid Dexamethasone can potently induce the calcium and copper buffering proteins Calbindin-D28k and Metallothionein, respectively. As a result, Calcipotriol and Dexamethasone may serve as a potential therapeutic option for Parkinson’s disease. The treatment of central nervous system disorders is often challenging due to the delivery of therapeutics to the central nervous system being hindered by the blood brain barrier and interactions with the periphery. As a result, considerable attention has been garnered by the nose to brain drug delivery route as it bypasses the blood brain barrier and periphery, thereby mitigating pharmacokinetic challenges faced with conventional delivery routes. A major limitation faced with the nose to brain delivery method is the removal of therapeutics such as sprays from the nasal mucosa due to the mucociliary clearance and lack of mucosal adherent properties in the therapeutic. This problem faced by conventional delivery vehicles is overcome by a new delivery vehicle, termed a soluble gel, which possesses muco-adhesive, thermo-responsive and sustained drug release properties. Hence it was hypothesized that the addition of Calcipotriol and Dexamethasone into the soluble gel formulation may upregulate Calbindin-D28k and Metallothionein in vitro, respectively. This study was divided into two objectives. The first objective involved formulating soluble gels containing Dexamethasone (DXN) or Calcipotriol (CP) which possessed optimal properties for nose to brain delivery. The second objective involved the soluble gels formulated as part of the first objective being applied to SH-SY5Y human neuroblastoma cells, in order to determine whether cytoplasmic Calbindin-D28K and Metallothionein could be upregulated. The gelation temperature and viscosity of the soluble gels were the two parameters which were evaluated for each soluble gel formulation, which were measured by a rheometer. The ranges deemed acceptable for nose to brain delivery for gelation temperature was between 25-34℃ and for viscosity was between 0.4-1 Pa.s at 34℃. The thermo-responsive and muco-adhesive agents employed for the soluble gels were Poloxomer-407 and Carbomer-934P, respectively. It was determined that a soluble gel with Poloxamer-407 15.5% w/w + Carbomer-934P 0.3% w/w + Dexamethasone 0.05% (P15.5/C0.3/DXN) had a gelation temperature of 28.156℃ and viscosity of 0.653 Pa.s at 34℃, which were both between the acceptable ranges for nose to brain delivery. As a result, P15.5/C0.3/DXN underwent a Dexamethasone drug release study involving the use of a Franz drug diffusion apparatus and high-performance liquid chromatography. P15.5/C0.3/DXN displayed sustained release of Dexamethasone over a 72-hour period. The same process was conducted for the soluble gels containing Calcipotriol. Two Calcipotriol containing soluble gels were formulated, which comprised of Poloxamer-407 15% w/w + Carbomer-934P 0.3% w/w + Calcipotriol 0.005% w/w (P15/C0.3/CP0.5) and Poloxamer-407 15.5% w/w + Carbomer-934P 0.3% w/w + Calcipotriol 0.0005% w/w (P15.5/C0.3/CP). P15/C0.3/CP0.5 had a gelation temperature of 28.517℃ and viscosity of 0.574 Pa.s at 34℃, which were both between the acceptable ranges for nose to brain delivery. P15.5/C0.3/CP had a gelation temperature of 28.530℃ and viscosity of 0.494 Pa.s at 34℃, which were also both between the acceptable ranges for nose to brain delivery. No Calcipotriol drug release data was obtained for P15/C0.3/CP0.5 and P15.5/C0.3/CP due to low detection sensitivity. P15.5/C0.3/DXN, P15/C0.3/CP0.5 and P15.5/C0.3/CP were then applied to SH-SY5Y human neuroblastoma cells as part of objective 2. It was determined that the application of these formulations significantly upregulated cytoplasmic Calbindin-D28k and Metallothionein expression. The application of P15.5/C0.3/DXN for 20-minutes demonstrated approximately a 1.871-fold increase in Metallothionein expression compared to the control cells. The application of P15/C0.3/CP0.5 and P15.5/C0.3/CP for 30-minutes and 1-hour displayed approximately a 2-fold increase in Calbindin-D28K expression compared to the control cells. In summary, these findings suggest that the intranasal delivery of soluble gels with active drug components may serve as a potential treatment for Parkinson’s disease by inhibiting metal ion dependent α-synuclein aggregation and subsequent Lewy Body formation.
Thesis (Masters)
Master of Medical Research (MMedRes)
School of Pharmacy & Med Sci
Griffith Health
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24

Ghadiri, Mahtab. "Peripheral Immune Phenotyping in Multiple Sclerosis: Immunomodulatory Treatment Effects and Treatment Response Biomarkers." Thesis, The University of Sydney, 2019. http://hdl.handle.net/2123/20809.

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Disease modifying therapies (DMTs) used in the treatment of relapsing remitting multiple sclerosis (RRMS) have broad effects on the immune system that are incompletely understood. There is great heterogeneity in treatment response to most DMTs. However, biomarkers predicting treatment response are lacking. In this thesis, the peripheral immune changes induced by treatment with two DMTs, fingolimod (FTY) and dimethyl fumarate (DMF), are examined in detail by immune phenotyping using multicolour flow cytometry. Chapter 3 presents a longitudinal study of T cell subsets in patients commencing treatment with DMF. Differential losses of T cell subsets are found, including relative changes in regulatory and effector subsets potentially relevant to the mechanism of action of DMF. DMF-induced lymphopaenia is further studied in an in vitro culture system. The study results suggest that differential susceptibility of distinct T cell subsets to DMF-induced apoptosis may underly differential T cell losses seen in treated patients. In Chapter 4, the effects of FTY on peripheral T cell subsets and the reversibility of these effects is explored in patients ceasing FTY treatment. Long-lasting alterations in circulating T cell subsets are documented, indicating that FTY-induced changes in the peripheral immune repertoire may persist beyond the time taken for clinical laboratory measures to normalise. Chapter 5 presents a longitudinal study of a broad range of immune cell subsets in patients commencing FTY. Changes in potentially disease-relevant immune cell subsets not previously examined in FTY-treated patients are documented. Using magnetic resonance imaging (MRI) and clinical information to assess disease activity in these patients, potential immune biomarkers of FTY treatment response are uncovered. This thesis expands on our understanding of the effects of MS DMTs on the peripheral immune repertoire and highlights the utility of immune phenotyping in exploring DMT mechanisms of action and treatment response biomarkers.

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25

Ingram, Wendy Merewyn. "Pharmacokinetic and pharmcodynamic studies of apomorphine in the treatment of idiopathic Parkinson's disease." Thesis, University of Plymouth, 2001. http://hdl.handle.net/10026.1/2824.

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There were two aspects to the study of apomorphine in the treatment of Parkinson' s disease: (i) a clinical pharmacokinetic-pharmacodynamic (PK-PD) study was designed and implemented in response to the challenges of apomorphine dose-titration in Parkinson's disease, and in view of the scarcity of available literature on the PK-PD relationships of apomorphine in Parkinson's disease, (ii) the PK(and tolerability)of apomorphine dosing using novel delivery/formulation combinations were explored in view of the inherent limitations associated with the conventional (ie. subcutaneous) route of administration of apomorphine (e.g. cutaneous nodule formation, needle-phobia). An HPLC assay was developed for the quantification of apomorphine in plasma, and stability issues relating to sample storage and assay were investigated. With regards to the first aspect of the research, simultaneous PK-PD modelling was performed, using an effect compartment model to account for counterclockwise hysteresis in a sub-group of patients. According to the traditional two-stage approach to data analysis, mean (standard deviation) clearance following subcutaneous bolus was 2.2 (0.5) L/kg/h, (apparent) volume of distribution was 1.9 (0.8) L/kg, absorption half-life was 4.1 (2.1) minutes and elimination half-life was 69.5 (21.1)minutes (n=7). Equilibration half-life was estimated for two patients at 8.3 and 16.5 minutes. Focus was given to investigating the relevance of a potential correlation (which had previously been identified using in-house pilot data) between post-distributional apomorphine PK and apomorphine-induced anti-parkinsonian response in patients with Parkinson's disease. It was hypothesised that this particular correlation may be of use in a dose-optimisation scheme. However it was demonstrated that, in the patients studied, the concept could not be applied to apomorphine dose-optimisation. The novel delivery systems under scrutiny were: (i) Britaject® (Britannia Pharmaceuticals Ltd.) apomorphine formulation administered subcutaneously using a needle-free (jet) injector (J-TIP®, National Medical Products Inc.), (ii) an intranasal apomorphine powder formulation delivered using a turbospin insufflator (CDFS), and (iii) an apomorphine hydrogel co-polymer produced as a dosage-form for buccal delivery (Controlled Therapeutics (Scotland) Ltd.). As a result of this work, a rationale for subsequent development of the novel systems was provided. Indeed, the needle-free and buccal systems were, in their existing format, shown not to convey a net advantage over the existing system. However the intranasal formulation, with a mean (standard deviation) relative bioavailability of 41 (18)% (n=16) compared to subcutaneous bolus administration (and with a favourable outcome as regards to tolerability), was considered to be potentially suitable for further development.

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26

Noble, Stephen Paul. "The role of neopterin derivatives in the pathogenesis and treatment of Parkinson's disease." Thesis, University of Birmingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398447.

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27

Wiemerslage, Lyle N. "Neuroprotection of Dopaminergic Neurons and their Subcellular Structures from Parkinson's Disease-like Treatment." Ohio University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1395669814.

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28

Welleford, Andrew. "Autologous Peripheral Nerve Grafts to the Brain for the Treatment of Parkinson's Disease." UKnowledge, 2019. https://uknowledge.uky.edu/neurobio_etds/23.

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Parkinson’s disease (PD) is a disorder of the nervous system that causes problems with movement (motor symptoms) as well as other problems such as mood disorders, cognitive changes, sleep disorders, constipation, pain, and other non-motor symptoms. The severity of PD symptoms worsens over time as the disease progresses, and while there are treatments for the motor and some non-motor symptoms there is no known cure for PD. Thus there is a high demand for therapies to slow the progressive neurodegeneration observed in PD. Two clinical trials at the University of Kentucky College of Medicine (NCT02369003, NCT01833364) are currently underway that aim to develop a disease-modifying therapy that slows the progression of PD. These clinical trials are evaluating the safety and feasibility of an autologous peripheral nerve graft to the substantia nigra in combination with Deep Brain Stimulation (DBS) for the treatment of PD. By grafting peripheral nerve tissue to the Substantia Nigra, the researchers aim to introduce peripheral nerve tissue, which is capable of functional regeneration after injury, to the degenerating Substantia Nigra of patients with PD. The central hypothesis of these clinical trials is that the grafted tissue will slow degeneration of the target brain region through neural repair actions of Schwann cells as well as other pro-regenerative features of the peripheral nerve tissue. This dissertation details analysis of the peripheral nerve tissue used in the above clinical trials with respect to tissue composition and gene expression, both of injury-naive human peripheral nerve as well as the post-conditioning injury nerve tissue used in the grafting procedure. RNA-seq analysis of sural nerve tissue pre and post-conditioning show significant changes in gene expression corresponding with transdifferentiation of Schwann cells from a myelinating to a repair phenotype, release of growth factors, activation of macrophages and other immune cells, and an increase in anti-apoptotic and neuroprotective gene transcripts. These results reveal in vivo gene expression changes involved in the human peripheral nerve injury repair process, which has relevance beyond this clinical trial to the fields of Schwann cell biology and peripheral nerve repair. To assess the neurobiology of the graft post-implantation we developed an animal model of the grafting procedure, termed Neuro-Avatars, which feature human graft tissue implanted into athymic nude rats. Survival and infiltration of human graft cells into the host brain were shown using immunohistochemistry of Human Nuclear Antigen. Surgical methods and outcomes from the ongoing development of this animal model are reported. To connect the results of these laboratory studies to the clinical trial we compared the severity of motor symptoms before surgery to one year post-surgery in patients who received the analyzed graft tissue. Motor symptom severity was assessed using the Unified Parkinson’s Disease Rating Scale Part III. Finally, the implications and future directions of this research is discussed. In summary, this dissertation advances the translational science cycle by using clinical trial findings and samples to answer basic science questions that will in turn guide future clinical trial design.

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29

Wong, Lai-na Lina. "Intensive voice treatment for Cantonese-speaking patients with Parkinson's disease effects on intonation and lexical tone production /." Click to view the E-thesis via HKU Scholars Hub, 2003. http://lookup.lib.hku.hk/lookup/bib/B38890847.

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Thesis (B.Sc.)--University of Hong Kong, 2003.
"A dissertation submitted in partial fulfilment of the requirements for the Bachelor of Science (Speech and Hearing Sciences), The University of Hong Kong, April 30, 2003." Includes bibliographical references (p. 26-30) Also available in print.

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30

Zhang, Zai Jun. "Pharmacological characterization of new neuroprotectants in Parkinson's disease models." Thesis, University of Macau, 2012. http://umaclib3.umac.mo/record=b2554086.

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31

Janis, Kelly Lynn. "Investigation of the efficacy of various neuroprotection agents for their potential use in the treatment of Parkinson's disease." Diss., Connect to online resource - MSU authorized users, 2008.

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32

Gaida, Razia. "Treatment of Parkinson's disease in South Africa and investigation of risk factors causing dyskinesias." Thesis, Nelson Mandela Metropolitan University, 2012. http://hdl.handle.net/10948/d1012466.

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Background: Levodopa is still thought of as the 'gold standard' symptomatic treatment for Parkinson’s disease. However, after four to five years of treatment, levodopa efficacy tends to decline even if there was a good initial therapeutic response. The ideal treatment of Parkinson’s disease is a much debated issue with a range of guidelines available. Objectives: This study was undertaken to analyse medication use and prescribing patterns as well as to determine the risk factors involved in causing dyskinesias in Parkinson’s sufferers. Methods: The study consisted of two parts, namely a drug utilisation review (DUR) and a questionnaire survey. There were 25 523 antiparkinsonian records consisting of 5 168 patients for the year 2010. The questionnaires were verbally administered to patients diagnosed with Parkinson’s disease. A total of 43 patients were interviewed. Results: The average age of the population was 70.74±10.37 years, with the oldest patient being 100 years. Females constituted 59.17percent (5 168: n = 3 058) of the total number of patients. The most common antiparkinsonian products dispensed were combination drugs containing levodopa with a decarboxylase inhibitor and some with a COMT-inhibitor as well (46.5percent; n = 11 875). Males represented 53.49percent (43: n = 23) of the patients included in the questionnaire survey. A review of the medical records showed that patients with dyskinesias were diagnosed with Parkinson’s disease at a younger age and had experienced longer disease duration. Conclusion: Parkinson’s disease is an under-recognised condition in South Africa. Treatment needs to be individualised and based on evidence-based guidelines. Further studies in South Africa, as well as SSA (sub-Saharan Africa), need to be conducted on both the prevalence as well as the treatment of Parkinson’s disease.

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33

Broadstock, Martin. "Group III metabotropic glutamate receptors as potential targets in the treatment of Parkinson's disease." Thesis, King's College London (University of London), 2006. https://kclpure.kcl.ac.uk/portal/en/theses/group-iii-metabotropic-glutamate-receptors-as-potential-targets-in-the-treatment-of-parkinsons-disease(41881507-54fb-43c0-8bf9-65fe891cbb72).html.

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34

Maharaj, Himant. "An investigation into the neuroprotective properties of acetylsalicylic acid and acetaminophen." Thesis, Rhodes University, 2005. http://hdl.handle.net/10962/d1003247.

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The potent analgesic property of acetylsalicylic acid and acetaminophen makes these the most commonly used analgesics in the world. Easy accessibility and cost effectiveness of these agents are attractive to patients seeking pain relief. However, the abuse of nonnarcotic analgesics such as acetaminophen and acetylsalicylic acid by alcoholics and patients seeking to relieve dysphoric moods is well documented. These agents therefore impact on the brain neurotransmitter levels and therefore all processes involved in the synthesis and metabolism of neurotransmitters may be affected. The use of non-narcotic analgesics has been reported to reduce the incidence of neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The mode of action by which acetylsalicylic acid and acetaminophen elicit neuroprotection is however unclear as many mechanisms of action have been inconclusively postulated. The first part of this study aims to elucidate the various mechanisms by which acetylsalicylic acid and acetaminophen affect the enzymes responsible for the catabolism of tryptophan, which is a precursor for the mood elevating neurotransmitter serotonin, as well as to investigate whether these agents alter the interplay between serotonin and pineal indole metabolism. The second part of this study focuses on the neuroprotective properties of acetylsalicylic acid and acetaminophen utilizing the neurotoxic metabolite of the kynurenine pathway, quinolinic acid and the potent Parkinsonian neurotoxin, 1-methyl-4-phenylpyridinium (MPP+). The ability of acetylsalicylic acid and acetaminophen to alter TRP metabolism was determined by investigating the effects of these agents on the primary enzymes of the kynurenine pathway i.e. tryptophan 2, 3-dioxygenase and indoleamine 2,3-dioxygenase as well as to investigate whether these agents would have any effects on 3-hydroxyanthranilic acid oxygenase. 3-Hydroxyanthranilic acid oxygenase is the enzyme responsible for the synthesis of quinolinic acid. Acetylsalicylic acid and acetaminophen alter tryptophan metabolism by inhibiting tryptophan 2, 3-dioxygenase and indoleamine 2,3-dioxygenase thus increasing the availability of tryptophan for the production of serotonin. Acetylsalicylic acid and acetaminophen also inhibit 3-hydroxyanthranilic acid oxygenase thus implying that these agents could reduce quinolinic acid production. Acetaminophen administration in rats induces a rise in serotonin and norepinephrine in the forebrain. Acetylsalicylic acid curtails the acetaminophen-induced rise in brain norepinephrine levels as well as enhances serotonin metabolism, indicating that analgesic preparations containing both agents would be advantageous, as this would prevent acetaminophen-induced mood elevation. The results from the pineal indole metabolism study show that acetylsalicylic acid enhances pineal metabolism of serotonin whereas acetaminophen induces an increase in melatonin levels in the pineal gland. Neuronal damage due to oxidative stress has been implicated in several neurodegenerative disorders such as AD and PD. The second part of the study aims to elucidate and characterize the mechanism by which acetylsalicylic acid and acetaminophen afford neuroprotection. The hippocampus is an important region of the brain responsible for memory. Agents such as quinolinic acid that are known to induce stress in this area have detrimental effects and could lead to various types of dementia. The striatum is also a vulnerable region to oxidative stress and hence (MPP+), which is toxic for this particular region of the brain, was also used as a neurotoxin. The results show that ASA and acetaminophen alone and in combination, are potent superoxide anion scavengers. In addition, the results imply that these agents offer protection against oxidative stress and lipid peroxidation induced by several neurotoxins in rat brain particularly, the hippocampus and striatum. Histological studies, using Nissl staining and Acid fuchsin, show that acetylsalicylic acid and acetaminophen are able to protect hippocampal neurons against quinolinic acidinduced necrotic cell death. Immunohistochemical investigations show that QA induces apoptotic cell death in the hippocampus, which is inhibited by ASA and acetaminophen. In addition, ASA and acetaminophen inhibited MPP+ induced apoptotic cell death in the rat striatum. The study also sought to elucidate possible mechanisms by which ASA and acetaminophen exert neuroprotective effects in the presence of MPP+ as these agents are shown to prevent the MPP+-induced reduction in dopamine levels. The results show that acetylsalicylic acid and acetaminophen inhibit the action of this neurotoxin on the mitochondrial electron transport chain, a common source of free radicals in the cell. In addition, these agents were shown to block the neurotoxic effects of MPP+ on the enzymatic defence system of the brain i.e. superoxide dismutase, glutathione peroxidase and catalase. The reduction in glutathione levels induced by MPP+ is significantly inhibited by acetylsalicylic acid and acetaminophen. The results imply that these agents are capable of not only scavenging free radicals but also enhance the cell defence mechanism against toxicity in the presence of MPP+. These agents also block the MPP+-induced inhibition of dopamine uptake into the cell. This would therefore reduce auto-oxidation of dopamine thus implying another mechanism by which these agents exert a neuroprotective role in MPP+-induced neurotoxicity. The discovery of neuroprotective properties of acetylsalicylic acid and acetaminophen is important considering the high usage of these agents and the increased incidence in neurological disorders. The findings of this thesis point to the need for clinical studies to be conducted as the results show acetylsalicylic acid and acetaminophen to have a definite role to play as antioxidants. This study therefore provides novel information regarding the neuroprotective effects of these agents and favours the use of these agents in the treatment of neurodegenerative disorders, such as AD and PD, in which oxidative stress is implicated.

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35

Chen, Tong Kai. "Development of Schisantherin A and baicalein nano-formulations with improved oral bioavailability, brain uptake, and anti-Parkinsonian activity." Thesis, University of Macau, 2017. http://umaclib3.umac.mo/record=b3690809.

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36

Lai, Tik-man Clare, and 賴迪雯. "Circulating biomarkers and right ventricular function in adolescents and young adults with congenital heart disease." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/197541.

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The population of adolescent and adults with congenital heart disease (CHD) has grown rapidly. Right ventricular (RV) dysfunction remains an important issue of concern in the long-term follow up of these patients. While circulating biomarkers have shown promise in the assessment and monitoring of adult patients with left heart diseases, little is known of the role of biomarkers in reflecting RV performance in CHD patients. Emerging circulating biomarkers that reflect underlying pathophysiologic processes have gained increasing attention. These include inflammatory cytokines namely tumour necrosis factor (TNF)-α, a biomarker of apoptosis annexin A5 (AnxA5), carboxy-terminal propeptide of type I procollagen (PICP) and amino-terminal propeptide of type III procollagen (PIIINP) that reflects collagen synthesis and turnover, low circulating levels of cardiac troponin T as detected by highly sensitive assay (hs-cTnT) that may reflect subclinical myocardial injury, and microRNAs found to be involved in cardiac remodeling. The studies in this thesis aimed to test the hypothesis that circulating biomarkers may be altered in patients with volume-overloaded right ventricles after repair of tetralogy (TOF) and pressure-overloaded right ventricles after atrial switch operation for complete transposition of the great arteries (TGA), and are related to indices of RV function. In patients after TOF repair, increased circulating PICP and PIIINP levels were associated with worse subpulmonary RV and left ventricular (LV) function. In particular, these propeptides correlated positively with LV mechanical dyssynchrony, implicating a possible role of increased collagen synthesis in its pathogenesis. Increased plasma levels of hs-cTnT were further found in 30% of female, but not male patients. Female patients with elevated hs-cTnT levels compared to those without had greater RV volumes and LV mechanical dyssynchrony. Independent correlates of hs-cTnT in patients as determined from multivariate analysis were sex and RV ejection fraction. MicroRNA profiling following validation confirmed alteration of circulating levels of miR-99b and miR-766 in repaired TOF patients, a pattern distinct from that reported for left heart diseases. The miRNA expression was, however, not related to the cardiac functional indices. Patients after atrial repair for TGA had significantly higher circulating AnxA5 and TNF-αlevels, but similar PICP, PIIINP levels, compared with controls. Elevated AnxA5 level was associated with impaired systemic RV myocardial deformation, increased subpulmonary ventricular eccentricity, and increased TNF-αlevel. Elevation of hs-cTnT is found in 39% of the patients. The positive correlation between hs-cTnT level and systemic RV volume may suggest a role of hs-cTnT in reflecting RV remodeling. Circulating microRNA expression profiling and further validation identified 11 upregulated microRNAs (miR-16, miR-106a, miR-144*, miR-18a, miR-25, miR-451, miR-486-3p, miR-486-5p, miR-505*, let-7e and miR-93). Among them, miR-18a and miR-486-5p correlated negatively with systemic ventricular myocardial acceleration during isovolumic contraction, a relatively-load independent measure of systemic RV contractility. To conclude, these biomarkers reflect in varying extent the structural, functional, biological alteration of the subpulmonary and systemic right ventricles of the CHD patients late after surgical repair. These data may provide new perspectives in the understanding of progressive RV dysfunction in the adult CHD population and hopefully shed more lights on novel therapeutic interventions.
published_or_final_version
Paediatrics and Adolescent Medicine
Doctoral
Doctor of Philosophy

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37

Cunningham, Clare. "Development of an electronic treatment decision aid for Parkinson's disease using mutli-criteria decision analysis." Thesis, Cardiff University, 2008. http://orca.cf.ac.uk/54501/.

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Clinicians constantly weigh the relative importance of multiple attributes when they make decisions about how to treat patients. The literature shows that this is generally done in a relatively informal manner using intuition rather than evidence-based medicine. Decision analysis methods and computer decision support systems (CDSS) have been developed to help implement evidence-based medicine and to aid clinicians in their decision making. Multi-criteria decision analysis (MCDA) is a methodology used to break complex problems into manageable pieces, allow data and judgement to bear on them and then reassemble them to present an overall picture of the problem. The aim of the study was to use MCDA to develop a model to aid practitioners to choose the most effective drug treatments for Parkinson's disease (PD). A CDSS was developed from this model. Two surveys were sent to 304 neurologists, 88 geriatricians as well as Parkinson's disease nurse specialists across the UK to determine the criteria for the model. The seven steps of developing a MCDA model were carried out. A value tree was created from the criteria established from the surveys. The drugs were scored for their performance against the criteria using data from clinical trials and the weights were determined by the clinician for each individual patient. Software was developed using Excel and Visual Basic for Applications (VBA) to implement the functions of the model. A sensitivity analysis was carried out to determine whether the model was suitable for use with individual PD patients and whether the software was quick and easy to use. A total of 68 criteria were generated from the surveys, which was reduced to 11 This showed that clinicians were perhaps using personal experience more than evidence-based medicine. Scoring the data on the drugs showed that some drugs performed either better or worse than expected. The weights were phrased so that users could use swing-weighting to weight the criteria for their importance to each patient. The combined scores and weights were calculated by Excel and the result returned on the screen to the user by VBA. An expert panel carried out the sensitivity analysis and showed that there were some issues with the scores developed, such as potential bias from the trials data and that not all the expected criteria were included in the model, for example bradykinesia and tremor were not included. However, the expert panel felt that the software was quick and easy to use and overall the principle of the model was approved, subject to some modifications. Therefore, a model was successfully developed for Parkinson's disease using MCDA and a CDSS developed to implement the model's functions. The model needs further refinement but has the potential to be successfully used in a clinical setting. MCDA could additionally be used to develop models for other diseases.

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38

Leung, Cheuk Hung. "Glutamate antagonism as a potential treatment of Parkinson's Disease : a study in a rat model." HKBU Institutional Repository, 2007. http://repository.hkbu.edu.hk/etd_ra/867.

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39

Prescott, Jeffrey William. "Computer-assisted discovery and characterization of imaging biomarkers for disease diagnosis and treatment planning." The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1280194844.

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40

Convey, Rachel Brooke. "Visual Feedback In Voice Therapy for Individuals with Parkinson's Disease." Scholarly Commons, 2019. https://scholarlycommons.pacific.edu/uop_etds/3657.

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Parkinson ’s disease (PD) is a progressive neurological disorder that affects one’s movement. As the disease develops, individuals begin to present with symptoms that include but are not limited to bradykinesia, rigidity, tremors, and hypokinetic dysarthria. These symptoms affect a person’s entire body, including his/her voice. The Lee Silverman Voice Treatment (LSVT) program for treating individuals with PD is supported by over twenty-five years of research. It is considered a safe, non-invasive method to improve vocal loudness and speech clarity in individuals with PD. However, simply because LSVT is effective in its current state, it does not mean that the protocol is the most efficient or effective it can be. One potential shortcoming of LSVT is that it does not provide patients with much, if any, visual feedback. We hypothesized that visual feedback would enable the client to more easily produce a voice characterized by increased loudness and vocal quality. The results of the study do not fully support this hypothesis. There was less variability in the client’s performance within each session during the experimental weeks the patients performance over the course of the week improved, this pattern was not observed during the non-experimental weeks. Additionally, the participant expressed preference for treatment days when the visual feedback was used, finding it helpful in more effectively regulating the volume of his voice.

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41

PASQUINI, JACOPO. "Multimodal Magnetic Resonance Imaging for the identification of early Multiple System Atrophy biomarkers." Doctoral thesis, Università degli Studi di Milano, 2022. http://hdl.handle.net/2434/890787.

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Background. Multiple system atrophy (MSA) is a rare, sporadic disease characterized by autonomic failure and a various combination of parkinsonism and cerebellar dysfunction. Currently, development of new treatment strategies in MSA is hampered by the lack of reliable diagnostic and disease-progression biomarkers. The aim of this study was to investigate brain microstructural abnormalities in MSA through diffusion and neuromelanin-sensitive magnetic resonance imaging (MRI) and their relationship with clinical manifestations. Methods. Clinical evaluation and MRI were performed on 11 MSA patients, 19 Parkinson’s Disease (PD) and 18 healthy controls (HC). MRI scans included structural, diffusion (dMRI) and neuromelanin-sensitive sequences. dMRI was applied through a novel technique, neurite orientation dispersion and density imaging (NODDI). Compared to previous dMRI techniques, NODDI allows the simultaneous evaluation of the integrity of the intracellular and extracellular compartments, while gathering information on the orientation of axons and dendrites. Neuromelanin-sensitive MRI was used to quantitively investigate the integrity of substantia nigra (SN) and locus coeruleus (LC). Results. Median duration of symptoms in MSA patients was 3 years (range 1-6). Age was not significantly different across subgroups. Compared to PD, MSA patients had reduced neurite density index (NDI) in the middle cerebellar peduncle (MCP) and in the pons (Mann-Whitney U=44.0, p=0.019 and U=52.0, p=0.050), indicating white matter degeneration in these locations, and increased free water fraction (FWF), indicating grey matter loss, in the putamen, caudate and cerebellar lobule VI grey matter (U=146.0, p=0.019; U=145.0, p=0.021; U=154.0, p=0.006 respectively). Neuromelanin content was not different in SN and LC between PD and MSA, although this was reduced in the posterior SN and intermediate part of LC compared to HCs (Kruskal Wallis H=11.363, p=0.003 and H=13.788, p=0.001), indicating similar, significant degeneration of these nuclei in both conditions. No significant correlations were found between motor scores and MRI parameters in the SN, putamen, and MCP and pons. LC neuromelanin loss in the rostral and/or intermediate sections was significantly associated with greater cognitive, depressive and REM sleep behaviour disorder (RBD) symptoms scores in MSA. Symptoms of dysautonomia were not associated with diffusion or neuromelanin content measures. Conclusion. Multimodal MRI with diffusion and neuromelanin evaluation may help define structural abnormalities in the early stages of MSA. NODDI seems a promising technique to simultaneously evaluate multiple microstructural parameters in critical locations of MSA pathology, such as the basal ganglia, cerebellum, and pons. Neuromelanin content evaluation is useful for defining SN and LC degeneration, although this occurs similarly in MSA and PD. In MSA, LC degeneration is associated with greater depressive, cognitive and RBD symptoms. Longitudinal investigations are needed to establish whether these MRI parameters may serve as disease-progression biomarkers.

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42

Trepanier, Lisa Laura. "Neuropsychological consequences of pallidal lesions and subthalamic stimulation for the treatment of Parkinsonian patients." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ59157.pdf.

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43

Betts, Matt. "Therapeutic potential of targeting group III metabotropic glutamate receptors as a disease modifying strategy in the treatment of Parkinson's disease." Thesis, King's College London (University of London), 2012. https://kclpure.kcl.ac.uk/portal/en/theses/therapeutic-potential-of-targeting-group-iii-metabotropic-glutamate-receptors-as-a-disease-modifying-strategy-in-the-treatment-of-parkinsons-disease(4771cee9-facd-4257-9e4f-1419dd4416b7).html.

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Parkinson’s disease (PD) is characterised by a progressive loss of dopaminergic neurones from the SNpc, leading to numerous downstream changes in the basal ganglia circuitry. Overactivity of the glutamatergic subthalamonigral pathway may underlie this continual degeneration of the nigrostriatal system. With this in mind, this thesis examined whether selective activation of group III metabotropic glutamate receptor subtypes may offer a novel strategy to halt persistent degeneration in PD. Initial distribution studies revealed mGlu4 and 7 group III mGlu receptor subtypes, demonstrated particularly intense immunoreactivity in the SNpc, suggesting these receptors may be ideally positioned to provide neuroprotective effects. Therefore, the first objective was to confirm this neuroprotective possibility using a broad spectrum agonist, L-AP4. Sub-chronic supranigral L-AP4 treatment mediated functional neuroprotection against a unilateral 6-OHDA lesion of the SN, confirmed by behavioural assessment and post-mortem analyses. Secondly, the pharmacological identity of the group III mGlu receptor mediating this protective effect was examined. To investigate mGlu4 receptors, the novel mGlu4 selective PAM VU0155041, was also shown to provide functional neuroprotection in the 6-OHDA rat model to an almost comparable level reached with L-AP4. Whilst these neuroprotective effects are likely mediated by an inhibition of glutamate to protect from glutamate-mediated excitotoxicity, VU015504 also led to a significant reduction in levels of GFAP and IBA-1 suggesting an additional anti-inflammatory action. Further studies revealed little evidence for co-localisation of mGlu4 receptors with GFAP in the SN suggesting this anti-inflammatory component likely reflects an indirect effect via stimulation of neuronal mGlu4 receptors. Finally, to investigate mGlu7 receptors, the selective allosteric agonist AMN082, was also shown to protect the nigrostriatal tract and demonstrate a degree of preservation of motor function. In contrast, mGlu8 receptor activation using the selective agonist DCPG, failed to protect the nigrostriatal tract or preserve motor behaviour. Collectively, these findings demonstrate that, of the group III mGlu receptors investigated, mGlu4 offers the most potential as a promising target for establishing disease modification in PD.

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44

Chua, Ka Kit. "Randomized controlled clinical trials for the evaluation of efficacy and safety of Chinese medicine in treatment of neurodegenerative diseases." HKBU Institutional Repository, 2015. https://repository.hkbu.edu.hk/etd_oa/231.

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Background: Neurodegenerative diseases (NDD) are very common in the aging population, of which Parkinson’s disease (PD) and Alzheimer disease (AD) are the two most common. Since the etiology of the neuronal death in these diseases remains unclear, currently no curative therapy is available. Traditional Chinese medicine (TCM) has been used to treat certain diseases, which based on their symptoms we now know that they are included PD and AD, for thousands of years. However, our pervious systematic review reports that the quality of current TCM clinical trials related to this area had limited internal validity due to methodological flaws and insufficient data reporting. Methods: This study includes two add-on double-blinded randomized controlled trials (RCT), PD full-scale study and AD pilot study. It aims to provide evidence for the efficacy and safety of two specific TCM decoctions, Jia-Wei-Liu-Jun-Zi Tang (JWLJZT) and Di-tan decoction (DTD) in treating PD and AD, respectively. These clinical trials follow the Consolidated Standards of Reporting Trials (CONSORT) as well as the International Conference on Harmonization guidelines on Good Clinical Practice (GCP). Also, this two RCT obtained the approval from the Human and Animal Research Ethics Committee of Hong Kong Baptist University before the study and registered on the Chinese Clinical Trial Registry. Result: In the PD trial, 111 idiopathic PD patients were randomly assigned to receive either JWLJZT or placebo for 32 weeks. Although there was not significant difference in the primary outcome of Movement Disorder Society Sponsored Revision of Unified PD Rating Scale (MDS-UPDRS) Part I total score (p = 0.216), significant improvements was observed in the secondary outcome of Non-motor symptom assessment scale for Parkinson’s disease (NMSS) total score (p = 0.019), subtype of mood/cognition (p = 0.005) and hallucinations (p = 0.024). In addition, post-hoc analysis showed a significant reduction in constipation (p < 0.001). On the other hand, 40 AD patients were randomly assigned to receive either DTD or placebo for 24 weeks in the AD trial. There was an improvement trend in the primary outcome of the cognitive subscale of Alzheimer’s Disease Assessment Scale (ADAS-cog) total score in the DTD group though the difference relative to the placebo group was not statistically significant (p = 0.315). No significant difference was found in the secondary outcomes. Adverse events were mild and comparable between treatment and placebo groups in both trials. Discussion: JWLJZT did show some improvement in non-motor symptoms, including mood, cognition, and constipation, in PD patients, while, DTD did show a reducing trend in the cognitive impairment based on rigorous RCT. Further study focusing on the effective dosage, pharmacologic mechanism of JWLJZT and DTD are needed to give a fuller picture as well as better support for using them in human being as a routine treatment. In fact, JWLJZT and DTD are the only two examples of TCM for treating NDD. These two clinical trials are served as examples of how to evaluate efficacy and safety of TCM for the treatment of various diseases using rigorous RCT methods and standard. Keywords: Randomized Controlled Trials, Parkinson’s disease, Alzheimer disease, Traditional Chinese medicine, Jia-Wei-Liu-Jun-Zi Tang, Di-tan decoction, Efficacy, Safety

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45

Lui, Nga Ping. "Endogenous neuroprotective mechanisms in early stages of rat parkinsonism." HKBU Institutional Repository, 2011. http://repository.hkbu.edu.hk/etd_ra/1251.

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46

Lin, Kaili. "Neural stem cells as therapeutic agents for treatments of Parkinson's disease in rat model." HKBU Institutional Repository, 2019. https://repository.hkbu.edu.hk/etd_oa/692.

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Parkinson's disease (PD) is the second most common neurodegenerative disease. With the rapid global increase in population aging, neurodegenerative diseases are considered a primary threat to human health. As dopaminergic neuronal cell death and dysfunction are the main pathogenic mechanisms of PD, neural stem cell (NSC) replacement therapy has been identified as a potentially effective and indeed ideal therapeutic strategy. However, current in vitro stem cell culture methods, which require various chemical growth factors (GFs), are unsafe and relatively inefficient. To solve this problem, we developed two strategies for enhancing the proliferation and differentiation of NSCs in vitro based on extracellular nanomatrices and natural active ingredients. First, we developed novel nanomatrices comprising biomaterials used for promoting NSCs proliferation and differentiation without requiring additional GFs. We developed two types of inorganic sculptured extracellular nanomatrices comprising SiO2 (iSECnMs) which deposited by glancing angle deposition (GLAD). The physiological properties of nanomatrices mediate the activation of multiple bio-signaling pathways. Accordingly, iSECnMs, especially those sculptured in zigzag forms, can significantly promote the proliferation and specific neuronal phenotypic differentiation of NSCs without requiring additional GFs. The differentiated neurons survived well in vivo and achieved outstanding therapeutic effects in a rat model of 6-OHDA-induced parkinsonism. Second, 20(S)-protopanaxadiol (PPD) and oleanolic acid (OA), two crucial active ingredients derived from ginseng, significantly enhanced the proliferation and neuronal differentiation of NSCs through activating Wnt/GSK-3β/β-catenin pathway. This research is expected to promote significant developments in the induction of NSCs and provide insights into stem cell therapies for PD without undesirable prognoses

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47

Liu, Liangfeng. "Pharmacological study of tianma gouteng yin: a traditional Chinese medicine formula for Parkinson's disease." HKBU Institutional Repository, 2015. https://repository.hkbu.edu.hk/etd_oa/197.

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Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting 2% of the population over 65 years old that lacks effective cure. The current available treatments for PD are largely symptomatic and palliative. Tianma Gouteng Yin (TGY) is a traditional Chinese medicine (TCM) formula belongs to the formulas that dispel wind. Nowadays, it has been a commonly prescribed formula to treat Parkinsonian-like symptoms such as tremor and paralysis in some of the patients. However, just as most of the TCM formula, the material basis and the underlying pharmacological effects of TGY are still lacking experimental evidence. In this study, a method using UHPLC/Q-TOF-MS and HPLC-ELSD has been developed and successfully applied to qualitatively and quantitatively determine the complex phytochemicals of TGY. Totally 28 phytochemicals were identified, of which 20 were simultaneously quantified. The material basis profile of TGY decoction was delineated for the first time. After full component analysis of TGY, the neuroprotective activity of TGY was verified both in vivo and in vitro. In Drosophila PD models, TGY mitigated rotenone induced toxicity and promoted α-synuclein clearance. In stereotaxic rotenone intoxication rats, TGY exerted neuroprotective effects in terms of preventing dopaminergic neurons loss and alleviating neuroinflammation. TGY alleviated rotenone induced apoptosis in SH-SY5Y cells. Furthermore, we discovered that Geniposide, an important component of TGY, is an autophagy inducer both in vivo and in vitro and is neuroprotective in transgenic Drosophila PD model. In general, our study proves that TGY is neuroprotective in PD models. In addition to the efficacy study, safety of TGY application in terms of TGY-drug interaction was also evaluated. In our study, herb-drug interactions between TGY and one of the most popular drugs used in PD treatment, Sinemet, were studied. The pharmacokinetics data showed that co-administration of TGY could suppress the absorption of Levodopa, the main component of Sinemet, for the first time. This information suggest that in clinical practice, TGY should avoid been administrated with Levodopa containing medicaments at the same time. In conclusion, the data of this study provides valuable information on the material basis, efficacy and safety of TGY. This information is useful reference for the clinical application of TGY in PD treatment. Keywords: Tianma Gouteng Yin, Parkinson’s disease, Drosophila, Rotenone, -synuclein, Geniposide, Autophagy, Sinemet, Herb-drug interaction

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48

CARLI, GIULIA. "Parkinson’s disease and dementia in the α-synuclein spectrum: the role of cognitive assessment and in vivo neuroimaging biomarkers". Doctoral thesis, Università Vita-Salute San Raffaele, 2021. http://hdl.handle.net/20.500.11768/122897.

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Parkinson’s disease (PD) is the neurological disease with the fastest growing rate. 1% of the world population over 60 years have a PD diagnosis. PD presents a complex and heterogenous clinical picture during the disease course, and dementia represents the most severe condition. This thesis investigates the neurobiological mechanisms and cognitive features of PD patients with a severe clinical phenotype – developing cognitive deterioration, reaching dementia condition. The studies included in this dissertation contributed to identifying risk factors, biomarkers, cognitive features, and sources of clinical variability of dementia in Lewy Bodies disorders (LBD) with multiple methodological approaches to neuroimaging data. Moreover, the cognitive picture of the LBD clinical spectrum has been explored by combining cross-sectional and longitudinal approaches. This dissertation provides new evidence on modifiable and non-modifiable risk factors that influence the development of severe phenotypes within LBD and those acting on the timing of dementia symptoms onset. Moreover, we identify valuable biomarker and cognitive marker candidates for dementia risk profiling since early preclinical stages.
La malattia di Parkinson è la malattia neurologica con il tasso di crescita più rapida. L'1% della popolazione mondiale oltre i 60 anni ha una diagnosi di Parkinson. Il morbo di Parkinson presenta un quadro clinico complesso ed eterogeneo durante il decorso della malattia, di cui la demenza rappresenta la condizione più grave. Questa tesi indaga i meccanismi neurobiologici e le caratteristiche cognitive dei pazienti affetti da Malattia di Parkinson con un grave fenotipo clinico – che sviluppano un deterioramento cognitivo raggiungendo la condizione di demenza. Gli studi inclusi in questo elaborato hanno contribuito a identificare fattori di rischio, biomarcatori, caratteristiche cognitive e fonti di variabilità clinica della demenza nei disturbi a corpi di Lewy (LBD) con molteplici approcci metodologici ai dati di neuroimaging. Inoltre, è stato esplorato il quadro cognitivo dello spettro clinico LBD combinando approcci cross-sectional e longitudinali. Questa tesi fornisce nuove evidenze sui fattori di rischio modificabili e non modificabili che influenzano lo sviluppo di fenotipi gravi all'interno della LBD e sui fattori che agiscono sui tempi di insorgenza dei sintomi della demenza. Identifica inoltre validi candidati biomarcatori e marcatori cognitivi per la profilazione del rischio di demenza sin dalle fasi precliniche.

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49

Chen, Leilei. "The molecular mechanism of Chinese medicine Uncaria Rhynchophylla (gouteng) for inducing autophagy and protecting neurons in Parkinson's disease." HKBU Institutional Repository, 2015. https://repository.hkbu.edu.hk/etd_oa/204.

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Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by the accumulation of protein aggregates (namely Lewy bodies) in dopaminergic neurons in the substantia nigra region of the brain. Alpha-synuclein (α- syn) is the major component of Lewy bodies (LBs) in PD, and impairment of the autophagy-lysosomal pathway has been linked to its accumulation. In our previous study, we identified corynoxine B (Cory B), an oxindole alkaloid isolated from Uncaria rhynchophylla (Miq.) Jacks (Gouteng in Chinese), as a Beclin-1-dependent autophagy enhancer. In this work, we continued to screen autophagy enhancers from Gouteng alkaloids, and found corynoxine (Cory), an isomer of Cory B, also induces autophagy in different neuronal cell lines and primary neurons. Meanwhile, Cory promotes the formation of autophagosomes in the fat bodies of Drosophila. By inducing autophagy, Cory promotes the clearance of wild-type and A53T α-syn in inducible PC12 cells. Interestingly, different from its enantiomer Cory B, Cory induces autophagy through the Akt/mTOR pathway as evidenced by the reduced levels of phospho-TSC2, phospho-Akt, phospho-mTOR and phospho-p70 S6 Kinase. To identify the different pathway between Cory and Cory B, we performed phosphoproteomic study on N2a cells. With the help of iGPS (In vivo Group-based Prediction System), protein kinases which were significantly regulated by Cory or Cory B were predicted. Based on these kinases, we drew the detailed kinasesubstrates network regulated by Cory or Cory B. The structures of Cory and Cory B differ only in the stereochemistry at the spiro carbon; however, Cory has more effect on the CAMK, Trb and TSSK families, while CDK and CDKL families are more sensitive to Cory B. Furthermore, we established a rotenone rat model of PD via injecting rotenone into the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA), and evaluated the neuroprotection of Cory and Cory B on this rat model. Motor dysfunction, decreased TH level, impairment of autophagy, aggregation of α-syn and activation of microglia were all found on this PD model, which were consistent with previous reports. After the treatment of Cory or Cory B, we found that both Cory and Cory B improve motor dysfunction, increase the TH level, and inhibit microglial activation. Both Cory and Cory B decrease the puncta number of aggregated α-syn, likely due to the induction of autophagy. All these results indicate the neuroprotection of Cory and Cory B against PD. Collectively, our findings (1) provide the original finding of Coy to be an autophagy enhancer with experimental evidences that Cory inhibited the pathway of Akt/mTOR; (2) provide cellular and animal experimental evidences for developing Cory or Cory B as anti-PD agent, by inducing autophagy in neurons; and (3) provide candidate pathways to identify the primary molecular target of Cory or Cory B, which may turn out to be potential therapeutic targets for treating PD. Keywords: Parkinson’s disease, Cory, Cory B, autophagy, phosphoproteomic, neuroprotection.

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50

Kum, Wan Fung. "Evaluation of effects of the Chinese herbal medicine jia wei liu jun zi granules on the treatment of idiopathic Parkinson's disease : a randomized, double-blind, placebo-controlled pilot study." HKBU Institutional Repository, 2008. http://repository.hkbu.edu.hk/etd_ra/1016.

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