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Development of an Objective Motor Score for Monitoring the Progression and Severity of Parkinson's DiseaseAlbers, Timothy W. 01 January 2011 (has links)
This thesis describes the development of an objective motor score (OMS) of Parkinson's disease that utilizes the Quantitative Motor Assessment Tool (QMAT) developed through efforts by the Intel Corporation and the Kinetics Foundation. Parkinson's disease (PD) is a movement disorder which is a member of a group of neurodegenerative diseases marked by the depletion or impairment of dopamine-producing cells in the brain. Since PD is chronic and degenerative, treatments are intended to either improve the quality of life for sufferers by superficially treating symptoms or slow and ultimately reverse the progression of the disease. No blood test or biomarker exists, so current assessment of the disease relies on a subjective tool called the Unified Parkinson's disease rating scale (UPDRS) which is a coarse scale that requires costly clinical administration and is subject to rater bias. The objective motor score described in this thesis exhibits excellent clinimetric properties, having demonstrated usability, validity, reliability, and responsiveness. It was calibrated to the motor section of the UPDRS, but in addition to high correlation with the motor UPDRS, it demonstrated an excellent ability to track deep brain stimulation treatment levels and to detect improvement in motor function of subjects due to dopaminergic treatment. With an excellent intraclass correlation coefficient, the OMS is a reliable measure and due to the objective nature of the test, it does not suffer from rater bias. Though these results come from the development phase, they suggest that confirmatory studies will firmly establish the excellent properties of the OMS. While further studies are in motion to improve upon the sensitivity of the OMS by exploring metrics of voice recordings and paced tapping tests, the OMS presented here is a complete and usable tool for assessing the severity of PD-related symptoms. In conjunction with the QMAT, it is ready to be used in clinical trials, clinical practice, and even in the homes of patients who suffer from PD. This makes it an invaluable tool that could begin to replace the UPDRS for use in PD research, reducing costs and confounding factors in studies as well as extending their capabilities into the home.
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Biomechanical Assessment of Parkinson's DiseaseKatz, Edward A. 01 January 2010 (has links)
Parkinson's disease is a chronic neurological disorder affecting hundreds of thousands of Americans. The current best practice for assessment of this disease is a clinical examination and subjective rating using the Unified Parkinson's Disease Rating Scale. Such ratings are coarse scaled, subject to rater bias, and costly. Instruments which provide objective measurements of disease state can eliminate rater bias, provide repeatable data, and increase the frequency and responsiveness of subject assessments, expediting the validation of new therapies and treatments. This thesis describes the design and implementation of a battery of bio-mechanical devices suitable for clinical and in home use, including descriptions of the instruments and the functionality of the data acquisition software, as well as the overall system used for data collection. A data analysis algorithm is fully described, and descriptive statistics of pilot data from twenty two subjects are reported. These statistics show promising correlations of time duration metrics with the motor subsection of the UPDRS, as well as good responsiveness to dopaminergic intervention. Data also suggests that these devices have an advantage over previously described devices in the ability to record the full range of motion in standard assessment tasks, thereby providing additional metrics related to hesitations and halts in prescribed movements.
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Quantitative Correlation Analysis of Motor and Dysphonia Features of Parkinsons DiseaseKoduri, Balaram 05 1900 (has links)
The research reported here deals with the early characterization of Parkinson’s disease (PD), the second most common degenerative disease of the human motor system after Alzheimer’s. PD results from the death of dopaminergic neurons in the substantia nigra region of the brain. Its occurrence is highly correlated with the aging population whose numbers increase with the healthcare benefits of a longer life. Observation of motor control symptoms associated with PD, such as gait and speech analysis, is most often used to evaluate, detect, and diagnose PD. Since speech and some delicate motor functions have provided early detection signs of PD, reliable analysis of these features is a promising objective diagnostic technique for early intervention with any remedial measures. We implement and study here three PD diagnostic methods and their correlation between each other’s results and with the motor functions in subjects diagnosed with and without PD. One initial test documented well in the literature deals with feature analysis of voice during phonation to determine dysphonia measures. Features of the motor function of two fingers were extracted in tests titled “Motor function of alternating finger tapping on a computer keyboard” and “Motor function of the index and thumb finger tapping with an accelerometer”, that we objectively scripted. The voice dysphonia measures were extracted using various software packages like PRAAT, Wavesurfer, and Matlab. In the initial test, several robust feature selection algorithms were used to obtain an optimally selected subset of features. We were able to program distance classifiers, support vector machine (SVM), and hierarchical clustering discrimination approaches for the dichotomous identification of non-PD control subjects and people with Parkinson’s (PWP). Validation tests were implemented to verify the accuracy of the classification processes. We determined the extent of functional agreement between voice and motor functions by correlating test results.
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The impact of developmental stress on the functioning and vulnerability of CNS neuronsPienaar, Ilse-Sanet 12 1900 (has links)
Thesis (PhD (Biomedical Sciences. Medical Physiology))--Stellenbosch University, 2008. / The overall objective of this thesis is to provide additional data to assist clinicians and
experimental neurologists alike in the quest for better understanding, more accurately
diagnosing and more successfully treating patients suffering from Parkinson’s disease (PD).
The general theme of the thesis is the interaction between certain environmental stimuli,
including the exposure to adverse events during early central nervous system (CNS)
development and the manifestation of elements of neurodegeneration, whether by means of
neurochemical changes or expressed as a dysfunctional voluntary motor system.
The first chapter provides a general introduction to the research theme of the thesis. This
includes, in particular, a discussion on current understanding concerning the etiology and
clinical profile of PD, the relative contribution made by genetic factors compared to
environmental ones, and current treatment strategies for treating the disease. Mention is also
made of the failure of these therapeutic applications for reversing or protecting against the
disease, due to the side-effects associated with them. The material covered in chapter 1
provides the basis for the more complete discussion concerning these various aspects,
contained in the chapters to follow.
The overall aim was also to characterise the effects of commonly used toxin-induced animal
models of PD, and the extent of vulnerability that the CNS displays towards them. The
destruction of dopaminergic neurons following the administration of 6-OHDA at targeted points
along the nigrostriatal tract is used extensively to model PD pathology in rats and is an
established animal model of the disease. However, mature or even aged animals are mainly
used in these studies, while the effects that the toxin might have on the developing CNS remain
unclear. The study reported in chapter 4 aimed to elucidate some of 6-OHDA’s actions on the
young adolescent (35 days-old) CNS by comparing the motor and biochemical effects of a
unilateral infusion of the toxin into two anatomically distinct basal ganglia loci: The medial
forebrain bundle (MFB) and the striatum. Animals were randomly assigned to receive either a
direct delivery of 6-OHDA (12μg/4μl) into the MFB or an indirect injection, into the striatum.
Although both lesion types were used, the MFB model is considered a more accurate portrayal
of end-stage PD, while the striatum-model better reflects the long-term progressive pathology of
the disease. The different lesions’ effects on motor function were determined by observing
animal’s asymmetrical forelimb use to correct for weigh shifting during the vertical exploration of
a cylindrical enclosure. Following the final behavioral assessment, the concentration of
dopamine (DA) and DA metabolites remaining in the post-mortem brains were determined using
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HPLC electrochemistry (HPLC-EC) and the levels compared between the two groups. The
HPLC-EC results revealed a compensatory effect for DA production and DA turnover on the
lesioned hemisphere side of the toxin-infused animal group. Thus, following 6-OHDA treatment,
there appears to be extensive adaptive mechanisms in place within the remaining dopaminergic
terminals that may be sufficient for maintaining relatively high extracellular and synaptic
concentrations of DA. However, since substantial changes in motor-function were observed, it is
suggested that the capacity of the remaining dopaminergic neurons to respond to increased
functional demands may be limited. In addition, the behavioral results indicate that the distinct
indices relating to different functional deficits depend on the lesioning of anatomically distinct
structures along the nigrostrial tract.
It has long been known that far fewer women are diagnosed with PD than men are. This
seeming protection offered to females against degenerative disease of the CNS may relate to
estrogen, although the hormone’s mechanism of action on the dopaminergic system is poorly
defined. With an estimated 10-15 million women using oral contraceptives (OCs) in the United
States alone, the aim of chapter 2 was to examine the evidence for a possible relationship
between PD and the female reproductive hormone estrogen. A review of the current literature
available on the topic was performed by consulting Medline, and by performing a search of the
case-reports contained within the World Health Organization’s (WHO) International Drug
Monitoring database, for possible PD-related symptoms that may arise from estrogen
replacement therapy (ERT). The results, whilst conflicting, seem to suggest that estrogen
protects women from obtaining the disease, or at least some features of it. Intensive research
efforts are called for, with sufficient power to establish the relationship between ERT and the
onset and development of parkinsonism. Chapter 3 reports on the results obtained from an
experiment that subjected young Sprague-Dawley rats, 35 days of age, to a lower and a higher
dose of 6-OHDA delivered to the MFB. Control rats received equivalent saline infusions. At 14
days post-surgery, the rats were evaluated for forelimb akinesia. For the higher dose of 6-
OHDA the female rats were less impaired than males in making adjustment steps in response
to a weight shift and in the vibrissae-evoked forelimb placing test. In addition, Tyrosine
hydroxylase (TH) immunoreactivity was significantly higher for the female rats. Early gender
differences in cell survival factors and/or other promoters of neuroplasticity may have
contributed to the beneficial outcome seen in the females. For example, nerve growth factor
(NGF) was found to be higher in the female rats following administration of the DA neurotoxin. It
is unclear whether gonadal steroids are involved, and, if so, whether female hormones are
protective or whether male hormones are prodegenerative. Determining the mechanisms for the
improved outcome seen in the young female rats may lead to potential treatment strategies
against PD.
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Many studies have shown that early life stress may lead to impaired brain development, and
may be a risk factor for developing psychiatric diseases, including clinical depression. However,
few studies have investigated the impact that early stress may have on the onset and
development of neurodegenerative disorders such as PD. The study reported on in chapter 5
conjointly subjected rat pups to a maternal separation (MS) paradigm that is a well
characterised model of adverse early life events, and a unilateral, intrastriatal injection of 6-
OHDA. The combined effects of these models on motor deficits and brain protein levels were
investigated. Specifically, the animals were assessed for behavioral changes at 28 days postlesion
with a battery of tests that are sensitive to the degree of DA loss sustained. The results
show that animals that had been subjected to MS display poorer performance in the vibrissae
and single-limb akinesia test compared to non-MS control animals (that had also been
subjected to the toxin exposure). In addition, there was a significant increase in the loss of TH
staining in MS rats compared to non-MS ones. The results from this study therefore suggest
that exposure to adverse experiences during the early stages of life may contribute towards
making dopaminergic neurons more susceptible to subsequent insults to the CNS occurring
during mature stages of life. Therefore, taken together, early exposure to stress may predispose
an individual towards the onset and development of neurodegenerative disease, which
especially becomes a threat during the later stages of adult life.
Moreover, within the framework of these characteristics, the capacity of a widely-used
pharmacological agent (statins) was tested for possible future therapeutic application in PD
(chapter 7). Although the precise cause of sporadic PD remains an enigma, evidence suggests
that it may associate with defective activity of complex I of the mitochondrial electron transport
chain. Mitochondrial DNA transmit and express this defect in host cells, resulting in increased
oxygen free radical production, depressed antioxidant enzyme activities, and greater
susceptibility to apoptotic cell death. Simvastatin is a member of the 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA) reductase inhibitors (statins) group of drugs that are widely used for
lowering cholesterol levels in patients who display elevated concentrations of low-density
lipoprotein cholesterol. The study aimed to investigate the effects that statin-treatment have on
motor-function and at the mitochondrial-protein level, using rotenone, a mitochondrial complex I
inhibitor, as a rat-model of PD. Adult male Sprague-Dawley rats were treated either with
simvastatin (6mg/day for 14 days) or with a placebo. Two different tests to assess motor
function were used: The apomorphine-rotation test, and the vibrissae-elicited forelimb
placement test. Following the drug administration protocol, the nigrostriatal tract was unilaterally
lesioned with either rotenone (3 μg/4 μl) or, for the controls, were sham-operated by infusing the
vehicle (DMSO:PEG) only. Five days later the rats were killed and a highly purified
concentration of isolated mitochondria was prepared from the substantia nigra (SN) sections. 2-
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Dimensional electrophoresis (2-DE) with subsequent identification of the spots using
electronspray ionization quadruple time-of-flight mass spectrometrical (ESI-Q-TOF MS) was
performed and the results BLAST-searched using bio-informatics tools for naming the identified
peptides. The motor test results indicate that while unilateral rotenone causes behavioral
asymmetries, treatment with simvastatin improved motor function relative to the rotenoneinduced
ones. Mass Spectroscopy identified 23 mitochondrial proteins that differ significantly in
protein expression (p < 0.05) following simvastatin treatment. The altered proteins were broadly
classified according to their cellular function into 6 categories, with the majority involved in
energy metabolism. This study effectively illustrated how neuroproteomics, with its sophisticated
techniques and non-biased ability to quantify proteins, provides a methodology with which to
study the changes in neurons associated with neurodegeneration. As an emerging tool for
establishing disease-associated protein profiles, it also generates a greater understanding as to
how these proteins interact and undergo post-translational modifications. Furthermore, due to
the advances made in bioInformatics, insight is created concerning their functional
characteristics. Chapter 4 summarises the most prominent proteomics techniques and discuss
major advances made in the fast-growing field of neuroproteomics in PD. Ultimately, it is hoped
that the application of this technology will lead towards a presymptomatic diagnosis of PD, and
the identification of risk factors and new therapeutic targets at which pharmacological
intervention can be aimed.
The final chapter (chapter 8) provides a retrospective look at the academic work that had
been performed for the purpose of this thesis, recaps on the main findings, and also highlights
certain aspects of the project and provides relevant suggestions for future research. Lastly, the
appendix provides a detailed overview of the methods followed for the experiments described in
this thesis. It provides not only a comprehensive description of the techniques that had been
followed, but provides information concerning the care taken with the animals (i.e. post-surgery)
in order to control for the potential influence of experimental variables on the results.
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A molecular investigation of a mixed ancestry family displaying dementia and movement disordersAbrahams-Salaam, Fatima 12 1900 (has links)
Thesis (MScMedSc (Biomedical Sciences. Molecular Biology and Human Genetics))--Stellenbosch University, 2008. / A South African family of Mixed Ancestry presented with a rapidly progressive dementia and a
movement disorder which affected a number of individuals across three generations. The initial
symptoms included personality changes and tremors that escalated to severe dementia and
eventually a completely bedridden state. It was determined that the mean age at onset was in the
third decade of life and affected individuals died within 10-15 years after the onset of symptoms.
The aim of the present study was to elucidate the genetic cause of the disorder in this family and to
further investigate the patho-biology of the disease.
Mutations that could possibly cause the observed phenotype in this family were screened for. These
included loci implicated in Huntington’s disease, Parkinson’s disease, Dentatorubral-Pallidoluysian
Atrophy, Spinocerebellar ataxias (types 1, 2, 3, 6, and 7), Huntington’s disease-like 2 (HDL2) and
several mitochondrial disorders. Single-strand Conformation Polymorphism (SSCP) analysis and
direct sequencing were used to detect possible mutations while genotyping on an ABI genetic
analyser was used to detect disorders caused by repeat expansions. Haplogroup and Short Tandem
Repeats (STRs) analyses of the Y-chromosome and mitochondrial DNA of one affected family
member was used to determine the family’s genetic ancestry. Reverse transcriptase polymerase
chain reaction (RT- PCR) and complementary DNA (cDNA) analyses of the Junctophlin-3 (JPH3)
gene was performed to provide information on the expression profile of this gene.
After the exclusion of several genetic loci it was shown that this family had HDL2. This is a rare
disease caused by a CAG/CTG repeat expansion in an alternatively spliced version of the JPH3
gene. HDL2 occurs almost exclusively in individuals of Black African ancestry. The genetic ancestry
data suggested that the family member was most likely of South African Mixed Ancestry making this
the first reported family of South African Mixed Ancestry with HDL2. A pilot study investigated the
repeat distribution amongst three South African sub-populations in order to determine whether there
was a bias in the repeat distribution that possibly predisposes Black Africans to develop the disease.
The results showed a statistically significant difference (P= 0.0014) in the distribution of the repeats
between the Black African and Caucasian cohorts. However, no conclusions could be drawn as to
whether Black Africans harboured larger repeats that predisposes them to developing HDL2.
The expanded repeat is located in an alternatively spliced version of the JPH3 mRNA. Interestingly,
this repeat is not present in the mouse homologue of the gene although the rest of the genomic
sequence is highly conserved across the human, mouse and chimpanzee genomes. Using foetal
brain cDNA and PCR primers designed to be specific for different JPH3 isoforms, independent
confirmation of the presence of two JPH3 mRNA transcripts (the full length and a shorter alternatively
spliced version) was provided. In the absence of brain tissue from an HDL2-affected individual, it was
investigated whether both JPH3 mRNA transcripts could be detected in lymphocytes. Using RNA
isolated from the transformed lymphocytes of two HDL2-affected family members, real-time PCR
was attempted. These experiments produced inconclusive results and required further optimisation.
Further RT-PCR experiments for JHP3 expression in different tissues (brain and other) obtained
from HDL2-affected individuals would be of interest.
The present study identified the first Mixed Ancestry family with HDL2. This family will now be able
to request genetic counselling and pre-symptomatic testing for all at-risk family members. Aspects of
this study provided independent confirmation of characteristics of the mutated gene. More research
on HDL2 will be crucial in understanding the pathogenesis of this disease.
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