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A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / Previous studies have shown that Parkinson’s disease (PD) patients are at an increased risk for a variety of complications impacting health related quality of life (HRQoL). Additionally, these various complications often lead to increased healthcare utilization. Wellness intervention in PD has shown to be effective in improving HRQoL and objective measures of disease burden such as motor functioning. What has not been demonstrated to date is whether patients who are given the opportunity to participate in regularly administered classes in these modalities will continue to attend and whether benefits will continue to be realized outside the strict confines of a controlled trial. This study examined whether intervening early in PD with a comprehensive Wellness Program is feasible and promotes lasting habits that will continue to provide sustained benefit. It was hypothesized that intervening early in PD with an intensive program involving structured exercise, socialization and PD specific education would serve to maintain or improve subject’s quality of life while decreasing healthcare utilization. Twenty‐one consenting ambulatory adult subjects diagnosed with PD within the last five years completed various screenings at baseline and following a required 6‐month Wellness Program intervention. Subjects were assessed at 12 and 18 months if they continued to participate. Patient demographics, disease specific quality of life, objective mobility, healthcare utilization and falls were assessed. Data were collected at Banner Sun Health Research Institute, located in Sun City, Arizona. All p‐values were 2‐tailed and P<0.05 was considered statistically significant. All data analyses were conducted using STATA‐14. Twenty of twenty‐one subjects completed the required 6‐month intervention. Continued participation was 70% at 12 months and 60% at 18 months. Overall HRQoL was stable at 18 months. Significant improvement was seen in patient reported mobility and emotion sub‐areas at 12 months. Communication specific HRQoL was significantly worsened at 12 months. Subjects demonstrated a stable level of physical activity while fatigue was significantly decreased. All objective measures were significantly improved from baseline. Healthcare utilization was decreased by 18 months. A total of 5 falls were reported by 3 subjects during the 6‐month interventional period. This pilot study demonstrates that comprehensive wellness intervention in early PD is feasible, effective, safe and valuable in establishing long‐term beneficial habits while potentially reducing healthcare utilization. The significant long‐term subject participation observed in this study establishes that wellness intervention may be practical for large scale implementation. The results also highlight the importance of addressing communication specific symptoms early in the course of the disease. Ultimately, this study will aid the design and implementation of future PD wellness interventions.

M. Pharm., Faculty of Health Sciences, University of the Witwatersrand, 2009 / Parkinson's disease, primarily defined as the depletion of dopaminergic neurons in the subtantia nigra of the brain, gives rise to severely debilitating motor symptoms. The pharmacological gold standard treatment for the disease, Levodopa , holds great limitations yet still remains the most effective treatment for the disease for the last 40 years. There has been research into novel drug delivery systems for the treatment of the disease that include the development of implantable devices however none have been introduced onto the market. As the neurodegenerative disorder ravages the younger-aged population so the urgency for the effective chronic treatment of the disease escalates. The field of nanotechnology brings promise for the targeted delivery of drugs which is highly sought after in the treatment of central nervous system disorders. A nano-enabled scaffold device (NESD) incorporating dopamine nanoparticles into a polymeric scaffold for implantation into the brain parenchyma may be able to address and overcome the limitations of the current treatment for Parkinson's disease. Investigations performed cellulose acetate phthalate dopamine-loaded nanoparticles, employing an adopted emulsification-diffusion approach, produced particles with a notably high drug entrapment efficiency (63.05±0.354%) and desirable controlled drug release profiles (16.23% in 24hr). The employment of an experimental design, namely the Box-Behnken design, allowed for the attainment of optimized nanoparticles with high zeta potentials (.34.00mV), minimal particle size (197.20nm) and extended mean dissolution times (40.96). Barium chloride was employed to crosslink calcium-alginate scaffolds formulated in an adopted freeze-drying approach. Highly resilient (63.58±5.13) and porous structures (pore sizes of 100-400μm) were developed. A statistical approach employing the Box- Behnken design resulted in the formulation of a candidate barium-alginate scaffold displaying maximum matrix resilience (82.46%) and minimal matrix erosion (18.23%) over in 30 days. In addition, dopamine-loaded nanoparticles were dispersed within the scaffold that formed the NESD with the desired drug release profiles (5.12% in 168hr). Nanosystems of levodopa, nicotine and dopamine nanofibers were preliminary investigated. Drug release profiles for levodopa (4.21%: in 75hr), nicotine (0.42% in 24hrs) and drug entrapment efficiency for the polymeric nanofibers (75-85%) as well as data from scanning electron microscopy, zetasize analysis and drug release studies proved that these systems hold potential for the treatment of the disease and therefore require further investigation. Ex vivo cytotoxic studies carried out on the NESD and it's separate entities proved that the NESD was biocompatible with the white blood (70-80% cell viability in 24hr) and carcinomic brain cells (25% cell viability in 48hr) despite literature reports of dopamine being highly toxic in vivo. Extensive in vivo studies resulted in the development of a protocol for the surgical implantation of the NESD in the parenchyma of the frontal lobe of the rat brain. Scanning electron microscope images showed the gradual bioerosion (26% in 30 days) of the NESD while histological findings of the brain tissue proved clinically insignificant (absence of ischemia or chronic inflammation). Ultra Liquid Performance Chromatography revealed higher concentrations of dopamine in the CSF of rats which received brain implants of the NESD (28%) than in those administered the oral preparation, Sinemet (0.000012%) in 3 days.

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Nanomaterials are widely used as pseudostationary and stationary phases in electrically driven capillary separations. The advantages of nanomaterial incorporation into capillary electrophoresis (CE) are numerous and include tunable sizes, multiple core compositions, flexible injection/introduction methods in separation techniques, and diverse surface chemistry options. Nanomaterials, however, exhibit inherently large surface energies which induce aggregation and as a result, yield unpredictable function in separations. Because nanomaterials can modify buffer conductivity, viscosity, and pH; separation optimization and nanoparticle stability must be considered. Successful incorporation of nanomaterials into reproducible separations requires (1) strict nanomaterial synthetic control and (2) detailed characterization of the nanoparticle in terms of both core material and surface chemistry. For this reason, this dissertation investigates how the surface chemistry on and morphology of gold nanoparticles impact capillary electrophoresis separations. The gold nanoparticle core composition, shape, size, self assembled monolayer (SAM) formation kinetics, and SAM ligand packing density are all evaluated for thioctic acid, 6-mercaptohexanoic acid, or 11-mercaptoundecanoic acid monolayers. Transmission electron microscopy (TEM), 1H NMR, extinction spectroscopy, zeta potential, X-ray photoelectron spectroscopy (XPS), and flocculation studies are used to assess the morphology, surface chemistry, optical properties, surface charge, SAM packing density, and effective stability of carboxylated nanoparticles, respectively. Using these well-characterized nanostructures, applications of gold nanoparticle pseudostationary phases in capillary electrophoresis is studied. Gold nanoparticles functionalized with mixed SAMs composed of thioctic acid and either 6-mercaptohexanoic acid or 6-aminohexanethiol impact the mobility of possible Parkinson's disease biomarkers in a concentration and surface chemistry dependent manner. From these data, a critical nanoparticle concentrations is developed to characterized nanoparticle stability during capillary electrophoresis separations. To understand the function of these and other carboxylated gold nanoparticles, extended DLVO theory is used to model interparticle interactions during electrically driven flow. 11-Mercaptoundecanoic acid functionalized gold nanoparticles suppress current, while 6-mercaptohexanoic acid and thioctic acid functionalized nanoparticles enhance separation current. Nanoparticle aggregation leads to electron tunneling effects between nanoparticles thereby increasing currents in poorly ordered SAMs while highly packed monolayers induce reversible flocculation characteristics and reduce current. In all cases, these effects are dependent on nanoparticle concentrations. Finally, surface chemistry optimized carboxylic acid functionalized gold nanoparticles effect the separation of hypothesized Parkinson's disease biomarkers. SAM composition and surface coverage impact separation efficiency, resolution, and selectivity. These effects are most systematic with well ordered SAMs. To understand the mechanism functionalized gold nanoparticles exhibit during a separation, their zeta potential with and without dopamine are evaluated. Nanoparticle to dopamine mole ratios (i.e. large dopamine concentrations), neutralize the three functionalized gold nanoparticles according to a dose response curve. The positively charged dopamine molecules saturate the negatively charged nanoparticle surfaces and aggregate thereby providing a plausible explanation to the biomarker concentration trends observed in capillary electrophoresis. These and future studies provide a rigorous experimental and theroretical evalauation of how nanoparticle structure impacts their function as pseudostationary phases in separations and other applications.

Doctor of Clinical Neuropsychology/Master of Science / Introduction: Parkinson’s disease (PD) is known to cause detrimental effects to motor function and cognition. The motor effects of the disease in turn impact emotion expression in patients with PD. There is conflicting evidence in research, however, as to whether PD also affects emotion comprehension, and if so, what emotions in particular are affected and across what modalities. This study aimed to investigate the effects of PD on a broad range of skills involved in basic and complex emotion comprehension. Whether these effects extend into other areas associated with emotion processing, such as social cognition and autobiographical memory, was also explored. Methods: Sixteen patients with PD participated in the study along with sixteen control subjects who were matched for age, gender, education level and estimated premorbid intelligence. The PD participants, on average, were in the moderate phase of the disease and taking PD medication, including dopamine. Participants were tested on a range of recognition measures including prototypical and morphed facial expressions with reduced intensity (40 and 80%), emotion prosody, written emotion vignettes, emotional imagery, pictures of emotion, social cognition, and a cued autobiographical memory task. A mood inventory was given, and disease severity and duration were noted. Results: The PD group did not show pervasive deficits in emotion recognition overall. Deficits were demonstrated in prosody recognition, specifically with fearful tones, and in an incongruent prosody task, specifically with angry and neutral tones. The PD group was not able to recognise facial expressions of disgust (mixed intensities) as well as controls, with the result showing a trend toward significance. PD participants were also significantly worse in Theory of Mind (TOM) reasoning but not at another social cognition measure involving recognising social emotions through expressions from the eyes only. There were no differences between the groups across all other tests. Discussion: PD is thought to cause subtle deficits in emotion comprehension which are only elucidated through complex tasks. The effects of PD on complex processing also impact TOM performance, which relies on skills involved in complex emotion recognition. Effects of mood and disease factors on performance were circumscribed. Evidence suggested that the basal ganglia and fronto-striatal connections play a role in emotion comprehension.

La maladie de Parkinson se caractérise entre autres par une dégénérescence progressive des neurones dopaminergiques de la substance noire pars compacta (SNpc) qui innervent le striatum. Cette dégénération entraîne une baisse de la sécrétion de dopamine dans le striatum qui est responsable de la majorité des symptômes moteurs de la maladie de Parkinson. Plusieurs approches ont été étudiées pour le traitement de la maladie de Parkinson : i) restaurer une synthèse de dopamine dans le striatum par une greffe striatale de neurones dopaminergique ou par un transfert striatal de gènes impliqués dans la synthèse de la dopamine ; ii) protéger et stimuler les neurones dopaminergiques survivants dans la substance noire pars compacta des patients ; iii) corriger les déséquilibres de la boucle motrice engendrés par la baisse de stimulation dopaminergique du striatum ; iv) stimuler et recruter des progéniteurs cérébraux pour les faire se différencier en neurones dopaminergiques dans le striatum. Toutes ces approches thérapeutiques peuvent impliquer des transferts de gènes. Les vecteurs dérivés des virus adéno-associés (rAAV) constituent des outils de choix pour le transfert de gènes dans les tissus cérébraux. Par ailleurs, de nombreuses applications nécessitent une régulation de l’expression du transgène. Nous disposons au laboratoire d’un vecteur rAAV inductible à la tétracycline (rAAV-TetON). Nous décrivons dans ce travail : i) le comportement du vecteur rAAV dérivé du sérotype 1 d’AAV utilisant la cassette d’expression TetON (rAAV2/1-TetON) comparé à celui du rAAV2/1 utilisant un promoteur constitutif pour l’expression du transgène (rAAV2/1-pCMV) dans le striatum et le mésencéphale (contenant la substance noire). A l’aide d’un vecteur rAAV2/1-TetON exprimant le GDNF, nous montrons que nous pouvons moduler le niveau d’expression du transgène dans le striatum par la dose d’inducteur administré aux animaux. Par ailleurs, nous montrons que le rAAV2/1-TetON présente dans le striatum une efficacité de transduction moindre que le rAAV2/1-pCMV mais qu’il présente un profil de biosécurité supérieur au rAAV2/1-pCMV car il limite fortement l’expression du transgène hors du striatum. De plus, le rAAV2/1-TetON n’entraîne pas de recrutement de lymphocytes T ni d’activation de la microglie dans le striatum. Lorsqu’il est injecté dans le mésencéphale, le vecteur rAAV2/1-TetON, contrairement au rAAV2/1-pCMV présente une expression préférentielle dans les neurones dopaminergiques de la SNpc et de l’aire tégmentale ventrale (VTA). ii) le comportement des vecteurs rAAV2/1-pCMV et scAAV2/1-pCMV (vecteur « self-complémentaire » permettant une expression du transgène indépendamment de la synthèse du second brin du génome viral) dans la région neurogénique de la zone sous-ventriculaire (ZSV). Nous avons montré que les vecteurs rAAV2/1 infectent efficacement la ZSV et s’y expriment rapidement. Les vecteurs scAAV2/1 s’expriment plus rapidement dans la ZSV que les vecteurs rAAV2/1 (expression maximum à 24h et 48h, respectivement). De plus, les vecteurs rAAV2/1 présentent une efficacité de transfection importante pour les progéniteurs neuraux en prolifération (cellules C, transient amplifying progenitors) et les neuroblastes en migration (cellules A) mais pas pour les cellules souches neurales (cellules B). Nous observons, par ailleurs, que les rAAV2/1 induisent une baisse transitoire de la prolifération de la ZSV. Cet effet est indépendant de l’expression du génome et dépend donc probablement de la capside virale de nos vecteurs. De plus, cette baisse de prolifération n’induit pas d’apoptose. A long terme, nous observons des cellules exprimant le transgène dans la zone granulaire du bulbe olfactif, indiquant que la transduction des progéniteurs de la ZSV n’interfère pas avec leurs capacités de migration et de différenciation. iii) l’efficacité de différents sérotypes de rAAV pour le transfert de gènes dans les cellules progénitrices neurales (NPC) in vitro. Nous avons montré que les rAAV peuvent transduire des NPC mais que l’efficacité spécifique des différents sérotypes testés varie en fonction de la région du cerveau fœtal et de l’espèce dont les NPC sont issues. Par ailleurs, les rAAV induisent une réduction drastique de la prolifération des cultures de NPC dépendante du sérotype de rAAV utilisé mais pas de l’origine fœtale des NPC ou de l’espèce dont elles sont issues.

Thesis (Ph. D.)--University of Massachusetts Amherst, 2009. / Open access. Includes bibliographical references (p. 100-112). Print copy also available.

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