The pedunculopontine nucleus (PPN) is a reticular collection of neurons at the junction of midbrain and pons. The PPN in animal models appears topographically organised and functionally related to locomotion and arousal. In Parkinson’s disease, the PPN degenerates and is susceptible to abnormal basal ganglia output. In patients with Parkinson’s disease, low frequency PPN stimulation is proposed to improve gait freezing and postural instability. However, the therapeutic mechanisms, optimal clinical application and precise effects on gait and posture of PPN stimulation are unclear. Here, a topographic arrangement of the PPN was supported by local field potential recordings in parkinsonian patients. In the PPN region, beta oscillations were recorded rostrally and alpha oscillations caudally. Alpha oscillations, consistent with their putative role in allocating attention, correlated with gait performance and attenuated with gait freezing. Thus the caudal PPN subregion may be the most relevant target for gait disorders. Accordingly, an unblinded clinical study suggested that stimulation of the caudal PPN subregion was beneficial for gait freezing, postural instability and falls. In a double-blinded study using spatiotemporal gait analysis, caudal PPN stimulation reduced triggered gait freezing, with bilateral stimulation more effective than unilateral. However, akinesia including akinetic gait did not improve with PPN stimulation. Accordingly, dopaminergic medication requirements did not change. Mechanisms underlying gait freezing and PPN stimulation were explored with reaction time experiments. Parkinsonian patients with severe gait freezing and postural instability demonstrated a ‘block’ to pre-programmed movement. This was evidenced by prolonged simple reaction times and the absence of ‘StartReact’, whereby pre-prepared responses are normally accelerated by loud acoustic stimuli. PPN stimulation improved simple reaction time and restored Startreact. The relief of this ‘motor block’ with PPN stimulation may therefore explain the associated improvement in gait freezing and postural instability, as these tend to occur in circumstances requiring triggered, pre-prepared adjustments.

Purpose: This study aimed to understand the effects of the Cognitive Orientation to daily Occupational Performance (CO-OP) on successful engagement in desired occupations (goals), health-related quality of life, and caregiver stress for individuals with Parkinson’s Disease (PD)-related cognitive impairment and their caregivers. Methods: A mixed methods single-subject design was used. Quantitative and qualitative data were combined to gain a comprehensive understanding of results. Results: Participants successfully engaged in all three trained goals and both untrained goals, generalized CO-OP strategies to perform trained goals outside of treatment sessions, and transferred CO-OP strategies to perform untrained goals independently. Conclusions: Individuals with PD-related cognitive impairment are capable of successfully engaging in self-selected treatment goals that are trained during CO-OP sessions, generalizing CO-OP strategies they have learned in treatment in order to perform the same goals outside of treatment, and transferring CO-OP strategies in order to perform untrained goals independently. / October 2016

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Neurodegeneration is a chronic, progressive and debilitating condition that affects majority of the World's elderly population who are at greater risk. Numerous scientific studies suggest that there could be a common underlying molecular mechanism that promotes the degeneration and the subsequent neuronal loss, however so far the progress in this direction is rather limited. Abnormal protein misfoldings, as well as protein plaque formations in the brain, are some of the hallmark characteristic features of neurodegenerative disorders (NDDs). Genetic and environmental factors, oxidative stress, excessive reactive oxygen species formation, mitochondrial dysfunction, energy depletion and autophagy disruption etc. are some of the widely suspected mechanisms that manifest the cognitive, motor and emotional symptoms of these NDDs. Motivated by some molecular traits found in common in several NDDs, network-based systems biology tools and techniques were used in this study to identify critical molecular players and underlying biological processes that are common for Parkinson's, Alzheimer's and Huntington's disease. Utilizing multiple microarray gene expression datasets, several biomolecular networks such as direct interaction, shortest path, and microRNA regulatory networks were constructed and analyzed for each of the disease conditions. The network-based analysis revealed 26 genes of potential interest in Parkinson's, 16 in Alzheimer's and 30 in Huntington's disease. Many new microRNA-target regulatory interactions were identified. For each disorder, several routes for possible disease initiation and protection scenarios were uncovered. A unified neurodegeneration mechanism network was constructed by utilizing the significantly differentially expressed genes found in common in Parkinson's, Alzheimer's and Huntington's microarray datasets. In this integrated network many key molecular partakers and several biological processes that were significantly affected in all three NDDs were uncovered. The integrated network also revealed complex dual-level interactions that occur between disease contributing and protecting entities. Possibilities of microRNA-target interactions were explored and many such pairs of potential interest in NDDs were suggested. Investigating the integrated network mechanism, we have identified several routes for disease initiating, as well as alleviating ones that could be utilized in common for Parkinson's, Alzheimer's and Huntington's disease. Finding such crucial and universal molecular players in addition to maintaining a delicate balance between neurodegeneration promoters and protectors is vital for restoring the homeostasis in the three NDDs.

Although Parkinson’s disease (PD) is commonly characterized by motor symptoms and physical limitations, there is growing recognition of nonmotor and mood symptoms associated with the disease as well. There has been limited research exploring how individual coping might affect the relationships between PD symptoms and mental health outcomes. The resilience construct was originally developed within the child literature, and it is often used in conceptualizing how people have adaptive or positive outcomes when facing adversity. Current resilience measures may not adequately assess the construct within an older population, however, given the unique emotion regulation and coping skills seen in late life. This survey study of 139 community-dwelling adults with PD (M age = 64.25 years, SD = 10.12, range 34-89 years) investigated whether resilience moderated the relationship between PD-related factors (nonmotor symptoms, functional impairment, and disease symptom-related QOL) and mental health outcomes (depression, apathy, satisfaction with and adjustment-quality of life). Further analyses explored whether hypothesized age-related resilience components (optimism, goal-flexibility, and meaning-making ability), accounted for unique variance above and beyond a standard resilience measure (Resilience Scale for Adults). Results indicated that disease symptom-related QOL predicted depression and adjustment-related QOL, while functional impairment predicted apathy, life satisfaction, and adjustment related QOL. Participants overall reported moderate to high resilience; resilience was a significant predictor of all mental health/QOL outcome measures, and those with comparatively lower self-reported resilience had worse disease symptoms. Resilience did not moderate the relationship between disease symptoms and mental health/QOL. Meaning-making ability and goal-flexibility accounted for unique variance above and beyond the standard resilience measure for several outcome variables. Age was a significant moderator, such that the protective value of meaning-making ability and optimism on depression were greater for younger compared to older participants. This study highlighted the presence of moderate to high resilience in PD patients, however those with comparatively lower resilience had poorer outcomes. Other coping variables appear to be important contributors to mental health/QOL beyond a standard resilience measure. Patient age also affected several outcomes, emphasizing the importance of further integration of developmental literature into our understanding of resilience in chronic disease management.

Alterations in the expression levels of α-synuclein (SNCA) provide an important link between familial and sporadic forms of Parkinson’s disease (PD). Multiplications of the human wild-type SNCA locus give rise to early-onset autosomal-dominant forms of PD and elevated α-synuclein expression has been linked to an increased risk for late-onset sporadic PD. The identification of α-synuclein’s physiological and pathophysiological functions has been hindered by a lack of animal models that accurately recapitulate the key disease features. Traditional cDNA-based transgenic models fail to correctly reflect the spatiotemporal expression pattern of α-synuclein and consequently do not accurately model the disease. Bacterial artificial chromosome (BAC) technology allows transgene expression from the entire genomic locus under the control of native regulatory elements and therefore allows improved modelling of disease mechanisms and phenotypes. This thesis describes a longitudinal characterisation of the molecular and behavioural effects of overexpressing human wild-type α-synuclein in a novel BAC transgenic PD mouse model, the SNCA-OVX model. Firstly, the work investigates transgene expression and localisation, dopamine neuron loss, synaptic function and PD-related motor and non-motor phenotypes. At 3 months of age, deficits in gastrointestinal function were observed while normal levels of dopaminergic markers and neurons were maintained. At 18 months, mice displayed a 30% decrease in nigrostriatal dopamine neurons, accompanied by reduced motor coordination and function. This novel PD model, which reflects accurate transgene expression and displays progressive dopamine neuron loss accompanied by characteristic behavioural PD phenotypes, will aid the investigation of molecular disease mechanisms and the development of novel therapies. Secondly, this thesis describes the generation of Translating Ribosome Affinity Purification (TRAP) transgenic mice, which express an EGFP-tagged ribosomal protein L10a transgene under the control of the tyrosine hydroxylase promoter. Finally, double transgenic TH bacTRAP SNCA-OVX mice were generated to investigate changes in genome-wide gene expression in dopaminergic cell populations of SNCA-OVX mice to identify novel drug targets.

Title: Brain Activity Changes During Walking Affected by Cuieng in Parkinson's Disease Patients Viewed by sLORETA Imaging. Objectives: The aim of this diploma thesis is to acertain changes in electrical activity of the brain, evaluated by sLORETA program, between gait affected by visual and auditory cueing and normal comfortable gait in patients with Parkinson's disease. Methods: This experiment was conducted on 11 patients with Parkinson's Disease aged between 60-78 years. The electrical activity of the brain was registred by scalp EEG during the whole experiment. The experiment consisted of 4 parts. In the beginning we measured resting EEG with closed and then opened eyes (5 + 5 minutes), after that we measured EEG during normal comfortable gait on 3 meters long track (3 minutes). Subsequently we measured EEG during walking affected by cueing, again on the 3 meters long track (3 + 3 minutes). The order of visual and auditory cueing was randomized. Visual cueing was mediated by white lines (tapes) stuck to the floor within 50 centimetres of each other. Auditory cueing was mediated by a metronome. The basic rhythm of the metronome was set on the 70 BPM. Next, the data from the experiment were transferred into the sLORETA program, which enabled statistical proccessing and also imaging of the active...

Os receptores canabinóides CB1 são abundantemente expressos nos núcleos da base (NB), sugerindo a participação do sistema canabinóide na Doença de Parkinson (DP). Os objetivos deste estudo foram investigar a localização do CB1 nos NB de ratos; avaliar o decurso temporal de sua expressão e de marcadores neuronais em modelo experimental da DP in vivo, e avaliar os efeitos do tratamento com compostos canabinóides em modelos experimentais da DP in vivo e in vitro. Nossos resultados mostraram que o CB1 é predominantemente expresso em neurônios GABAérgicos nos NB. A lesão dopaminérgica produziu mudanças temporais distintas da expressão do CB1 nas estruturas dos NB. O tratamento com o agonista canabinóide ACEA agravou à lesão dopaminérgica e o desempenho comportamental motor. Por outro lado, o tratamento com o antagonista AM 251, embora não tenha gerado diferenças neuroquímicas, gerou melhoras nos testes comportamentais. Por fim, em nosso modelo in vitro, o tratamento com inibidor de recaptação da anandamida AM 404 gerou uma discreta redução dos níveis de morte celular. / Cannabinoid receptors CB1 are abundantly expressed in the basal ganglia (BG), suggesting the involvement of the cannabinoid system in Parkinson\'s disease (PD). The objectives of this study were to investigate the location of CB1 in BG of rats; evaluate the time course expression of CB1 and neuronal markers in an experimental model of PD in vivo, and evaluate the effects of treatment with cannabinoids compounds in experimental models of PD in vivo and in vitro. Our results showed that CB1 is predominantly expressed in GABAergic neurons in BG. The dopamine lesion produced distinct temporal changes in the expression of CB1 in BG structures. Treatment with the cannabinoid agonist ACEA aggravated the dopaminergic lesion and the motor behavioral performance. Moreover, the treatment with the antagonist AM 251, although have not generated neurochemical changes,it promoted improvements in behavioral tests. Finally, in our in vitro model, the treatment with Anandamide transport inhibitor AM 404 led to a slight reduction in the levels of cell death.

O objetivo deste projeto foi investigar as alterações histológicas e comportamentais do exercício físico no modelo da doença de Parkinson (DP) induzida por 6-hidroxidopamina (6-OHDA) em ratos, e o papel do BDNF nas alterações encontradas. O estudo foi dividido em duas etapas, sendo elas voltadas para o efeito neuroprotetor e para o efeito preventivo do exercício. Para analisar o efeito do BDNF realizou-se injeção intraestriatal do bloqueador do receptor de BDNF (K252a). O protocolo de exercício consistiu de treino em esteira (3x/semana; 40 minutos). Realizaram-se testes comportamentais e análises histológicas da substância negra pars compacta e estriado. Os resultados obtidos revelaram, de modo geral, que o exercício foi eficaz na melhora do sistema dopaminérgico e capaz de recuperar o comportamento dos ratos injetados com 6-OHDA. Demonstramos ainda que o beneficio promovido pelo exercício intermitente parece ter o envolvimento do sistema BDNF-TrkB, sugerindo ser esse um importante sistema para prevenção e neuroproteção na DP. / Exercise is known to produce beneficial effects to the nervous system, The objective of this project was to investigate the histological and behavioral changes promoted by physical exercise in the PD model induced by 6-hydroxydopamine (6-OHDA) in rats, and the role of BDNF in the changes. The study was divided into two stages, aimed at evaluating the neuroprotective and the preventive effects of exercise. To analyze the effects of BDNF we used intrastriatal injections of a BDNF receptor blocker (K252a). The exercise protocol consisted of treadmill exercise (3x/week, 40 minutes). We carried out behavioral tests and histological analysis of the substantia nigra pars compacta and the striatum. The results showed, in general, that exercise is effective in improving the dopaminergic system and able to improve the behavior of rats injected with 6-OHDA. We also demonstrated that the positive effects of intermittent exercise appear to involve the BDNF-TrkB system, suggesting this as an important preventive and neuroprotective system in PD.

Recentemente, estudos indicam que, juntamente com os sintomas motores clássicos, possam ocorrer déficits de função executiva, cognição e linguagem na Doença de Parkinson (DP). Este estudo objetivou avaliar a recepção de sentenças e relacionar seus suportes de atenção e memória, em pacientes não-demenciados com DP. Participaram do estudo 80 sujeitos, sendo 40 do grupo controle e 40 com diagnóstico de DP, subdivididos em 2 grupos de acordo com a gravidade da doença. Foram aplicados os seguintes testes: Token Test, Extensão de dígitos, Fluência Verbal, Mini Exame do Estado Mental e Escala de Depressão Geriátrica. O presente estudo indica a existência de déficit de compreensão sintática na DP, principalmente nos estágios mais avançados da doença. As sentenças em que ocorrem tais déficits são analisadas e as bases de atenção e memória necessárias à compreensão de sentenças são discutidas. / Recently, studies have indicated that it can occur executive function, cognition and language deficits associated with the classic motor symptoms of Parkinson´s Disease (PD). The aim of this study is to verify sentence comprehension and relate it to attention and memory basis in non-dementia patients with PD. We studied 80 subjects in total, 40 of control group and 40 with a diagnosis of PD, subdivided into 2 groups according to the severity of the disease. The following tests were applied: Token Test, Digit Span, Verbal Fluency, Mini-Mental State Examination and the Geriatric Depression Scale. This study indicates that there is a deficit in sentence comprehension in PD, mainly in more advanced stages of the disease. The sentences which such deficits occur are analyzed and attention and memory basis that are necessary for sentence comprehension are discussed