Human genetic data suggests DISC1 (Disrupted-in-schizophrenia 1) is a susceptibility gene for schizophrenia and depression. Disc1 Q31L-/- mutants show depression-like behaviour and Disc1 L100P-/- mutants schizophrenia-like behaviour. Heterozygous mutants show an intermediate phenotype. In a gene-environment interaction study, we exposed heterozygotes to chronic social defeat (CSD) stress and phenotyped behaviour. Disc1, Bdnf(III) and Pde4b mRNA levels were also measured. Moreover, as epigenetic mechanisms may mediate some effects of CSD, we also exposed wildtype mice to CSD concurrently with the histone deacetylase inhibitor valproate. We found that CSD increased anxiety in L100P-/+ mutants, and that levels of Disc1, Bdnf(III) and Pde4b mRNA were higher in this mutant. Valproate treatment did not correct CSD-induced behavioural changes. In conclusion, we have demonstrated an interaction between a strong susceptibility gene for psychiatric disease and an environmental manipulation similar to stressors known to affect mental illness.

Human genetic data suggests DISC1 (Disrupted-in-schizophrenia 1) is a susceptibility gene for schizophrenia and depression. Disc1 Q31L-/- mutants show depression-like behaviour and Disc1 L100P-/- mutants schizophrenia-like behaviour. Heterozygous mutants show an intermediate phenotype. In a gene-environment interaction study, we exposed heterozygotes to chronic social defeat (CSD) stress and phenotyped behaviour. Disc1, Bdnf(III) and Pde4b mRNA levels were also measured. Moreover, as epigenetic mechanisms may mediate some effects of CSD, we also exposed wildtype mice to CSD concurrently with the histone deacetylase inhibitor valproate. We found that CSD increased anxiety in L100P-/+ mutants, and that levels of Disc1, Bdnf(III) and Pde4b mRNA were higher in this mutant. Valproate treatment did not correct CSD-induced behavioural changes. In conclusion, we have demonstrated an interaction between a strong susceptibility gene for psychiatric disease and an environmental manipulation similar to stressors known to affect mental illness.

Introduction: Coronary artery disease (CAD) has been associated with depressive symptoms and deficits in cognitive performance, both of which have been associated with poorer medical prognoses and poorer psychosocial outcomes. Physical activity can improve cognitive and depressive symptoms, and, for those with CAD, improve medical prognoses. It was hypothesized that depressive symptoms and poorer cognitive performance would be associated with poorer cardiopulmonary fitness in patients with CAD, and that these sequelae would be associated prospectively with noncompletion of cardiac rehabilitation (CR). The benefits of physical activity are thought to result, in part, from decreased inflammatory activity and increased adaptive neural plasticity, to which the ratio of kynurenine to tryptophan (K/T) and brain derived neurotrophic factor (BDNF), respectively, in peripheral blood may pertain. Methods and Results: In a cohort study of patients entering CR, depressive symptoms (Center for Epidemiological Studies Depression scale; CES-D scores) were associated with cardiopulmonary fitness (peak volume of oxygen uptake; VO2Peak) during an exercise stress test (B=-.404, p=.001, n=366). The VO2Peak was also associated with performance across multiple cognitive domains, but most strongly with performance on tests involving executive function, attention and psychomotor processing speed (β=.322, p=.002 for composite score, n=81) in a cohort of patients entering CR. In prospective cohort studies, Major Depressive Disorder (adjusted hazard ratio [HR] 2.5, 95% confidence interval [CI] 1.3–4.7, n=195) and poorer performance on a verbal memory test (HR 0.86, 95% CI 0.77-0.96, p=.009, n=131) predicted non-completion of CR. In patients undertaking CR, higher serum K/T ratios were associated with CES-D scores (β=.322, p=.002, n=95) and with VO2Peak (β=-.391, p<.001, n=95), and in a cohort of patients entering CR (n=88), serum concentrations of BDNF were associated with psychomotor processing speed (F1,87=9.620, p=.003), overall cognitive status (Mini Mental Status Exam) scores (F1,87=15.406, p<.0005) and VO2Peak (β=.305, p=.013). Conclusions: Depressive symptoms and poorer cognitive performance are clinically important in patients with CAD entering CR and they are both associated with poorer cardiopulmonary fitness. Poorer cardiopulmonary fitness was also associated with higher K/T ratios and with lower BDNF concentrations in serum, which predicted depressive symptoms and poorer cognitive performance, respectively.

Introduction: Coronary artery disease (CAD) has been associated with depressive symptoms and deficits in cognitive performance, both of which have been associated with poorer medical prognoses and poorer psychosocial outcomes. Physical activity can improve cognitive and depressive symptoms, and, for those with CAD, improve medical prognoses. It was hypothesized that depressive symptoms and poorer cognitive performance would be associated with poorer cardiopulmonary fitness in patients with CAD, and that these sequelae would be associated prospectively with noncompletion of cardiac rehabilitation (CR). The benefits of physical activity are thought to result, in part, from decreased inflammatory activity and increased adaptive neural plasticity, to which the ratio of kynurenine to tryptophan (K/T) and brain derived neurotrophic factor (BDNF), respectively, in peripheral blood may pertain. Methods and Results: In a cohort study of patients entering CR, depressive symptoms (Center for Epidemiological Studies Depression scale; CES-D scores) were associated with cardiopulmonary fitness (peak volume of oxygen uptake; VO2Peak) during an exercise stress test (B=-.404, p=.001, n=366). The VO2Peak was also associated with performance across multiple cognitive domains, but most strongly with performance on tests involving executive function, attention and psychomotor processing speed (β=.322, p=.002 for composite score, n=81) in a cohort of patients entering CR. In prospective cohort studies, Major Depressive Disorder (adjusted hazard ratio [HR] 2.5, 95% confidence interval [CI] 1.3–4.7, n=195) and poorer performance on a verbal memory test (HR 0.86, 95% CI 0.77-0.96, p=.009, n=131) predicted non-completion of CR. In patients undertaking CR, higher serum K/T ratios were associated with CES-D scores (β=.322, p=.002, n=95) and with VO2Peak (β=-.391, p<.001, n=95), and in a cohort of patients entering CR (n=88), serum concentrations of BDNF were associated with psychomotor processing speed (F1,87=9.620, p=.003), overall cognitive status (Mini Mental Status Exam) scores (F1,87=15.406, p<.0005) and VO2Peak (β=.305, p=.013). Conclusions: Depressive symptoms and poorer cognitive performance are clinically important in patients with CAD entering CR and they are both associated with poorer cardiopulmonary fitness. Poorer cardiopulmonary fitness was also associated with higher K/T ratios and with lower BDNF concentrations in serum, which predicted depressive symptoms and poorer cognitive performance, respectively.

Progressive degeneration in the central nervous system (CNS) of Huntington’s disease (HD) patients is a relentless debilitating process, resulting from the inheritance of a single gene mutation. With limited knowledge of the underlying pathological molecular mechanisms, pharmaceutical intervention has to-date not provided any effective clinical treatment strategies to attenuate or compensate the neuronal cell death. Attention has therefore turned to biotherapeutic molecules and novel treatment approaches to promote restoration and protection of selectively vulnerable populations of neurons in the HD brain. Rapid advances in vectorology and gene-based medicine over the past decade have opened the way for safe and efficient delivery of biotherapeutics to the CNS. With numerous factors known to regulate the development, plasticity and maintenance of the mammalian nervous system many proteins have emerged as potential therapeutic agents to alleviate HD progression. This investigative study utilised gene delivery vectors derived from the non-pathogenic adeno-associated virus (AAV) to direct high-level expression of brain-derived neurotrophic factor (BDNF), glial cell-line derived neurotrophic factor (GDNF), Bcl-xL or X-linked inhibitor of apoptosis protein (XIAP) within the rodent striatum. Maintenance of the basal ganglia and functional behaviour deficits were assessed following excitotoxic insult of the striatum by quinolinic acid (QA), a neurotoxic model of HD pathology. Enhanced striatal expression of BDNF prior to QA-induced lesioning provided maintenance of the striosome-matrix organisation of the striatum, attenuating impairments of sensorimotor behaviour with a 36-38% increase in the maintenance of DARPP-32 / krox-24 expressing striatal neurons, reduced striatal atrophy and increased maintenance of striatonigral projections. Higher levels of BDNF however induced seizures and weight-loss highlighting the need to provide regulatable control over biotherapeutic protein expression. Continuous high-expression of BDNF or GDNF resulted in a downregulation of intracellular signal mediating proteins including DARPP-32, with AAV-GDNF not found to enhance the overall maintenance of striatal neurons. Neither of the anti-apoptotic factors provided significant protection of transduced striatal neurons but tended towards ameliorating QA-induced behavioural deficits, displaying behaviour – pathology correlations with the survival of parvalbumin-expressing neurons in the globus pallidus. The results of this thesis suggest BDNF as a promising putative biotherapeutic for HD, but emphasises the requirement to control expression following gene delivery, and for further elucidation of the physiological impact that enhanced expression of endogenous factors has on the host cells. Additionally the maintenance of neural networks beyond the caudate-putamen will be vital to ensuring efficient clinical outcomes for HD. / Auckland Medical Research Foundation. Foundation for Research, Science and Technology. The University of Auckland.

Progressive degeneration in the central nervous system (CNS) of Huntington’s disease (HD) patients is a relentless debilitating process, resulting from the inheritance of a single gene mutation. With limited knowledge of the underlying pathological molecular mechanisms, pharmaceutical intervention has to-date not provided any effective clinical treatment strategies to attenuate or compensate the neuronal cell death. Attention has therefore turned to biotherapeutic molecules and novel treatment approaches to promote restoration and protection of selectively vulnerable populations of neurons in the HD brain. Rapid advances in vectorology and gene-based medicine over the past decade have opened the way for safe and efficient delivery of biotherapeutics to the CNS. With numerous factors known to regulate the development, plasticity and maintenance of the mammalian nervous system many proteins have emerged as potential therapeutic agents to alleviate HD progression. This investigative study utilised gene delivery vectors derived from the non-pathogenic adeno-associated virus (AAV) to direct high-level expression of brain-derived neurotrophic factor (BDNF), glial cell-line derived neurotrophic factor (GDNF), Bcl-xL or X-linked inhibitor of apoptosis protein (XIAP) within the rodent striatum. Maintenance of the basal ganglia and functional behaviour deficits were assessed following excitotoxic insult of the striatum by quinolinic acid (QA), a neurotoxic model of HD pathology. Enhanced striatal expression of BDNF prior to QA-induced lesioning provided maintenance of the striosome-matrix organisation of the striatum, attenuating impairments of sensorimotor behaviour with a 36-38% increase in the maintenance of DARPP-32 / krox-24 expressing striatal neurons, reduced striatal atrophy and increased maintenance of striatonigral projections. Higher levels of BDNF however induced seizures and weight-loss highlighting the need to provide regulatable control over biotherapeutic protein expression. Continuous high-expression of BDNF or GDNF resulted in a downregulation of intracellular signal mediating proteins including DARPP-32, with AAV-GDNF not found to enhance the overall maintenance of striatal neurons. Neither of the anti-apoptotic factors provided significant protection of transduced striatal neurons but tended towards ameliorating QA-induced behavioural deficits, displaying behaviour – pathology correlations with the survival of parvalbumin-expressing neurons in the globus pallidus. The results of this thesis suggest BDNF as a promising putative biotherapeutic for HD, but emphasises the requirement to control expression following gene delivery, and for further elucidation of the physiological impact that enhanced expression of endogenous factors has on the host cells. Additionally the maintenance of neural networks beyond the caudate-putamen will be vital to ensuring efficient clinical outcomes for HD. / Auckland Medical Research Foundation. Foundation for Research, Science and Technology. The University of Auckland.

Progressive degeneration in the central nervous system (CNS) of Huntington’s disease (HD) patients is a relentless debilitating process, resulting from the inheritance of a single gene mutation. With limited knowledge of the underlying pathological molecular mechanisms, pharmaceutical intervention has to-date not provided any effective clinical treatment strategies to attenuate or compensate the neuronal cell death. Attention has therefore turned to biotherapeutic molecules and novel treatment approaches to promote restoration and protection of selectively vulnerable populations of neurons in the HD brain. Rapid advances in vectorology and gene-based medicine over the past decade have opened the way for safe and efficient delivery of biotherapeutics to the CNS. With numerous factors known to regulate the development, plasticity and maintenance of the mammalian nervous system many proteins have emerged as potential therapeutic agents to alleviate HD progression. This investigative study utilised gene delivery vectors derived from the non-pathogenic adeno-associated virus (AAV) to direct high-level expression of brain-derived neurotrophic factor (BDNF), glial cell-line derived neurotrophic factor (GDNF), Bcl-xL or X-linked inhibitor of apoptosis protein (XIAP) within the rodent striatum. Maintenance of the basal ganglia and functional behaviour deficits were assessed following excitotoxic insult of the striatum by quinolinic acid (QA), a neurotoxic model of HD pathology. Enhanced striatal expression of BDNF prior to QA-induced lesioning provided maintenance of the striosome-matrix organisation of the striatum, attenuating impairments of sensorimotor behaviour with a 36-38% increase in the maintenance of DARPP-32 / krox-24 expressing striatal neurons, reduced striatal atrophy and increased maintenance of striatonigral projections. Higher levels of BDNF however induced seizures and weight-loss highlighting the need to provide regulatable control over biotherapeutic protein expression. Continuous high-expression of BDNF or GDNF resulted in a downregulation of intracellular signal mediating proteins including DARPP-32, with AAV-GDNF not found to enhance the overall maintenance of striatal neurons. Neither of the anti-apoptotic factors provided significant protection of transduced striatal neurons but tended towards ameliorating QA-induced behavioural deficits, displaying behaviour – pathology correlations with the survival of parvalbumin-expressing neurons in the globus pallidus. The results of this thesis suggest BDNF as a promising putative biotherapeutic for HD, but emphasises the requirement to control expression following gene delivery, and for further elucidation of the physiological impact that enhanced expression of endogenous factors has on the host cells. Additionally the maintenance of neural networks beyond the caudate-putamen will be vital to ensuring efficient clinical outcomes for HD. / Auckland Medical Research Foundation. Foundation for Research, Science and Technology. The University of Auckland.

Progressive degeneration in the central nervous system (CNS) of Huntington’s disease (HD) patients is a relentless debilitating process, resulting from the inheritance of a single gene mutation. With limited knowledge of the underlying pathological molecular mechanisms, pharmaceutical intervention has to-date not provided any effective clinical treatment strategies to attenuate or compensate the neuronal cell death. Attention has therefore turned to biotherapeutic molecules and novel treatment approaches to promote restoration and protection of selectively vulnerable populations of neurons in the HD brain. Rapid advances in vectorology and gene-based medicine over the past decade have opened the way for safe and efficient delivery of biotherapeutics to the CNS. With numerous factors known to regulate the development, plasticity and maintenance of the mammalian nervous system many proteins have emerged as potential therapeutic agents to alleviate HD progression. This investigative study utilised gene delivery vectors derived from the non-pathogenic adeno-associated virus (AAV) to direct high-level expression of brain-derived neurotrophic factor (BDNF), glial cell-line derived neurotrophic factor (GDNF), Bcl-xL or X-linked inhibitor of apoptosis protein (XIAP) within the rodent striatum. Maintenance of the basal ganglia and functional behaviour deficits were assessed following excitotoxic insult of the striatum by quinolinic acid (QA), a neurotoxic model of HD pathology. Enhanced striatal expression of BDNF prior to QA-induced lesioning provided maintenance of the striosome-matrix organisation of the striatum, attenuating impairments of sensorimotor behaviour with a 36-38% increase in the maintenance of DARPP-32 / krox-24 expressing striatal neurons, reduced striatal atrophy and increased maintenance of striatonigral projections. Higher levels of BDNF however induced seizures and weight-loss highlighting the need to provide regulatable control over biotherapeutic protein expression. Continuous high-expression of BDNF or GDNF resulted in a downregulation of intracellular signal mediating proteins including DARPP-32, with AAV-GDNF not found to enhance the overall maintenance of striatal neurons. Neither of the anti-apoptotic factors provided significant protection of transduced striatal neurons but tended towards ameliorating QA-induced behavioural deficits, displaying behaviour – pathology correlations with the survival of parvalbumin-expressing neurons in the globus pallidus. The results of this thesis suggest BDNF as a promising putative biotherapeutic for HD, but emphasises the requirement to control expression following gene delivery, and for further elucidation of the physiological impact that enhanced expression of endogenous factors has on the host cells. Additionally the maintenance of neural networks beyond the caudate-putamen will be vital to ensuring efficient clinical outcomes for HD. / Auckland Medical Research Foundation. Foundation for Research, Science and Technology. The University of Auckland.

Progressive degeneration in the central nervous system (CNS) of Huntington’s disease (HD) patients is a relentless debilitating process, resulting from the inheritance of a single gene mutation. With limited knowledge of the underlying pathological molecular mechanisms, pharmaceutical intervention has to-date not provided any effective clinical treatment strategies to attenuate or compensate the neuronal cell death. Attention has therefore turned to biotherapeutic molecules and novel treatment approaches to promote restoration and protection of selectively vulnerable populations of neurons in the HD brain. Rapid advances in vectorology and gene-based medicine over the past decade have opened the way for safe and efficient delivery of biotherapeutics to the CNS. With numerous factors known to regulate the development, plasticity and maintenance of the mammalian nervous system many proteins have emerged as potential therapeutic agents to alleviate HD progression. This investigative study utilised gene delivery vectors derived from the non-pathogenic adeno-associated virus (AAV) to direct high-level expression of brain-derived neurotrophic factor (BDNF), glial cell-line derived neurotrophic factor (GDNF), Bcl-xL or X-linked inhibitor of apoptosis protein (XIAP) within the rodent striatum. Maintenance of the basal ganglia and functional behaviour deficits were assessed following excitotoxic insult of the striatum by quinolinic acid (QA), a neurotoxic model of HD pathology. Enhanced striatal expression of BDNF prior to QA-induced lesioning provided maintenance of the striosome-matrix organisation of the striatum, attenuating impairments of sensorimotor behaviour with a 36-38% increase in the maintenance of DARPP-32 / krox-24 expressing striatal neurons, reduced striatal atrophy and increased maintenance of striatonigral projections. Higher levels of BDNF however induced seizures and weight-loss highlighting the need to provide regulatable control over biotherapeutic protein expression. Continuous high-expression of BDNF or GDNF resulted in a downregulation of intracellular signal mediating proteins including DARPP-32, with AAV-GDNF not found to enhance the overall maintenance of striatal neurons. Neither of the anti-apoptotic factors provided significant protection of transduced striatal neurons but tended towards ameliorating QA-induced behavioural deficits, displaying behaviour – pathology correlations with the survival of parvalbumin-expressing neurons in the globus pallidus. The results of this thesis suggest BDNF as a promising putative biotherapeutic for HD, but emphasises the requirement to control expression following gene delivery, and for further elucidation of the physiological impact that enhanced expression of endogenous factors has on the host cells. Additionally the maintenance of neural networks beyond the caudate-putamen will be vital to ensuring efficient clinical outcomes for HD. / Auckland Medical Research Foundation. Foundation for Research, Science and Technology. The University of Auckland.

Submitted by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2014-12-17T14:07:27Z No. of bitstreams: 2 adriano_prado_simao.pdf: 14603272 bytes, checksum: 6a0e234b9d484325125c4f251d688d0b (MD5) license_rdf: 22974 bytes, checksum: 99c771d9f0b9c46790009b9874d49253 (MD5) / Approved for entry into archive by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2014-12-17T14:08:37Z (GMT) No. of bitstreams: 2 adriano_prado_simao.pdf: 14603272 bytes, checksum: 6a0e234b9d484325125c4f251d688d0b (MD5) license_rdf: 22974 bytes, checksum: 99c771d9f0b9c46790009b9874d49253 (MD5) / Approved for entry into archive by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2014-12-17T14:08:31Z (GMT) No. of bitstreams: 2 adriano_prado_simao.pdf: 14603272 bytes, checksum: 6a0e234b9d484325125c4f251d688d0b (MD5) license_rdf: 22974 bytes, checksum: 99c771d9f0b9c46790009b9874d49253 (MD5) / Approved for entry into archive by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2014-12-17T14:09:21Z (GMT) No. of bitstreams: 2 adriano_prado_simao.pdf: 14603272 bytes, checksum: 6a0e234b9d484325125c4f251d688d0b (MD5) license_rdf: 22974 bytes, checksum: 99c771d9f0b9c46790009b9874d49253 (MD5) / Made available in DSpace on 2014-12-17T14:09:21Z (GMT). No. of bitstreams: 2 adriano_prado_simao.pdf: 14603272 bytes, checksum: 6a0e234b9d484325125c4f251d688d0b (MD5) license_rdf: 22974 bytes, checksum: 99c771d9f0b9c46790009b9874d49253 (MD5) Previous issue date: 2013 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (Capes) / Funda??o de Amparo ? Pesquisa do estado de Minas Gerais (FAPEMIG) / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico (CNPq) / Introdu??o: Recentemente, a vibra??o de todo o corpo (VTC) tem sido um m?todo de exerc?cio f?sico indicado para aumentar o desempenho e a capacidade f?sico-funcional de idosos com osteoartrite (OA) de joelho. No entanto, os mecanismos relacionados aos efeitos produzidos por essa modalidade ainda n?o foram completamente investigados. Objetivos: O objetivo deste estudo foi investigar os efeitos da adi??o de VTC aos exerc?cios de agachamento na concentra??o plasm?tica de marcadores inflamat?rios e no desempenho e capacidade funcionais de idosos com OA de joelho na fase remissiva da doen?a (Estudo 1) e investigar os efeitos da adi??o do treinamento de VTC ao exerc?cio de agachamento em mulheres idosas com OA de joelho na fase remissiva da doen?a nos seguintes par?metros: 1) for?a isom?trica do m?sculo quadr?ceps; 2) concentra??o plasm?tica de BDNF; e 3) na concentra??o salivar da raz?o testosterona/cortisol (Estudo 2). Investigar a rela??o entre os n?veis plasm?ticos e no l?quido sinovial do TNF-? e seus receptores sol?veis (sTNFR1 e sTNFR2) assim como de BDNF em idosos com OA de joelho e ainda verificar a rela??o destes com a gravidade da OA e o autorrelato de dor, rigidez e fun??o f?sica com o WOMAC (Western Ontario and McMaster University Osteoarthritis Index) em idosos com OA de joelho na fase inflamat?ria aguda (Estudo 3). Metodologia: No estudo 1, trinta e dois idosos com OA de joelho foram divididos em tr?s grupos: grupo que realizou exerc?cio de agachamento associado a plataforma vibrat?ria (grupo plataforma N=11), grupo que realizou exerc?cio de agachamento sem vibra??o (grupo agachamento N=10) e o grupo controle (N=11). Um programa estruturado de exerc?cios de agachamento foi executado tr?s vezes por semana em dias alternados por doze semanas nos grupos plataforma e agachamento. A concentra??o plasm?tica de receptores sol?veis de TNF-? (sTNFR1 e sTNFR2) foi analisada usando a t?cnica de ELISA. O WOMAC foi usado para avaliar o autorrelato da fun??o f?sica, dor e rigidez. O teste de caminhada de 6 minutos, a escala de Berg e o teste de velocidade da marcha foram utilizados para avaliar a fun??o f?sica. No estudo 2, foram selecionadas quinze mulheres idosas com idade maior ou igual a 60 anos que tinham sido diagnosticadas com OA em pelo menos um joelho. A interven??o consistiu de doze semanas seguidas de exerc?cios de agachamento, 3 vezes por semana. O protocolo de exerc?cio foi similar em ambos os grupos diferindo apenas da presen?a de vibra??o. J? no estudo 3 participaram vinte e sete idosos diagnosticados com osteoartrite de joelho e dezenove idosos saud?veis. Radiografias ?ntero-posteriores do joelho foram realizadas para determinar a gravidade da doen?a no joelho afetado. A classifica??o radiogr?fica da OA do joelho foi realizada utilizando os crit?rios Kellgren-Lawrence. Os n?veis de TNF-?, sTNFR1, sTNFR2 e BDNF no plasma e no l?quido sinovial foram determinados por ELISA. Resultados: No estudo 1, o grupo que realizou exerc?cios de agachamento na plataforma vibrat?ria mostrou diminui??o nas concentra??es plasm?ticas dos marcadores inflamat?rios sTNFR1 e sTNFR2 (p<0,001 e p<0,05, respectivamente), no autorrelato da dor (p<0,05), melhora no equil?brio (p<0,05) e na velocidade e dist?ncia caminhada (p<0,05 e p<0,001, respectivamente) comparado com o grupo controle. O teste de velocidade da marcha tamb?m apresentou aumento no grupo plataforma quando comparado ao grupo agachamento (p<0,01). Os resultados do estudo 2 demonstraram uma varia??o (?) positiva dos valores da for?a isom?trica muscular do quadr?ceps (p=0,02) e da concentra??o plasm?tica de BDNF (p=0,03) no grupo vibra??o ap?s o per?odo de interven??o. A varia??o (?) na raz?o testosterona/cortisol (T/C) n?o diferiu significativamente, entre os grupos (p=0,61). No estudo 3, os n?veis de BDNF no l?quido sinovial correlacionou-se significativamente com dor autorrelatada [WOMAC] (rs = 0,39, p=0,04). Com rela??o aos receptores sol?veis para TNF-?, observou-se uma diferen?a entre os n?veis de sTNFR1 e de sTNFR2, tanto no plasma quanto no l?quido sinovial em pacientes com OA do joelho (1091 ? 99,48 pg / mL versus 2249 ? 126,3 pg / mL e 2587 ? 66,12 pg / mL versus 2021 ? 107,0 pg / mL, respectivamente). Al?m disso, os n?veis de sTNFR1 no l?quido sinovial foram, negativamente, correlacionadas com a dor e a fun??o f?sica autorrelatada (rs -0,6785, p<0,0001 e rs -0,4194; p=0,03, respectivamente). Ao passo que, os n?veis de sTNFR2 no l?quido sinovial foram negativamente correlacionadas com dor e rigidez articular (rs -0,5433, p=0,01 e rs -0,4249; p=0,02, respectivamente). Conclus?es: Os resultados dos estudos supracitados indicam que a adi??o da vibra??o de todo o corpo ao treinamento com exerc?cio de agachamento, nas condi??es experimentais propostas, melhora o equil?brio est?tico e din?mico e o desempenho da marcha e ao mesmo tempo reduz a autopercep??o de dor e a concentra??o de marcadores inflamat?rios (sTNFR1 e sTNFR2) em idosos com OA de joelho na fase de remiss?o da doen?a. Al?m disso, a associa??o da vibra??o de todo o corpo ao exerc?cio de agachamento promove uma melhora na for?a muscular de membros inferiores em mulheres idosas com OA de joelho na fase de remiss?o da doen?a e proporciona uma resposta adaptativa na concentra??o de BDNF sem altera??o na rela??o muscular de anabolismo/catabolismo. J? os resultados da rela??o entre sist?mico e local, indicam que os n?veis de BDNF sist?micos est?o associados com o mecanismo da dor articular na OA de joelho. Com rela??o aos receptores sol?veis de TNF-?, evidenciou-se a presen?a de receptores sol?veis para TNF-? no l?quido sinovial de pacientes com OA prim?ria de joelho e a rela??o destes receptores com par?metros cl?nicos. / Tese (Doutorado) ? Programa Multic?ntrico de P?s-Gradua??o em Ci?ncias Fisiol?gicas, Universidade Federal dos Vales do Jequitinhonha e Mucuri, 2013. / ABSTRACT Introduction: Recently, whole body vibration (WBV) has been an alternative method of exercise that has been indicated to improve the physical performance of the elderly with osteoarthritis (OA) knee. However, the mechanisms related to the effects produced by this training mode have not been fully elucidated in the literature. Objectives: 1) To investigate the effects of the adittion of whole-body vibration to squat exercises on the plasma concentration of inflammatory markers and the functional performance of elderly individuals with knee OA remission phase (Study 1) and investigate the effects of WBV in addition to squat exercise training in elderly women with knee OA remission phase on the following parameters: 1) isometric strength of the quadriceps muscle; 2) BDNF plasma concentration; and 3) the testosterone/cortisol salivary concentration ratio (Study 2). 3). To analyze the concentrations of TNF-?, soluble receptors (sTNFR1 and sTNFR2) and BDNF in both plasma and synovial fluid of patients with inflammatory acute phase primary knee osteoarthritis during inflammatory acute phase, and to determine the possible correlations of plasma and synovial fluid TNF-?, soluble receptors (sTNFR1 and sTNFR2) and BDNF with the radiographic grading of knee OA and with self-reported pain, stiffness and physical function (Study 3). Methods: In study 1 thirty-two elderly subjects with knee osteoarthritis were divided into three groups [i.e., squat exercises on a vibratory platform (platform group N= 11), squat exercises without vibration (squat group N= 10) and the control group (N=11)]. The structured program of squat exercises in the platform and squat groups was conducted three times per week, on alternate days, for twelve weeks. The plasma concentration of TNF-? soluble receptors (sTNFR1 and sTNFR2) were analyzed using ELISA. The Western Ontario and McMaster University Osteoarthritis Index (WOMAC) questionnaire were used to evaluate self-reported physical function, pain and stiffness. The 6-minute walk test, the Berg balance scale, and gait speed were used to evaluate physical function. In study 2 the eligible patients were fifteen (15) elderly women ? 60 years of age who had been diagnosed with OA in at least one knee. The intervention consisted of uninterrupted squatting exercises for twelve weeks, 3x/week. The exercise protocol was similar in both groups differing only in the presence of vibration. In study 3 samples of plasma taken from the peripheral blood and of synovial fluid taken from the knee of patients with osteoarthritis (OA) were collected (n=27). Anteroposterior knee radiographs were taken to determine disease severity in the affected knee. Radiographic grading of OA in the knee was performed using the Kellgren-Lawrence criteria. Furthermore, plasma was collected from the peripheral blood of 19 healthy individuals, with no radiographic change in the hips and knees. The Western Ontario and McMaster University Osteoarthritis Index (WOMAC) questionnaire was used to evaluate self-reported physical function, pain and stiffness. ELISA measured the TNF-?, sTNFR1, sTNFR2 and BDNF levels in the plasma and synovial fluid. Results: In the study 1 the group that performed squat exercises on a vibratory platform, there were significant differences in plasma concentrations of the inflammatory markers sTNFR1 and sTNFR2 (p<0.001 and p<0.05, respectively), self-reported pain (p<0.05), balance (p<0.05) and speed and distance walked (p<0.05 and p<0.001, respectively) compared with the control group. The gait speed test also showed significant differences between the squat and platform groups (p<0.01). In the results of the study 2, the VG group demonstrated a significantly greater change (?) in IQMS values (p = 0.02) and in BDNF plasma concentrations (p = 0.03) after the intervention period compared with the EG group. The change (?) in T/C ratio showed no difference between the groups (p = 0.61). In the results of the study 3, the plasma BDNF levels significantly correlated with self-reported pain [WOMAC] (rs=0.39, p=0.04). According to soluble receptors to TNF-?, there was a difference between sTNFR1 and sTNFR2 levels in plasma as well as in synovial fluid in patients with knee (1091 ? 99,48 pg / mL versus 2249 ? 126,3 pg / mL e 2587 ? 66,12 pg / mL versus 2021 ? 107,0 pg / mL, respectively). Synovial fluid sTNFR1 levels were negatively correlated with pain and physical function self-reported (rs-0.6785, p<0.0001 and rs-0.4194, p=0.03, respectively). Synovial fluid sTNFR2 levels were negatively correlated with pain and joint stiffness (rs-0.5433, p=0.01 and rs-0.4249, p=0.02, respectively). Conclusions: The results of the above studies indicate that the addition of vibration training the whole body to squat exercise in the experimental conditions resulted in improvement in static and dynamic balance and gait performance and reduced the self-perception of pain and the concentration of inflammatory markers (sTNFR1 and sTNFR2) in elderly patients with knee OA. We also demonstrate that the combination of vibration training the whole body to squat exercise can promote an improvement in lower limb muscle strength in elderly women with knee OA and still provide an adaptive response to the concentration of BDNF compared with no change in muscle anabolism/catabolism. The results of the relationship between systemic and local concentration indicate that the systemic BDNF levels are associated with the mechanism of joint pain in knee OA. With respect to TNF-? soluble receptors, the findings demonstrated the presence of soluble receptors for TNF-alpha, particularly sTNFR1, in the synovial fluid of patients with primary knee OA and the relationship between these receptors and clinical parameters.