O objetivo central desta tese de doutorado foi investigar as características clínicas de sintomas obsessivo-compulsivos (SOC), como fenômeno intermediário entre o desenvolvimento normal e o transtorno obsessivo-compulsivo (TOC), em uma ampla amostra comunitária (não-clínica) composta por crianças em idade escolar (6 a 12 anos) e seus familiares biológicos. Para tal, determinou-se a prevalência e a distribuição sociodemográfica dos SOC descrevendo sua fenomenologia caracterizada a partir de dimensões de SOC, agregação familiar, associação com outras comorbidades psiquiátricas e outras variáveis de comprometimento clínico (ex: fatores de risco, problemas sociais, escolares e de comportamento). Dividimos o presente estudo em duas etapas. Na Etapa I, o objeto de estudo foram 9.937 crianças de 6 a 12 anos regularmente matriculadas em escolas públicas (crianças-index) e seus familiares biológicos (n total=29.459). Nesta etapa utilizou-se a Family History Screening (FHS), escala de rastreamento para sintomas psiquiátricos internacionalmente validada, e um módulo adicional com sete itens para identificar quatro dimensões de SOC (\"Agressão/ sexual/ religiosa\"; \"arranjo/ simetria\"; \"contaminação/ lavagem\" e colecionismo\"). Nessa primeira etapa obtivemos dados sobre 9.937 crianças-index (podendo ser irmãos entre si), 3.305 irmãos biológicos (13 a 18 anos) e 16.218 pais. As mães biológicas foram informantes em 88% das entrevistas. Os SOC estiveram presentes em 19.4% da amostra total, sendo 14,7% das crianças-index; 15,6% dos irmãos; 34,6% das mães e 12,1% dos pais. A presença dos SOC foi associada ao sexo masculino e aumento da idade em crianças e adolescentes. Houve agregação familiar das dimensões de SOC nas famílias, sendo que a dimensão de \"contaminação/ lavagem\" foi a mais familiar (OR: 1,44; IC 95% 1,23-1,67; p < 0,001). Crianças-index com SOC apresentaram maior frequência de outros sintomas psiquiátricos, bem como maior comprometimento escolar, social e busca por tratamentos prévios. As principais limitações desta etapa incluem entrevista indireta (by proxy) e utilização de um instrumento ainda não validado para triagem de dimensões de SOC. Na Etapa II, o objeto de estudo foi uma sub-amostra da Etapa I e foram coletados dados de 2.512 crianças-index [média de idade: 8,86 anos (DP: 1,84); 44,59% sexo feminino], com um rigoroso e abrangente protocolo de avaliação clínica, incluindo diagnósticos de transtornos mentais pela DSM-IV/ DAWBA (Development and Well-Being Assessment), padrões específicos de comportamento pelo CBCL (Child Behavior Checklist), fatores de risco, comprometimento escolar, social e tratamentos prévios. A amostra foi dividida em grupos TOC (n=77; 3,07%), SOC (n=488; 19,43%) e controles (n=1.947; 77,5%), que foram comparados em relação às suas características fenotípicas. Não houve diferenças significativas de sexo, idade e classificação socioeconômica entre os três grupos estudados. O grupo TOC apresentou, mais frequentemente, obsessões ou compulsões em geral, obsessões de contaminação, compulsões de lavagem, repetição e colecionismo. Os grupos TOC e SOC foram semelhantes em relação às frequências de obsessões de agressão e compulsões de simetria, verificação e contagem. Em relação às comorbidades pelo DAWBA, o grupo TOC apresentou mais frequentemente transtornos de humor (agrupados), transtorno de ansiedade de separação, transtorno de ansiedade generalizada, transtorno de déficit de atenção e hiperatividade, e transtornos disruptivos (agrupados), quando comparado aos grupos SOC e controles. Os grupos TOC e SOC apresentaram prevalências semelhantes de fobia social, transtornos ansiosos (agrupados), transtorno de oposição e desafio, transtorno de tiques e transtornos alimentares, com prevalência superior àquela encontrada entre controles. Fatores de risco perinatais e abuso físico ou sexual foram significativamente mais frequentes no grupo TOC, em relação a SOC e controles. O grupo SOC exibiu padrão intermediário entre TOC (maior pontuação) e controles (menor pontuação) em relação aos escores totais e às dimensões de problemas de comportamento \"internalizantes\", \"externalizantes\" e sociais da CBCL. O grupo SOC revelou o mesmo padrão encontrado no grupo TOC acerca de vulnerabilidade social, problemas escolares (repetência, expulsão ou abandono), comprometimento funcional, comportamento delinquente e busca por tratamentos prévios. A principal limitação dessa etapa foi a adaptação dos critérios do DAWBA para a DSM-IV, para se estabelecer o diagnóstico de TOC na infância e adolescência. Portanto, este estudo transversal sugere que os SOC são um fenômeno relativamente frequente (aproximadamente 15 a 20%) em escolares de 6 a 12 anos e, sua prevalência se assemelha àquela descrita em adolescentes e adultos. Os dados desta tese fornecem evidências adicionais de que há um contínuo psicopatológico e de impacto clínico entre SOC e TOC o que é importante, não apenas para aprimorar a compreensão da natureza do TOC, mas para estabelecer estratégias de tratamento e prevenção / The present thesis investigated the clinical characteristics of obsessive-compulsive symptoms (OCS), as an intermediate phenomenon between normal development and obsessive-compulsive disorder (OCD) by assessing an extensive community (non- clinical) sample of schoolchildren (6-12 years) and their biological relatives. We determined the prevalence and sociodemographic status of OCS, describing its phenomenology characterized from OCS dimensions, familial aggregation, association with other psychiatric comorbidities, and other variables of clinical impairment (e.g.: risk factors , social, school and behavior problems). The study was divided in two phases. In phase I, 9,937 children (aged 6 to 12 years) enrolled in regular public schools (index-children) and their biological relatives (overall n = 29,459) were assessed. In this phase, we used the Family History Screening (FHS), an internationally validated instrument developed for psychiatric symptoms assessment. An additional seven-item module to identify four OCS dimensions (\"aggressive/ sexual/ religious\"; \"symmetry/ arranging\", \"contamination/ cleaning\" and \"hoarding \") was also used. In the first phase data on 9,937 index-children (may be siblings to each other), 3,305 biological siblings (13-18 years) and 16,218 parents were obtained. The biological mothers were informants in 88 % of the interviews. OCS were present in 19.4 % of the total sample, 14.7 % of index-children, 15.6 % of siblings, 34.6 % of mothers and 12.1 % of parents. The presence of OCS was associated with male gender and increasing age in children and adolescents. Familial aggregation of OCS dimensions was found; the \"contamination/ cleaning\" was the most familial dimension (OR: 1.44; 95% IC 1.23 to 1.67; p < 0.001). OCS were associated with higher frequency of other psychiatric symptoms as well as greater rates of social/ school problems and searching for previous treatments. The main limitations of this phase include by proxy interviews and use of an instrument for assessing OCS dimensions not yet validated. In phase II, a sub-sample (n=2,512) of phase I index-children [mean age: 8.86 (PD: 1.84); 44.59% female] was submitted to a rigorous and comprehensive clinical evaluation protocol, including structural diagnoses of mental disorders DSM-IV/ DAWBA (Development and Well-Being Assessment), specific behavioral patterns from CBCL (Child Behavior Checklist), risk factors, school/ social problems and searching for previous treatments. The sample was divided in three groups: OCD (n = 77; 3.07 %), OCS (N=488; 19.43 %) and controls (n=1,947; 77.5 %), compared according to their clinical features. There were no significant age/ gender and socio-economic status differences between groups. OCD group presented higher rates of overall obsessions and compulsions, contamination obsessions, cleaning and repetition compulsions and \"hoarding\". OCD and OCS groups showed similar prevalence rates of aggressive, symmetry, checking and counting symptoms. Regarding DAWBA comorbidities, OCD group showed increased prevalence of mood disorders (as a group), separation anxiety disorder, generalized anxiety disorder, attention deficit hyperactivity disorder, and disruptive disorders (as a group) compared to OCS and control groups. OCD and OCS groups showed similar prevalences of social phobia, anxiety disorders (as a group), oppositional defiant disorder, tic disorders and eating disorders, showing higher prevalence than controls. Perinatal risk factors and physical or sexual abuse were significantly more frequent in the OCD group in comparison to OCS and control groups. The OCS group exhibited intermediate pattern between OCD (higher scores) and controls (lower scores) concerning total and \"internalizing\", \"externalizing\" and social dimensions scores of the CBCL. The OCS group showed the same pattern found in the OCD group concerning social vulnerability, school problems (failure, expulsion or dropout), functional impairment, delinquent behavior, and searching for previous treatments. The main limitation of this phase was the adaptation of the DAWBA criteria for DSM -IV diagnosis for pediatric OCD. Therefore, this cross-sectional study suggests that OCS is fairly frequent in schoolchildren 6-12 years (about 15 to 20%) and its prevalence is similar to that described in adolescents and adults. Data from this thesis provide further evidence that there is a psychopathological and clinical impact continuum between OCS and OCD, which is important not only to enhance the understanding of the nature of OCD but to develop treatment and prevention strategies

Introdução: Com o envelhecimento da população mundial projeta-se o crescimento das taxas de doenças potencialmente relacionadas à idade como as demências, especialmente a doença de Alzheimer (DA). Os sujeitos com Comprometimento Cognitivo Leve (CCL) são considerados uma população de risco para desenvolver demência, no entanto, as taxas de incidência de CCL e conversão para demência apresentam considerável variabilidade em parte atribuída a características da amostra e aos diferentes critérios utilizados. Objetivos: Determinar a incidência de demência e Comprometimento Cognitivo Leve em uma coorte de idosos saudáveis de base comunitária; determinar as variáveis demográficas, clínicas e sociais associadas ao desenvolvimento de prejuízo cognitivo, e avaliar o risco de progressão dos indivíduos com Comprometimento Cognitivo Leve para demência comparada com sujeitos cognitivamente normais. Métodos: Os dados foram derivados de uma coorte de idosos residentes na comunidade (N = 345), inicialmente saudáveis e independentes (Estudo PALA - Porto Alegre Longitudinal Aging - study). O seguimento inicial com duração máxima de oito anos teve o objetivo de avaliar a incidência de DA e CCL. Para avaliar a progressão de CCL para DA partimos de 10 anos de seguimento, incluindo os oito anos da primeira análise e consideramos um máximo de 70 meses (média de 45 meses) para avaliar a ocorrência dos novos desfechos. Os participantes que preencheram os critérios de inclusão do estudo e consentiram em participar foram avaliados com uma detalhada entrevista clínica composta de variáveis demográficas, clínicas e sociais. Os sintomas psiquiátricos foram avaliados pela escala SRQ - Self Report Questionnaire, escala MADRS - Montgomery-Asberg Depression Rating Scale e aplicados os critérios para depressão maior do Manual de Diagnóstico e Estatístico de Transtornos Mentais (4ª Edição; DSM-IV). O Mini Exame do Estado Mental (MEEM) e a Escala Clínica de Demência (CDR – Clinical Dementia Rating) foram aplicados para avaliação cognitiva. Adicionalmente a independência para as atividades da vida diária foram acessadas pela escala ADL - Activities of Daily Living. Para diagnóstico dos casos incidentes de doença de Alzheimer foi utilizado os critérios diagnósticos do DSM-IV e do NINCDS/ADRDA, associado à descrição dos critérios de Kawas para DA consistente. Para diagnóstico de Comprometimento Cognitivo Leve, o critério da Clínica Mayo foi aplicado para a primeira análise, e o critério para CCL do tipo Alzheimer (ou DA prodrômica) foi utilizado para a segunda análise tendo em vista a incorporação de dados disponíveis e a evolução dos critérios. As trajetórias possíveis do CCL foram classificadas em três categorias: conversão, estabilização e reconversão. Os sujeitos considerados para a primeira análise - casos incidentes de CCL e DA foram os participantes que apresentavam pelo menos uma visita de seguimento no período de oito anos a partir da linha de base (N = 245) e as análises estatísticas foram baseadas no diagnóstico estabelecido na última visita de seguimento. Para os falecidos durante o período, dados retrospectivos foram obtidos através de uma entrevista telefônica com um informante confiável. Os dados clínicos e demográficos de linha de base foram utilizados para cálculo dos fatores preditivos dos desfechos do estudo. Para a segunda análise – risco de conversão de CCL para DA – trajetórias do CCL, a amostra foi composta dos 21 indivíduos que desenvolveram CCL e 220 indivíduos cognitivamente normais (N = 241). Resultados: Os resultados da primeira análise mostraram taxa de incidência de CCL de 13,2 por 1.000 pessoas-ano e incidência de DA de 14,8 por 1.000 pessoas-ano. O desenvolvimento de prejuízo cognitivo foi associado com educação (razão de chance [RC] = 0,86) e o escore do MEEM de base (RC = 0,81). Os resultados da segunda análise mostraram que dos 21 sujeitos com CCL, 38% desenvolveram demência, 24% permaneceram estáveis e 38% melhoraram. A taxa de conversão anual para DA foi de 8,5%, CCL foi associado significativamente a maior risco de conversão para DA (HR = 49,83; p = 0,004), mesmo ajustado para idade, escolaridade, sexo e escore no MEEM. Conclusão: A incidência de DA nessa amostra foi maior do que a descrita em estudo prévio realizado no Brasil, mas está dentro da variabilidade observada internacionalmente. Escores mais baixos no Mini Exame do Estado Mental na linha de base, mesmo que dentro da normalidade, e níveis mais baixos de educação foram preditores da ocorrência de prejuízo cognitivo. Quanto à trajetória do CCL, independentemente da heterogeneidade observada, os participantes com CCL do tipo Alzheimer apresentaram risco significativamente maior de desenvolver demência na DA, demonstrando o impacto do uso destes critérios que enfatizam o comprometimento da memória episódica de longo prazo e buscam identificar sujeitos com maior probabilidade de ser portadores de patologia Alzheimer. / Background: The increase of the rates of age-related diseases as dementia, especially Alzheimer's disease (AD), is projected with the aging of the world population. Subjects with Mild Cognitive Impairment (MCI) are considered a population at risk for developing dementia. However, MCI incidence rates and rates of conversion to dementia have shown considerable variability that could be partially attributed to characteristics of the sample and to different criteria. Objective: To determine the incidence of dementia and mild cognitive impairment in a cohort of community-based healthy elderly individuals; to determine the demographic, clinical and social variables associated with the development of cognitive impairment; and to assess the risk of progression of individuals with mild cognitive impairment to dementia compared with cognitively normal subjects. Methods: Data were derived from a cohort of elderly community residents (N = 345), who were initially healthy and independent (PALA – Porto Alegre Longitudinal Aging – study). The follow-up of a maximum of eight years was used to evaluate the incidence of AD and MCI. To evaluate the progression of MCI to dementia due to AD we set off the 10-year follow-up, including the previous 8-year of the first analysis, and consider the maximum of 70 months (mean 45 months) for these new outcomes. Participants who met the inclusion criteria of the study and consented to participate were evaluated with a detailed clinical interview consisted of demographic, clinical and social variables. Psychiatric symptoms were assessed with the SRQ scale (Self Report Questionnaire), the MADRS (Montgomery-Asberg Depression Rating Scale), and the Diagnostic and Statistical Manual of Mental Disorders (4th edition, DSM-IV) criteria for Major Depression. Cognitive assessment was checked with the Mini Mental State Examination (MMSE) and the Clinical Dementia Rating Scale (CDR). Independence for the activities of daily living was assessed with the ADL scale (Activities of Daily Living). Incident cases of probable Alzheimer's disease were assigned through the DSM-IV and the NINCDS-ADRDA diagnostic criteria, with the additional designation from Kawas and colleagues of consistent AD. Detection of Mild Cognitive Impairment for the first analysis was carried out with the MCI Mayo Clinic criteria. The MCI of the Alzheimer type criteria (or Prodromal AD) were used for the second analysis, incorporating available data of the sample and the ongoing evolution of the criteria. The possible MCI trajectories were classified into three categories: conversion, stabilization, and reconversion. The subjects for the first analysis – MCI and AD incidence – were the participants who had at least one follow-up visit in the 8-year period from the baseline (N = 245), and the statistical analyzes were based on the diagnosis established in last follow-up interview. For the deceased during the period, retrospective data were obtained through a telephone interview with a knowledgeable collateral source focusing on dementia. The baseline clinical and demographic data were analyzed as predictors of the study outcomes. For the second analysis – risk of MCI progression to AD, and MCI trajectories – the sample was composed of 21 individuals who developed MCI and 220 cognitively normal subjects (N = 241). Results: The results of the first analysis showed the MCI incidence rate of 13.2 per 1,000 person-years and the AD incidence of 14.8 per 1,000 person-years. The development of cognitive impairment was associated with education (odds ratio [OR] = 0.86) and baseline MMSE scores (OR = 0.81). The results of second analysis showed that of the 21 MCI subjects, 38% developed dementia, 24% remained stable, and 38% improved. The annual AD conversion rate was 8.5%, and MCI was significantly associated with increased risk of progression to AD (HR = 49.83; p = 0.004), even adjusted for age, education, gender and MMSE scores. Conclusion: The AD incidence in this sample was higher than that described in a previous study carried out in Brazil, but was within the international estimates. Lower baseline scores on the Mini Mental State Examination, although within the normal range, and lower levels of education were predictors of cognitive impairment. Regardless the observed heterogeneity of the MCI trajectories, participants with MCI of the Alzheimer type showed significantly higher risk of developing dementia due to AD, demonstrating the impact of the emphasis on the episodic long-term memory impairment of the criteria, which finally searches to identify those individuals more likely to have Alzheimer's pathology.

Introdução: Com o envelhecimento da população mundial projeta-se o crescimento das taxas de doenças potencialmente relacionadas à idade como as demências, especialmente a doença de Alzheimer (DA). Os sujeitos com Comprometimento Cognitivo Leve (CCL) são considerados uma população de risco para desenvolver demência, no entanto, as taxas de incidência de CCL e conversão para demência apresentam considerável variabilidade em parte atribuída a características da amostra e aos diferentes critérios utilizados. Objetivos: Determinar a incidência de demência e Comprometimento Cognitivo Leve em uma coorte de idosos saudáveis de base comunitária; determinar as variáveis demográficas, clínicas e sociais associadas ao desenvolvimento de prejuízo cognitivo, e avaliar o risco de progressão dos indivíduos com Comprometimento Cognitivo Leve para demência comparada com sujeitos cognitivamente normais. Métodos: Os dados foram derivados de uma coorte de idosos residentes na comunidade (N = 345), inicialmente saudáveis e independentes (Estudo PALA - Porto Alegre Longitudinal Aging - study). O seguimento inicial com duração máxima de oito anos teve o objetivo de avaliar a incidência de DA e CCL. Para avaliar a progressão de CCL para DA partimos de 10 anos de seguimento, incluindo os oito anos da primeira análise e consideramos um máximo de 70 meses (média de 45 meses) para avaliar a ocorrência dos novos desfechos. Os participantes que preencheram os critérios de inclusão do estudo e consentiram em participar foram avaliados com uma detalhada entrevista clínica composta de variáveis demográficas, clínicas e sociais. Os sintomas psiquiátricos foram avaliados pela escala SRQ - Self Report Questionnaire, escala MADRS - Montgomery-Asberg Depression Rating Scale e aplicados os critérios para depressão maior do Manual de Diagnóstico e Estatístico de Transtornos Mentais (4ª Edição; DSM-IV). O Mini Exame do Estado Mental (MEEM) e a Escala Clínica de Demência (CDR – Clinical Dementia Rating) foram aplicados para avaliação cognitiva. Adicionalmente a independência para as atividades da vida diária foram acessadas pela escala ADL - Activities of Daily Living. Para diagnóstico dos casos incidentes de doença de Alzheimer foi utilizado os critérios diagnósticos do DSM-IV e do NINCDS/ADRDA, associado à descrição dos critérios de Kawas para DA consistente. Para diagnóstico de Comprometimento Cognitivo Leve, o critério da Clínica Mayo foi aplicado para a primeira análise, e o critério para CCL do tipo Alzheimer (ou DA prodrômica) foi utilizado para a segunda análise tendo em vista a incorporação de dados disponíveis e a evolução dos critérios. As trajetórias possíveis do CCL foram classificadas em três categorias: conversão, estabilização e reconversão. Os sujeitos considerados para a primeira análise - casos incidentes de CCL e DA foram os participantes que apresentavam pelo menos uma visita de seguimento no período de oito anos a partir da linha de base (N = 245) e as análises estatísticas foram baseadas no diagnóstico estabelecido na última visita de seguimento. Para os falecidos durante o período, dados retrospectivos foram obtidos através de uma entrevista telefônica com um informante confiável. Os dados clínicos e demográficos de linha de base foram utilizados para cálculo dos fatores preditivos dos desfechos do estudo. Para a segunda análise – risco de conversão de CCL para DA – trajetórias do CCL, a amostra foi composta dos 21 indivíduos que desenvolveram CCL e 220 indivíduos cognitivamente normais (N = 241). Resultados: Os resultados da primeira análise mostraram taxa de incidência de CCL de 13,2 por 1.000 pessoas-ano e incidência de DA de 14,8 por 1.000 pessoas-ano. O desenvolvimento de prejuízo cognitivo foi associado com educação (razão de chance [RC] = 0,86) e o escore do MEEM de base (RC = 0,81). Os resultados da segunda análise mostraram que dos 21 sujeitos com CCL, 38% desenvolveram demência, 24% permaneceram estáveis e 38% melhoraram. A taxa de conversão anual para DA foi de 8,5%, CCL foi associado significativamente a maior risco de conversão para DA (HR = 49,83; p = 0,004), mesmo ajustado para idade, escolaridade, sexo e escore no MEEM. Conclusão: A incidência de DA nessa amostra foi maior do que a descrita em estudo prévio realizado no Brasil, mas está dentro da variabilidade observada internacionalmente. Escores mais baixos no Mini Exame do Estado Mental na linha de base, mesmo que dentro da normalidade, e níveis mais baixos de educação foram preditores da ocorrência de prejuízo cognitivo. Quanto à trajetória do CCL, independentemente da heterogeneidade observada, os participantes com CCL do tipo Alzheimer apresentaram risco significativamente maior de desenvolver demência na DA, demonstrando o impacto do uso destes critérios que enfatizam o comprometimento da memória episódica de longo prazo e buscam identificar sujeitos com maior probabilidade de ser portadores de patologia Alzheimer. / Background: The increase of the rates of age-related diseases as dementia, especially Alzheimer's disease (AD), is projected with the aging of the world population. Subjects with Mild Cognitive Impairment (MCI) are considered a population at risk for developing dementia. However, MCI incidence rates and rates of conversion to dementia have shown considerable variability that could be partially attributed to characteristics of the sample and to different criteria. Objective: To determine the incidence of dementia and mild cognitive impairment in a cohort of community-based healthy elderly individuals; to determine the demographic, clinical and social variables associated with the development of cognitive impairment; and to assess the risk of progression of individuals with mild cognitive impairment to dementia compared with cognitively normal subjects. Methods: Data were derived from a cohort of elderly community residents (N = 345), who were initially healthy and independent (PALA – Porto Alegre Longitudinal Aging – study). The follow-up of a maximum of eight years was used to evaluate the incidence of AD and MCI. To evaluate the progression of MCI to dementia due to AD we set off the 10-year follow-up, including the previous 8-year of the first analysis, and consider the maximum of 70 months (mean 45 months) for these new outcomes. Participants who met the inclusion criteria of the study and consented to participate were evaluated with a detailed clinical interview consisted of demographic, clinical and social variables. Psychiatric symptoms were assessed with the SRQ scale (Self Report Questionnaire), the MADRS (Montgomery-Asberg Depression Rating Scale), and the Diagnostic and Statistical Manual of Mental Disorders (4th edition, DSM-IV) criteria for Major Depression. Cognitive assessment was checked with the Mini Mental State Examination (MMSE) and the Clinical Dementia Rating Scale (CDR). Independence for the activities of daily living was assessed with the ADL scale (Activities of Daily Living). Incident cases of probable Alzheimer's disease were assigned through the DSM-IV and the NINCDS-ADRDA diagnostic criteria, with the additional designation from Kawas and colleagues of consistent AD. Detection of Mild Cognitive Impairment for the first analysis was carried out with the MCI Mayo Clinic criteria. The MCI of the Alzheimer type criteria (or Prodromal AD) were used for the second analysis, incorporating available data of the sample and the ongoing evolution of the criteria. The possible MCI trajectories were classified into three categories: conversion, stabilization, and reconversion. The subjects for the first analysis – MCI and AD incidence – were the participants who had at least one follow-up visit in the 8-year period from the baseline (N = 245), and the statistical analyzes were based on the diagnosis established in last follow-up interview. For the deceased during the period, retrospective data were obtained through a telephone interview with a knowledgeable collateral source focusing on dementia. The baseline clinical and demographic data were analyzed as predictors of the study outcomes. For the second analysis – risk of MCI progression to AD, and MCI trajectories – the sample was composed of 21 individuals who developed MCI and 220 cognitively normal subjects (N = 241). Results: The results of the first analysis showed the MCI incidence rate of 13.2 per 1,000 person-years and the AD incidence of 14.8 per 1,000 person-years. The development of cognitive impairment was associated with education (odds ratio [OR] = 0.86) and baseline MMSE scores (OR = 0.81). The results of second analysis showed that of the 21 MCI subjects, 38% developed dementia, 24% remained stable, and 38% improved. The annual AD conversion rate was 8.5%, and MCI was significantly associated with increased risk of progression to AD (HR = 49.83; p = 0.004), even adjusted for age, education, gender and MMSE scores. Conclusion: The AD incidence in this sample was higher than that described in a previous study carried out in Brazil, but was within the international estimates. Lower baseline scores on the Mini Mental State Examination, although within the normal range, and lower levels of education were predictors of cognitive impairment. Regardless the observed heterogeneity of the MCI trajectories, participants with MCI of the Alzheimer type showed significantly higher risk of developing dementia due to AD, demonstrating the impact of the emphasis on the episodic long-term memory impairment of the criteria, which finally searches to identify those individuals more likely to have Alzheimer's pathology.

Introdução: Com o envelhecimento da população mundial projeta-se o crescimento das taxas de doenças potencialmente relacionadas à idade como as demências, especialmente a doença de Alzheimer (DA). Os sujeitos com Comprometimento Cognitivo Leve (CCL) são considerados uma população de risco para desenvolver demência, no entanto, as taxas de incidência de CCL e conversão para demência apresentam considerável variabilidade em parte atribuída a características da amostra e aos diferentes critérios utilizados. Objetivos: Determinar a incidência de demência e Comprometimento Cognitivo Leve em uma coorte de idosos saudáveis de base comunitária; determinar as variáveis demográficas, clínicas e sociais associadas ao desenvolvimento de prejuízo cognitivo, e avaliar o risco de progressão dos indivíduos com Comprometimento Cognitivo Leve para demência comparada com sujeitos cognitivamente normais. Métodos: Os dados foram derivados de uma coorte de idosos residentes na comunidade (N = 345), inicialmente saudáveis e independentes (Estudo PALA - Porto Alegre Longitudinal Aging - study). O seguimento inicial com duração máxima de oito anos teve o objetivo de avaliar a incidência de DA e CCL. Para avaliar a progressão de CCL para DA partimos de 10 anos de seguimento, incluindo os oito anos da primeira análise e consideramos um máximo de 70 meses (média de 45 meses) para avaliar a ocorrência dos novos desfechos. Os participantes que preencheram os critérios de inclusão do estudo e consentiram em participar foram avaliados com uma detalhada entrevista clínica composta de variáveis demográficas, clínicas e sociais. Os sintomas psiquiátricos foram avaliados pela escala SRQ - Self Report Questionnaire, escala MADRS - Montgomery-Asberg Depression Rating Scale e aplicados os critérios para depressão maior do Manual de Diagnóstico e Estatístico de Transtornos Mentais (4ª Edição; DSM-IV). O Mini Exame do Estado Mental (MEEM) e a Escala Clínica de Demência (CDR – Clinical Dementia Rating) foram aplicados para avaliação cognitiva. Adicionalmente a independência para as atividades da vida diária foram acessadas pela escala ADL - Activities of Daily Living. Para diagnóstico dos casos incidentes de doença de Alzheimer foi utilizado os critérios diagnósticos do DSM-IV e do NINCDS/ADRDA, associado à descrição dos critérios de Kawas para DA consistente. Para diagnóstico de Comprometimento Cognitivo Leve, o critério da Clínica Mayo foi aplicado para a primeira análise, e o critério para CCL do tipo Alzheimer (ou DA prodrômica) foi utilizado para a segunda análise tendo em vista a incorporação de dados disponíveis e a evolução dos critérios. As trajetórias possíveis do CCL foram classificadas em três categorias: conversão, estabilização e reconversão. Os sujeitos considerados para a primeira análise - casos incidentes de CCL e DA foram os participantes que apresentavam pelo menos uma visita de seguimento no período de oito anos a partir da linha de base (N = 245) e as análises estatísticas foram baseadas no diagnóstico estabelecido na última visita de seguimento. Para os falecidos durante o período, dados retrospectivos foram obtidos através de uma entrevista telefônica com um informante confiável. Os dados clínicos e demográficos de linha de base foram utilizados para cálculo dos fatores preditivos dos desfechos do estudo. Para a segunda análise – risco de conversão de CCL para DA – trajetórias do CCL, a amostra foi composta dos 21 indivíduos que desenvolveram CCL e 220 indivíduos cognitivamente normais (N = 241). Resultados: Os resultados da primeira análise mostraram taxa de incidência de CCL de 13,2 por 1.000 pessoas-ano e incidência de DA de 14,8 por 1.000 pessoas-ano. O desenvolvimento de prejuízo cognitivo foi associado com educação (razão de chance [RC] = 0,86) e o escore do MEEM de base (RC = 0,81). Os resultados da segunda análise mostraram que dos 21 sujeitos com CCL, 38% desenvolveram demência, 24% permaneceram estáveis e 38% melhoraram. A taxa de conversão anual para DA foi de 8,5%, CCL foi associado significativamente a maior risco de conversão para DA (HR = 49,83; p = 0,004), mesmo ajustado para idade, escolaridade, sexo e escore no MEEM. Conclusão: A incidência de DA nessa amostra foi maior do que a descrita em estudo prévio realizado no Brasil, mas está dentro da variabilidade observada internacionalmente. Escores mais baixos no Mini Exame do Estado Mental na linha de base, mesmo que dentro da normalidade, e níveis mais baixos de educação foram preditores da ocorrência de prejuízo cognitivo. Quanto à trajetória do CCL, independentemente da heterogeneidade observada, os participantes com CCL do tipo Alzheimer apresentaram risco significativamente maior de desenvolver demência na DA, demonstrando o impacto do uso destes critérios que enfatizam o comprometimento da memória episódica de longo prazo e buscam identificar sujeitos com maior probabilidade de ser portadores de patologia Alzheimer. / Background: The increase of the rates of age-related diseases as dementia, especially Alzheimer's disease (AD), is projected with the aging of the world population. Subjects with Mild Cognitive Impairment (MCI) are considered a population at risk for developing dementia. However, MCI incidence rates and rates of conversion to dementia have shown considerable variability that could be partially attributed to characteristics of the sample and to different criteria. Objective: To determine the incidence of dementia and mild cognitive impairment in a cohort of community-based healthy elderly individuals; to determine the demographic, clinical and social variables associated with the development of cognitive impairment; and to assess the risk of progression of individuals with mild cognitive impairment to dementia compared with cognitively normal subjects. Methods: Data were derived from a cohort of elderly community residents (N = 345), who were initially healthy and independent (PALA – Porto Alegre Longitudinal Aging – study). The follow-up of a maximum of eight years was used to evaluate the incidence of AD and MCI. To evaluate the progression of MCI to dementia due to AD we set off the 10-year follow-up, including the previous 8-year of the first analysis, and consider the maximum of 70 months (mean 45 months) for these new outcomes. Participants who met the inclusion criteria of the study and consented to participate were evaluated with a detailed clinical interview consisted of demographic, clinical and social variables. Psychiatric symptoms were assessed with the SRQ scale (Self Report Questionnaire), the MADRS (Montgomery-Asberg Depression Rating Scale), and the Diagnostic and Statistical Manual of Mental Disorders (4th edition, DSM-IV) criteria for Major Depression. Cognitive assessment was checked with the Mini Mental State Examination (MMSE) and the Clinical Dementia Rating Scale (CDR). Independence for the activities of daily living was assessed with the ADL scale (Activities of Daily Living). Incident cases of probable Alzheimer's disease were assigned through the DSM-IV and the NINCDS-ADRDA diagnostic criteria, with the additional designation from Kawas and colleagues of consistent AD. Detection of Mild Cognitive Impairment for the first analysis was carried out with the MCI Mayo Clinic criteria. The MCI of the Alzheimer type criteria (or Prodromal AD) were used for the second analysis, incorporating available data of the sample and the ongoing evolution of the criteria. The possible MCI trajectories were classified into three categories: conversion, stabilization, and reconversion. The subjects for the first analysis – MCI and AD incidence – were the participants who had at least one follow-up visit in the 8-year period from the baseline (N = 245), and the statistical analyzes were based on the diagnosis established in last follow-up interview. For the deceased during the period, retrospective data were obtained through a telephone interview with a knowledgeable collateral source focusing on dementia. The baseline clinical and demographic data were analyzed as predictors of the study outcomes. For the second analysis – risk of MCI progression to AD, and MCI trajectories – the sample was composed of 21 individuals who developed MCI and 220 cognitively normal subjects (N = 241). Results: The results of the first analysis showed the MCI incidence rate of 13.2 per 1,000 person-years and the AD incidence of 14.8 per 1,000 person-years. The development of cognitive impairment was associated with education (odds ratio [OR] = 0.86) and baseline MMSE scores (OR = 0.81). The results of second analysis showed that of the 21 MCI subjects, 38% developed dementia, 24% remained stable, and 38% improved. The annual AD conversion rate was 8.5%, and MCI was significantly associated with increased risk of progression to AD (HR = 49.83; p = 0.004), even adjusted for age, education, gender and MMSE scores. Conclusion: The AD incidence in this sample was higher than that described in a previous study carried out in Brazil, but was within the international estimates. Lower baseline scores on the Mini Mental State Examination, although within the normal range, and lower levels of education were predictors of cognitive impairment. Regardless the observed heterogeneity of the MCI trajectories, participants with MCI of the Alzheimer type showed significantly higher risk of developing dementia due to AD, demonstrating the impact of the emphasis on the episodic long-term memory impairment of the criteria, which finally searches to identify those individuals more likely to have Alzheimer's pathology.

Bakgrund: Hjärtinfarkt bedöms vara den ledande dödsorsaken världen över. Trots att fler män än kvinnor insjuknar i hjärtinfarkt är dödligheten bland kvinnor högre. Bilden av hjärt- kärlsjukdom har länge präglats av ett manligt perspektiv vilket är en livshotande inställning som leder till att kvinnors symtom inte tas på allvar. Syfte: Syftet med studien var att beskriva kvinnors upplevelser av symtomen vid hjärtinfarkt. Metod: En litteraturöversikt där elva  artiklar från databaserna CINAHL Complete och PubMed granskats och analyserats. Resultat: De vanligaste symtomen hos kvinnor med hjärtinfarkt var smärta, fatique, andningspåverkan, gastrointestinala besvär och kroppstemperaturförändringar. Många kvinnor hade svårt att förstå och relatera sina symtom och blev inte tagna på allvar i vården. Det fanns en tydlig frustration då symtomen i många fall inte överensstämde med de symtomförväntningar som fanns. Slutsats: Litteraturöversikten lyfter fram kvinnors symtom vid hjärtinfarkt och bidrar till att skapa en förståelse för kvinnans tankemönster vid vårdsökandet. Hjärtinfarkt ska inte baseras på kön utan på kliniska fynd. Genom att vidga en större förståelse för hur kvinnor tolkar sina symtom kan vårdpersonal förbättra utgången för kvinnor med hjärtinfarkt. / Background: Myocardial infarction is considered to be the leading cause of death worldwide. Although the number of cases is higher in men, the mortality rate is higher amongst women. The image of cardiovascular disease has long been characterized by a male perspective, which is a life-threatening attitude that leads to women's symptoms not being taken seriously. Aim: The aim of this study was to describe women’s experiences of myocardial infarction symptoms. Method: A literature study where eleven articles from the databases CINAHL Complete and PubMed were reviewed and analyzed. Results: The most common symptoms in women with myocardial infarction were pain, fatigue, respiratory distress, indigestion and body temperature changes. Many women had a hard time understanding and relating their symptoms to cause and were hence not taken seriously in care. There was a clear frustration as the symptoms in many cases did not match the expectations that existed. Conclusion: This literature review highlights women’s symptoms of myocardial infarction and helps to create an understanding of the woman's thought patterns when seeking care. Assessment of myocardial infarction should not be based on gender but on clinical findings. By broadening a greater understanding of how women interpret their symptoms, healthcare professionals can improve the outcome for women with myocardial infarction.

La psychose est un syndrome apparaissant progressivement à l’adolescence chez des individus à risque selon un processus dynamique appelé transition psychotique. Ces individus à risque sont repérables cliniquement mais les données biologiques actuelles sont insuffisantes pour expliquer l’apparition de la psychose. Au cours de cette thèse, nous avons cherché à identifier les facteurs biologiques responsables de ce processus. Les hypothèses permettant d’expliquer la transition psychotique privilégient l’interaction gène x environnement, sous-tendue par des mécanismes épigénétiques. Nous avons mené une étude des modifications de la méthylation de l’ADN et de la transcription à l’aide de techniques de biologie moléculaire et de bio-informatique à l’échelle pan-génomique. La transition psychotique semble être liée à des modifications de méthylation et de transcription de gènes impliqués dans des mécanismes comme le guidage axonal ou la régulation du stress oxydatif. Ces modifications longitudinales pourraient refléter l’influence de l’environnement. Les facteurs environnementaux pourraient déréguler l’axe biologique du stress dès les phases précoces de la maladie, comme le suggère l’augmentation de la sécrétion de cortisol basal que nous avons montré chez les individus à risque. En outre, il est probable que des spécificités au niveau des gènes et des processus régulant l’épigénome soient également impliquées dans cette réponse individuelle à l’environnement. Nous avons montré l’importance du métabolisme mono-carboné au moins dans un sous-groupe spécifique de patients. Ces résultats doivent être répliqués et étendus dans d’autres paradigmes pour valider l’implication de ces processus dans la transition psychotique. En cas de confirmation, ces voies biologiques pourraient s’avérer être des pistes intéressantes pour développer des thérapeutiques ciblées et relever le défi de la prévention de la psychose chez des individus à risque. / Psychosis is a progressive mental disorder which normally occurs during adolescence in at-risk subjects following a dynamic process termed “psychotic transition”. These at-risk subjects are clinically identifiable but biological data are still insufficient in explaining the onset of psychosis. Throughout this thesis, we aim to identify biological factors implicated in this pathophysiological process. Current hypotheses explaining the psychotic transition favor the interaction between genes and the environment mediated by epigenetic mechanisms. We conducted studies examining methylomic and transcriptomic changes during psychotic transition using molecular biology and bioinformatics techniques at a whole genome scale. Our results suggest that psychotic transition may be linked to methylomic and transcriptomic changes in genes implicated in axon guidance or oxidative stress. These longitudinal changes could be related to environmental factors. Some of these factors could deregulate the hormonal stress response at the earliest phases of psychosis. Indeed, our results show that secretion of basal cortisol is increased in prodromal individuals. Moreover, it is likely that genes and processes regulating epigenetic modifications are also implicated in the individual response to the environment. We have shown the importance of the one-carbon metabolism for at least one sub-group of patients affected by psychosis. Our results should be replicated using other paradigms in order to definitively validate the implication of these various actors in the psychotic transition. If confirmed, knowledge of these biological mechanisms could lead to the development of targeted therapeutics to prevent psychosis in at-risk individuals.

Τα δημογραφικά χαρακτηριστικά και η συμπτωματολογία και της παρανοειδούς μορφής σχιζοφρένειας πρώιμης και όψιμης έναρξης μελετήθηκαν σε 88 ασθενείς, που νοσηλεύθηκαν στην Ψυχιατρική Κλινική του Πανεπιστημίου Πατρών, από 15-3-2005 έως 7-5-2008. Εξ’ αυτών, 60, 46 άνδρες και 14 γυναίκες, ενεφάνιζαν πρώιμη έναρξη της νόσου, πριν από την ηλικία των 30 ετών, ενώ 21, 8 άνδρες και 13 γυναίκες, ασθένησαν όψιμα, με έναρξη νόσου σε ηλικία ≥35 ετών. Συνεκρίθησαν τα δημογραφικά στοιχεία, η συχνότητα κατάχρησης ή εξάρτησης τον καπνό, οινόπνευμα και κάνναβη, τα στοιχεία προνοσηρών διαταραχών προσωπικότητας, ο αριθμός και ο τύπος των προδρόμων συμπτωμάτων, η διάρκεια της πρόδρομης φάσης και η συμπτωματολογία της ενεργού φάσης μεταξύ των ασθενών πρώιμης και όψιμης έναρξης, συνολικά και χωριστά για τα δύο φύλα, καθώς και μεταξύ ανδρών και γυναικών, στις δύο ηλικιακές ομάδες. Οι κλίμακες που εφαρμόσθηκαν ήταν οι SCID-I/P, PANSS, Calgary Depression Scale, SCID-II, καθώς και κλινική συνέντευξη για τα πρόδρομα συμπτώματα. Τα στοιχεία αναλύθηκαν με τις στατιστικές δοκιμασίες Wilcoxon rank-sum και χ2. Οι ασθενείς πρώιμης έναρξης, και ιδιαίτερα οι άνδρες, είχαν στατιστικώς σημαντικά μεγαλύτερη πιθανότητα να έχουν γεννηθεί σε αστική περιοχή σε σχέση με τους ασθενείς όψιμης έναρξης. Οι γυναίκες όψιμης έναρξης είχαν το μεγαλύτερο ποσοστό έγγαμης συμβίωσης από όλες τις άλλες ομάδες. Δεν παρατηρήθηκε στατιστικώς σημαντική διαφορά στη χρήση καπνού, οινοπνεύματος και κάνναβης μεταξύ των ομάδων πρώιμης και όψιμης έναρξης, συνολικά ή χωριστά στα δύο φύλα. Στην ομάδα πρώιμης έναρξης, οι άνδρες παρουσίαζαν σε μεγαλύτερη συχνότητα χρήση αλκοόλ και κάνναβης σε σχέση με τις γυναίκες. Παρομοίως, οι άνδρες όψιμης έναρξης κάπνιζαν και έτειναν να χρησιμοποιούν κάνναβη σε μεγαλύτερο ποσοστό από τις γυναίκες. Στην προνοσηρή περίοδο, οι πρώιμης έναρξης ασθενείς έχουν σημαντικά περισσότερα στοιχεία αποφευκτικής διαταραχής προσωπικότητας σε σχέση με τους όψιμης έναρξης. Αυτό το εύρημα πλησιάζει τη στατιστική σημαντικότητα και στο δείγμα των γυναικών. Οι ασθενείς όψιμης έναρξης, στο συνολικό δείγμα και στο δείγμα των ανδρών, εμφανίζουν στατιστικώς σημαντικά περισσότερα στοιχεία παθητικο-επιθετικής διαταραχής προσωπικότητας σε σχέση με τους ασθενείς πρώιμης έναρξης. Στην ομάδα με την πρώιμη έναρξη, οι άνδρες είχαν περισσότερα στοιχεία σχιζότυπης και παρανοειδούς διαταραχής προσωπικότητας από τις γυναίκες, ενώ οι τελευταίες είχαν περισσότερα στοιχεία καταθλιπτικής διαταραχής προσωπικότητας. Στους ασθενείς όψιμης έναρξης, οι άνδρες είχαν περισσότερα στοιχεία ιστριονικής, ναρκισσιστικής και αντικοινωνικής διαταραχής από τις γυναίκες. Στην πρόδρομη φάση, οι ασθενείς πρώιμης έναρξης παρουσιάζουν στατιστικώς σημαντικά μεγαλύτερο αριθμό αρνητικών συμπτωμάτων, στο συνολικό δείγμα και στο δείγμα των ανδρών. Στο συνολικό δείγμα, τα συμπτώματα της εκσεσημασμένης κοινωνικής απομόνωσης και της έκπτωσης της συγκέντρωσης παρατηρούνται σε στατιστικώς σημαντικά μεγαλύτερο ποσοστό στην ομάδα με την πρώιμη έναρξη σε σχέση με την ομάδα όψιμης έναρξης. Στους ασθενείς που νόσησαν πρώιμα, οι γυναίκες είχαν μικρότερη διάρκεια πρόδρομης περιόδου από τους άνδρες. Κατά την ενεργό φάση, η ομάδα πρώιμης έναρξης εμφάνιζε βαρύτερη συνολική αρνητική συμπτωματολογία, καθώς και βαρύτερα τα συμπτώματα της έλλειψης αυθορμητισμού και των διαταραχών της βούλησης. Αντίθετα, οι ασθενείς όψιμης έναρξης έτειναν νε έχουν βαρύτερο το σύμπτωμα της καχυποψίας/ιδεών δίωξης. Στο δείγμα των ανδρών, οι ασθενείς πρώιμης έναρξης είχαν στατιστικώς σημαντικά βαρύτερη συνολική αρνητική συμπτωματολογία, συναισθηματική αμβλύτητα και έλλειψη αυθορμητισμού. Στο δείγμα των γυναικών δεν ανευρέθησαν στατιστικώς σημαντικές διαφορές. Στους ασθενείς όψιμης έναρξης, οι άνδρες εμφάνιζαν σημαντικά βαρύτερες παραληρητικές ιδέες σε σχέση με τις γυναίκες. Ως προς την καταθλιπτική συμπτωματολογία, δεν παρατηρήθηκαν διαφορές μεταξύ των ομάδων. Συνολικά τα παραπάνω ευρήματα υποδεικνύουν την τροποποιητική επίδραση του φύλου και της ηλικίας έναρξης στην κλινική εμφάνιση της παρανοϊκής μορφής σχιζοφρένειας, κατά την προνοσηρή περίοδο, πρόδρομη και ενεργό φάση, πιθανόν ως αποτέλεσμα των διεργασιών ανάπτυξης και ωρίμανσης του εγκεφάλου με την πάροδο της ηλικίας, στα δύο φύλα. / The demographic features and symptomatology of young and late onset paranoid schizophrenia were studied in a sample of 88 patients who were consecutively hospitalized in the Psychiatric Department of the University Hospital of Patras, from 3-15-2005 to 5-7-2008. The sample consisted of 60 patients, 46 men and 14 women, with young onset paranoid schizophrenia, before the age of 30, and 21 late onset patients, 8 men and 13 women, with onset of the illness after the age of 35 years old. Demographic features, rates of smoking and alcohol and cannabis use, premorbid personality disorder features, the number and type of prodromal symptoms, the duration of the prodromal period and the symptomatologies of the active phase were compared between young and late onset groups, in the total sample and separately for the two sexes, and between the two sexes in each age group. SCID-I/P, PANSS, Calgary Depression Scale, SCID-II, and a clinical interview for the prodromal symptoms were applied. Statistical analysis was performed by applying the Wilcoxon rank-sum and chi-square tests. Young onset patients, particularly men, were more likely to have been born in urban regions, compared with late onset patients. Late onset women were most frequently married, compared with all other groups. There was not any significant difference regarding use of nicotine, alcohol or cannabis between young and late onset patients. In the young onset group, men more frequently used alcohol and cannabis than women. Similarly, late onset men smoked and tended to use cannabis more often than late onset women. In the premorbid period, young onset patients have significantly more traits of avoidant personality disorder compared with late onset patients. This finding tended to be significant in the female sample, as well. Late onset patients had significantly more traits of passive-aggressive personality disorder than young onset patients, in the total and male sample. In the young onset group, men had significantly more traits of paranoid and schizotypal personality disorder than women, whereas women had more traits of the depressive personality disorder. In the late onset group, men had more histrionic, narcissistic and antisocial traits than women. In the prodromal phase, young onset patients present with significantly more negative prodromal symptoms, in the total and the male sample. In the total sample, marked isolation and impairment of concentration are observed at a significantly higher rate in the young onset group, than in late onset patients. Also, in the young onset group, women had significantly shorter duration of prodromal period than men. During the active phase, young onset patients had significantly heavier total score of negative symptomatology, heavier lack of spontaneity and heavier disturbances of volition. On the other hand, late onset patients tended to suffer from heavier suspiciousness/ideas of persecution. In the male sample, young onset patients had heavier total negative symptomatology, blunted affect and lack of spontaneity. There were not any significant differences in the female sample. In the late onset group, men had heavier delusions than women. There was not any significant difference regarding depressive symptoms among the groups. Our findings indicate the modulatory effect of age of onset and sex on the clinical presentation of paranoid schizophrenia, in the premorbid period, prodromal and active phases, possibly following the developmental and maturational procedures that take place in the brain, throughout the life span, in the two sexes.