Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Missouri--Columbia, 1998. / Typescript. Vita. Includes bibliographical references (leaves: 138-170). Also available on the Internet.

Στην παρούσα μελέτη παρουσιάσαμε τα αποτελέσματα της λειτουργικής απεικόνισης με SPECT αιμάτωσης εγκεφάλου σε δύο διαφορετικές παθολογικές καταστάσεις, την νόσο του Παρκινσον και τη δευτεροπαθή δυστονία. Στο πρώτο μέρος της μελέτης διερευνήσαμε την ακεραιότητα της μελανοραβδωτής οδού και την αιματική εγκεφαλική ροή στα διάφορα στάδια της νόσου Parkinson. Στη μελέτη συμμετείχαν συνολικά 53 ασθενείς (27 άνδρες, 26 γυναίκες) που πληρούσαν τα κριτήρια της Ιδιοπαθούς νόσου του Parkinson και αξιολογήθηκαν σύμφωνα με την κλίμακα Unified Parkinson Disease Rating Scale (UPDRS) καθώς και την κλίμακα Hoehn-Yahr. Οι ασθενείς χωρίστηκαν σε 4 ομάδες σύμφωνα με την κλίμακα Hoehn-Yahr. Το πρωτόκολλο μελέτης των 53 ασθενών περιελάμβανε 2 απεικονιστικές εξετάσεις: Α) το SPECT εγκεφάλου με το ραδιοφάρμακο 123Ι- Ioflupane (DaTSCAN) και Β) το SPECT αιμάτωσης εγκεφάλου με το ραδιοφάρμακο 99m Tc-ECD (Neurolite ). Η νόσος Πάρκινσον είναι ένα υποκινητικό σύνδρομο και όπως καταδείξαμε από τη μέλετη ασθενών σε διάφορα στάδια της νόσου, το πρότυπο της αιμάτωσης του εγκεφάλου είναι αυτό της σταδιακής προσβολής περιοχών του φλοιού ως συνέπεια της απόσχισης των συνδέσεων του κυκλώματος βασικών γαγγλίων με το φλοιό. Συγκεκριμένα αποδείξαμε ότι στα αρχικά στάδια της νόσου παρατηρείται υποαιμάτωση περιοχών του μετωπιαίου λοβού (κινητικών, προκινητικών και περιοχών του προμετωπαίου λοβού) ενώ σε πιο προχωρημένα στάδια η προσβολή του φλοιού επεκτείνεται σε περιοχές του βρεγματικού και κροταφικού λοβού. Επίσης βρέθηκε θετική συσχέτιση μεταξύ της ειδικής σύνδεσης του ρ/φ στον αριστερό κερκοφόρο πυρήνα και της αιματικής εγκεφαλικής ροής στην περιοχή DLPFC του προμετωπιαίου λοβού αριστερά, καθώς επίσης και μεταξύ της ειδικής σύνδεσης του ρ/φ στο αριστερό κέλυφος και της αιματικής εγκεφαλικής ροής στην πρωτοταγή κινητική περιοχή αριστερά. Στο δεύτερο μέρος της εργασίας μελετήσαμε 21 ασθενείς με Ιδιοπαθή νόσο Parkinson που πληρούσαν τα κριτήρια για χειρουργική αντιμετώπιση με εν τω βάθει εγκεφαλικό ερεθισμό (DBS). Οι ασθενείς ήταν 11 γυναίκες και 10 άνδρες, μέσης ηλικίας 63±8 χρόνια, μέσης διάρκειας της νόσου 11.5±4.8 και σταδίου 2.9±0.8 κατά Hoehn and Yahr. Οι ασθενείς αυτοί υπεβλήθησαν σε 2 ξεχωριστές μελέτες SPECT αιμάτωσης εγκεφάλου, η πρώτη πριν το χειρουργείο (meds off) και η δεύτερη 6 μήνες μετά το χειρουργείο (DBS on/ off meds). Οι δύο αυτές μελέτες συγκρίθηκαν μεταξύ τους με το πρόγραμμα Neurogam και εξετάστηκαν συγκεκριμένα οι μεταβολές στην αιματική εγκεφαλική ροή των κινητικών περιοχών του εγκεφάλου. Παράλληλα εξετάσθηκε η κινητική βελτίωση των ασθενών κλινικά και με βάση την κλίμακα mUPDRS. Τα αποτελέσματα της μελέτης ήταν πολύ καλά καθώς οι 20 ασθενείς παρουσίασαν σημαντική κλινική βελτίωση μειώνοντας την κλίμακα mUPDRS κατά 44% και τη χορηγούμενη δόση levodopa από 850 ± 108 mg πριν το χειρουργείο σε 446 ± 188 mg στο διάστημα επανελέγχου. Επίσης στους 6 μήνες παρατηρήθηκε σημαντική αύξηση της αιματικής εγκεφαλικής ροής στην προκινητική και πρωτοταγή κινητική περιοχή του εγκεφαλικού φλοιού κατά 10.9% και σημαντική συσχέτιση αυτής με την κινητική βελτίωση των ασθενών (r=.89, p<.001). Από τη μελέτη μας προκύπτει ότι το DBS είναι ικανό να άρει την υποαιμάτωση τουλάχιστον των κινητικών περιοχών του φλοιού, οδηγώντας στην κινητική βελτίωση των ασθενών. Στο τρίτο μέρος της μελέτης μας ασχοληθήκαμε με την μελέτη ασθενών με δευτεροπαθή δυστονία που αποτελεί ένα υπερκινητικό σύνδρομο με ετερογένεια όσον αφορά την αιτιολογία του. Συγκεκριμένα μελετήσαμε το αποτέλεσμα της δράσης του DBS στην περιοχική αιματική εγκεφαλική ροή των κινητικών περιοχών του φλοιού σε συνάρτηση με το κλινικό αποτέλεσμα. Στο πρωτόκολλο πριελήφθησαν 6 ασθενείς με φαρμακευτικά ανθεκτική δευτεροπαθή δυστονία που υπεβλήθησαν σε DBS. Οι ασθενείς υπεβλήθησαν σε SPECT αιμάτωσης εγκεφάλου σε δύο διαφορετκές λειτουργικές καταστάσεις μετεγχειρητικά: DBS on & DBS off κατάσταση. Οι δύο μελέτες συγκρίθηκαν μεταξύ τους με το πρόγραμμα Neurogam. Η κινητική εκτίμηση των ασθενών έγινε με την κλίμακα Burke–Fahn–Mardsen Dystonia Rating Scale (BFMDRS) στις δυο διαφορετικές καταστάσεις (DBS on & DBS off). Δύο ασθενείς έδειξαν άριστη κλινική βελτίωση στον επανέλεγχο, σε δύο άλλους τα αποτελέσματα ήταν μέτρια και σε δύο τα αποτελέσματα της επέμβασης κρίθηκαν φτωχά. Ο μέσος βαθμός βελτίωσης της κλίμακας BFMDRS ήταν 49.1% (0–90.7%). Επίσης η ανάλυση των SPECT μελετών έδειξε σημαντική μείωση της rCBF στην κατάσταση on DBS κάτι που συσχετίστηκε με την κλινική βελτίωση. Όσον αφορά το μηχανισμό δράσης του εν τω βάθη εγκεφαλικού ερεθισμού, παρά τις πολλαπλές θεωρίες που υπάρχουν, φαίνεται, τουλάχιστον από το δικό μας μικρό δείγμα ασθενών, να λειτουργεί με το να επαναρυθμίζει το υπάρχων παθολογικό λειτουργικό κύκλωμα σε ένα νέο πιο αρμονικό ρυθμό, προσφέροντας στους ασθενείς μία νέα οδό επικοινωνίας του συστήματος των βασικών γαγγλίων με το φλοιό και στις περισσότερες περιπτώσεις να καταφέρνει να προσφέρει κινητική βελτίωση. / In the present study we present the results of functional brain imaging with regional Cerebral Blood Flow SPECT (rCBF SPECT) in two different neurological disorders; Parkinson’ Disease (PD) and Secondary Dystonia. In the first case of Parkinson’s Disease, our first purpose was to investigate the differences and associations between cortical perfusion and nigrostriatal dopamine pathway in different stages of Parkinson’s disease (PD). For that purpose we recruited 53 non-demented PD patients divided into four groups according to the Hoehn and Yahr (HY) staging system. Each patient underwent two separate brain single photon emission computed tomography (SPECT) studies (perfusion and dopamine transporter binding). Perfusion images of each patient were quantified and compared with a normative database provided by the NeuroGam software manufacturers. Compared with controls, PD patients showed impairments of cerebral perfusion that increased with clinical severity. Furthermore Dopamine transporter binding in the left caudate nucleus and putamen significantly correlated with blood flow in the left dorsolateral prefrontal cortex (DLPFC) and primary motor cortex respectively. We concluded that there are significant perfusion deficits, that are associated with PD progression, implying a multifactorial neurodegeneration process apart from dopamine depletion in the substantia nigra pars compacta (SNc). Given the fact that high-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become an established therapeutic approach for the management of patients with medically intractable idiopathic Parkinson’s disease (PD), our second purpose was to to assess regional cerebral blood flow (rCBF) changes related to motor improvement after Deep Brain Stimulation of the Subthalamic Nucleus (STN DBS). For that purpose we studied twenty-one PD patients (11 females and 10 males, mean age 63±8, mean disease duration 11.5±4.8, mean Hoehn and Yahr stage:2.9±0.8), that underwent two rCBF SPECT studies at rest, once preoperatively in the off-meds state and the other postoperatively (at 6±2 months) in the off-meds/on-stimulation state. Patients were classified according to the Unified Parkinson Disease Rating Scale (UPDRS) and Hoehn and Yahr (H&Y) scale. Neurogam software was used to register, quantify and compare two sequential brain SPECT studies of the same patient in order to investigate rCBF changes during STN stimulation in comparison with preoperative rCBF. The results showed that all patients presented clinical improvement during the first months after surgery resulting in a 44% reduction of the UPDRS motor score. The administered mean daily levodopa dose significantly decreased from 850 ± 108 mg before surgery to 446 ± 188 mg during off meds state (p < .001, paired t-test). At the 6 month postoperative assessment we noticed rCBF increases in the pre-supplementary motor area (pre-SMA) and the premotor cortex (PMC) (mean rCBF increase=10.9%), the dorsolateral prefrontal cortex and in associative and limbic territories of the frontal cortex (mean rCBF increase=8.2%). A correlation was detected between the improvement in motor scores and the rCBF increase in the pre-SMA and PMC (r=.89, p<.001). Our study suggests that STN stimulation leads to improvement in neural activity in the frontal motor/associative areas. The correlation between motor improvement and rCBF increase in higher order motor cortical areas suggests that even the short term stimulation achieves its therapeutic benefit by restoring the activity within these cortical regions. In the third part of our study we investigated the effect of deep brain stimulation (DBS) on regional cerebral blood flow (rCBF) in cases of secondary dystonia in correlation with clinical outcomes. For that purpose we studied six patients with medically intractable secondary dystonia who underwent DBS surgery. Burke–Fahn–Mardsen Dystonia Rating Scale (BFMDRS) was used for the assessment of dystonia, in the on & off DBS state. Single photon emission computed tomography (SPECT) of the brain was performed postoperatively in the two stimulation states (ON-DBS and OFFDBS) and the changes of rCBF in the three following brain regions of interest (ROIs): primary motor cortex, premotor and supplementary motor cortex, and prefrontal cortex were evaluated. Two patients exhibited excellent response to DBS, two patients got moderate benefit after the procedure, and in two patients, no clinical improvement was achieved. A mean improvement of 49.1% (0–90.7%) in BFMDRS total scores was found postoperatively. Brain SPECT data analysis revealed an overall decrease in rCBF in the investigated ROIs, during the ON-DBS state. Clinical improvement was significantly correlated with the observed decrease in rCBF in the presence of DBS. We concluded that when conservative treatment fails to relieve severely disabled patients suffering from secondary dystonia, DBS may be a promising therapeutic alternative. Moreover, thiat study indicates a putative role of brain SPECT imaging as a postoperative indicator of clinical responsiveness to DBS.

Os mecanismos moleculares que levam ao dano da via nigroestriatal durante a progressão da Doença de Parkinson (DP) ainda não estão totalmente elucidados. Dessa forma, existe a necessidade de desenvolver modelos experimentais adequados para o estudo desse distúrbio neurodegenerativo. A linhagem de neuroblastoma humano SH-SY5Y tratada com neurotoxinas indutoras deste distúrbio (ex.: 6-hidroxidopamina - 6-OHDA) é amplamente utilizada como modelo in vitro da DP. Muitos estudos mostram que esta linhagem pode ser diferenciada em células dopaminérgicas através da combinação da diminuição do soro fetal bovino (SFB) em meio de cultura e da adição de neurotrofinas como o ácido retinóico (AR). No entanto, há poucos estudos mostrando as diferenças entre células proliferativas e diferenciadas da linhagem de neuroblastoma SH-SY5Y, além do efeito do tratamento com 6-OHDA. Ainda, não há um consenso nos protocolos de diferenciação. Dessa forma, o objetivo deste estudo foi estabelecer um protocolo de diferenciação dopaminérgica da linhagem de neuroblastoma humano SH-SY5Y, bem como avaliar a potencialidade do modelo como plataforma para o screening de neurotoxicidade/neuroproteção de compostos e a possibilidade de manipulação gênica. As células proliferativas SH-SY5Y foram mantidas em meio de cultura DMEM/F12 (1:1) suplementado com 10% de SFB. A diferenciação foi induzida pela combinação de 10 μM de AR e meio de cultura com 1% de SFB durante 4, 7 e 10 dias. Foram avaliados parâmetros morfológicos (presença de neuritos) e neuroquímicos, através marcadores de diferenciação neuronal (DAT- transportador de dopamina; TH – tirosina hidroxilase; ENS – enolase neurônio específica; NeuN – proteína nuclear de neurônio; Nestina). Ainda, avaliamos parâmetros de estresse oxidativo através da atividade de enzimas antioxidantes e dos níveis de tióis reduzidos. Nossos dados mostraram que as células SH-SY5Y diferenciadas por 7 dias apresentaram mudanças morfológicas e o aumento do imunoconteúdo de todos os marcadores neuronais testados, e a concomitantemente diminuição do imunoconteúdo de nestina (marcador de células indiferenciadas). Além disso, o fenótipo neuronal apresentou uma maior atividade de alguns sistemas antioxidantes. Também foi avaliada a citotoxicidade frente ao H2O2 e à 6-OHDA nos dois fenótipos. As células diferenciadas se mostraram mais resistentes ao dano causado pelo H2O2 e mais sensíveis à 6-OHDA. Dessa forma, a citotoxicidade da 6-OHDA pode estar relacionada com o aumento do imunoconteúdo do DAT, visto que a neurotoxina entra na célula dopaminérgica através deste transportador. Interessantemente, as células diferenciadas apresentaram aumento dos níveis da proteína neuroprotetora DJ-1, que está relacionada a uma forma prematura de Parkinsonismo em humanos. Após a caracterização do modelo, nós utilizamos o fenótipo diferenciado como plataforma experimental para o screening de compostos neuroprotetores como os organocalcogênios. Nós determinamos a citotoxidade destes compostos em células diferenciadas da linhagem de neuroblastoma SH-SY5Y. A partir destes dados, foram selecionados compostos com baixa citotoxicidade e avaliamos a morfologia celular (densidade de neuritos). Nós verificamos que antes da perda de viabilidade, ocorre a perda de neuritos, sendo que este parâmetro é outra vantagem do modelo de célula diferenciada para avaliação da neurototoxicidade. Ainda, verificamos que estes compostos são capazes de prevenir o dano celular causado pela 6-OHDA. Além disso, nós caracterizamos a capacidade do modelo de ser manipulado geneticamente através da transfecção e superexpressão de plasmídeo contendo a proteína verde fluorescente, onde verificamos que a expressão é mantida durante a diferenciação. Dessa forma, nossos dados mostraram a eficácia da padronização da diferenciação induzida por AR da linhagem de neuroblastoma humano SH-SY5Y, pois estas células apresentam características morfológicas e neuroquímicas adequadas de neurônio dopaminérgico bem como pode ser aplicado não só para avaliação de neurototoxicidade/neuroproteção, mas também pode ser manipulado geneticamente. / The molecular mechanisms underlying the massive cellular loss found in the nigrostriatal pathway during the progression of Parkinson’s disease (PD) are not completely understood. Therefore, it is important to develop more suitable experimental models to study the molecular mechanisms of this neurodegenerative disorder. Proliferative human neuroblastoma cell line SH-SY5Y challenged with neurotoxins (e.g.: 6-hydroxydopamine – 6-OHDA) has been widely used as an in vitro model for PD. Many lines of evidence showed that this cell line differentiates with the combination of lower fetal bovine serum (FBS) and retinoic acid (RA) to dopaminergic-like neural cell. However, there are few studies addressing the differences between proliferative and RA-differentiated SH-SY5Y cells as well as their responses to 6-OHDA cytotoxicity. Moreover, there is no consensus in differentiation protocols. Hence, the objective of this study was to establish a RAinduced dopaminergic differentiation protocol and also evaluate its capabilities for drug screening of neurotoxicity/neuroprotection and genetic manipulation. Exponentially growing SH-SY5Y cells were maintained with DMEM/F12 (1:1) medium plus 10% FBS. Differentiation was triggered by the combination of 10 μM of RA plus medium with 1% of FBS during 4, 7 and 10 days. We evaluated the cell morphology (neurites) and the neuronal markers (Dopamine Transporter- DAT, Tyrosine Hydroxylase-TH, Neuron-Specific Enolase-NSE, Neuronal Nuclei Protein- NeuN, and Nestin immunocontent). Furthermore, we verify the activity of antioxidant enzymes and the reduced thiol levels. Our data demonstrated that SH-SY5Y cells differentiated for 7 days expresses all neuronal markers tested with concomitant decrease in nondifferentiated marker (nestin). Besides, they showed a higher activity of some antioxidant systems. We also evaluated the cytotoxicity of H2O2 and 6-OHDA in both phenotypes. Differentiated cells are more resistant to H2O2 and more sensitive to 6- OHDA. Hence, the damage caused by 6-OHDA could be related with the increase of DAT immuncontent, because this neurotoxin enters into the dopaminergic cell through this transporter. Interestingly, the differentiated cells have more levels of neuroprotective DJ-1 protein, which is related with a juvenile Parkinsonism. After establish the conditions of differentiation, we used the neuronal phenotype to perform a drug screening with organoselenide compounds. We verify the cytotoxicity of these compounds in differentiated cells. From these data, we selected compounds with low toxicity and evaluated the cell morphology (neurites density). We verify that before the loss of viability, there is a loss of neurites. This parameter is another advantage of the differentiated cells model to neurotoxicity evaluation. Moreover, these compounds were able to prevent neuronal cell death caused by 6-OHDA. We also characterized the ability of the model to be manipulated genetically through transfection and overexpression of a green fluorescent protein (GFP) plasmid. We verify that the expression of GFP is maintained during the differentiation. Hence, our data showed the efficacy of the RA-induced differentiation protocol of the neuroblastoma cell line SH-SY5Y, because these cells have morphological and neurochemical characteristics of dopaminergic neurons. Furthermore, the neuronal phenotype can be applyed not only to evaluate neurocytotoxicity/neuroprotection but also can be manipulated genetically.

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Evidências crescentes mostram que os distúrbios de sono associados à doença de Parkinson (DP) são mais relacionados à doença per se, do que apenas fenômenos secundários. Dados apresentados pela literatura sugerem a hipótese de que o sistema dopaminérgico nigroestriatal esteja envolvido na regulação de padrões de sono. Demonstrou-se no presente trabalho que uma lesão de 50% dos neurônios dopaminérgicos residentes na substância negra pars compacta (SNpc) foi capaz de gerar um prejuízo em diversos parâmetros de sono em ratos. Essa redução neuronal provocou uma diminuição importante na porcentagem de sono paradoxal durante os três primeiros dias de registro de sono. Observou-se também uma forte correlação (r=0.91) entre o número de neurônios e a porcentagem de sono paradoxal. A partir disso, propomos que os neurônios dopaminérgicos presentes na SNpc possuem um papel fundamental para a regulação dos padrões de sono, particularmente na promoção de sono paradoxal. Em outro experimento, apresentamos evidências de que a proteína tirosina hidroxilase (TH) encontra-se com sua expressão reduzida no sistema dopaminérgico nigroestriatal após um período de 24 h de privação de sono paradoxal (PSP) em camundongos. De acordo com esses resultados, sugerese que a redução da expressão da TH, produzida pela (PSP), possa explicar em parte a existência da supersensibilidade dopaminérgica de receptores D2. As implicações dessas alterações podem reverberar diretamente sobre anormalidades motoras e de sono encontradas em pacientes portadores da DP. xiii Achados eletrofisiológicos demonstraram que o bloqueio dos receptores D2 (por haloperidol) produziu uma redução de sono paradoxal durante o período de rebote, realizado após 96 h de PSP. Essa redução foi acompanhada por um incremento de sono de ondas lentas, o que possivelmente tenha ocorrido em decorrência de um observado aumento de eficiência de sono. Os resultados também indicaram que a administração de piribedil não pôde gerar um aumento adicional de sono paradoxal. Sugerimos a existência de uma ação particular da neurotransmissão dopaminérgica recaindo sobre a ativação dos receptores D2. As evidências demonstradas no presente trabalho e na literatura permitem sugerir que os neurônios dopaminérgicos presentes na SNpc e na aérea tegmental ventral podem ser considerados essenciais para a regulação de sono, em particular no disparo e manutenção do sono paradoxal, respectivamente. Propõe-se que o paradigma que envolve a dopamina como sendo responsável apenas pela vigília, não é totalmente acurado. A teoria proposta nessa tese alega que esse neurotransmissor pode apresentar uma importante participação em ambos os estados: vigília e sono, e que cada estado deva ser gerado por intermédio de diferentes graus de modulação dopaminérgica. A conclusão delineada a partir desses achados é que a dopamina apresenta implicações significantes na regulação de sono, e essa condição particular deve ser considerada em relação ao tratamento de pacientes com a DP. / Dopamine (DA) is critically involved in regulating neural processes responsible for complex movements and emotions. Alterations in central dopaminergic neurotransmission have been implicated in important neurological and psychiatric disorders such as Parkinson’s disease (PD) and schizophrenia. In addition, DA has recently been recognized as instrumental in the regulation of sleep-wake states. Herein, we present evidence that tyrosine hydroxylase (TH) is down-regulated in the nigrostriatal pathway after 24 h of sleep deprivation (SD) in mice. To identify the involvement of DA in SD and sleep rebound (R) we administered reserpine (1 mg/kg) associated to a-methyl-p-tyrosine (aMT) (250 mg/kg) to produce DA depletion, and rotenone (10 mg/kg) to increase striatal DA turnover. Behavioral tests (catalepsy, grasping and open-field) were conducted to evaluate muscular rigidity and motor alterations inflicted by the drugs immediately after SD and R. Western blot and immunohistochemistry demonstrated that SD alone produced important down-regulation on TH protein expression within the substantia nigra (SN), without affecting the number of dopaminergic neurons. Pharmacological depletion of DA or increase of its turnover affected the entire nigrostriatal pathway. We propose that downregulation of TH expression produced by SD greatly explains the existence of supersensitivity of dopaminergic D2 receptors, especially along the nigrostriatal pathway, and suggest a novel role of DA in the mediation of sleep-wake states as a consequence of the modulation of TH protein expression along that pathway. The implications of these alterations may directly reverberate in motor and sleep abnormalities found in patients with PD. / TEDE / BV UNIFESP: Teses e dissertações

Submitted by MAIRA PELOGGIA CURSINO null (maira_cursino@hotmail.com) on 2016-05-02T20:29:20Z No. of bitstreams: 1 dissertacao Maira Cursino.pdf: 2521886 bytes, checksum: 862681ed4fd4899b3eae13a3cd63d24c (MD5) / Approved for entry into archive by Felipe Augusto Arakaki (arakaki@reitoria.unesp.br) on 2016-05-04T19:52:20Z (GMT) No. of bitstreams: 1 cursino_mp_me_rcla.pdf: 2521886 bytes, checksum: 862681ed4fd4899b3eae13a3cd63d24c (MD5) / Made available in DSpace on 2016-05-04T19:52:20Z (GMT). No. of bitstreams: 1 cursino_mp_me_rcla.pdf: 2521886 bytes, checksum: 862681ed4fd4899b3eae13a3cd63d24c (MD5) Previous issue date: 2016-04-08 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Introdução: A doença de Parkinson (DP) é uma das doenças que mais acarreta distúrbios do movimento. Objetivo: analisar os efeitos do treino de marcha em esteira com Suporte Parcial de Peso (SPP) e do treino com Estímulo Auditivo (EA) sobre variáveis cinemáticas da marcha, comprimento de passo (CP), variabilidade do comprimento de passo (VCP), largura de passo (LP), variabilidade da largura de passo (VLP) e velocidade de marcha (VM) de pacientes com DP, e sobre os testes de mobilidade, a qualidade de vida (QV) e a preocupação com quedas. Método: Participaram 21 voluntários diagnosticados com DP, com marcha independente, divididos igualmente em: grupo com SPP (GSPP), grupo com EA (GEA), e grupo controle (GC), o qual treinou somente com esteira. Foram avaliadas a mobilidade pelo Short Physical Performance Battery (SPPB) e pelo Timed up and go (TUG), a QV pelo Parkinson Disease Questionnary – 39 (PDQ-39), a preocupação com quedas pelo Falls Efficacy Scale – International (FES-I) e a avaliação biomecânica da marcha em solo pelo programa Peak Motus Motion Measurement System 9.0. O treinamento foi realizado durante seis semanas, com três sessões semanais de 30 minutos. Foi realizado o teste ANOVA Medidas Repetidas Two Way com post Hoc de Bonferroni no software PASW statistics 18.0® (SPSS), adotado nível de significância p<0,05 e a magnitude de efeito das variáveis. Resultados: Os grupos eram homogêneos (p>0,05) para idade, massa corpórea, altura, IMC, tempo de diagnóstico da DP, classificação da escala de Hoehn & Yahr, função cognitiva e quedas. Considerando a magnitude de efeito, tem-se uma diferença clínica inicial e final no GC, GSPP e GEA respectivamente (1,44; 1,46 e 1,86 para o SPPB, 0,96; 0,88 e 2,59 para o TUG, 1,15; 0,92 e 0,25 para o FES-I e 2,17; 1,09 e 2,88 para o PDQ-39); o GEA apresentou melhora significativa inicial e final no SPPB (p=0,018), TUG (p=0,07) e no PDQ-39 (p=0,006) e o GC só no PDQ-39 (p=0,005). Houve grande efeito clínico para as variáveis CP do GC, VCP do GSPP e GEA, LP dos três grupos, VLP do GSPP, VM do GC e GEA, comparando o período inicial e final intragrupo, e, independente dos grupos, houve melhora significativa para velocidade de marcha (p=0,048), no medo de cair (p=0,044) e na QV (p=0,002). Conclusão: treinar em esteira com ou sem estímulos é vantajoso para a melhora da mobilidade, da preocupação com quedas, da marcha e da QV, entretanto, quando o objetivo é melhorar a mobilidade, a preocupação com quedas e a velocidade de marcha, a associação com EA é mais indicada. / Introduction: Parkinson's disease (PD) is one of the diseases that causes movement disorders. Objective: To analyze the effects of gait training on a treadmill with weight Partial body weight support (PBWS) and training with Auditory Stimulus (AS) on kinematic variables of gait, stride length (SL), stride length variability (SLV) step width (SW), step width variability (SWV) and gait speed (GP) in PD patients, and on the mobility tests, quality of life (QOL) and concern about falls. Method: 21 volunteers diagnosed with PD, with independent walking, equally divided into: group with PBWS (GPBWS), a group with AS (GAS) and control group (CG), which only trained with treadmill. Were evaluated mobility by Short Physical Performance Battery (SPPB) and the Timed Up and Go (TUG), QOL by Parkinson Disease Questionnary - 39 (PDQ-39), the concern about falls at Falls Efficacy Scale - International (FES-I ) and the biomechanics of gait evaluation on the soil in Peak Motus Motion Measurement System 9.0. The training was conducted over six weeks, with three weekly sessions of 30 minutes. Statistical analysis ANOVA Two Way Repeated Measures with Bonferroni post hoc in PASW Statistics software 18.0® (SPSS), adopted significance level of p <0.05 and the magnitude of the variable effect was made. Results: The groups were homogeneous (p> 0.05) for age, body mass, height, BMI, PD diagnostic time scale rating Hoehn & Yahr of, cognitive function and falls. Considering the magnitude of effect, it has an initial clinical difference and end the CG, GPBWS and GAS respectively (1.44, 1.46 and 1.86 for SPPB, 0.96, 0.88 and 2.59 for TUG, 1.15, 0.92 and 0.25 for FES-I and 2.17, 1.09 and 2.88 for the PDQ-39); GAS had initial and final significant improvement in SPPB (p = 0.018), TUG (p = 0.07) and the PDQ-39 (p = 0.006) and CG only in the PDQ-39 (p = 0.005). There was great clinical effect in variables SL in CG, SLV in GPBWS and GAS, SW in the three groups, SWV in GPBWS, GP in CG and GAS, comparing the initial and end period intragroup, and independent groups, there was significant improvement to WS (p = 0.048), fear of falling (p = 0.044) and QOL (p = 0.002). Conclusion: training on a treadmill with or without stimuli is advantageous for the improvement of mobility, concern about falls, gait and QOL, however, when the objective is to improve mobility, concern about falls and gait speed, the association with AS is most appropriate.

This study aimed to review the specialized literature on respiratory, postural and vocal manifestations, associated to stages in Parkinson´s Disease and its possible interrelations, as well as, aging in phonation. Method: Some researches were carried based in articles in some databases: Lilacs, Bireme, PubMed, MedLine, Scielo and Google Schoolar, besides books, theses, dissertations and the Internet. Results: senescence is a physiological process to all human beings, generating anatomical and functional changes, especially at the age of 60, as muscular atrophy, calcification of the laryngeal cartilage, and reduction in respiratory capacity, reflecting on the voice through changes in pitch, instability, decrease in the maximum phonation time and restriction of vocal intensity. Parkinson´s Disease causes a series of functional alterations, e.g., rigidity, shaking, bradikinesia, reduction in the respiratory muscular strength, in maximum phonation time and vocal intensity, as well as postural changes. Its repercussions occur simultaneously, due to the muscle chains, body posture, respiratory and, consequently, phonation. Postural deviations, as the head forward positioning, shoulder protrusion and chest hyperciphosis are common in aging and PD and contribute to vocal disturbances through biomechanic disadvantages, especially in the cervical-scapular segment. Associated to postural alterations, is the decreasing in the respiratory muscular strength, causing the chest to expand less, reduction in the lungs volume and capacity, interfering in vocal production. There is a tendency for these disturbances to occur more frequently and with more gravity according to the stage in which the parkinsonian is. Conclusion: Based in the premisse that the human movement and its disorders, as well as the comunication disturbances, from aging and neurological diseases are interrelated by means of complex neural and muscle-skeleton nets, it becomes essential for a better understanding of the integration of physiotherapy and speech therapy, in order to have a complementarity, aiming the Parksonian's well-being. / Este estudo objetivou realizar uma revisão de literatura sobre as manifestações respiratórias, posturais e vocais, associadas aos estágios da Doença de Parkinson e suas possíveis inter-relações, bem como, o envelhecimento na fonação. Método: Realizaram-se buscas a partir de publicações nas bases de dados Lilacs, Bireme, PubMed, MedLine, Scielo e Google Schoolar, tendo sido utilizados também livros, teses, dissertações e Internet. Resultados: a senescência é um processo fisiológico a todos os seres humanos, gerando modificações anátomo-funcionais, especialmente a partir dos 60 anos, como atrofia muscular, calcificação das cartilagens laríngeas, e redução na capacidade respiratória, refletindo-se na voz através de alterações no pitch, instabilidade, decréscimo dos tempos máximos de fonação e restrição à intensidade vocal. A Doença de Parkinson ocasiona uma série de alterações funcionais, por exemplo, rigidez, tremor, bradicinesia, redução na força muscular respiratória, nos tempos máximos de fonação e na intensidade vocal, bem como alterações posturais. Suas repercussões ocorrem simultaneamente, devido às cadeias musculares, na postura corporal, na respiração e, conseqüentemente, na fonação. Desvios posturais, como anteriorização da cabeça, protrusão de ombros e hipercifose torácica são comuns no envelhecimento e na DP e contribuem para os distúrbios vocais, por meio de desvantagens biomecânicas, especialmente no segmento cérvico-escapular. Associado às alterações posturais, ocorre o decréscimo na força muscular respiratória que propicia menor expansibilidade da caixa torácica, redução nos volumes e capacidades pulmonares, interferindo na produção vocal. Há uma tendência de que esses distúrbios ocorram com maior freqüência e gravidade de acordo com o estágio em que o parkinsoniano se encontra. Conclusão: Baseado na premissa de que o movimento humano e suas desordens, assim como os distúrbios da comunicação advindos tanto do envelhecimento quanto de doenças neurológicas apresentam-se inter-relacionados por meio de complexas redes neurais e músculoesqueléticas, torna-se essencial uma melhor compreensão da fisioterapia e da fonoaudiologia acerca dessas interações, a fim de que haja complementaridade, visando ao bem-estar do indivíduo.

Made available in DSpace on 2016-12-06T17:07:02Z (GMT). No. of bitstreams: 1 Dissertacao Antonia Natalia Costa.pdf: 813590 bytes, checksum: 3f40fdc60d74cfd09af0df86e64c147f (MD5) Previous issue date: 2015-05-21 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Parkinson Disease (PD) is a neurological infirmity of chronic, slow, degenerative and progressive features of the substantia nigra neurons. PD presents alterations which affect motricity and quality of life of patients. Motor aptitude and quality of life evaluations can allow better comprehension of the disease, guidance of the patients about the motor deficits and performance of interventions based on more concrete evidence. Therefore, this research had as main objective to evaluate and analyze motor aptitude and quality of life in elderly with Parkinson Disease in Grande Florianópolis-SC. The methodologic design of this study was characterized as a transversal, descriptive-correlational, field study. The sample was composed by 43 elderly with diagnosis of PD (20 men and 23 women), with ages in between 60 and 85 years old, with mean age of 69,8 years old (7,2± PD) and medical diagnosis between 1 and 30 years. it was used two instruments for the target population, in this case, Escala Motora para a Terceira Idade (EMTI) and a questionnaire to evaluate quality of life (Parkinson Disease Questionary-39 PDQ-39), which were applied directly in the reality of the involved subjects. Data were treated by means of descriptive statistics using mean and standard deviation, and by inferential statistics using Spearman Test and T tests. Significance was adopted as p<0,05. Theoric data and empiric results of this study were systemized in three different chapters, presented as articles. Thus, based on the theoretical findings of chapter 3, it can be suggested that physical exercise programs and physical therapy are benefic to the quality of life of subjects with PD, even though the samples are reduced and studies are scarce about this thematic, even in the beginning stages of PD. Empiric findings in chapter 4 allow us to say that the classification of general motor aptitude of elderly with Parkinson presented results in the much lower level; that the motor prejudice is related with the global motricity and balance with lesser scores, indicating a much lower classification; that the most affected domains of quality of life were mobility (44.2), bodily discomfort (37.7) and activities of daily living (35.8). Men possess worse perception of QV in the mobility (43.2), activities of daily living (43.7) and bodily discomfort (39.9) domains, and women in mobility (45.1), bodily discomfort (35.8) and cognition (31.4). Empiric results of chapter 5 showed significant statistical relation between PDQ-39 and fine motricity, global motricity, balance and spatial organization of motor aptitude. Therefore, based on the theoretical and empirical findings, it can be suggested that motor and quality of life evaluations can identify most affected areas in patients with PD and can assist in physical exercise and physical therapy interventions which focus on PD, mainly in the improvement of quality of life. / A Doença de Parkinson (DP) é uma enfermidade neurológica de caráter crônica, lenta, degenerativa e progressiva dos neurônios da substância negra. A DP apresenta alterações que afetam a motricidade e a qualidade de vida dos pacientes. A avaliação da aptidão motora e da qualidade de vida pode permitir melhor compreensão da doença, orientação dos pacientes quanto aos déficits motores e realização de intervenções baseadas em evidências mais concretas. Assim, esta pesquisa teve como objetivo principal avaliar a Aptidão Motora e a qualidade de vida de idosos com doença de Parkinson da Grande Florianópolis-SC. O desenho metodológico deste estudo foi caracterizado como um estudo descritivo-correlacional, de campo e transversal. A amostra foi composta por 43 idosos com diagnóstico de DP (20 homens e 23 mulheres), com idades compreendidas entre 60 e 85 anos, com média de idade de 69,8 anos (7,2± DP) anos e tempo de diagnóstico médico de 1 a 30 anos. Foram utilizados dois instrumentos para a população alvo, neste caso, a Escala Motora para a Terceira Idade (EMTI) e o questionário de avaliação da Qualidade de Vida (Parkinson Disease Questionary-39 - PDQ-39), que foram aplicados diretamente na realidade dos sujeitos envolvidos. Os dados foram tratados por meio de estatística descritiva, utilizando-se de média e desvio-padrão; e por meio de estatística inferencial, utilizando-se os testes t e de Spearman. Foi adotada significância de p <0,05. Os dados empíricos deste estudo foram sistematizados em dois capítulos diferentes, apresentados sob a forma de artigos. Deste modo, com base nos achados empíricos do capítulo 3, permitem afirmar que a classificação da Aptidão Motora Geral dos idosos com Parkinson apresentou resultados no nível Muito Inferior; que o maior prejuízo motor está relacionado à motricidade global e equilíbrio com pontuações mais baixas, indicando classificação Muito Inferior; que os domínios mais afetados da QV foram mobilidade (44,2), desconforto corporal (37,7) e atividades de vida diárias (35,8), sendo que os homens possuem pior percepção da Qualidade de Vida nos domínios da Mobilidade (43,2), das Atividades de Vida Diárias (43,7) e do Desconforto Corporal (39,9), e as mulheres nos domínios da Mobilidade (45,1), do Desconforto Corporal (35,8) e do comprometimento cognitivo (31,4). Os resultados empíricos do capítulo 4 demonstraram relações estatisticamente significativas entre o PDQ-39 e a Motricidade Fina, Motricidade Global, Equilíbrio e Organização Espacial da Aptidão Motora. Portanto, com base nos achados , pode-se sugerir que foi possível detectar os maiores déficits nas áreas avaliadas e orientar quanto à prática de exercícios físicos e atividades que poderiam retardar o progresso da DP e consequentemente melhorar a qualidade de vida.

Made available in DSpace on 2014-12-17T15:37:11Z (GMT). No. of bitstreams: 1 JuliaJD_DISSERT.pdf: 2580317 bytes, checksum: 265bbbe6825ce7a3d27c569cde32cf8d (MD5) Previous issue date: 2012-06-29 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / Neuropeptide S (NPS) is the endogenous ligand of a G-protein coupled receptor. Preclinical studies have shown that NPSR receptor activation can promote arousal, anxiolytic-like behavioral, decrease in food intake, besides hyperlocomotion, which is a robust but not well understood phenomenon. Previous findings suggest that dopamine transmission plays a crucial role in NPS hyperactivity. Considering the close relationship between dopamine and Parkinson Disease (PD), and also that NPSR receptors are expressed on dopaminergic nuclei in the brain, the current study attempted to investigate the effects of NPS in motor deficits induced by intracerebroventricular (icv) administration of 6-OHDA and systemic administration of haloperidol. Motor deficits induced by 6-OHDA and haloperidol were evaluated on Swiss mice in the rota-rod and catalepsy test. Time on the rotating rod and time spent immobile in the elevated bar were measured respectively in each test. L-Dopa, a classic antiparkinsonian drug, and NPS were administrated in mice submitted to one of the animal models of PD related above. 6-OHDA injection evoked severe motor impairments in rota-rod test, while the cataleptic behavior of 6-OHDA injected mice was largely variable. The administration of L-Dopa (25 mg/kg) and NPS (0,1 and 1 nmol) reversed motor impairments induced by 6-OHDA in the rota-rod. Haloperidolinduced motor deficits on rota-rod and catalepsy tests which were reversed by L-Dopa (100 e 400 mg/kg), but not by NPS (0,1 and 1 nmol) administration. The association of L-Dopa 10 mg/kg and NPS 1 nmol was also unable to counteract haloperidol-induced motor deficits. To summarize, 6-OHDA-, but not haloperidol-, induced motor deficits were reversed by the central administration of NPS. These data suggest that NPS possibly facilitates dopamine release in basal ganglia, what would explain the overcome of motor performance promoted by NPS administration in animals pretreated with 6-OHDA, but not haloperidol. Finally, the presented findings point, for the first time, to the potential of NPSR agonist as an innovative treatment for PD. / O neuropept?deo S (NPS) ? o ligante end?geno do receptor NPSR acoplado ? prote?na G. Estudos pr?-cl?nicos mostraram que a ativa??o do receptor NPSR promove aumento da vig?lia, ansi?lise, efeito anor?xico, al?m de hiperlocomo??o. Este ?ltimo efeito ? robusto e ainda pouco entendido. Evid?ncias apontam para o envolvimento do sistema dopamin?rgico no efeito estimulat?rio do NPS. Tendo em vista a modula??o exercida pelo sistema NPS-receptor NPSR na locomo??o espont?nea de animais, a express?o do receptor NPSR em n?cleos dopamin?rgicos e a rela??o intr?nseca entre a dopamina e a Doen?a de Parkinson, o presente estudo visou investigar o papel exercido pelo sistema do NPS no preju?zo motor de camundongos induzido pela administra??o intracerebroventricular (icv) de 6-OHDA e sist?mica de haloperidol. Para avalia??o dos preju?zos motores induzidos por 6-OHDA e haloperidol, camundongos Swiss foram submetidos aos testes do rota-rod e da catalepsia e o desempenho motor na barra girat?ria do rota-rod e o tempo de imobilidade na plataforma elevada foram registrados, respectivamente. O efeito do tratamento dos camundongos com L-Dopa (via oral), um antiparkinsoniano cl?ssico, e do NPS (icv) foi avaliado nos dois testes comportamentais citados acima. No teste do rota-rod, tr?s dias ap?s a administra??o de 6-OHDA, os animais apresentaram significativo preju?zo motor. A revers?o do preju?zo motor foi verificada ap?s a administra??o de L-Dopa (25 mg/kg) ou de NPS (0,1 e 1 nmol). A administra??o de 6-OHDA tamb?m elevou o tempo de perman?ncia na plataforma elevada (teste da catalepsia), mas este efeito foi muito vari?vel, n?o sendo, portanto, utilizado para investigar a a??o do NPS. O preju?zo motor induzido pelo haloperidol no teste do rota-rod e catalepsia foi revertido pela administra??o de L-Dopa (100 e 400 mg/kg), mas n?o pelo NPS (0,1 e 1 nmol) ou pela associa??o de LDopa 10 mg/kg e NPS 1 nmol. Em conclus?o, os danos motores induzidos pela administra??o de 6-OHDA, mas n?o de haloperidol, foram revertidos pelo tratamento central com NPS. Estes dados sugerem que o NPS parece facilitar a libera??o de dopamina na via nigroestriatal, o que justificaria a melhora do desempenho motor induzida pela administra??o do NPS em animais tratados com 6-OHDA, mas n?o com haloperidol (que causa bloqueio de receptores dopamin?rgicos). Por fim, os achados aqui apresentados apontam, pela primeira vez, para a possibilidade de agonistas do receptor NPSR atuarem como agentes terap?uticos ou adjuvantes no tratamento da Doen?a de Parkinson.