La maladie de parkinson est une affection neurologique caractérisée par une dégénérescence des neurones dopaminergiques du mésencéphale ventral et une perte de l’innervation dopaminergique striatale à l’origine de symptômes moteurs (akinésie, rigidité et tremblement de repos). L’absence de traitements curatifs s’explique notamment par notre large méconnaissance des mécanismes conduisant à la mort neuronale. De nombreuses données supportent un rôle du système immunitaire inné dans ces processus de dégénérescence. Récemment, plusieurs études ont également suggéré le rôle de la réponse immunitaire adaptative dans ces phénomènes. Ainsi une infiltration cérébrale de lymphocytes T CD4+ est observée chez les patients parkinsoniens. Celle-ci pourrait jouer un rôle délétère dans les mécanismes conduisant à la mort des neurones dopaminergiques comme le suggèrent certaines données in vivo dans des modèles de la maladie. Par conséquent, le blocage de cette infiltration lymphocytaire pourrait constituer une stratégie thérapeutique intéressante pour ralentir la dégénérescence neuronale. Notre hypothèse de travail est qu’un processus actif de remodelage de la barrière hématoencéphalique permettrait aux cellules du système immunitaire adaptatif de pénétrer le parenchyme cérébral. Ainsi les chimiokines et les molécules d’adhésion constituent deux grandes familles de protéines impliquées dans les phénomènes d’infiltration tissulaire des leucocytes en condition inflammatoire. A notre connaissance, aucune étude détaillée des mécanismes permettant l’infiltration cérébrale des lymphocytes dans les syndromes parkinsoniens n’a été réalisée. Afin de tester cette hypothèse, le projet a eu plusieurs objectifs : (1) caractériser l’expression des chimiokines et des molécules d’adhésion dans un modèle murin de lésion du système nigro-strié (2) déterminer le rôle du réseau chimiokinique dans le processus d’infiltration lymphocytaire et la dégénérescence dopaminergique dans ce modèle (3) étudier l’expression des facteurs candidats dans la substance noire des patients parkinsoniens. Dans notre étude, nous avons pu montrer une augmentation d’expression transcriptionnelle et protéique très importante des trois chimiokines CCL3, CCL4 et CXCL10 dans le mésencéphale ventral de souris intoxiquées par le MPTP (un modèle expérimental de maladie de Parkinson). La source cellulaire de ces facteurs était les cellules microgliales pour CCL3 et CCL4 et les astrocytes pour CXCL10. Pour aborder le rôle de ces facteurs dans les processus physiopathologiques, notre stratégie a été de cibler les récepteurs des ligands identifiés, en particulier CXCR3, CCR5 et CCR1. Bien que la déficience constitutive de chacun de ces récepteurs ne confère qu’une faible protection des neurones dopaminergiques et une faible diminution de l’infiltration lymphocytaire, une stratégie de blocage multiple des récepteurs aux chimiokines a permis de réduire l’ampleur de ces deux processus. En outre, nous avons détecté une augmentation d’expression de CCL3 et CCL4 dans la substance noire de patients parkinsoniens. Au total, nos résultats montrent une modulation importante du réseau chimiokinique associée à la réaction gliale dans un contexte de lésion du système nigro-strié et suggèrent que le réseau chimiokinique joue vraisemblablement un rôle important dans le recrutement cérébral des lymphocytes T et la physiopathologie de la maladie de Parkinson. / Study of the molecular mechanisms involved in the cerebral infiltration of lymphocytes T in the Parkinson's disease

Parkinson�s disease is a neurodegenerative disorder, which is typically characterised in terms of its debilitating effects on motor function. However, ubiquitous neuropsychological deficits are also an integral feature of the progression of this disease. This thesis investigated these cognitive deficits as they manifest in language, with the overarching goal being to elucidate the word-finding problems that are associated with Parkinson�s disease. Making semantic judgements and identifying semantic relations are two processes that are particularly germane to word-finding. Therefore, the present thesis examined: 1) the ability of people with Parkinson�s disease to make judgements about semantic categories, and 2) the integrity of associative semantic networks in Parkinson�s disease. In the first series of studies, Cups and Bowls, a novel semantic categorisation task was used to investigate the ability of people with Parkinson�s disease to consistently categorise common kitchen items across a number of trials. The Parkinson�s group was impaired relative to an age-matched control group on this task. This inconsistent categorisation was particularly apparent for the less typical category exemplars at the category boundaries, suggesting that the Parkinson�s group had less salient or less elaborated semantic categories, which particularly compromised categorisation of the less typical category exemplars. This finding is discussed in terms of selective attention deficits and inappropriate weightings of semantic features. In the second series of studies, Verbal Memory, the structure of the semantic network and access to the semantic system were further investigated using a verbal memory task, which required participants to recall word lists. These word lists consisted of semantically associated words and were designed to elicit false recall of another, non-presented, close semantic associate (the critical lure). The results of this second series of studies, particularly the fact that the Parkinson�s group recalled more of the false critical lures than the control group, suggested an intact semantic network in Parkinson�s disease and normal saliency of semantic categories. The potentiated false recall effect in the Parkinson�s group is discussed in terms of poor modulation of attention in Parkinson�s disease, both as the result of an executive deficit leading to poor controlled processing and in terms of a dopamine-modulated decrease in the signal-to-noise ratio leading to impaired automatic processing. Taken together, the results reported in the present thesis suggest that basal ganglia pathology and striatofrontal deafferentation in Parkinson�s disease do not diminish the integrity of semantic memory, but do compromise operation of semantic memory due to impaired modulation of activation/inhibition mechanisms. This finding of a selective attention deficit has implications for word-finding, suggesting that the word-finding difficulties associated with Parkinson�s disease are the result of impaired lexical access. In particular, retrieval of specific lexical items from semantic memory is impeded because of failure to modulate activation/inhibition mechanisms effectively for the target word to be distinguished from close semantic associates. An intact semantic checking mechanism in anterior language cortex prevents the production of semantic paraphasias, and results in the tip-of-the-tongue word-finding problems displayed by some people with Parkinson�s disease.

The current study examined cognitive effects of unilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) patients. Neuropsychological evaluations were conducted at baseline and follow-up. Data was collected from 28 unilateral STN DBS patients (15 English- and 13 Spanish-speaking), and 15 English-speaking matched PD control patients. English-speaking DBS patients demonstrated significant declines in verbal fluency and attention/executive function, whereas PD control patients did not experience significant cognitive decline. Cognitive performance did not differ based on side of DBS. Spanish-speaking DBS patients experienced significant declines in verbal fluency, confrontational naming and visuospatial abilities. Among Spanish-speaking DBS patients, older age and later age of disease onset predicted verbal fluency decline, even after controlling for education.

Thesis (Ph. D.)--Ohio State University, 2006. / Title from first page of PDF file. Includes bibliographical references (p. 124-131).

It is well established that there are many intrinsic and extrinsic risk factors associated with falls in older adults. Less well-known is what risk factors predict falls in more vulnerable populations, such as those with neurological conditions living in long-term care homes or receiving home care services. Furthermore, evidence comparing those with neurological conditions to those without is lacking in the literature. The primary purpose of this thesis was to determine risk factors for falls in long-term care residents and home care clients with no recent history of falls to determine if risk factors differed between individuals with dementia or Parkinson’s disease and those without any neurological conditions. Secondary data analysis was performed on a database of standardized health assessments completed for long-stay home care clients and long-term care residents in Ontario. Within each major diagnostic group, observations were stratified based on ambulatory status (ambulatory vs. non-ambulatory). Bivariate analyses followed by generalized estimating equations were used to determine statistically significant predictors of falls in each group within each care setting. The results of multivariable analyses showed that there is not a distinct set of risk factors associated with falls in home care clients and long-term care residents with dementia or Parkinson’s disease that is systematically different from risk factors associated with falls in clients and residents not diagnosed with any of the neurological conditions in this study. These results suggest that a common set of risk factors may effectively predict falls in all clients and residents with no recent falls history, regardless of certain neurological diagnoses.

Parkinson’s disease (PD) is the most common movement neurodegenerative disease affecting approximately 1% of the population over 60. Though originally thought to be sporadic in nature, a genetic component is increasingly being linked to the disease. Of these genes, mutations in DJ-1 (PARK7) cause early onset autosomal recessive PD. Initial workup of the DJ-1 protein has suggested that it may act in the cell by combatting oxidative stress though the mechanism by which it does so is unclear. Thus, though much work has attempted to elucidate a function at the biochemical, cellular and organismal level, the overt physiological role of DJ-1 remains elusive. In this dissertation, we explore the mechanisms through which DJ-1 confers neuroprotection, particularly in the case of oxidative stress insult. We demonstrate that DJ-1 acts through the pro-survival protein AKT to accomplish its neuroprotective function. Moreover, we note that DJ-1 likely serves its role as an antioxidant through the NRF2 master antioxidant regulator pathway a pathway that is, itself, likely to be regulated by AKT. Together, our results demonstrate that neuroprotection by DJ-1 is done through a signaling pathway involving both AKT and NRF2 and that disruption of the former in PD likely results in abolishing this signaling pathway. Finally, to generate a better animal model of PD, we demonstrate that backcrossing DJ-1 null mice - which originally did not demonstrate any gross histopathological or behavioral phenotypes – display unilateral dopaminergic degeneration that progresses to bilateral degeneration with aging, a feature reminiscent of classical PD progression. Collectively, this thesis takes a two-sided approach to address the biochemical and physiological functions of DJ-1 within the cell and the mouse in hopes of elucidating mechanisms of neuronal death to devise better translational therapies.

The enzyme CYP2D6 can metabolize many centrally acting drugs and endogenous neural compounds (e.g. catecholamines); it can also inactivate neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1,2,3,4-tetrahydroisoquinoline (TIQ) and β-carbolines that have been associated with Parkinson’s disease (PD). CYP2D6 is ideally situated in the brain to inactivate these neurotoxins. The CYP2D6 gene is also highly polymorphic, which leads to large variation in substrate metabolism. Furthermore, CYP2D6 genetically poor metabolizers are known to be at higher risk for developing PD, a risk that increases with exposure to pesticides. Conversely, smokers have a reduced risk for PD and smokers are suggested to have higher brain CYP2D6 levels. Our studies furthered the characterization and involvement of CYP2D6 in neuroprotection against PD. METHODS: We investigated the effects of CYP2D6 inhibition on MPP+-induced cell death in SH-SHY5Y human neuroblastoma cells. We compared levels of brain CYP2D6, measured by western blotting, between human smokers and non-smokers, between African Green monkeys treated with saline or nicotine, and between PD cases and controls. In addition, we assessed changes in human brain CYP2D6 expression with age. RESULTS: Blocking CYP2D6 activity in SH-SY5Y cells with four diverse inhibitors significantly increased MPP+-induced neurotoxicity. Smokers have higher brain CYP2D6 compared to non-smokers. In monkeys, basal expression of CYP2D6 varied across brain regions and was increased by chronic nicotine treatment in select regions (notably the basal ganglia) and specific cell types. Expression of human brain CYP2D6 increased from fetal to 80 years of age in the frontal cortex; the influence of age on CYP2D6 expression was brain region specific. Compared to age-matched controls, PD cases had ~40% lower CYP2D6 levels in the frontal cortex, cerebellum and hippocampus consistent with lower CYP2D6 increasing the risk for PD. In the caudate and substantia nigra, CYP2D6 levels were similar between PD case and controls using Western blotting. This is likely due to the increase in CYP2D6-expressing astrocytes and much higher cellular CYP2D6 in PD affected areas as observed with immunocytochemical staining. CONCLUSIONS: Brain CYP2D6 can meaningfully inactivate neurotoxins, and it can be increased by nicotine in brain regions of interest to PD. These findings support the contention that higher brain CYP2D6 is protective and lower levels may contribute to increased risk for PD.

The enzyme CYP2D6 can metabolize many centrally acting drugs and endogenous neural compounds (e.g. catecholamines); it can also inactivate neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1,2,3,4-tetrahydroisoquinoline (TIQ) and β-carbolines that have been associated with Parkinson’s disease (PD). CYP2D6 is ideally situated in the brain to inactivate these neurotoxins. The CYP2D6 gene is also highly polymorphic, which leads to large variation in substrate metabolism. Furthermore, CYP2D6 genetically poor metabolizers are known to be at higher risk for developing PD, a risk that increases with exposure to pesticides. Conversely, smokers have a reduced risk for PD and smokers are suggested to have higher brain CYP2D6 levels. Our studies furthered the characterization and involvement of CYP2D6 in neuroprotection against PD. METHODS: We investigated the effects of CYP2D6 inhibition on MPP+-induced cell death in SH-SHY5Y human neuroblastoma cells. We compared levels of brain CYP2D6, measured by western blotting, between human smokers and non-smokers, between African Green monkeys treated with saline or nicotine, and between PD cases and controls. In addition, we assessed changes in human brain CYP2D6 expression with age. RESULTS: Blocking CYP2D6 activity in SH-SY5Y cells with four diverse inhibitors significantly increased MPP+-induced neurotoxicity. Smokers have higher brain CYP2D6 compared to non-smokers. In monkeys, basal expression of CYP2D6 varied across brain regions and was increased by chronic nicotine treatment in select regions (notably the basal ganglia) and specific cell types. Expression of human brain CYP2D6 increased from fetal to 80 years of age in the frontal cortex; the influence of age on CYP2D6 expression was brain region specific. Compared to age-matched controls, PD cases had ~40% lower CYP2D6 levels in the frontal cortex, cerebellum and hippocampus consistent with lower CYP2D6 increasing the risk for PD. In the caudate and substantia nigra, CYP2D6 levels were similar between PD case and controls using Western blotting. This is likely due to the increase in CYP2D6-expressing astrocytes and much higher cellular CYP2D6 in PD affected areas as observed with immunocytochemical staining. CONCLUSIONS: Brain CYP2D6 can meaningfully inactivate neurotoxins, and it can be increased by nicotine in brain regions of interest to PD. These findings support the contention that higher brain CYP2D6 is protective and lower levels may contribute to increased risk for PD.

As wireless devices are becoming more powerful, more flexible and less costly to produce, they are often being applied in new ways. Combining wireless technology with new types of sensors results in the ability to monitor and control the environment in ways not previously possible. For example, an intelligent wireless sensor system that consists of a sensor, digital processor and a transceiver can be mounted on a board the size of a coin. The data collected by these devices are then transmitted to a central unit which is able to thoroughly process and store this data. Not only can the central processing station provide reports about certain physical parameters in the environment, it can also control the environment and other parameters of interest. The design process of these wireless sensor platforms is a well-developed area of research that covers concepts like networking, circuit design, Radio-Frequency (RF) circuits and antenna design. The design of a wireless sensor can be as simple as putting together a microcontroller, a transceiver and a sensor chip or as complicated as implementing all the necessary circuitry into a single integrated circuit. One of the main applications of the sensors is in a control loop which controls physical characteristics in an environment. Specifically, if the objective of a control system is to limit the amount of vibrations in a structure, vibration sensors such as accelerometers are usually used. In environments where the use of wires is costly or impossible, it makes sense to use wireless accelerometers instead. Among the numerous applications that can use such devices are the automotive and medical vibration control systems. In the automotive industry it is desirable to reduce the amount of vibrations in the vehicle felt by the passengers. These vibrations can originate from the engine or the uneven road, but they are damped using passive mechanical elements like rubber, springs and shocks. It is possible however, to have a more effective vibration suppression using active sensor-actuator systems. Since adding and maintaining wires in a vehicle is costly, a wireless accelerometer can be put to good use there. A medical application for wireless accelerometers can be used with a procedure called Deep Brain Stimulation (DBS). DBS is a relatively new and very effective treatment for advanced Parkinson’s disease. The purpose of DBS is to reduce tremors in the patients. In DBS a set of voltages is applied to the brain of the patient as some optimum combinations of voltages will have a very positive effect on the tremors. Those optimum voltages are currently found by trial and error while a doctor is observing the patient for tremors. Wireless accelerometers with the use of a computer algorithm can assist in this process by finding the optimum voltages using the feedback provided by the accelerometers. The algorithm will assist the doctor in making decisions and has the potential of finding the optimums completely on its own.

Microglia have the potential to produce specific neurotrophic molecules in response to injury and brain diseases. Activated microglia are seen after brain injury or in neurological disease, such as Parkinson¡¦s disease (PD). PD is a progressive neurodegenerative disorder. Although its cause remains unknown, it is believed that enhanced oxidative stress is a major component in the pathogenesis of nigral cell death in PD. Previous results have shown that DA induces apoptosis of dopaminergic neurons in a time- and concentration- dependent manner. In addition, a number of studies have shown that Zn2+ may enter the cell to reach toxic concentrations and that Zn2+ concentration is higher in the striatum of the postmortem brains of PD patients than that of the control brains. We have previously shown that Zn2+ synergistically enhanced the dopamine- and H2O2- induced PC12 cell death. To study the role of microglia in the cell death, I have examined the effect of conditioned medium from a human microglia cell line on the PC12 cell death induced by dopamine and Zn2+. The result shows that conditioned medium inhibits the PC12 cell death and the phosphorylation of JNK induced by dopamine and Zn2+ is diminished by the conditioned medium. It appears that the factor(s) that are responsible for the protection is heat-stable because the conditioned medium heated in 70¢Jfor 30 minutes still has the ability to protect the cell death. Cell death induced by A23187 and C2-ceramide, but not by staurosporine can be protected by the conditioned medium. Results from this study suggest that the microglia secrete some factors which can protect neuron.