L’Eye Tracking est une méthode de mesure précise et non invasive des mouvements oculaires permettant d’accéder aux paramètres neurophysiologiques du système oculomoteur. L’analyse des mouvements oculaires est un outil qui contribue au diagnostic des syndromes parkinsoniens. En Guadeloupe, les syndromes parkinsoniens atypiques, sont présents en proportion anormalement élevée. Ils représentent environ 70% des syndromes parkinsoniens. Notre travail a été de réaliser des normes oculomotrices des sujets sains et de caractériser les syndromes parkinsoniens sur le plan oculomoteur à partir des normes oculomotrices réalisées. Les normes oculomotrices des sujets sains antillais différents de celles des témoins d’origine tchèque. Ces différences suggèrent la possibilité d’une variabilité des standards oculomoteurs entre deux populations de sujets sains. Nos résultats témoignent de la nécessité de constituer des groupes témoins spécifiques à la population étudiée lors des études cliniques et les travaux de recherche sur les mouvements oculaires. Ils soulèvent également la question de l’influence de facteurs génétiques et/ou environnementaux sur les paramètres oculomoteurs. Les patients porteurs d’une maladie de Parkinson originaires et résidants aux Antilles présentent des anomalies oculomotrices plus fréquentes qu’attendues avec notamment un taux élevé d’erreurs aux antisaccades. Cette caractéristique ne semble pas corrélée aux performances cognitives. Chez les parkinsoniens atypiques l’altération parfois sévère de l’ensemble des paramètres oculomoteurs est en accord avec les données cliniques et d’imagerie cérébrale et témoignent de lésions diffuses corticales fronto-pariétales et sous corticales. / Eye Tracking is a precise and non-invasive method of measuring eye movements that provides access to the neurophysiological parameters of the oculomotor system. Eye movement analysis is a tool that contributes to the diagnosis of parkinsonian syndromes. In Guadeloupe, atypical parkinsonian syndromes are present in an abnormally high proportion. They represent about 70% of Parkinson's syndromes. Our work has been to achieve oculomotor standards of healthy subjects and characterize the parkinsonian syndromes on the oculomotor level from oculomotor standards. The oculomotor standards of Caraibbean healthy subjects differ from those of Czech origin. These differences suggest the possibility of variability of oculomotor standards between two populations of healthy subjects. Our results demonstrate the need to establish control groups specific to the population studied in clinical studies and research work on eye movements. They also raise the question of the influence of genetic and / or environmental factors on oculomotor parameters. Patients with Parkinson's disease coming from and residing in the Caribbean have more frequent oculomotor abnormalities than expected with a high percentage of error in antisaccade task. This characteristic does not seem to correlate with cognitive performance. In atypical parkinsonian patients, there are severe deterioration of all the oculomotor parameters is in agreement with the clinical and cerebral imaging data and show diffuse fronto-parietal and sub-cortical cortical lesions

Parkinson’s Disease (PD) is a neurological movement disorder characterized by depletion of dopaminergic cell bodies in the substantia nigra pars compacta with subsequent loss of dopamine in the nigrostriatal pathway. PD is definitively diagnosed by the presence of intracytoplasmic inclusions in dopaminergic neurons. These inclusions are composed of a-synuclein aggregates, known as “Lewy bodies.” Lewy Bodies are known to be toxic to neurons leading to cell death. Individuals with PD most commonly manifest with bradykinesia (slowness in movement), tremors, and rigidity, but may also suffer orthostatic hypotension, dysphagia, anosmia, constipation, and sleep dysregulation. Mechanisms of PD pathogenesis may include defective protein handling, mitochondrial dysfunction, oxidative stress, and inflammation. Exposure to pesticides has long been implicated in the etiology of Parkinson’s Disease. An increasing number of epidemiological studies have linked the incidence of Parkinson’s Disease to environmental risk factors such as exposure to occupational pesticides and rural living where pesticides are known to leak into the soil and water systems far from their original area of use. The epidemiologic literature is lacking studies with large enough cohorts and accurate means to measure the exact pesticide exposure and duration of exposure. Given the extensive worldwide use of pesticides it is important to further study the associations between Parkinson’s disease and occupation exposures in larger populations.

Over 15 million contact sports players and military veterans are at risk for the development of chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with exposure to repetitive head impacts (RHI) that sometimes presents with parkinsonian motor symptoms, although very little is understood about how these individuals develop parkinsonism. CTE is characterized by accumulation of hyperphosphorylated tau protein (p-tau), and diagnosis requires the presence of neuronal tau in the form of neurofibrillary tangles at the depth of cortical sulci. We performed quantitative immunoassays for markers of neurovascular inflammation within the postmortem dorsolateral frontal cortex of participants with and without a history of RHI and CTE (n = 156), and tested for associations with RHI, microgliosis, and tau pathology measures. Levels of vascular injury-associated markers were increased in CTE compared to RHI-exposed and -naïve controls. Markers increased with RHI exposure duration and were associated with increased microglial density and tau pathology. Histologically, there was significantly increased ICAM1 staining of the microvasculature, extracellular space, and astrocytes at the sulcal depths in high stage CTE compared to both low stage CTE and controls. Multifocal perivascular immunoreactivity for serum albumin was present in all RHI-exposed individuals. These findings demonstrate that vascular injury markers are associated with RHI exposure, duration, and microgliosis, are elevated in CTE, and increase with disease severity. We next performed a cross-sectional analysis of all brain donors with CTE and without comorbid neurodegenerative disease (n=495) in the UNITE Brain Bank. Participants with parkinsonism (CTE-p, n=119) had a higher mean age at death (71.5 years (y)) than participants without parkinsonism (CTE-np, n=362, 54.1 y) and exhibited a higher rate of dementia than CTE-np participants. CTE-p participants had a more severe CTE stage and nigral pathology (NFTs, neuronal loss, and more frequent Lewy bodies), though the majority of cases were negative for nigral Lewy bodies. In American football players, simultaneous regression analysis demonstrated that nigral NFTs and neuronal loss mediate a connection between years of play and parkinsonism in CTE. In this cross-sectional study of contact sports athletes with CTE, years of contact sports participation was associated with SN proteinopathy and neuronal loss, and these pathologies were associated with parkinsonism. Finally, in a postmortem cohort (n=392) of brain donors with CTE without comorbid neurodegenerative disease, we used linear regression modelling to analyze the associations between isodendritic core nuclei pathology (semiquantitative neurofibrillary tangles (NFTs), neurites, and neuronal loss scores) and CTE disease severity, RHI exposure duration (years of contact sport play), and informant-reported cognitive and daily function as assessed by the Cognitive Difficulties Scale (CDS) and Functional Activities Questionnaire (FAQ), respectively. Overall, isodendritic core (IC) NFT scores increase with disease stage, Initially in the locus coeruleus and finally in the median raphe nuclei. Neuronal loss occurred at later disease stages than NFT accumulation. RHI exposure was associated with p-tau pathology for all IC regions. NFTs and neuronal loss in the substantial nigra were associated with increased CDS scores (i.e., worse cognitive function), and neuronal loss in the substantia nigra and locus coeruleus were associated with increased FAQ scores (i.e., worse daily function). We are able to show CTE is similar in distribution of p-tau pathology to progressive supranuclear palsy (PSP), a disease that is thought to primarily affect subcortical regions, especially by end stage disease. These results demonstrate the vulnerability of the isodendritic core nuclei to p-tau pathology and neuronal loss in CTE, and suggest that their involvement contributes to cognitive and functional symptoms during life. This work highlights the possible linkage between neuroinflammation leading to nigral p-tau accumulation and neuron loss which likely underlies the development and progression of parkinsonian motor symptoms in CTE.

The basal ganglia (BG) is a complex set of heavily interconnected nuclei located in the central part of the brain that receives inputs from the several areas of the cortex and projects via the thalamus back to the prefrontal and motor cortical areas. Despite playing a significant part in multiple brain functions, the physiology of the BG and associated disorders like dystonia remain poorly understood. Dystonia is a devastating condition characterized by ineffective, twisting movements, prolonged co-contractions and contorted postures. Evidences suggest that it occurs due to abnormal discharge patterning in BG-thalamocortocal (BGTC) circuitry. The central purpose of this study was to understand the electrophysiology of BGTC circuitry and its role in motor control and dystonia. Toward this goal, an advanced multi-target multi-unit recording and analysis system was utilized, which allows simultaneous collection and analysis of multiple neuronal units from multiple brain nuclei. Over the cause of this work, neuronal data from the globus pallidus (GP), subthalamic nucleus (STN), entopenduncular nucleus (EP), pallidal receiving thalamus (VL) and motor cortex (MC) was collected from normal, lesioned and dystonic rats under awake, head restrained conditions. The results have shown that the neuronal population in BG nuclei (GP, STN and EP) were characterized by a dichotomy of firing patterns in normal rats which remains preserved in dystonic rats. Unlike normals, neurons in dystonic rat exhibit reduced mean firing rate, increased irregularity and burstiness at resting state. The chaotic changes that occurs in BG leads to inadequate hyperpolarization levels within the VL thalamic neurons resulting in a shift from the normal bursting mode to an abnormal tonic firing pattern. During movement, the dystonic EP generates abnormally synchronized and elongated burst duration which further corrupts the VL motor signals. It was finally concluded that the loss of specificity and temporal misalignment between motor neurons leads to corrupted signaling to the muscles resulting in dystonic behavior. Furthermore, this study reveals the importance of EP output in controlling firing modes occurring in the VL thalamus.

A descoberta de que a expansão da repetição do hexanucleotídeo GGGGCC no gene C9ORF72 é uma das principais causas da Demência Frontotemporal (DFT) e da Esclerose Lateral Amiotrófica (ELA) foi um importante avanço para o entendimento dessas doenças. Essa mutação é responsável por grande parte dos casos hereditários e esporádicos. O indivíduo acometido pode se manifestar clinicamente como ELA, DFT e como a combinação fenotípica ELA-DFT. No entanto, vários outros fenótipos clínicos já foram descritos, como o de doenças que cursam com parkinsonismo atípico, ou mesmo formas que se assemelham à Doença de Parkinson e à Doença de Alzheimer. O objetivo do trabalho foi fazer uma revisão dos fenótipos associados à mutação do gene C9ORF72 descritos na literatura e descrever os casos associados à mutação identificados nos ambulatórios do Hospital das Clínicas de Ribeirão Preto (HCRP). A revisão foi feita a partir de artigos publicados entre 2011 e 2014, buscados na base de dados eletrônica PubMed. Foram selecionados 99 artigos em inglês, em que a mutação do gene C9ORF72 foi objetivo de estudo e, a partir destes, foram selecionados 44 artigos que apresentavam uma descrição individualizada dos fenótipos de um total de 219 pacientes. Nessa revisão, foram identificados 31 fenótipos. No HCRP, os pacientes com sintomas sugestivos eram encaminhados para coleta de sangue após consentimento informado. A extração do DNA a partir do material fornecido pelos pacientes foi realizada no Centro de Medicina Genômica do HCRP de forma automatizada e a amplificação dos fragmentos de interesse foi obtida pela reação de cadeia em polimerase (PCR) e pelo método qualitativo Repeat-Primed PCR (RPPCR). Foram identificados 17 pacientes com a mutação e as manifestações clínicas desses pacientes foram descritas. Foram identificados 6 fenótipos, dentre eles ELA, ELA-DFT, variante comportamental da DFT, Afasia Progressiva associada à ELA, Esquizofrenia e Esclerose Lateral Primária. Conclui-se que a variabilidade da apresentação clínica incial dos indivíduos com a mutação é extensa. Ainda não se sabe o que faz com que a mutação se manifeste de uma forma ou de outra. Saber o real tamanho da expansão do gene que causa essas doenças e ter um maior conhecimento sobre a penetrância do gene são fundamentais para aconselhamento genético das famílias acometidas. / Hexanucleotide repeat expansion GGGGCC in the C9ORF72 gene is one of the main causes of Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) being an important step towards the understanding of these disorders. This mutation is responsible for much of hereditary and sporadic cases. The affected subject may manifest ALS, FTD and ALS-FTD phenotype. However, several other clinical phenotypes have been described as atypical parkinsonism or forms that resemble Parkinson\'s disease and even Alzheimer\'s disease. The objective was to review phenotypes associated with C9ORF72 mutation described in literature and describe cases associated with the mutation identified in outpatient clinics of the Hospital das Clínicas de Ribeirão Preto (HCRP). The review was made from articles published between 2011 and 2014 searched on electronic database PubMed. We selected 99 papers in English in which mutation of the gene C9ORF72 was analyzed, and 44 were selected. We described phenotypes of 219 patients. We found 31 different phenotypes. In HCRP, patients with suggestive symptoms were selected to collect blood after informed consent. DNA extraction from the blood was done by an automated way in Genomic Medical Center in HCRP. Amplification of fragments of interest was obtained by polymerase chain reaction (PCR) and the qualitative method Repeat-primed PCR (RP-PCR). We identified 17 patients with mutation and their clinical manifestations were described. Six phenotypes were described including ALS, ALS-FTD, behavioral variant FTD, progressive aphasia associated with ALS, schizophrenia and Primary Lateral Sclerosis. We conclude variability of initial clinical presentation of patients with mutation is extensive. It is not known why this mutation manifests itself in different ways. Its important to understand how repeat expansion size causes distinct diseases, and to achieve a greater knowledge of the gene penetrance for genetic counseling of affected families.

Background: Idiopathic parkinsonism is a neurodegenerative syndrome of unknown cause and includes Parkinson’s disease (PD) and atypical parkinsonian disorders. The atypical parkinsonian disorders are: Multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). The incidence rates of these diseases in Sweden are largely unknown. The diagnosis of each disease relies mainly on clinical examination although several imaging and laboratory parameters may show changes. A diagnosis based on clinical examination is especially difficult early in the course of each disease; diagnosis is easier later on when disease-charactersistic signs have evolved and become more prominent. However, even in later stages it is not uncommon that patients are misdiagnosed. PD can be divided into subgroups based on the main clinical symptoms, i. e. tremor dominant, postural instability and gait difficulty (PIGD), and indeterminate. The PIGD subtype has worse prognosis including higher risk of dementia. The aims were to study the incidence of idiopathic parkinsonism and the different specific parkinsonian disorders in the Umeåregion and to investigate the patients early in the course of the disease with brainmagnetic resonance tomography (MRI), external anal sphincterelectromyography (EAS-EMG) and oculomotor examination. Can these methods improve the differential diagnostic work-up and/or differentiate between the subtypes of PD? Methods: We examined all patients in our catchment area (142,000 inhabitants) who were referred to us due to a suspected parkinsonian syndrome. Our clinic is the only clinic in the area receiving referrals regarding movement disorders. During the period (January 1, 2004 through April 30,2009) 190 patients fulfilled the inclusion criteria and were included in the study. Healthy volunteers served as controls.  Results: Incidence: We found the highest incidences reported in the literature: PD (22.5/100,000/year), MSA(2.4/100,000/year), and PSP (1.2/100,000/year). No CBD patients were encountered. Brain MRI: Degenerative changes were common both in controls and PD. There were no differences between the PD subtypes. EAS-EMG: Pathological changes in EAS-EMG examination were common in PD, MSA and PSP. It was not possible to separate PD, MSA and PSP by the EAS-EMG examination. Oculomotor examination: Pathological results were common in all diagnosis groups compared to controls. It was not possible to separate PD, MSA and PSP or the PD subtypes with the help of oculomotor examination. Conclusions: The incidences of idiopathic parkinsonism, PD, MSA and PSP were higher than previously reported in the literature. It is not clear weather this is due to a true higher incidence in the Umeå region or a more effective casefinding than in other studies. MRI, EAS-EMG and oculomotor examination could not contribute to the differential diagnostic work-up between PD, MSA and PSP nor differentiate between PD subtypes early in the course of the disease.

A descoberta de que a expansão da repetição do hexanucleotídeo GGGGCC no gene C9ORF72 é uma das principais causas da Demência Frontotemporal (DFT) e da Esclerose Lateral Amiotrófica (ELA) foi um importante avanço para o entendimento dessas doenças. Essa mutação é responsável por grande parte dos casos hereditários e esporádicos. O indivíduo acometido pode se manifestar clinicamente como ELA, DFT e como a combinação fenotípica ELA-DFT. No entanto, vários outros fenótipos clínicos já foram descritos, como o de doenças que cursam com parkinsonismo atípico, ou mesmo formas que se assemelham à Doença de Parkinson e à Doença de Alzheimer. O objetivo do trabalho foi fazer uma revisão dos fenótipos associados à mutação do gene C9ORF72 descritos na literatura e descrever os casos associados à mutação identificados nos ambulatórios do Hospital das Clínicas de Ribeirão Preto (HCRP). A revisão foi feita a partir de artigos publicados entre 2011 e 2014, buscados na base de dados eletrônica PubMed. Foram selecionados 99 artigos em inglês, em que a mutação do gene C9ORF72 foi objetivo de estudo e, a partir destes, foram selecionados 44 artigos que apresentavam uma descrição individualizada dos fenótipos de um total de 219 pacientes. Nessa revisão, foram identificados 31 fenótipos. No HCRP, os pacientes com sintomas sugestivos eram encaminhados para coleta de sangue após consentimento informado. A extração do DNA a partir do material fornecido pelos pacientes foi realizada no Centro de Medicina Genômica do HCRP de forma automatizada e a amplificação dos fragmentos de interesse foi obtida pela reação de cadeia em polimerase (PCR) e pelo método qualitativo Repeat-Primed PCR (RPPCR). Foram identificados 17 pacientes com a mutação e as manifestações clínicas desses pacientes foram descritas. Foram identificados 6 fenótipos, dentre eles ELA, ELA-DFT, variante comportamental da DFT, Afasia Progressiva associada à ELA, Esquizofrenia e Esclerose Lateral Primária. Conclui-se que a variabilidade da apresentação clínica incial dos indivíduos com a mutação é extensa. Ainda não se sabe o que faz com que a mutação se manifeste de uma forma ou de outra. Saber o real tamanho da expansão do gene que causa essas doenças e ter um maior conhecimento sobre a penetrância do gene são fundamentais para aconselhamento genético das famílias acometidas. / Hexanucleotide repeat expansion GGGGCC in the C9ORF72 gene is one of the main causes of Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) being an important step towards the understanding of these disorders. This mutation is responsible for much of hereditary and sporadic cases. The affected subject may manifest ALS, FTD and ALS-FTD phenotype. However, several other clinical phenotypes have been described as atypical parkinsonism or forms that resemble Parkinson\'s disease and even Alzheimer\'s disease. The objective was to review phenotypes associated with C9ORF72 mutation described in literature and describe cases associated with the mutation identified in outpatient clinics of the Hospital das Clínicas de Ribeirão Preto (HCRP). The review was made from articles published between 2011 and 2014 searched on electronic database PubMed. We selected 99 papers in English in which mutation of the gene C9ORF72 was analyzed, and 44 were selected. We described phenotypes of 219 patients. We found 31 different phenotypes. In HCRP, patients with suggestive symptoms were selected to collect blood after informed consent. DNA extraction from the blood was done by an automated way in Genomic Medical Center in HCRP. Amplification of fragments of interest was obtained by polymerase chain reaction (PCR) and the qualitative method Repeat-primed PCR (RP-PCR). We identified 17 patients with mutation and their clinical manifestations were described. Six phenotypes were described including ALS, ALS-FTD, behavioral variant FTD, progressive aphasia associated with ALS, schizophrenia and Primary Lateral Sclerosis. We conclude variability of initial clinical presentation of patients with mutation is extensive. It is not known why this mutation manifests itself in different ways. Its important to understand how repeat expansion size causes distinct diseases, and to achieve a greater knowledge of the gene penetrance for genetic counseling of affected families.

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2016-04-05T14:57:05Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação - Rebecca Cristina Linhares de Carvalho, 2015.pdf: 1343136 bytes, checksum: 87551351118cac05985078a5ee318616 (MD5) / Made available in DSpace on 2016-04-05T14:57:05Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação - Rebecca Cristina Linhares de Carvalho, 2015.pdf: 1343136 bytes, checksum: 87551351118cac05985078a5ee318616 (MD5) Previous issue date: 2015-02-25 / FACEPE / Parkinsonismo é uma síndrome neurológica em que os neurônios que normalmente produzem o hormônio chamado dopamina se deterioram, causando a perda de controle progressivo do movimento (ex. bradicinesia, a rigidez muscular, o temor de repouso e os reflexos posturais prejudicados). Um mal com sintomas semelhantes ao parkinsonismo é a síndrome ScansWithout Evidence of Dopaminergic Deficits (SWEDDs), na qual os pacientes não apresentam evidências de déficit de dopamina. As causas de parkinsonismo primário como a doença de Parkinson (DP), bem como SWEDDs, não são completamente conhecidos. Os estudos de associações no genoma completo (Genome-wide association studies - GWAS) têm proporcionado ganhos tangíveis para a compreensão da arquitetura genética de doenças complexas, trazendo contribuições consistentes e importantes para DP. GWASs foram realizados no passado com os dados de DP com resultados que influenciaram fortemente desenvolvimentos posteriores. Nesse trabalho, nós desenvolvemos um estudo sobre fatores genéticos que possam contribuir para o entendimento da ocorrência da DP e SWEDDs. Para isso, nós usamos o conjunto de ferramentas de análise de associação envolvendo estudo de caso-controle do método PLINK para executar GWASs, a fim de identificar SNPs que estão associados à DP e SWEDDs. Para fixar o nível de significância dos nossos resultados, nós optamos por usar somente dados reais fornecidos por Parkinson’s Progression Markers Initiative (PPMI). O PPMI é um consórcio internacional projetado para identificar biomarcadores de progressão da DP, tanto para melhorar a compreensão da etiologia da doença, como para fornecer ferramentas cruciais para aumentar a probabilidade de sucesso na elaboração de novos ensaios terapêuticos para DP. Na análise de associação, feita com dados genótipos de três grupos de indivíduos (indivíduos saudáveis, indivíduos com DP e indivíduos com SWEDDs), recuperamos SNPs que mostram forte ligação com PD e SWEDDs, alguns deles já associados na literatura científica com a DP ou a outras doenças degenerativas. Mas, também encontramos cerca de 60 SNPs que não estão relatados na literatura, que mostram evidências de serem fortemente relacionadas com a propensão para DP ou SWEDDs. Estes resultados apresentam alvos promissores para futuros estudos genômicos e podem contribuir para o entendimento da ocorrência da DP e SWEDDs. Curiosamente, embora SWEDDs seja uma doença clinicamente ligada a DP por uma série de sintomas comuns, os SNPs recuperados com as melhores classificações a partir do conjunto de dados DP não faziam parte do conjunto de dados SWEDDs, e vice-versa, o que sugere que esses dois conjuntos de marcadores poderiam ser mais cuidadosamente explorados nos estudos genômicos como SNPs comuns de interesse para as duas doenças. / Parkinsonism is a neurological disorder neurons that normally produce the hormone called dopamine deteriorate, causing progressive loss of movement control (e.g. bradykinesia, muscle rigidity, tremor at rest, and impaired postural reflexes). A syndrome with similar symptoms is Scans Without Evidence of Dopaminergic Deficits (SWEDDs), in which the patients not present evidence of dopaminergic deficits. The causes of primary parkinsonism, or Parkinson’s disease (PD), as well as SWEDDs, are not completely known. Genome-wide association studies (GWASs) have provided substantial contribution to the understanding of the architecture of complex diseases, bringing consistent and important contributions to PD. GWASs have been performed in the past with PD data with results that strongly influenced later developments. In this work, a study of genetic factors that contributes to the set of tools of association analysis for a better understanding of occurency of PD and SWEDDs. To that end, the set of tools of association analysis is involved in a study case for the PLINK method to execute GWASs with the objective of identifying SNPs which are associated to DP and SweDDs. To determine the level of significance of our results, only real data provided by Parkinson’s Progression Markers Initiative (PPMI) was used. PPMI is an international consortium created to indetify biomarkers of DP progression, to better comprehend the etiology of this disease and to provide key tools to increase the probability of success in the development of new therapeutic trials for PD. The association analysis, done with genotype data from three groups of individuals (healthy, affected by PD and affected by SWEDDs), SNPS that have shown strong connection to PD and SWEDDs were recovered, some of them are already linked in the scientific literature to PD or other degenerative diseases. But, we also have found about 60 SNPs that are not reported in the literature, which show evidence to be strongly related to the propensity to PD or SWEDDs. These results are promising targets for future genomic studies and may contribute to the understanding of the occurrence of PD and SWEDDs. Interestingly, although SWEDDs is a disorder clinically linked to PD by a series of common symptoms, the top ranked SNPs recovered from the PD dataset were not part of the SWEDDs dataset and conversely, that suggests that those two sets of markers could be more carefully explored in the genomic studies as common SNPs of interest for the two diseases.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Studies have shown that pesticide exposure is a risk factor to Parkinson Disease (PD) development in urban areas and mainly in rural areas. One of these pesticides, Deltamethrin (DM), is used indiscriminately for vector control in crops, veterinary medicine and control of domestic pests. The aim of the study is investigate the motor, cognitive and neurochemical changes caused by repeated administration of DM in rats. 38 Male Wistar rats were used, 9-10 months-old, from the Neurophysiology Laboratory animal house of UFS. The study was divided into two experiments: (1) intranasal (i.n.) and (2) intracerebroventricular (i.c.v.). In the (1), the animals were divided into 2 groups (CTR, 0.9% saline solution, n=9) and DM 0.5 (treated with DM 0.5 mg, n=10), that received 3 infusions administrated one every 7 days. During the treatment, the animal were subjected to behavior test: catalepsy, novel object recognition task, spontaneous alternation and contextual conditioned fear. In i.c.v. experiment, the animals were divided into 3 groups: control (CTR, n=7); DM 0.5 (treated with DM 0.5 μg diluted in 2 μL, n=7) and DM 5 (treated with DM 5 μg diluted in 2 μL, n=5). In the experiment (2), the animals received 3 i.c.v. injections (2 μL/injection), one each 48 hours. During the treatment, the rats were submitted to behavior test: catalepsy, open field test and spontaneous alternation. After the behavior tests of both experiments, the rats were anesthized, perfused transcardially, their brains removed and submitted to Tyrosine Hydroxylase (TH) immunochemistry in Substancia Nigra pars compacta (SNpc), Ventral Tegmental Area (VTA) and dorsal striatum areas. In i.n. experiment, there were motor changes in open field and cognitive changes in novel object recognition task and contextual conditioned fear. The immunohistochemistry shows a reduction of TH+ cells in SNpc and VTA and an increase of Optical Density in dorsal striatum. In i.c.v. experiment, it was observed motor changes in open field and cognitive changes in spontaneous alternation. In immunohistochemical there was a decrease of TH + cells in DM 5ug animals in SNpc and VTA and decreased their levels in DM 0.5 g and DM 5 ug groups in the dorsal striatum. In both experiments, cognitive changes preceded the motor changes. The data presented contribute to understanding of physiological and behavioral changes after exposure to DM and more studies are needed to elucidate the DM as a possible cause of parkinsonism symptoms. / Estudos tem demonstrado que a exposição a pesticidas é um fator de risco para o desenvolvimento da doença de Parkinson (DP) em áreas urbanas e principalmente em áreas rurais. Um desses pesticidas, a deltametrina (DM), é utilizada indiscriminadamente no controle de vetores na lavoura, na medicina veterinária e no controle de pestes domésticas. Diante disso, o objetivo da pesquisa é avaliar as alterações motoras, cognitivas e neuroquímicas causadas pela administração repetida da DM em ratos. Foram utilizados 38 ratos Wistar machos, com idade entre 9-10 meses, provenientes do Biotério do Laboratório de Neurofisiologia da UFS. O trabalho foi dividido em dois experimentos: (1) administração intranasal (i.n.) e (2) intracerebroventricular (i.c.v.) de DM. No experimento 1 (intranasal), os animais foram divididos em 2 grupos: controle (CTR, solução salina 0,9%, n=9) e DM 0,5 (tratados com DM 0,5 mg, n=10), que receberam 3 infusões intranasais administradas 1 a cada 7 dias. Durante o tratamento, os animais foram submetidos a testes comportamentais: catalepsia, reconhecimento de objeto novo, alternação espontânea e medo condicionado ao contexto. No experimento 2 (i.c.v.), os animais foram divididos em 3 grupos: controle (CTR, n=7), DM 0,5 (tratados com DM 0,5 μg em 2 μL, n=7) e DM 5 (tratados com DM 5 μg em 2 μL, n=5). Nessa etapa, os animais receberam 3 injeções i.c.v. (2 μL por injeção), uma a cada 48h. Ao longo do tratamento, os ratos foram avaliados nos testes da catalepsia, campo aberto e alternação espontânea. Após os testes de comportamento em ambos experimentos, os ratos foram anestesiados, perfundidos, seus cérebros removidos e submetidos a imunohistoquímica para Tirosina Hidroxilase (TH) na substância negra parte compacta, área tegmental ventral e estriado dorsal. Foi observado no experimento i.n. que houve alterações motoras no campo aberto e cognitivas no reconhecimento de objeto novo e no medo condicionado ao contexto. A imunohistoquímica mostrou redução de células TH+ na SNpc e VTA e aumento de TH+ no estriado dorsal. No experimento i.c.v., foram observadas alterações motoras no campo aberto e cognitivas na alternação espontânea. Na imunohistoquímica houve diminuição de células TH+ nos animais DM 5 μg na SNpc e em VTA e redução de seus níveis nos grupos DM 0,5 μg e DM 5 μg no estriado dorsal. Em ambos os experimentos, alterações cognitivas precederam as alterações motoras. Os dados apresentados contribuem no entendimento sobre alterações fisiológicas e comportamentais após exposição a DM e mais estudos deverão ser realizados para elucidar a DM como um possível causador de sintomas de parkinsonismo.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Reserpine treatment is a putative animal model of orofacial dyskinesia, tremor, and Parkinsonism. Here, we examined the effects of resveratrol, a polyphenol with neuroprotective properties primarily contained in red grapes and red wine, in an animal model of vacuous chewing movements (VCM) induced by treatment with reserpine in mice. Mice were treated with reserpine (1 mg/kg, subcutaneously administered on days 1 and 3) and/or resveratrol (5 mg/kg, intraperitonealy administered 3 consecutive days). VCM, locomotor, and exploratory performance were evaluated. It was also analysed nonproteic thiol groups and Vitamin C levels in cortex and region containing both substantia nigra and striatum as antioxidant defense parameters. Reserpine treatment produced an increase in VCM intensity, which was significantly reduced by resveratrol co-treatment. Reserpine also decreased locomotor and exploratory activity in the open field test. However, resveratrol co-treatment was not able to protect against these effects. We did not find any statistical differences among the groups when antioxidant defense parameters were evaluated. The data suggest that resveratrol could be a promising pharmacological tool for treating VCM in rodents. However, further investigations are needed to understand the exact mechanisms involved in the neuroprotective effects of resveratrol. / A administração de reserpina consiste num modelo animal de discinesia orofacial, tremor e parkinsonismo. Neste trabalho, investigamos o efeito do resveratrol, um polifenol com propriedades neuroprotetoras encontrado principalmente em frutas vermelhas e no vinho tinto, em um modelo animal de movimentos de mascar no vazio induzidos (MMVs) por tratamento com reserpina em camundongos. Os camundongos foram tratados com reserpina (1 mg/kg, administrado subcutaneamente nos dias 1 e 3) e/ou resveratrol (5 mg/kg, administrado intraperitonealmente durante 3 dias consecutivos). Foram avaliados os MMVs, atividade locomotora e exploratória. Também analisamos os níveis de tióis nãoprotéicos e de ácido ascórbico em córtex e região contendo ambos, substância negra e estriado, como parâmetros de defesa antioxidante. O tratamento com reserpina produziu um aumento na intensidade dos MMVs, os quais foram significativamente reduzidos pelo cotratamento com resveratrol. A reserpina também diminuiu a atividade locomotora e exploratória no teste de campo aberto. Contudo, o co-tratamento com resveratrol não foi capaz de modificar estes efeitos. Não foram encontradas diferenças estatisticamente significativas entre os grupos quando os parâmetros de defesa antioxidantes foram avaliados. Os dados obtidos sugerem que o resveratrol poderia ser um agente promissor no tratamento de MMVs em camundongos. Contudo, investigações adicionais são necessárias para entender os exatos mecanismos envolvidos nos efeitos neuroprotetores do resveratrol.