L’objectif de cette recherche est d’étudier les processus d’activation et d’inhibition lexico-émotionnelles dans le vieillissement. Plusieurs études suggèrent un déficit des processus d’activation et d’inhibition lexicales lors de l’avancée en âge. Cependant, de nombreux travaux évoquent l’hypothèse d’une meilleure régulation émotionnelle dans le vieillissement visant à maintenir un bien-être subjectif constant. Ce maintien du bien-être subjectif entrainerait chez les adultes âgés, une sensibilité accrue envers les stimuli positifs tandis que les stimuli négatifs seraient désengagés. Dans cette thèse, il s’agit de préciser les processus d’activation et d’inhibition lexico-émotionnelles en présence d’un contexte fortement prédictible lors de tâches impliquant la complétion de phrases (Expérience 1, 2a) ou la reconnaissance des mots (Expérience 3a). Globalement, les résultats suggèrent une atteinte conjointe des processus d’activation et d’inhibition lexicales chez les adultes âgés comparés aux adultes jeunes, ainsi qu’un traitement privilégié de la valence positive des mots, tandis que les mots négatifs semblent désengagés. Dans un second temps, nous avons testés l’hypothèse d’une mobilisation de l’attention spécifique en fonction de l’âge et de la valence des mots à un niveau automatique (Expérience 4, 5a) ainsi que lors de la mobilisation attentionnelle volontaire (Expérience 6). Les résultats suggèrent une mobilisation attentionnelle à un niveau automatique mais aussi contrôlé envers les stimuli positifs dans le vieillissement normal. Dans l’ensemble, les données obtenues sont compatibles avec la littérature suggérant chez les adultes âgés une diminution de l’efficience des processus d’activation et d’inhibition lexicales, ainsi qu’une régulation émotionnelle effective qui s’étend au domaine du langage. La compréhension des processus lexico-émotionnels dans le vieillissement normal pourrait être étendue aux pathologies du vieillissement telle la maladie de Parkinson (Expériences 2b, 3b et 5b) afin de mieux comprendre le rôle et l’évolution du système affectif dans ces pathologies. / The aim of this research is to study lexico-emotional processes of activation and inhibition in aging. Studies suggest that normal aging is characterized by lexical activation and inhibition impairment. Nonetheless, recent findings showed that emotional regulation tend to enhance with aging in order to maintain subjective well-being effective. This subjective well-being could enhance sensitivity in older adults toward positive stimuli whereas negative ones could be disengaged. We investigate lexico-emotional activation and inhibition processing with high predictable sentence context in a sentence completion task (Experiment 1, 2a) and in word recognition (Experiment 3a). As a whole, results indicate in older adults both activation and inhibition impairment, and also better performances toward positive stimuli whereas negative ones seem to be disengaged compared to younger ones. Furthermore, we hypothesized an automatic attention allocation (Experiment 4, 5a) and a voluntary attention allocation (Experiment 6) toward positive stimuli than negative. Results obtained reported an attentional bias toward positive stimuli in aging. Generally, it seems that our results are in line with literature concerning both-damage of lexical activation and inhibition processes, and also in the enhancement of positive stimuli treatment in aging. Understanding of lexico-emotional processing in normal aging could be extended to pathology like Parkinson’s disease (Experiments 2b, 3b and 5b) in order to understand affective system role’s in pathological aging.

Participation is generally considered the ultimate rehabilitation outcome and, for individuals with progressive illnesses, elucidating the factors that impact participation is critical. Parkinson’s disease (PD) is a chronic degenerative, neurological condition affecting nearly 1 million people in the United States, making PD the second most prevalent neurodegenerative disorder. PD has a profound negative effect on functioning and activity, but limited literature exists assessing the relationship between PD and community participation. The purpose of this study was to use the World Health Organization (WHO) International Classification of Functioning, Disability, and Health (ICF) as a framework for explaining how PD affects participation. Additionally, because the ICF explains the impact of chronic illness and disability as consisting of interactions between different contextual and disease-related factors, this investigation also addressed whether the personal factors, Positive Psychological Capital (PsyCap), mediated the relationship between functioning with PD and community participation. A total of 114 individuals were surveyed from peer-led PD support groups in a Midwestern state. The study examined the individual and collective contributions of demographic characteristics, activities/functioning, environmental factors, and personal factors on community participation. Results from the hierarchical regression analysis suggest that demographic characteristics account for only 15% of the variance in participation, but when functioning was added to the model, 65% of the variance was accounted for. The addition of environmental and personal covariates did not result in any significant change in overall variance in participation. These results, along with the strong, positive linear correlations between functioning and participation (r = .78), indicate that functioning largely predicts an individual’s participation. The study also sought to identify any mediating effect of personal factors (PsyCap) on the relationship between functioning and participation. The results indicated that the completely standardized indirect coefficient was not significant, b = .065, SE = .0617, 95% CI = -.213, .029, with 0 falling within the CI, which confirms no significant effect of the mediator PsyCap. The study contributes new knowledge to the association between the symptoms associated with PD and one’s community participation. Clearly, functioning is the primary predictor of participation. The lack of mediation of PsyCap, again, supports the strength of the relationship between functioning and participation. Although PsyCap did not mediate the relationship, implications for future research are discussed.

La maladie de Parkinson est une maladie neurodégénérative dont la physiopathologie fait intervenir des causes génétiques qui contribuent non seulement aux formes familiales mais aussi au développement des formes sporadiques, les plus fréquentes, en interagissant sans doute alors avec des facteurs environnementaux. La découverte des déterminants génétiques a permis d’identifier plusieurs mécanismes moléculaires contribuant au développement de la maladie. Ils en ont démontré le caractère complexe. Pour mieux comprendre l’étendue des perturbations moléculaires liées à la maladie, nous avons entrepris des analyses globales du transcriptome par le biais de puces ou de séquençage des ARNs (RNAseq) à partir de cellules mononuclées périphériques sanguines de patients présentant des formes génétiques et sporadiques de la maladie ainsi que de sujets sains.Nous avons identifiés la dérégulation de nombreux gènes dans les cellules mononuclées périphériques sanguines de sujets porteurs de la mutation G2019S de LRRK2 et de sujets sporadiques par rapport à des sujets sains appariés. L’analyse des voies et des processus cellulaires associés à ces gènes met en exergue une altération de la voie de signalisation EIF2 commune aux sujets porteurs de la mutation G2019S de LRRK2 et aux sujets sporadiques. Cette voie fait écho à la régulation de la traduction et de l’épissage, deux processus faisant partie du métabolisme des ARNs. Ces altérations sont retrouvées dans les cellules mononuclées périphériques sanguines de sujets parkinsoniens porteurs de mutations du gène ATXN2, essentiellement connu pour son rôle dans la stabilité, l’épissage et la traduction des ARNm. Cette perturbation des ARNs semble être une altération commune à l’ensemble des formes de maladie de Parkinson étudiées et pourrait donc être un mécanisme sous-tendant la maladie.Les résultats du séquençage des ARNs obtenus chez des parkinsoniens présentant une forme sporadique ou porteurs de mutations délétères ainsi que chez des sujets sains corroborent cette hypothèse en montrant d’une part des différences quantitatives et qualitatives de variants d’épissage au sein d’ARNm eux-mêmes impliqués dans le métabolisme des ARNs et d’autres part des variations de l’épissage de gènes impliqués dans des mécanismes moléculaires connus de la maladie.Ainsi, nos données s’inscrivent dans la dynamique physiopathologique actuelle qui fait état de nombreuses perturbations du métabolisme des ARNs dans les maladies neurodégénératives. Dans la maladie de Parkinson, ces défauts impliqueraient des variations quantitatives et qualitatives de variants d’épissage au sein de gènes liés à l’épissage mais aussi dans des mécanismes connus pour contribuer à la maladie. Une analyse approfondie de ces dérèglements devraient permettre de déterminer leur spécificité et d’évaluer leur potentiel en tant que marqueurs de la maladie et cibles thérapeutiques. / Parkinson’s disease is a neurodegenerative disorder with genetic determinants not only contributing to rare familial forms of the disease but also involved in prevalent sporadic forms by interacting with environmental factors. Thanks to the identification of these determinants, several molecular mechanisms contributing to the disease have been found highlighting also its complexity. In order to better understand the molecular perturbations underlying the disease, we performed whole transcriptome analyses using microarrays and RNA sequencing (RNAseq) from peripheral blood mononuclear cells of Parkinson’s disease patients with genetic and sporadic forms of the disease as well as healthy controls.We identified several dysregulated genes in the cells of Parkinson’s disease patients with a G2019S LRRK2 mutation and sporadic patients compared to healthy controls. Pathways and cellular processes related to those genes mainly display disturbances of EIF2 signaling common to G2019S LRRK2 mutation carriers and sporadic patients. These data pinpoint potential perturbations of translation and RNA splicing both related to RNA metabolism. Involvement of RNA metabolism is also observed in peripheral blood mononuclear cells of Parkinson’s disease patients carrying mutations of ATXN2 gene encoding for ataxin-2 protein. It is mainly known as a regulator of the stability, the splicing and the translation of mRNA. Such RNA-mediated perturbations seem to be a common to all forms of Parkinson’s disease and might be a physiological mechanism of the disease. RNAseq data from Parkinson’s disease patients having or not deleterious mutations are in agreement with this hypothesis showing quantitative and qualitative discrepancies of splicing variants inside genes involved in RNA metabolism but also in known molecular pathways of the disease.As a conclusion, our results support the current view of RNA metabolism association with neurodegenerative disorders. In Parkinson’s disease, those alterations could involve quantitative and qualitative variations of splicing variants inside genes involved in RNA metabolism but also in known perturbed molecular pathways of the disease. Further analyses of these dysregulations should be helpful to determine their specificity and evaluate their potential as biomarkers and therapeutic targets.

Parkinson’s disease (PD) has been reported to negatively affect adult neurogenesis. Mitochondrial dysfunction associated with PD may be involved, given that recent studies have identified mitochondria to be central regulators of neural stem cell (NSC) fate decisions. For this thesis, we sought to characterize adult neurogenesis in PINK1 and parkin knockout (KO) mouse models of PD. Immunohistochemical staining of subventricular zone (SVZ) and subgranular zone (SGZ) tissue sections from 6 month old mice was performed in order to identify and quantify changes in specific cell populations involved with adult neurogenesis. The loss of PINK1 or parkin was found to cause aberrant changes in adult neurogenesis, particularly in the SGZ. Going forward, it would be interesting to determine if the observed changes in adult neurogenesis were the result of mitochondrial dysfunction.

Parkinson’s disease is a progressive neurodegenerative disorder, characterized by a depletion of the dopaminergic neurons in the substantia nigra. The cause of the disease is yet unknown but age, oxidative stress, and neuroinflammation are some of the features involved in the degeneration. In addition, substantial cell death of noradrenergic neurons occurs in the locus coeruleus (LC). Noradrenaline has been suggested to protect the dopamine neurons from oxidative stress and neuroinflammation. The main treatment of Parkinson’s disease is Levo-dopa, although severe side effects arise from this therapy. Hence, grafting fetal ventral mesencephalic (VM) tissue into the adult striatum has been evaluated as an alternative treatment for Parkinsons’s disease. However, the survival of the grafted neurons is limited, and the dopamine-denervated striatum does not become fully reinnervated. Therefore, elucidating factors that enhance dopamine nerve fiber formation and/or survival of the grafted neurons is of utmost importance. To investigate dopamine nerve fiber formation and the interactions with glial cells, organotypic VM tissue cultures were utilized. Two morphologically different nerve fiber outgrowths from the tissue slice were observed. Nerve fibers were initially formed in the absence of migrating astrocytes, although thin vimentin-positive astrocytic processes were detected within the same area. A second, persistent nerve fiber outgrowth was observed associated with migrating astrocytes. Hence, both of these nerve fiber outgrowths were to some extent dependent on astrocytes, and appeared as a general feature since this phenomenon was demonstrated in β-tubulin, tyrosine hydroxylase (TH), and aldehyde dehydrogenase A1 (ALDH1)-positive nerve fibers. Neither oligodendrocytes (NG2-positive cells), nor microglia (Iba-1-positive cells) exerted any effect on these two neuronal growths. Since astrocytes appeared to influence the nerve fiber formation, the role of proteoglycans, i.e. extracellular matrix molecules produced by astrocytes, was investigated. β-xyloside was added to the cultures to inhibit proteoglycan synthesis. The results revealed a hampered astrocytic migration and proliferation, as well as a reduction of the glia-associated TH-positive nerve fiber outgrowth. Interestingly, the number of cultures displaying the non-glia-mediated TH-positive nerve fibers increased after β-xyloside treatment, although the amount of TH-protein was not altered. Thus, proteoglycans produced by astrocytes appeared to be important in affecting the dopamine nerve fiber formation. The noradrenaline neurons in LC have been suggested to protect dopamine neurons from damage. Therefore, the interaction between VM and LC was evaluated. Using the intraocular grafting method, fetal VM and LC were grafted either as single grafts or as VM+LC co-grafts. Additionally, the recipient animals received 2% blueberry-enriched diet. The direct contact of LC promoted graft volume and survival of TH-positive neurons in the VM grafts. The number of dopamine neurons, derived preferably from the A9 (ALDH1/TH-positive) was increased, whereas the dopamine neurons from the A10 (calbindin/TH-positive) were not affected. A dense dopamine-β-hydroxylase (DBH)-positive innervation was correlated to the improved survival. Blueberry-enriched diet enhanced the number of TH-positive neurons in VM, although the graft size was not altered. The combination of blueberries and the presence of LC did not yield additive effects on the survival of VM grafts. The attachment of VM or the addition of blueberries did not affect the survival of TH-positive neurons in LC grafts. The number of Iba-1-positive microglia was decreased in co-grafted VM compared to single VM transplants. The addition of blueberries reduced the number of Iba-1-positive microglia in single VM transplants. Hence, the direct contact of LC or the addition of blueberries enhanced the survival of VM grafts. Taken together, these data demonstrate novel findings regarding the importance of astrocytes for the nerve fiber formation of dopamine neurons. Further, both the direct attachment of LC or antioxidant-enriched diet promote the survival of fetal VM grafts, while LC is not affected.

Parkinson’s disease (PD) is frequently compounded by neruropsychiatric complications, increasing disability. The combined effect of motor and mental status on care-dependency in PD outpatients is not well characterized. We conducted a cross-sectional study of 1449 PD outpatients. The assessment comprised the Montgomery–Asberg Depression Rating Scale (MADRS) and the diagnostic criteria for dementia. PD severity and treatment complications were rated using Hoehn and Yahr staging and the Unified Parkinson’s Disease Rating Scale (UPDRS) IV. The acknowledged level of care-dependency was documented. Care-dependency was present in 18.3% of all patients. A total of 13.9% had dementia, 18.8% had depression, and 14.3% had both. Regression analyses revealed increasing effects of age, PD duration, and PD severity on care-dependency in all three mental-disorder subgroups with the strongest effects in patients with depression only. Depressed patients with antidepressive treatment still had significantly higher PD severity, higher MADRS and UPDRS-IV scores but were not more likely to be care-dependent than non-depressed patients. Older age, longer duration and increased severity of PD contribute to care-dependency in patients with untreated depression. Treatment of depression is associated with lower rates of care-dependency.

Background In advanced Parkinson’s disease (PD) the motor symptoms can be treated with deep brain stimulation (DBS). Subthalamic nucleus (STN) has been the most common target and caudal zona incerta (cZi) is a more recent target for stimulation. Stimulation in both of these targets has proved to be positive for the motor symptoms but there is no consensus about how DBS affects the speech and the articulation. Aim The aim of this study was to investigate how fricatives are realized within patients suffering from PD treated with DBS in STN or cZi. Method 9 patients stimulated in STN and 10 patients stimulated in cZi were recorded reading a shorter text.  The recordings were made preoperatively (Pre) and 12 months after surgery with the stimulation switched off (sOff) and on (sOn). From the recordings the fricatives were extracted and assessed in a blinded and randomized procedure. Results For the patients stimulated in cZi the target fricative /s/ had significant lower correct realizations in the sOn condition compared to the other two conditions. The other target fricatives in cZi showed the same pattern as well. For the STN group no unequivocal pattern could be seen. Conclusions The results suggest that stimulation in cZi may affect the patients’ articulation of fricatives and thereby their extended articulatory movements more negative than stimulation in STN.

Abstract Background Deep brain stimulation (DBS) is a viable surgical treatment method for Parkinson’s disease (PD). It has positive effects on the classical motor symptoms, but effects on speech and voice are not equally beneficial. The speech disorder related to PD is hypokinetic dysarthria, with impaired articulatory precision as a prominent symptom. Studies have shown effects on different aspects of speech due to DBS of the subthalamic nucleus (STN) but the effects of stimulation of the caudal zona incerta (cZi) are less explored. Aims The aim of the current study was to investigate the effect of STN-DBS and cZi-DBS on perceptually measured articulatory precision in PD patients. Method Read speech productions were collected from 19 DBS-treated PD patients, ten STN and nine cZi. The recordings were made before surgery and 12 months postoperatively with stimulator on and off. Levodopa medication was always on. From the reading passage, three-syllable words were selected and isolated. Articulatory precision of the words was rated in two different assessments; an overall rating of articulatory precision and an identification of occurring misarticulations. Results The results from the perceptual assessment showed a decrease in articulatory precision after surgery for both groups. The decrease was significant for the cZi group, but not for the STN group. There was no significant difference between the groups. The frequency of observed misarticulations increased as an effect of DBS for both patient groups, with significant increase for the STN group but not for the cZi group. There was no significant difference between the groups. The most commonly observed misarticulation categories were stop-plosive reduced in quality, fricative realized as other fricative and stop-plosive realized as fricative . Conclusions The results obtained in the current study show that STN-DBS and cZi-DBS may have adverse effects on articulatory precision in PD patients. Keywords Articulatory precision, Parkinson’s disease, DBS, STN, cZi

Tyrimo objektas: moterų ir vyrų sergančių Parkinsono liga pusiausvyra ir gyvenimo kokybė. Darbo tikslas: nustatyti kineziterapijos poveikį vyrų ir moterų, sergančių Parkinsono liga pusiausvyrai ir gyvenimo kokybei. Uždaviniai: 1. Nustatyti ir palyginti vyrų ir moterų, sergančių Parkinsono liga gyvenimo kokybę prieš ir po kineziterapijos. 2. Nustatyti ir palyginti vyrų ir moterų, sergančių Parkinsono liga dinaminę ir statinę pusiausvyrą prieš ir po kineziterapijos. Hipotezė: mes manome, jog gyvenimo kokybė ir pusiausvyra gerės po kineziterapijos taikymo. Tyrimo metodai: 1. ,,Stotis ir eiti“ testas 2. Berg pusiausvyros skalė 3. Gyvenimo kokybės klausimynas (SF-36) Tyrimo išvados: 1. Kineziterapija reikšmingai sumažino moterų, sergančių Parkinsono liga skausmą, o kiti gyvenimo kokybės rodikliai kaip ir vyrų nepakito. 2. Sergančiųjų Parkinsono liga moterų ir vyrų dinaminė ir statinė pusiausvyra po kineziterapijos nepakito. / The object of study: women and men suffering from Parkinson's disease, balance and quality of life. The aim: determine the effects of physiotherapy for men and women, suffering from Parkinson's disease, balance and quality of life. Objectives: 1. Identify and compare men and women with Parkinson's disease quality of life before and after physiotherapy. 2. Identify and compare men and women with Parkinson's disease, dynamic and static balance before and after physiotherapy. Hypothesis: we are guessing that after physiotherapy will improve the quality of life and the balance. Methods: 1. „Up and go“ test 2. Berg Balance Scale 3. Quality of life questionnaire (SF – 36) Conclusions: 1. Physiotherapy significantly reduced the pain in women with Parkinson's disease other quality of life indicators as men not changed. 2. Men and women with Parkinson's disease static and dynamic balance after physiotherapy not changed.

Currently L-DOPA is the drug most commonly used for the treatment of Parkinson’s disease (PD). However, the long-term use of L-DOPA is associated with the development of motor fluctuations and dyskinesias. Treatment mainly addresses the dopaminergic features of the disease and leaves its progressive course unaffected. An optimal treatment would be a combination of both motor and non-motor symptom relief with neuroprotective properties. Two drug targets have attracted the attention for PD treatment, namely monoamine oxidase B (MAOB) and adenosine A2A receptors. MAO-B inhibitors enhance the elevation of dopamine levels after L-DOPA treatment, improve motor functions and may also possess neuroprotective properties. The antagonistic interaction between A2A and dopamine receptors in the striatopallidal pathway, which modulates motor behaviour, has also become a potential strategy for PD treatment. Blockade of the A2A receptor exerts both anti-symptomatic and neuroprotective activities and offer benefit for motor symptoms and motor complications. This thesis seeks to synthesize novel drug treatments for PD by exploring both MAO-B inhibitors and adenosine A2A receptor antagonists and to assess the prospects for drug modification to increase activity. MAO-B inhibitors - Based on a recent report that the phthalimide moiety may be a useful scaffold for the design of potent MAO-B inhibitors, the present study examines a series of 5-sulfanylphthalimide analogues as potential inhibitors of both human MAO isoforms. The results document that 5- sulfanylphthalimides are highly potent and selective MAO-B inhibitors with all of the examined compounds possessing IC50 values in the nanomolar range. The most potent inhibitor, 5- (benzylsulfanyl)phthalimide, exhibits an IC50 value of 0.0045 μM for the inhibition of MAO-B with a 427–fold selectivity for MAO-B compared to MAO-A. We conclude that 5-sulfanylphthalimides represent an interesting class of MAO-B inhibitors and may serve as lead compounds for the design of antiparkinsonian therapy. It has recently been reported that nitrile containing compounds frequently act as potent MAO-B inhibitors. In an attempt to identify additional potent and selective inhibitors of MAO-B and to contribute to the known structure-activity relationships of MAO inhibition by nitrile containing compounds, the present study examined the MAO inhibitory properties of series of novel sulfanylphthalonitriles and sulfanylbenzonitriles. The results document that the evaluated compounds are potent and selective MAO-B inhibitors with most homologues possessing IC50 values in the nanomolar range. In general, the sulfanylphthalonitriles exhibited higher binding affinities for MAO-B than the corresponding sulfanylbenzonitrile homologues. Among the compounds evaluated, 4-[(4-bromobenzyl)sulfanyl]phthalonitrile is a particularly promising inhibitor since it displayed a high degree of selectivity (8720-fold) for MAO-B over MAO-A, and potent MAO-B inhibition (IC50 = 0.025 μM). Based on these observations, this structure may serve as a lead for the development of therapies for neurodegenerative disorders such as Parkinson’s disease. Adenosine A2A receptor antagonism - Most adenosine A2A receptor antagonists belong to two different chemical classes, the xanthine derivatives and the amino-substituted heterocyclic compounds. In an attempt to discover high affinity A2A receptor antagonists for PD and to further explore the structure-activity relationships of A2A antagonism by the xanthine class of compounds, this study examines the A2A antagonistic properties of series of (E)-8-styrylxanthine, 8-(phenoxymethyl)xanthine and 8-(3- phenylpropyl)xanthine derivatives. The results document that among these series, the (E)-8- styrylxanthines are the most potent antagonists with the most potent homologue, (E)-1,3-dietyl- 7-methyl-8-[(3-trifluoromethyl)styryl]xanthine, exhibiting a Ki value of 11.9 nM. This compound was also effective in reversing haloperidol-induced catalepsy in rats. The importance of substitution at C8 with the styryl moiety was demonstrated by the finding that none of the 8- (phenoxymethyl)xanthines and 8-(3-phenylpropyl)xanthines exhibited high binding affinities for the A2A receptor. It was also concluded that (E)-8-styrylxanthines are potent A2A antagonists with particularly the 1,3-dietyl-7-methylxanthine substitution pattern being most appropriate for high affinity binding. Conclusion - The results of these studies have established that all of the sulfanylphthalimides, sulfanylphthalonitriles and sulfanylbenzonitriles examined display significant MAO-B inhibitory properties in vitro with IC50 values in the low μM to nM range. Good A2A receptor affinity was demonstrated by the xanthines containing a styryl moiety, while the phenoxymethyl and phenylpropyl xanthines exhibited poor activity. / Thesis (PhD (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013