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. / Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is widely used and proven to be highly effective in helping alleviate symptoms of Parkinson’s disease (PD). Nevertheless, although high‐frequency DBS (>120 Hz) is initially effective in improving patients’ motor symptoms (mainly bradykinesia and tremors), many patients still develop gait disturbances, such as freezing of gait (FOG). Recent studies have reported that stimulation of the STN with low frequencies produce positive effects on gait disorders and reduces the number of FOG events. As research is being done to investigate how reduced DBS frequencies will affect gait and balance control, it is also important to understand what effects reduced DBS stimulation will have on their PD symptoms. The aim of this study was to investigate the effects that reduced DBS frequencies have on the severity of PD patients’ symptoms. The effects were studied in twelve PD patients (receiving DBS treatment) after reducing their DBS frequency. The varied DBS frequencies included: their clinically determined stimulation setting (CDS), a low stimulation setting (30 Hz), and an intermediate stimulation frequency (80 Hz). Symptom severity was measured using the Unified Parkinson’s Disease Rating Scale (UPDRS‐III), and the Hoehn‐Yahr (HY) stage score. The results were supportive of what we expected; that as DBS frequencies are decreased from the patients’ clinically determined setting, the clinical symptoms worsened. This is an important observation which will allow the appropriate clinical decisions be made as we continue to investigate the effects of reduced frequency DBS on gait and posture control.

Nurr1 is a transcription factor essential for the establishment, development, terminal differentiation and maintenance of mesencephalic dopamine neurons. Nurr1 is thought to coordinate the expression of dopamine neurotransmission genes. Nurr1-null heterozygous (+/-) mice have reduced Nurr1 function, which impacts dopamine neuron function in a region specific manner. Since aging can affect Nurr1 expression, we hypothesize that aging and +/- genotype will have significant effects on dopamine regulation and dopamine related behaviors. To test this hypothesis, regional neurochemistry and behavioral tests of wild type (+/+) and +/- mice at 3 months of age (young) and 12-16 months of age (aged)was performed. We also hypothesize that aging will reduce Nurr1 expression in substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) and also reduce expression of the genes associated with dopamine (DA) neurotransmission that are regulated by Nurr1. To test this we isolated dopamine neurons in SNpc and VTA using laser capture microdissection, and measured the expression of Nurr1 and other associated DA neurotransmission genes using quantitative PCR. Nurr1 protein levels in DA neurons in SNpc and VTA and tyrosine hydroxylase (TH) protein levels in dopamine target regions were measured using quantitative immunohistochemistry. A significant increase in openield activity after stress in young +/- mice was observed. Significant reductions in tissue dopamine levels in the ventral striatum, including the core and shell of the nucleus accumbens were seen. In the SNpc, there was a significant increase in D2 receptor expression and a trend toward reduced TH expression, while in the VTA there was a significant decrease in D2 receptor expression and TH expression due to +/- genotype. The +/- genotype caused a significantly lower Nurr1 protein expression in the VTA which was not observed in the SNpc. Thus, it can be concluded that Nurr1 +/- genotype has a greater impact on the mesoaccumbens system as compared to the nigrostriatal system. The amount of Nurr1 protein expressed due to +/- genotype was not a 50% reduction as expected due to knockout of one gene of Nurr1 suggesting compensatory mechanisms that can maintain Nurr1 protein expression closer to the +/+ level.

BACKGROUND AND RATIONALE Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder affecting the central nervous system, primarily, the substantia nigra. It is characterized by loss of dopaminergic neurons in the nigro-striatal pathway, and ultimately patients with Parkinson’s disease may lose up to 80% of their dopamine-producing cells in the brain. Symptoms include bradykinesia, muscle rigidity, resting tremor and impaired postural balance. Symptomatic relief is obtained by using levodopa and various adjunct therapy including dopamine agonists, catechol-O-methyltransferase inhibitors and monoamine oxidase B inhibitors. Levodopa is used as the gold-standard for treatment of this disease. It effectively controls motor symptoms, however, motor complications that impair the quality of life develop with continued levodopa use. No treatments currently available can halt disease progression, therefore novel drugs that can slow down or stop disease progression are urgently required. The monoamine oxidase (MAO) A and B enzymes are flavoenzymes that play an important role in the oxidative degradation of amine neurotransmitters such as dopamine, serotonin and epinephrine. Early attempts to block dopamine metabolism in the brain using nonselective MAO inhibitors was effective but led to side effects such as hypertensive crisis, thus they lost favor. The MAO-B enzyme is of particular importance in Parkinson’s disease because it is more active than MAO-A in the basal ganglia, and is thus primarily responsible for the catabolism of dopamine in the brain. Selegiline and rasagiline, both irreversible, selective MAO-B inhibitors have proven efficacy in symptomatic treatment of Parkinson’s disease, but due to the irreversible nature of their binding, it can take several weeks after treatment termination for the enzyme to recover. Use of reversible inhibitors such as lazabemide and safinamide do not have this disadvantage, and have safer side effect profiles. Unfortunately, clinical trials for lazabemide use in Parkinson’s disease have been discontinued. Therefore, due to the lack of disease modifying agents for Parkinson’s disease, as well as safety concerns of current PD therapy, an urgent need exists for novel, safe and efficient MAO inhibitors. Current research is thus aimed at designing selective or non-selective reversible inhibitors that bind competitively to the enzyme. The MAO inhibitory potential of chromone derivatives has been illustrated previously. Evaluation of C6- and C7-alkyloxy substituted chromones, for example revealed that these compounds were potent, selective and reversible MAO-B inhibitors. It has further been shown that chromone 3-carboxylic acid is a potent selective, irreversible MAO-B inhibitor. Phenylcarboxamide substitution in position 3 of chromone 3-carboxylic acid also results in potent, selective MAO-B inhibitory activity. Therefore, further evaluation of the effect of substitution with flexible side chains in the 3-position to evaluate MAO-B inhibition is of importance. The chromone ring system is thus a privileged scaffold for the design of inhibitors that are selective for MAO-B and has the additional advantages of generally exhibiting low mammalian toxicity and ease of synthesis. AIM The aim of this study was to design, synthesize and evaluate novel chromone derivatives as inhibitors of monoamine oxidase. RESULTS Design and Synthesis 3-Aminomethylene-2,4-chromandiones and ester chromone derivatives were synthesized by coupling several aromatic and aliphatic amines and alcohols, to chromone 3-carboxylic acid, in the presence of CDI (carbonyldiimidazole). 15 Compounds were successfully synthesized and characterized by using NMR and IR spectroscopy, as well as mass spectrometry. X-ray crystallography was used to obtain a crystal structure for the 3-aminomethylene-2,4- chromandione derivative, 46, in a bid to verify the structures of the synthesized compounds. Melting points of all compounds were determined, and the purity determined using HPLC techniques. MAO inhibition studies A fluorometric assay was employed using kynuramine as substrate, to determine the IC50 (50% inhibition concentration) values and SI (selectivity index) of the synthesized compounds. Generally, the esters exhibited weak MAO-A and MAO-B inhibition, while the 3- aminomethylene-2,4-chromandione derivatives showed promise as selective MAO-B inhibitors, with IC50 values in the micromolar range. Compound 38, 3- [(benzylamino)methylidene]-3,4-dihydro-2H-1-benzopyran-2,4-dione, was the most potent MAO-B inhibitor with an IC50 value of 0.638 μM and a SI of 122 for MAO-B inhibition. Interesting trends were revealed through analysis of the structure activity relationships, for example, for the 3-aminomethylene-2,4-chromandione derivatives, the presence of a chlorine moiety in the side chains of the compounds resulted in a decrease of MAO-B inhibition activity. Chain elongation further also resulted in weakening the MAO-B inhibition activity, while chain elongation in the ester derivatives led to a slight increase in MAO-B inhibition activity. Reversibility studies The reversibility of binding of the most potent compound in the 3-aminomethylene-2,4- chromandione series, 38, was evaluated. None of the synthesized inhibitors were potent MAO-A inhibitors, therefore reversibility of MAO-A inhibition was not examined. Recovery of enzyme activity was determined after dialysis of the enzyme-inhibitor complexes. Analysis of the kinetic data obtained showed that MAO-B catalytic activity was recovered to 115% of the control value. This suggests that compound 38 is a reversible inhibitor of MAO-B. Mode of inhibition A set of Lineweaver-Burk plots were constructed to determine mode of inhibition of compound 38. The results show linear lines that intersect at a single point just to the left on the y-axis. This indicates that compound 38 interacts competitively with the MAO-B enzyme. In conclusion, chromone derivatives were synthesized and evaluated as inhibitors of MAO. Compound 38 was the most potent MAO-B inhibitor with an IC50 value of 0.638 μM. The effect of chain elongation and introduction of flexible substituents in position 3 of the chromone 3-carboxylic acid nucleus was explored and the results showed that 3- aminomethylene-2,4-chromandione substitution is preferable over ester substitution. / MSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2015

BACKGROUND AND RATIONALE Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder affecting the central nervous system, primarily, the substantia nigra. It is characterized by loss of dopaminergic neurons in the nigro-striatal pathway, and ultimately patients with Parkinson’s disease may lose up to 80% of their dopamine-producing cells in the brain. Symptoms include bradykinesia, muscle rigidity, resting tremor and impaired postural balance. Symptomatic relief is obtained by using levodopa and various adjunct therapy including dopamine agonists, catechol-O-methyltransferase inhibitors and monoamine oxidase B inhibitors. Levodopa is used as the gold-standard for treatment of this disease. It effectively controls motor symptoms, however, motor complications that impair the quality of life develop with continued levodopa use. No treatments currently available can halt disease progression, therefore novel drugs that can slow down or stop disease progression are urgently required. The monoamine oxidase (MAO) A and B enzymes are flavoenzymes that play an important role in the oxidative degradation of amine neurotransmitters such as dopamine, serotonin and epinephrine. Early attempts to block dopamine metabolism in the brain using nonselective MAO inhibitors was effective but led to side effects such as hypertensive crisis, thus they lost favor. The MAO-B enzyme is of particular importance in Parkinson’s disease because it is more active than MAO-A in the basal ganglia, and is thus primarily responsible for the catabolism of dopamine in the brain. Selegiline and rasagiline, both irreversible, selective MAO-B inhibitors have proven efficacy in symptomatic treatment of Parkinson’s disease, but due to the irreversible nature of their binding, it can take several weeks after treatment termination for the enzyme to recover. Use of reversible inhibitors such as lazabemide and safinamide do not have this disadvantage, and have safer side effect profiles. Unfortunately, clinical trials for lazabemide use in Parkinson’s disease have been discontinued. Therefore, due to the lack of disease modifying agents for Parkinson’s disease, as well as safety concerns of current PD therapy, an urgent need exists for novel, safe and efficient MAO inhibitors. Current research is thus aimed at designing selective or non-selective reversible inhibitors that bind competitively to the enzyme. The MAO inhibitory potential of chromone derivatives has been illustrated previously. Evaluation of C6- and C7-alkyloxy substituted chromones, for example revealed that these compounds were potent, selective and reversible MAO-B inhibitors. It has further been shown that chromone 3-carboxylic acid is a potent selective, irreversible MAO-B inhibitor. Phenylcarboxamide substitution in position 3 of chromone 3-carboxylic acid also results in potent, selective MAO-B inhibitory activity. Therefore, further evaluation of the effect of substitution with flexible side chains in the 3-position to evaluate MAO-B inhibition is of importance. The chromone ring system is thus a privileged scaffold for the design of inhibitors that are selective for MAO-B and has the additional advantages of generally exhibiting low mammalian toxicity and ease of synthesis. AIM The aim of this study was to design, synthesize and evaluate novel chromone derivatives as inhibitors of monoamine oxidase. RESULTS Design and Synthesis 3-Aminomethylene-2,4-chromandiones and ester chromone derivatives were synthesized by coupling several aromatic and aliphatic amines and alcohols, to chromone 3-carboxylic acid, in the presence of CDI (carbonyldiimidazole). 15 Compounds were successfully synthesized and characterized by using NMR and IR spectroscopy, as well as mass spectrometry. X-ray crystallography was used to obtain a crystal structure for the 3-aminomethylene-2,4- chromandione derivative, 46, in a bid to verify the structures of the synthesized compounds. Melting points of all compounds were determined, and the purity determined using HPLC techniques. MAO inhibition studies A fluorometric assay was employed using kynuramine as substrate, to determine the IC50 (50% inhibition concentration) values and SI (selectivity index) of the synthesized compounds. Generally, the esters exhibited weak MAO-A and MAO-B inhibition, while the 3- aminomethylene-2,4-chromandione derivatives showed promise as selective MAO-B inhibitors, with IC50 values in the micromolar range. Compound 38, 3- [(benzylamino)methylidene]-3,4-dihydro-2H-1-benzopyran-2,4-dione, was the most potent MAO-B inhibitor with an IC50 value of 0.638 μM and a SI of 122 for MAO-B inhibition. Interesting trends were revealed through analysis of the structure activity relationships, for example, for the 3-aminomethylene-2,4-chromandione derivatives, the presence of a chlorine moiety in the side chains of the compounds resulted in a decrease of MAO-B inhibition activity. Chain elongation further also resulted in weakening the MAO-B inhibition activity, while chain elongation in the ester derivatives led to a slight increase in MAO-B inhibition activity. Reversibility studies The reversibility of binding of the most potent compound in the 3-aminomethylene-2,4- chromandione series, 38, was evaluated. None of the synthesized inhibitors were potent MAO-A inhibitors, therefore reversibility of MAO-A inhibition was not examined. Recovery of enzyme activity was determined after dialysis of the enzyme-inhibitor complexes. Analysis of the kinetic data obtained showed that MAO-B catalytic activity was recovered to 115% of the control value. This suggests that compound 38 is a reversible inhibitor of MAO-B. Mode of inhibition A set of Lineweaver-Burk plots were constructed to determine mode of inhibition of compound 38. The results show linear lines that intersect at a single point just to the left on the y-axis. This indicates that compound 38 interacts competitively with the MAO-B enzyme. In conclusion, chromone derivatives were synthesized and evaluated as inhibitors of MAO. Compound 38 was the most potent MAO-B inhibitor with an IC50 value of 0.638 μM. The effect of chain elongation and introduction of flexible substituents in position 3 of the chromone 3-carboxylic acid nucleus was explored and the results showed that 3- aminomethylene-2,4-chromandione substitution is preferable over ester substitution. / MSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2015

There is much interest in the study of midbrain dopaminergic (mDA) neurons as their functions include the regulation of motor function, emotion and reward pathways. Furthermore the dysfunction of these neurons is implicated in a number of human disorders such as Parkinson’s disease (PD), addiction and schizophrenia. PD is characterised by the degeneration of mDA neurons of the substantia nigra pars compacta (SNc), therefore, research into the specification and development of mDA neurons is of particular interest in relation to this disease. An understanding of the development of mDA neurons may lead to new methods of preventing their degeneration or potentially a human ES cell derived source of mDA neurons that could be used for transplantation in PD patients. Pitx3 is a bicoid-related homeodomain protein with an expression pattern restricted to the mDA neurons of the SNc and ventral tegmental area (VTA), within the central nervous system. To directly investigate a role for Pitx3 in mDA neuron development, I have analysed a line of transgenic mice with a green fluorescent protein (GFP) reporter under the control of the endogenous Pitx3 promoter. Use of the targeted GFP reporter as a midbrain dopaminergic lineage marker in the phenotypically normal heterozygous mice identified previously unrecognised ontogenetically distinct subpopulations of dopaminergic cells within the ventral midbrain. These subpopulations were detectable at E12.5 based on their temporal and topographical expression of Pitx3 and TH. Analysis of the Pitx3 null mice revealed that Pitx3 is required for the survival of a subset of nascent mDA neurons at the beginning of their terminal differentiation. The loss of mDA neurons via apoptosis continued throughout development resulting in a complete absence of SNc neurons whilst the VTA remained relatively intact in adult Pitx3 null mice. In addition, during embryonic development Pitx3 deficiency caused a loss of tyrosine hydroxylase (TH) expression specifically in the SNc dopaminergic neurons. Analysis of chimeric mice made with Pitx3 null and Pitx3 heterozygous ES cells revealed that Pitx3 acts in a cell autonomous manner. These findings point to two roles for Pitx3 in SNc mDA neurons, one in their survival and the other in regulation of TH expression. Taken together, these studies suggest that the ontogenetically distinct subpopulations may provide the molecular basis for the specific dependence of substantia nigra DA neurons on Pitx3. In addition, to establish whether the subpopulations identified at E12.5 do form the SNc and VTA, respectively, a strategy to track the fate of the earliest Pitx3- expressing cells has been initiated. In order to achieve this I have created transgenic mice in which a tamoxifen inducible form of Cre recombinase is under the control of the endogenous Pitx3 promoter. These mice can be crossed with existing mice which contain a ubiquitously expressed Cre-inducible reporter, such as LacZ or GFP, to give a temporally and spatially restricted reporter expression.

La maladie de Parkinson et l’atrophie multisystématisée ont ceci de particulier que le diagnostic de certitude ne peut être obtenu du vivant du patient. L’un des enjeux actuels est d’approcher au plus prêt le diagnostic clinique réel du patient, pré requis indispensable à l’étude de l’histoire naturelle de la maladie, à une analyse fiable des données épidémiologiques de la maladie, à la bonne pratique des études de recherche pharmaceutique, à l’évaluation clinique des thérapeutiques innovantes. S’il est relativement aisé de poser le diagnostic de maladie de Parkinson à un stade avancé, il est en revanche beaucoup plus délicat de l’établir au stade initial de l’affection. C’est avec l’AMS que le diagnostic différentiel initial est le plus difficile. Actuellement les séquences morphologiques d’IRM représentent une aide incontestable, mais les anomalies observées sont souvent inconstantes et apparaissent à un stade tardif. La première partie du travail visait à étudier de manière simultanée et complémentaire la macro et la microstructure cérébrale dans les deux pathologies en utilisant de manière combinée les techniques de morphométrie voxel à voxel (VBM) et d’imagerie du tenseur de diffusion appliqué à l’ensemble du cerveau (VB-DTI). Cette étude confirme les données classiques d’atrophie putaminale dans l’AMS-P et d’augmentation de la diffusivité putaminale ; nous avons de surcroît mis en évidence une diminution de densité de substance grise dans le circuit moteur (cortex moteur primaire CMP gauche versus MP et aire motrice supplémentaire versus témoins) et une diminution de la fraction d’anisotropie dans le CMP gauche versus témoins. Il existait donc des anomalies macro et microstructurelles dans le circuit moteur des patients AMS-P en révélant la destruction tissulaire dans le circuit moteur - indépendamment de la perte de volume détecté par VBM et en accord avec les données anatomopathologiques et les caractéristiques cliniques motrices.La deuxième partie du travail consistait à étudier la connectivité cérébrale et les modifications des connexions cortico-putaminales à l’aide de la tractographie probabiliste. Nous avons étudié les modifications volumiques et les modifications microstructurales putaminales et tenté de dégager des profils utiles au diagnostic différentiel. Des séquences T1 haute résolution volumique et en tenseur de diffusion ont été acquises. Le putamen était segmenté de manière manuelle, le cortex de manière automatique à l’aide du logiciel free surfer. Nous avons calculé la probabilité de connectivité entre le putamen et les régions corticales ipsilatérales motrice, associative et limbique. Les volumes putaminaux, surfaces corticales, paramètres de diffusion (diffusivité moyenne et fraction d’anisotropie) ont été étudiés et comparés entre les groupes. Nous avons mis en évidence pour la première fois une altération des projections putamino-corticales motrices dans l’AMS-P en bonne concordance avec l’atteinte du putamen moteur dorsolatéral et l’atteinte corticale motrice et prémotrice dans la maladie. L’analyse multivariée permettait de discriminer AMS-P d’AMS-C (forme cérébelleuse de l’AMS), de MP et de témoins avec une sensibilité de plus de 75%. La troisième et dernière partie consistait à étudier les profils cognitifs dans les deux pathologies et les corrélations anatomo-cognitives à l’aide de la VBM et de la VB-DTI. La pertinence de l’évaluation cognitive classiquement effectuée dans le diagnostic différentiel maladie de Parkinson et atrophie multisystématisée est quasi nulle. De plus, les principales corrélations imagerie-cognition sont en bonne concordance avec les données de la littérature. L’implication du système moteur dans l’AMS sur le versant moteur semble se confirmer sur le plan cognitif. A notre connaissance aucune étude de corrélation imagerie-cognition en imagerie de diffusion dans la maladie de Parkinson ou l’atrophie multisystématisée n’a été publiée. / A definite diagnosis of Parkinson’s disease (PD) and multiple system atrophy (MSA) can only be confirmed neuropathologically. The clinical differentiation of the parkinsonian variant of multiple system atrophy (MSA-P) from PD is challenging, especially during the early stages of the disease. Early differentiation of these diseases is particularly important because the disorders differ in terms of progression, prognosis, and treatment responses. The aim of the first part of the study was to evaluate in vivo changes in the brain’s macro- and microstructure in MSA-P and in PD and to characterize the cerebral anatomical differences between the two conditions. We used a combination of voxel-based morphometry (VBM) and whole-brain, voxel-based diffusion tensor imaging analysis (VB-DTI). In MSA-P patients, VBM analysis revealed a lower density of grey matter (GM) in a motor related circuit (especially in the left primary motor cortex, PMC), relative to PD patients, and in the left supplementary motor area (SMA), relative to controls). Diffusion tensor imaging analysis revealed lower fractional anisotropy (FA) values in the left PMC and the right cerebellum in MSA-P patients, compared with controls. Using a volumetric diffusion technique, our study revealed selective tissue degeneration in motor circuits, regardless of the volume loss detected in VBM and in agreement with pathology reports and clinical motor characteristics. Our findings suggest that MSA-P is characterized by both macro- and microstructural changes in the sensorimotor circuit. The aim of the second part of the study was to evaluate brain connectivity especially cortico putaminal connectivity using probabilistic tractography. We assessed volumetric and microstructural changes that occur within each of these subregions and try to establish the potential value of these changes in differential diagnosis.DTI and T1-weighted images were obtained using 1.5 T MRI. Putamen was manually segmented. The cortex was segmented using Freesurfer software and cortical regions were classified in three functional systems: motor, associative and limbic. Then, we calculated the connection probability between putamen and ipsilateral cortical target. Volumes and DTI parameters (fractional anisotropy FA, mean diffusivity MD) of the resulting DTI-based parcellations of the putamen were compared between groups. Comparisons between groups were carried out using bivariate non parametrics tests. Putamen microstructural changes were present in the two variants of MSA according to anatomopathological knowledge. Loss of motor connectivity in MSA-P patients can be explained partially by important volume loss of putamen. Statistical multivariate model combining few clinical criteria and data obtained by MRI-based parcellation allows discriminating MSA-P from MSA-C from PD patients and controls in more than 75% of cases.The third part’s aim was to study the cognitive profile of MSA patients compared to PD patients and to evaluate the cognitive clinical correlations with VBM and VB-DTI brain MRI data. The contribution of standard neuropsychological examination to the differential diagnosis of both syndromes remains still limited. Our study revealed the main involvement of motor cortex in cognitive functions. From our knowledge, there is no study of cognitive correlations and DTI parameters in PD or in MSA.

<p>Parkinsons sjukdom är en neurologisk sjukdom, som främst drabbar motorik, men även kan påverka psykosociala och kognitiva funktioner. Studiens syfte var att kartlägga aktiviteter och upplevd delaktighet hos en grupp personer med Parkinsons sjukdom (n = 10). En semistrukturerad intervju gjordes med genomgång av aktiviteter under ett dygn. Data analyserades utifrån aktivitets- och delaktighetsdomänerna i ICF. Jämförelse med tidigare forskningsresultat visade att personerna i den aktuella undersökningsgruppen ägnade mer tid åt personlig vård, men mindre tid åt vila och TV-tittande. Upplevd delaktighet i aktiviteterna skattades generellt som hög, men en negativ korrelation sågs mellan tid sedan diagnos och delaktighet inom domänen Viktiga livsområden. En stor spridning i materialet indikerar att exempelvis rehabiliteringsinsatser bör baseras på individuell aktivitetsanalys.</p>

Parkinsons sjukdom är en neurologisk sjukdom, som främst drabbar motorik, men även kan påverka psykosociala och kognitiva funktioner. Studiens syfte var att kartlägga aktiviteter och upplevd delaktighet hos en grupp personer med Parkinsons sjukdom (n = 10). En semistrukturerad intervju gjordes med genomgång av aktiviteter under ett dygn. Data analyserades utifrån aktivitets- och delaktighetsdomänerna i ICF. Jämförelse med tidigare forskningsresultat visade att personerna i den aktuella undersökningsgruppen ägnade mer tid åt personlig vård, men mindre tid åt vila och TV-tittande. Upplevd delaktighet i aktiviteterna skattades generellt som hög, men en negativ korrelation sågs mellan tid sedan diagnos och delaktighet inom domänen Viktiga livsområden. En stor spridning i materialet indikerar att exempelvis rehabiliteringsinsatser bör baseras på individuell aktivitetsanalys.

Impaired gait and postural instability in patients living with Parkinson’s disease (PD) are regarded as the main aspects of the disease that causes disability in their home and work environment. As a progressive neurological movement disorder due to degeneration in the basal ganglia, PD is the second most common neurological disease after stroke and the fourth most common neuro-degenerative disease in the elderly. Functional Electrical Sensory Stimulation (FESS) (Group 1) and Functional Electrical Sensory and Motor Stimulation (FES&MS) (Group 2) was administered to the common peroneal nerve as external cues to facilitate the initiation of taking a step in patients with akinesia. The hypotheses that were tested were: Hypothesis 1 (H1) FESS and FES&MS decrease freezing/akinesia and bradykinesia/hypokinesia during gait in patients suffering from PD. Null Hypothesis (H0) FESS and FES&MS do not decrease freezing/akinesia and bradykinesia/hypokinesia during gait in patients suffering from PD. Hypothesis 2 (H2) FESS and FES&MS decrease freezing/akinesia and bradykinesia/hypokinesia during gait in patients suffering from PD to such an extent that it improves the quality of life of patients. Null Hypothesis 2 (H02) FESS and FES&MS do not decrease freezing/akinesia and bradykinesia/hypokinesia during gait in patients suffering from PD to such an extent that it improves the quality of life of the patients. Hypothesis 3 (H3) FESS decreases freezing/akinesia and bradykinesia/hypokinesia during gait in patients suffering from PD more than FES&MS. Null Hypothesis 3 (H03) FESS does not decrease freezing/akinesia and bradykinesia/hypokinesia during gait in patients suffering from PD more than FES&MS. A single blind, randomized active controlled clinical trial was conducted. Patients with PD who experienced freezing/akinesia and bradykinesia / hypokinesia and met the inclusion and exclusion criteria of the study were allocated randomly into two groups. Ten (10) patients were randomly allocated to each group. The baseline measurement was determined by calculating the average of the measurements at week zero (0) and week two (2). Results of the participants in each group at week fourteen (14) (after twelve (12) weeks of FESS and FES&MS respectively) were compared to their baseline measurement, as well as between Group 1 and Group 2. The FESS and FES&MS was removed at week fourteen (14) and measurements were repeated at week twenty four (24). Parameters of gait that were used in the trial included; the time, speed, number of steps, average step length, Freezing of gait scale and PCI to complete a walking task. The Qol was determined by using the PDQ-39 and the motor part of the UPDRS. From the results obtained the alternative hypotheses H1, H2 and H3 was accepted for Group 1. The null hypothesis H0 and the alternative hypothesis H3 was accepted for Group 2 It can be concluded from the results of this clinical trial that FESS decreases akinetic episodes in patients with PD statistically significantly and clinically improves their Qol. Qol was statistically significantly improved in Group 2 although hypothesis H1 was not accepted for Group 2. / Dissertation (MPhysT)--University of Pretoria, 2009. / Physiotherapy / unrestricted

Parkinson’s disease (PD) is next to Alzheimer’s disease (AD) the second most common neurodegenerative disease. PD has traditionally been characterised as a motor disorder, but more recent research has revealed that cognitive impairments are frequent. Cognitive impairments in executive functions, attention, and working memory with reliance on dopaminergic transmission, are often described as dominating the cognitive profile in early-phase PD. However, although knowledge about the neuropathology that underlies the cognitive impairments in PD has increased, its features are complex and knowledge remains insufficient. Therefore, the aim of the current thesis was to improve the understanding of how task-evoked brain responses relate to cognitive status in patients with PD, with and without mild cognitive impairment (MCI), and to evaluate the predictive value of PD-MCI in respect of prodromal Parkinson’s disease dementia (PDD). This was conducted within the “new Parkinsonism in Umeå” (NYPUM) project, which is a prospective cohort study. Patients with idiopathic PD were included in this thesis, and the patients were examined with a comprehensive neuropsychological battery and with a functional MRI (fMRI) working memory protocol. During scanning, patients conducted a verbal two-back task in which they needed to maintain and actively update relevant information, and the primary outcome measure was blood-oxygen-level-dependent (BOLD) signal. This thesis shows that patients with PD-MCI had significantly lower BOLD signal responses than patients without MCI in frontal (anterior cingulate cortex) and striatal (right caudate) regions (Study I). The altered BOLD response in the right caudate was associated with altered presynaptic dopamine binding. The fronto-striatal alterations persisted across time but without any additional change. However, decreased posterior cortical (right fusiform gyrus) BOLD signal responses were observed in patients with PD-MCI relative to patients without MCI across time (Study II). Finally, PD-MCI at baseline examination is highly predictive for prodromal PDD with a six-fold increased risk. Cognitive tests with a posterior cortical basis, to a greater extent, are predictive for prodromal PDD than tests with a fronto-striatal basis. The observed working memory related alterations in patients with PD-MCI suggest that early cognitive impairments in PD are linked to fronto-striatal dopaminergic dysfunction. The longitudinal development of cognitive impairment in PD reflects additional posterior cortical dysfunction. This might reflect a dual syndrome, with dopamine-depleted fronto-striatal alterations that characterise PD-MCI in general, whereas additional posterior cortical cognitive alterations with a non-dopaminergic basis to a greater extent characterise prodromal PDD. If, and how, the two potential syndromes interact, is still unclear. Thus, this thesis provides information on cognitive neuropathological changes in PD that might contribute to more relevant choices of pharmacotherapy and diagnostic accuracy in respect of PDD. However, additional large-scale longitudinal imaging studies are needed to further clarify the neuropatholgogical features of PD-MCI in respect of prodromal PDD.