Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two devastating neurodegenerative diseases in urgent need of therapeutic intervention. The last seven years has been a period of great progress in understanding these disorders separately and as a disease spectrum. Most notable is the discovery of the hexanucleotide GGGGCC expansion in the C9ORF72 (C9) gene, which is the greatest known cause of inherited and sporadic forms of these two diseases. In response to this groundbreaking discovery, we set out to elucidate the molecular mechanisms of C9 pathogenesis with a focus on the expanded RNA transcripts derived from the C9 expansion. Our two primary goals have been to contribute to the worldwide efforts to understand the primary toxic insults of this mutation that will ultimately shape therapeutic development, and to identify molecular criteria that can be used to define new links between these diseases and undetermined genetic factors. In the introduction, we review the broad conceptual links between RNA binding proteins (RBPs), mRNA regulation, and neurodegeneration. This review contains substantial discussion of ALS, FTD, and C9, as well as related neurodegenerative, neuromuscular and repeat expansion diseases. In addition to providing a detailed history of molecular mechanisms proposed for these disorders, this section serves as a justification for our focus on the C9 RNA, RBP sequestration, and altered splicing that we describe in the following chapters. Chapter two consists of our 2016 Elife paper on sequestration of the RBP hnRNP H and resulting splicing changes in C9ALS-FTD afflicted individuals. In this paper, we sought to identify the most biochemically sound candidate for the proposed RBP sequestration hypothesis. We found that the splicing factor hnRNP H binds with high affinity to the repeat sequence and likely has a role in regulating the transition of the repeat RNA from linear to G-quadruplex (G-Q) conformation. Importantly, we identified functional deficiency of this protein in patient brains, as evidenced by dysregulation of known hnRNP H splicing targets, and loss of soluble hnRNP H. Chapter three consists of recently submitted work on the molecular links between C9ALS/FTD, and sporadic ALS/FTD at large. Building upon our findings in C9ALS-FTD, we have sought to ask whether the changes to hnRNP H we predicted would occur in C9 expansion carriers as a result of the repeat RNA might also occur independent of this expansion. We found that indeed half of all patients in a cohort of 50 sporadic ALS, ALS-FTD, and FTD brains demonstrated hnRNP H sequestration and accompanying splicing changes, a pattern we refer to as like-C9. Like-C9 patients may be thought of as phenocopies of C9 expansion carriers, in that they not only present with similar clinical symptoms, but also possess remarkably similar molecular signatures of RBP dysfunction. While the genomic origins of like-C9 remain unknown, we propose that they are suggestive of repeat expansions analogous to C9, much like what is seen in DM1 and DM2, and HD and HDL2 (discussed in Ch. 1). This work has provided the foundation for our ongoing search for novel genomic expansions that confer increased susceptibility to ALS/FTD.

Neurodegenerative disorders are a group of age-related conditions resulting in neuronal cell death and protein accumulation. It is estimated that around 5-10% of these cases are genetically mediated. Most commonly this is by pathogenic single nuclear variants (SNVs), though combinations of rare variants (termed oligogenic variation), copy-number variation (CNVs), somatic mutations in nuclear DNA, and somatically acquired mitochondrial DNA variants have all been hypothesised to increase disease risk or cause disease. Firstly, using a combination of exome sequencing and array genotyping on 1511 post-mortem brain samples within the MRC Brain Bank, we detected 61 monogenic cases of disease, 349 brains carrying disease risk factors, and identified that variants in GRN and PRPH may increase the risk of developing dementia with lewy bodies (DLB) and Alzheimer’s disease (AD) respectively. Secondly, we detected a previously unknown systematic bias in the interpretation of oligogenic interactions with implications for our understanding of disease mechanisms and coexistent clinical diagnostic utility. Thirdly, we detected a novel copy-number gain in LAMA5 associated with Creutzfeldt-Jakob disease (CJD), and fourthly, we determine that at least 1% of the population carry high level somatic protein-coding mutations affecting at least 10% of cells within the brain. Subsequently, additional focussed deep-sequencing studies revealed that several regions of the brain are likely to contain clones of low-level somatic mutations that are pathogenic when present in the germline, and that age-related clonal mutations that arise in blood are present at high levels within the aging brain and are associated with Lewy Body pathology. Finally, using transgenic mice that over express human α-synuclein and which either accrue or transmit mtDNA mutations, we determine that the presence of mtDNA mutations exacerbate some phenotypic traits of Lewy body disorders, and may reduce the volume of critical neuroanatomical brain regions whilst paradoxically reducing α-synuclein accumulation. Taken together, these data enable the first genetically stratified brain tissue resource in the UK, describe new disease genetic risk factors (both SNVs and CNVs) for neurodegenerative disorders, and also help define the somatic genetic architecture of the human brain. In addition, we describe the in vivo interaction between mutations in the mitochondrial genome and a progressive neurodegenerative disorder in mice.

Introdução: A demência frontotemporal (DFT) inclui a variante comportamental da demência frontotemporal (vcDFT), a variante semântica da afasia progressiva primária (vsAPP), e a variante não fluente da APP (vnfAPP). Os genes em que são encontradas mutações causadoras de DFT mais frequentemente são: GRN (que codifica a progranulina), MAPT (que codifica a proteína tau) e C9orf72. Métodos: Foram incluídos probandos diagnosticados com vcDFT, vsAPP ou vnfAPP, com base com os critérios diagnósticos mais recentes, e um grupo de indivíduos cognitivamente normais. Os éxons 2-12 de GRN e os éxons 1, 9-13 de MAPT foram sequenciados pelo método de Sanger, e foi realizada dosagem de progranulina no plasma. Resultados: foram incluídos 62 probandos, sendo 44 com vcDFT, 9 com vsAPP, e 9 com vnfAPP. Antecedente familiar de demência foi positivo em 45,1% dos probandos, e de DFT, em 24,1%. Os 60 indivíduos do grupo controle tinham idade média de 60,8±8,5 anos. Foram identificadas seis mutações nulas em GRN (p.Q130X, p.V200Gfs*18, p.Q257Pfs*26, p.Q300X, p.S301Cfs*60 e p.D317Afs*11) e uma mutação patogênica em MAPT (p.N279K). A dosagem média de progranulina plasmática nos pacientes com mutações de GRN foi de 29,8±11,9ng/ml Conclusões: A frequência de mutações patogênicas em GRN nesta casuística foi de 9,6%, e a de mutações em MAPT foi de 1,6%. Entre casos familiais de DFT, a frequência de mutações em GRN foi de 33,3%, e em MAPT foi de 6,7%. Duas das mutações encontradas em GRN (p.Q130X e p.D317Afs*11) ainda não foram descritas em casos de DFT. O valor de corte de 70ng/ml identificou as mutações nulas de GRN com sensibilidade e especificidade de 100% / Introduction: Frontotemporal dementia (FTD) encompasses behavioral variant of frontotemporal dementia (bvFTD), semantic variant of primary progressive aphasia (svPPA), and nonfluent variant PPA (nfvPPA). The genes in which FTD-causing mutations are most frequently found are: GRN (which encodes progranulin), MAPT (which encodes tau protein) and C9orf72. Methods: We included probands diagnosed with bvFTD, svPPA or nfvPPA, based on the most recent diagnostic criteria, and a group of cognitively normal individuals. GRN exons 2-12 and MAPT exons 1, 9-13 were sequenced by the Sanger method, and plasma progranulin levels were measured. Results: we included 62 probands (44 with bvFTD, 9 with svPPA, and 9 with nfvPPA). Family history of dementia was positive in 45.1% of probands, and of DFT, in 24.1%. The control group of 60 individuals had a mean age of 60.8±8.5 years. Six null GRN mutations were identified in (p.Q130X, p.V200Gfs*18, p.Q257Pfs*26, p.Q300X, p.S301Cfs*60 e p.D317Afs*11) and one MAPT pathogenic mutation (p.N279K). The mean plasma progranulin level in patients with GRN mutations was 29.8±11,9ng/ml. Conclusions: The frequency of pathogenic mutations in GRN was 9.6%, and of MAPT mutations was 1.6%. Among cases of familial FTD, the frequency of GRN mutations was 33.3%, and of MAPT mutations was 6.7%. Two of the mutations found in GRN (p.Q130X and p.D317Afs*11) are novel. The cutoff value of 70ng/ml identified null GRN mutations with sensitivity and specificity of 100%

TAR DNA Binding Protein-43 (TDP-43) proteinopathy is a disease pathology that underlies a broad field of neurodegenerative disorders. Most prominently, TDP-43 aggregates are the hallmark of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). The implication of TDP-43 in ALS, in particular, has helped initiate a cascade of research to determine the properties of the previously obscure protein. From these studies, it is now known that TDP-43 is a DNA and RNA binding protein, important for the splicing and regulation of many transcripts. In the disease state, TDP-43 is modified in a way that fuels its accumulation into cytoplasmic aggregates called inclusions. This paper will delineate the current understanding of the mechanisms behind TDP-43 proteinopathy and the resultant clinical conditions. The body of evidence firmly supports a clinical spectrum of TDP-43 proteinopathy that ranges between pure motor neuron disease (MND) and pure frontotemporal dementia (FTD). It also appears that the root cause of neurodegeneration in these disorders comes about through a combination of a gain of toxic function and a loss of normal TDP-43. Continued research into the molecular processes leading to the capitulation of TDP-43 holds great promise for the development of new drug targets to help treat the spectrum of TDP-43 proteinopathy.

Yes / Objectives: Studies on service needs of people with young onset dementia have taken a problem-oriented approach with resulting recommendations focusing on reducing service shortcomings. This study aimed to build on ‘what works’ in real-life practice by exploring the nature of post-diagnostic support services that were perceived positively by younger people with dementia and carers. Method: Positive examples of support were gathered between August 2017 and September 2018, via a national survey. Inductive thematic analysis was employed to explore the nature of positively experienced services provided for younger people with dementia, including analysis of what was provided by positively experienced services. Results: Two hundred and thirty-three respondents reported 856 positive experiences of support. Data analysis yielded eight themes regarding the objectives of positive services: Specialist Advice and Information on Young Onset Dementia, Access to Age-appropriate Services, Interventions for Physical and Mental Health, Opportunities for Social Participation, Opportunities to Have a Voice, Enablement of Independence while Managing Risk, Enablement of Financial Stability, and Support Interventions for family relationships. Conclusion: The study findings (a) suggest that positive services may collectively create an enabling-protective circle that supports YPD to re-establish and maintain a positive identity in the face of young onset dementia, and (b) provide a basis from which future good practice can be developed. / This work was supported by the Alzheimer’s Society under grant number 278 AS-PG-15b-034.

Introdução: A doença por grãos argirofílicos (DGA) é uma tauopatia esporádica distinta, bastante frequente, com uma prevalência atingindo 31,3% em centenários, porém pouco reconhecida A manifestação clínica mais comum da DGA é de um comprometimento cognitivo de lenta evolução associado a uma alta frequência de sintomas psiquiátricos. O diagnóstico de DGA é possível somente através da análise do encéfalo post-mortem com os achados das três principais alterações patológicas: grãos argirofílicos, corpúsculos em embrião e pré-emaranhados neuronais. O presente estudo investigou as características demográficas, clínicas e neuropatológicas dos indivíduos com DGA e possíveis associações clínico-patológicas. Métodos: Foram estudados 983 casos (acima de 50 anos de idade) provenientes da amostra do Banco de Encéfalos do Grupo de Estudos em Envelhecimento Cerebral. A avaliação clínica e funcional foi realizada através de uma ampla entrevista semiestruturada respondida por um informante com contato próximo com o paciente. Os participantes foram estratificados conforme a presença de comprometimento cognitivo (de acordo com Escala de Avaliação Clinica da Demência) e, posteriormente, pela presença de DGA em quatro grupos: DGA com e sem comprometimento cognitivo e não-DGA com e sem comprometimento cognitivo. Análise descritiva foi realizada para dados socioeconômicos, genótipo de APOE e variáveis clínico-funcionais, neuropsiquiátricas e neuropatológicas na amostra DGA e em cada grupo. Foi utilizado um modelo de regressão logística multivariada para investigar as associações entre perfil cognitivo e sintomas neuropsiquiátricos com DGA. Resultados: DGA foi identificada em 150 indivíduos (15,1%). Idade avançada e baixo nível socioeconômico foram associados com DGA independente da presença de comprometimento cognitivo. A presença de DGA foi associada a uma redução de 60% na probabilidade de um escore >= 3.8 no Questionário do informante sobre o Declínio Cognitivo do Idoso (OR=0,40; IC de 95% 0,22-0,74; p=0,004). Adicionalmente, o subitem apetite do inventário neuropsiquiátrico foi associado à DGA em indivíduos cognitivamente normais (OR=1,85; IC de 95% 1,09-3,12; p=0,02). Conclusão: A DGA pode preservar a cognição em indivíduos com patologias neurodegenerativas associadas em particular nos casos com patologia tipo Alzheimer concomitante. A investigação dos mecanismos subjacentes a esse efeito pode auxiliar no desenvolvimento de novos tratamentos para a Doença de Alzheimer / Background: Argyrophilic grain disease (AGD) is an underrecognized, distinct, highly frequent sporadic tauopathy, with prevalence reaching 31.3% in centenarians. The most common presentation of AGD is a slowly progressive amnestic mild cognitive impairment, accompanied by high frequency of neuropsychiatric symptoms. AGD can only be diagnosed postmortem by the finding of its three main pathologic features: argyrophilic grains, oligodendrocytic coiled bodies and neuronal pretangles. The present study investigated demographic, clinical, and neuropathological profiles and analyzed clinicopathological associations. Methods: We studied 983 participants (over 50 years of age) from the Brain Bank of the Brazilian Aging Brain study group sample. Clinical and functional evaluation included demographics and a semi-structured interview covering various cognitive domains conducted with a knowledgeable informant. Participants were stratified by cognitive status (based on Clinical Dementia Rating scale), followed by the presence of AGD in four groups: AGD with and without cognitive impairmet, and non-AGD with and without cognitive impairment. Descriptive statistics were used for sociodemographic data, APOE genotypes, and the clinical, cognitive, neuropsychiatric, functional, and neuropathological variables in AGD samples and in each group. We used multivariate logistic regression models to investigate the association between the cognitive status and neuropsychiatric symptoms with AGD. Results: AGD was identified in 150 participants (15.1%). Older age and lower socioeconomic status were associated with AGD independent of cognitive status. Multivariate analyses revealed that AGD was associated with a 60% reduction in the odds of having an IQCODE >= 3.8 (OR = 0.40, 95% CI 0.22-0.74, p = 0.004) and that the NPI sub-item \"appetite and eating abnormalities\" was associated with AGD in controls (OR = 1.85, 95% CI 1.09-3.12, p = 0.02). Conclusion: AGD might preserve cognition in individuals with coexistent neurodegenerative pathologies, in particular those of the Alzheimer-type. Investigating whether the mechanisms underlying this effect could provide novel therapeutic approaches to the treatment of Alzheimer´s disease

INTRODUÇÃO: O aumento da expectativa de vida tem contribuído para o crescimento da população idosa em todo o mundo. O envelhecimento é uma condição de risco para o desenvolvimento de doenças, entre as quais as demências, que responderão nas próximas décadas por um número significativo de idosos com comprometimento cognitivo, comportamental e funcional. A ampliação de cuidados a esses pacientes está associada ao aumento de sua expectativa de vida; por isso é crescente o número de indivíduos dementes em estágios avançados. Os quadros demenciais comprometem gradualmente o comportamento e a cognição, e observa-se uma progressiva deterioração também na comunicação. As características da linguagem em fases mais avançadas têm sido pouco detalhadas nas demências. Daí a necessidade de se disponibilizar instrumento, em língua portuguesa brasileira, para avaliação da linguagem na demência em fases moderada e grave, o FLCI (Inventário de Comunicação Lingüístico Funcional). O FLCI gera dados para auxiliar o diagnóstico, acompanhamento e evolução da doença e, além disso, para orientar familiares e cuidadores. O FLCI foi aplicado a população com doença de Alzheimer (DA). Desconhece-se sua aplicabilidade em outros quadros demenciais como doença de Alzheimer associada a demência vascular (DA+DV), demências do espectro lobar frontotemporal (DLFT) em fases avançadas. OBJETIVOS: 1.realizar a tradução e adaptação transcultural do FLCI para uso na população brasileira; 2.comparar o desempenho de pacientes com DA, DA+DV e DLFT em fase moderada e grave e 3.correlacionar as habilidades lingüístico-cognitivas com a funcionalidade na vida cotidiana. MÉTODOS: A amostra foi composta por 57 sujeitos, sendo 24 com DA, 24 com DA+DV e 09 com DLFT, com idade a partir de 60 anos e CDR (Clinical Dementia Rating) em níveis 2 e 3, moderado e grave respectivamente. Foi realizada a tradução e adaptação transcultural do FLCI e verificada a consistência interna, confiabilidade inter e intra-examinadores, assim como a validade de critério do instrumento pela correlação com o Mini-Exame do Estado Mental (MEEM). O desempenho lingüístico-cognitivo dos sujeitos agrupados segundo diagnóstico foi analisado por meio da aplicação do FLCI, para comparação de médias de desempenho nos diferentes sub-testes. Foi possível correlacionar os aspectos cognitivos com a funcionalidade por meio da escala FAST (Functional Assessment Staging) e analisar a correlação desta com o FLCI. Verificou-se também o efeito da idade e da escolaridade no desempenho comunicativo dos pacientes. RESULTADOS: As análises estatísticas indicaram que o FLCI apresenta consistência interna satisfatória (alfa de Cronbach=0,890), ótima confiabilidade intra e interexaminador (coeficiente de correlação interclasse - ICC=0,999 e 0,100 respectivamente) e ótima validade de critério ao ser correlacionado com o MEEM. Todos os sub-testes que compõem o FLCI apresentaram diferenças significativas para a amostra total classificada de acordo com a gravidade da demência após ser correlacionada a pontuação total do teste com a escala FAST. De acordo com a classificação nosológica da demência, somente um sub-teste do FLCI apresentou diferenças estatisticamente significativas: \"compreensão de sinais e emparelhamento objeto-figura\". As variáveis idade e a escolaridade não apresentaram influência sobre o desempenho comunicativo da amostra. Comparando-se o perfil de desempenho, a partir da pontuação média em cada sub-teste do FLCI, observou-se melhor desempenho na maioria dos sub-testes para o grupo DLFT, em seguida o grupo DA e por último o grupo de DA+DV. A partir da comparação da pontuação total do FLCI com a FAST modificada, foi possível correlacionar a funcionalidade com as habilidades de comunicação. Verificou-se correlação significativa nas análises entre a escala FAST e a pontuação total do FLCI e escala FAST entre os itens dicotômicos (pontuados como sim/não) e itens pontuáveis (pontuação aberta) que compõem o FLCI. CONCLUSÃO: O FLCI, versão em português, é instrumento válido e confiável para avaliação de pacientes com demência avançada, útil para identificar as habilidades de comunicação de dementes em fases moderada e grave. O FLCI vem preencher importante lacuna de carência de instrumentos eficazes para intervenções de linguagem e comunicação em pacientes com demência em fase avançada. / BACKGROUND: The increase in life expectancy has contributed to the growth of elderly population all over the world. Aging is a risk factor for many diseases - including dementia - that, in the next decades, will answer for a significant number of elderly with cognitive, behavioral and functional deficits. The expansion of care for these patients is associated to the increase in their life expectancy; therefore there is also an increase in the number of demented individuals in advanced stages. Dementia gradually undertakes behavior and cognition, and a progressive deterioration in communication is also observed. Language characteristics in advanced stages of dementia have been little detailed in literature, hence the need to provide a Brazilian Portuguese version of an instrument to evaluate language in moderate and severe dementia, the Functional Linguistic Communication Inventory (FLCI). The FLCI generates data to help diagnosis, monitoring and evolution of the disease and, moreover, for the orientation of family and caregivers. The FLCI have been used in population with Alzheimer\"s disease (AD), but its applicability in other types of dementia, such as Alzheimer\"s associated to vascular dementia (AD+VD) and frontotemporal lobar degeneration spectrum dementia (FTLD) in advanced stages, is unknown. PURPOSE: 1. to translate and culturally adapt the FLCI for use with the Brazilian population; 2. to compare the performances of patients with moderate and severe AD, AD+VD, and FTLD; and 3. to correlate cognitive-linguistic abilities and functionality in daily life. METHODS: Participants were 57 subjects (24 with AD, 24 with AD+VD, and 09 with FTLD) with ages 60 years and up and levels 2 or 3 in the Clinical Dementia Rating (CDR), moderate or severe, respectively. It was carried out the translation and cultural adaptation of the FLCI, and internal consistency, intra- and inter-examiners reliability were verified, as well as the criterion validity of the instrument through its correlation with the Mini-Mental State Examination (MMSE). The cognitive-linguistic performance of the subjects grouped according to diagnosis was analyzed by comparing mean scores on different subtests of the FLCI. It was possible to correlate cognitive aspects and functionality through the FAST scale (Functional Assessment Staging) and to analyze its correlation with the FLCI. It was also verified the effects of age and education level on the communicative performance of these patients. RESULTS: Statistical analysis indicated that the FLCI presents satisfactory internal consistency (Cronbach\"s ?=.890), great intra- and inter-examiner reliability (interclass correlation coefficient - ICC=.999 and .100, respectively), and great criterion validity when correlated to the MMSE. All subtests that compose the FLCI presented significant differences for the total sample classified according to the severity of dementia, after total score on the test was correlated to the FAST scale. According to the nosological classification of dementia, only one FLCI subtest showed significant differences: \"sign comprehension and object-to-picture matching\". The variables age and education level did not influence the communicative performance of the sample. When performance profiles based on the average score in each FLCI subtest were compared, it was observed better performance of the FTLD group in most subtests, followed by the AD group and, last, by the AD+VD group. Functionality and communication abilities were correlated based on the comparison between total score on the FLCI and the modified FAST scale. It was verified a correlation between total, dichotomous (scored yes/no) and scored (open scored) items of FLCI and the FAST scale. CONCLUSION: The Brazilian Portuguese version of the FLCI is a valid and reliable instrument to evaluate patients with advanced dementia, useful to identify communication abilities of demented in moderate and severe stages. The FLCI fulfills an important lack of efficient instruments for language and communication intervention in patients with dementia in advanced stages.

Introdução: A doença por grãos argirofílicos (DGA) é uma tauopatia esporádica distinta, bastante frequente, com uma prevalência atingindo 31,3% em centenários, porém pouco reconhecida A manifestação clínica mais comum da DGA é de um comprometimento cognitivo de lenta evolução associado a uma alta frequência de sintomas psiquiátricos. O diagnóstico de DGA é possível somente através da análise do encéfalo post-mortem com os achados das três principais alterações patológicas: grãos argirofílicos, corpúsculos em embrião e pré-emaranhados neuronais. O presente estudo investigou as características demográficas, clínicas e neuropatológicas dos indivíduos com DGA e possíveis associações clínico-patológicas. Métodos: Foram estudados 983 casos (acima de 50 anos de idade) provenientes da amostra do Banco de Encéfalos do Grupo de Estudos em Envelhecimento Cerebral. A avaliação clínica e funcional foi realizada através de uma ampla entrevista semiestruturada respondida por um informante com contato próximo com o paciente. Os participantes foram estratificados conforme a presença de comprometimento cognitivo (de acordo com Escala de Avaliação Clinica da Demência) e, posteriormente, pela presença de DGA em quatro grupos: DGA com e sem comprometimento cognitivo e não-DGA com e sem comprometimento cognitivo. Análise descritiva foi realizada para dados socioeconômicos, genótipo de APOE e variáveis clínico-funcionais, neuropsiquiátricas e neuropatológicas na amostra DGA e em cada grupo. Foi utilizado um modelo de regressão logística multivariada para investigar as associações entre perfil cognitivo e sintomas neuropsiquiátricos com DGA. Resultados: DGA foi identificada em 150 indivíduos (15,1%). Idade avançada e baixo nível socioeconômico foram associados com DGA independente da presença de comprometimento cognitivo. A presença de DGA foi associada a uma redução de 60% na probabilidade de um escore >= 3.8 no Questionário do informante sobre o Declínio Cognitivo do Idoso (OR=0,40; IC de 95% 0,22-0,74; p=0,004). Adicionalmente, o subitem apetite do inventário neuropsiquiátrico foi associado à DGA em indivíduos cognitivamente normais (OR=1,85; IC de 95% 1,09-3,12; p=0,02). Conclusão: A DGA pode preservar a cognição em indivíduos com patologias neurodegenerativas associadas em particular nos casos com patologia tipo Alzheimer concomitante. A investigação dos mecanismos subjacentes a esse efeito pode auxiliar no desenvolvimento de novos tratamentos para a Doença de Alzheimer / Background: Argyrophilic grain disease (AGD) is an underrecognized, distinct, highly frequent sporadic tauopathy, with prevalence reaching 31.3% in centenarians. The most common presentation of AGD is a slowly progressive amnestic mild cognitive impairment, accompanied by high frequency of neuropsychiatric symptoms. AGD can only be diagnosed postmortem by the finding of its three main pathologic features: argyrophilic grains, oligodendrocytic coiled bodies and neuronal pretangles. The present study investigated demographic, clinical, and neuropathological profiles and analyzed clinicopathological associations. Methods: We studied 983 participants (over 50 years of age) from the Brain Bank of the Brazilian Aging Brain study group sample. Clinical and functional evaluation included demographics and a semi-structured interview covering various cognitive domains conducted with a knowledgeable informant. Participants were stratified by cognitive status (based on Clinical Dementia Rating scale), followed by the presence of AGD in four groups: AGD with and without cognitive impairmet, and non-AGD with and without cognitive impairment. Descriptive statistics were used for sociodemographic data, APOE genotypes, and the clinical, cognitive, neuropsychiatric, functional, and neuropathological variables in AGD samples and in each group. We used multivariate logistic regression models to investigate the association between the cognitive status and neuropsychiatric symptoms with AGD. Results: AGD was identified in 150 participants (15.1%). Older age and lower socioeconomic status were associated with AGD independent of cognitive status. Multivariate analyses revealed that AGD was associated with a 60% reduction in the odds of having an IQCODE >= 3.8 (OR = 0.40, 95% CI 0.22-0.74, p = 0.004) and that the NPI sub-item \"appetite and eating abnormalities\" was associated with AGD in controls (OR = 1.85, 95% CI 1.09-3.12, p = 0.02). Conclusion: AGD might preserve cognition in individuals with coexistent neurodegenerative pathologies, in particular those of the Alzheimer-type. Investigating whether the mechanisms underlying this effect could provide novel therapeutic approaches to the treatment of Alzheimer´s disease

INTRODUÇÃO: O aumento da expectativa de vida tem contribuído para o crescimento da população idosa em todo o mundo. O envelhecimento é uma condição de risco para o desenvolvimento de doenças, entre as quais as demências, que responderão nas próximas décadas por um número significativo de idosos com comprometimento cognitivo, comportamental e funcional. A ampliação de cuidados a esses pacientes está associada ao aumento de sua expectativa de vida; por isso é crescente o número de indivíduos dementes em estágios avançados. Os quadros demenciais comprometem gradualmente o comportamento e a cognição, e observa-se uma progressiva deterioração também na comunicação. As características da linguagem em fases mais avançadas têm sido pouco detalhadas nas demências. Daí a necessidade de se disponibilizar instrumento, em língua portuguesa brasileira, para avaliação da linguagem na demência em fases moderada e grave, o FLCI (Inventário de Comunicação Lingüístico Funcional). O FLCI gera dados para auxiliar o diagnóstico, acompanhamento e evolução da doença e, além disso, para orientar familiares e cuidadores. O FLCI foi aplicado a população com doença de Alzheimer (DA). Desconhece-se sua aplicabilidade em outros quadros demenciais como doença de Alzheimer associada a demência vascular (DA+DV), demências do espectro lobar frontotemporal (DLFT) em fases avançadas. OBJETIVOS: 1.realizar a tradução e adaptação transcultural do FLCI para uso na população brasileira; 2.comparar o desempenho de pacientes com DA, DA+DV e DLFT em fase moderada e grave e 3.correlacionar as habilidades lingüístico-cognitivas com a funcionalidade na vida cotidiana. MÉTODOS: A amostra foi composta por 57 sujeitos, sendo 24 com DA, 24 com DA+DV e 09 com DLFT, com idade a partir de 60 anos e CDR (Clinical Dementia Rating) em níveis 2 e 3, moderado e grave respectivamente. Foi realizada a tradução e adaptação transcultural do FLCI e verificada a consistência interna, confiabilidade inter e intra-examinadores, assim como a validade de critério do instrumento pela correlação com o Mini-Exame do Estado Mental (MEEM). O desempenho lingüístico-cognitivo dos sujeitos agrupados segundo diagnóstico foi analisado por meio da aplicação do FLCI, para comparação de médias de desempenho nos diferentes sub-testes. Foi possível correlacionar os aspectos cognitivos com a funcionalidade por meio da escala FAST (Functional Assessment Staging) e analisar a correlação desta com o FLCI. Verificou-se também o efeito da idade e da escolaridade no desempenho comunicativo dos pacientes. RESULTADOS: As análises estatísticas indicaram que o FLCI apresenta consistência interna satisfatória (alfa de Cronbach=0,890), ótima confiabilidade intra e interexaminador (coeficiente de correlação interclasse - ICC=0,999 e 0,100 respectivamente) e ótima validade de critério ao ser correlacionado com o MEEM. Todos os sub-testes que compõem o FLCI apresentaram diferenças significativas para a amostra total classificada de acordo com a gravidade da demência após ser correlacionada a pontuação total do teste com a escala FAST. De acordo com a classificação nosológica da demência, somente um sub-teste do FLCI apresentou diferenças estatisticamente significativas: \"compreensão de sinais e emparelhamento objeto-figura\". As variáveis idade e a escolaridade não apresentaram influência sobre o desempenho comunicativo da amostra. Comparando-se o perfil de desempenho, a partir da pontuação média em cada sub-teste do FLCI, observou-se melhor desempenho na maioria dos sub-testes para o grupo DLFT, em seguida o grupo DA e por último o grupo de DA+DV. A partir da comparação da pontuação total do FLCI com a FAST modificada, foi possível correlacionar a funcionalidade com as habilidades de comunicação. Verificou-se correlação significativa nas análises entre a escala FAST e a pontuação total do FLCI e escala FAST entre os itens dicotômicos (pontuados como sim/não) e itens pontuáveis (pontuação aberta) que compõem o FLCI. CONCLUSÃO: O FLCI, versão em português, é instrumento válido e confiável para avaliação de pacientes com demência avançada, útil para identificar as habilidades de comunicação de dementes em fases moderada e grave. O FLCI vem preencher importante lacuna de carência de instrumentos eficazes para intervenções de linguagem e comunicação em pacientes com demência em fase avançada. / BACKGROUND: The increase in life expectancy has contributed to the growth of elderly population all over the world. Aging is a risk factor for many diseases - including dementia - that, in the next decades, will answer for a significant number of elderly with cognitive, behavioral and functional deficits. The expansion of care for these patients is associated to the increase in their life expectancy; therefore there is also an increase in the number of demented individuals in advanced stages. Dementia gradually undertakes behavior and cognition, and a progressive deterioration in communication is also observed. Language characteristics in advanced stages of dementia have been little detailed in literature, hence the need to provide a Brazilian Portuguese version of an instrument to evaluate language in moderate and severe dementia, the Functional Linguistic Communication Inventory (FLCI). The FLCI generates data to help diagnosis, monitoring and evolution of the disease and, moreover, for the orientation of family and caregivers. The FLCI have been used in population with Alzheimer\"s disease (AD), but its applicability in other types of dementia, such as Alzheimer\"s associated to vascular dementia (AD+VD) and frontotemporal lobar degeneration spectrum dementia (FTLD) in advanced stages, is unknown. PURPOSE: 1. to translate and culturally adapt the FLCI for use with the Brazilian population; 2. to compare the performances of patients with moderate and severe AD, AD+VD, and FTLD; and 3. to correlate cognitive-linguistic abilities and functionality in daily life. METHODS: Participants were 57 subjects (24 with AD, 24 with AD+VD, and 09 with FTLD) with ages 60 years and up and levels 2 or 3 in the Clinical Dementia Rating (CDR), moderate or severe, respectively. It was carried out the translation and cultural adaptation of the FLCI, and internal consistency, intra- and inter-examiners reliability were verified, as well as the criterion validity of the instrument through its correlation with the Mini-Mental State Examination (MMSE). The cognitive-linguistic performance of the subjects grouped according to diagnosis was analyzed by comparing mean scores on different subtests of the FLCI. It was possible to correlate cognitive aspects and functionality through the FAST scale (Functional Assessment Staging) and to analyze its correlation with the FLCI. It was also verified the effects of age and education level on the communicative performance of these patients. RESULTS: Statistical analysis indicated that the FLCI presents satisfactory internal consistency (Cronbach\"s ?=.890), great intra- and inter-examiner reliability (interclass correlation coefficient - ICC=.999 and .100, respectively), and great criterion validity when correlated to the MMSE. All subtests that compose the FLCI presented significant differences for the total sample classified according to the severity of dementia, after total score on the test was correlated to the FAST scale. According to the nosological classification of dementia, only one FLCI subtest showed significant differences: \"sign comprehension and object-to-picture matching\". The variables age and education level did not influence the communicative performance of the sample. When performance profiles based on the average score in each FLCI subtest were compared, it was observed better performance of the FTLD group in most subtests, followed by the AD group and, last, by the AD+VD group. Functionality and communication abilities were correlated based on the comparison between total score on the FLCI and the modified FAST scale. It was verified a correlation between total, dichotomous (scored yes/no) and scored (open scored) items of FLCI and the FAST scale. CONCLUSION: The Brazilian Portuguese version of the FLCI is a valid and reliable instrument to evaluate patients with advanced dementia, useful to identify communication abilities of demented in moderate and severe stages. The FLCI fulfills an important lack of efficient instruments for language and communication intervention in patients with dementia in advanced stages.

Abstract Frontotemporal lobar degeneration (FTLD) is the second commonest cause of dementia after Alzheimer’s disease (AD) in patients <65 years. Its most frequent clinical subtype is behavioral variant frontotemporal dementia (bvFTD) characterized by behavioral change and executive deficits. FTLD also encompasses two variants of primary progressive aphasia (PPA) characterized by language deficits. The majority of familial FTLD cases are linked to the C9ORF72 expansion mutation. As both cognitive and behavioral changes are core diagnostic features of FTLD, neuropsychological assessment is vital. However, neuropsychological literature is inconclusive regarding the most functional measures for detecting FTLD. Current knowledge on the cognitive profile of patients with the C9ORF72 expansion is scarce. The aims of this thesis were threefold: (1) to identify the cognitive measures that optimally serve the differential diagnosis of FTLD, (2) to characterize the neuropsychological profile of C9ORF72 expansion; and (3) to examine the utility of the Modified Frontal Behavioral Inventory (FBI-mod) in differentiating FTLD, AD, and mild cognitive impairment (MCI). The participants comprised FTLD, AD, and MCI patients diagnosed in the University Hospitals of Oulu and Kuopio. The patients underwent a detailed neuropsychological assessment including the CERAD neuropsychological battery (CERAD-NB) and the FBI-mod. While bvFTD was characterized by verbal fluency, working memory, and verbal comprehension deficits relative to AD, AD was associated with greater episodic memory impairments. The poorer delayed recall in AD was further evident on the memory tests of the CERAD-NB; however, its overall utility in the differentiation between FTLD and AD was limited. The C9ORF72 expansion carriers showed more severe executive deficits than non-carriers. The C9ORF72 expansion may further be associated with slowly progressing FTLD. On the FBI-mod, bvFTD was linked to amplified behavioral symptoms relative to AD, MCI, and PPA. Findings highlight the importance of incorporating a broad cognitive battery in the neuropsychological evaluation of FTLD. Though the clinical phenotype of C9ORF72 expansion appears broad, executive impairment likely is a core feature of bvFTD patients with the expansion. The use of the FBI-mod is recommended as a structured measure for behavioral symptoms of bvFTD. / Tiivistelmä Otsa-ohimolohkorappeumat on Alzheimerin taudin (AT) jälkeen yleisin työikäisten dementiaa aiheuttava sairausryhmä. Sen yleisin alamuoto on otsalohkodementia, jonka ensioireita ovat käyttäytymisen muutokset ja toiminnanohjauksen ongelmat. Sairausryhmään kuuluu myös kaksi kielellisin oirein ilmenevää alatyyppiä. C9ORF72-toistojaksomutaation on todettu selittävän suurimman osan perinnöllisistä tapauksista. Kognitiivisten ja käyttäytymiseen liittyvien muutosten arvioiminen on keskeinen osa taudin diagnostiikkaa. Tutkimustiedon perusteella on epäselvää, mitkä neuropsykologiset menetelmät soveltuvat parhaiten otsa-ohimolohkorappeumien tunnistamiseen. Tieto C9ORF72-mutaation kantajien kognitiivisesta profiilista on niukkaa. Tutkimuksen tavoitteena oli löytää neuropsykologisia menetelmiä, joista on hyötyä otsa-ohimolohkorappeumien erotusdiagnostiikassa ja selvittää C9ORF72-mutaation kantajien neuropsykologisia erityispiirteitä. Lisäksi haluttiin tutkia käytösoireita kartoittavan FBI-mod -läheiskyselyn hyödyllisyyttä otsa-ohimolohkorappeumien, AT:n ja lievän kognitiivisen heikentymän (MCI) erottamisessa. Aineisto koostui Oulun ja Kuopion yliopistosairaaloissa diagnosoiduista otsa-ohimolohkorappeuma-, AT- ja MCI-potilaista, joille oli tehty CERAD-tehtäväsarja, laaja neuropsykologinen tutkimus sekä FBI-mod. Otsalohkodementiaa sairastavat suoriutuivat AT-potilaita heikommin sanasujuvuutta, työmuistia ja kielellistä käsityskykyä arvioivissa tehtävissä, kun taas tapahtumamuisti oli heikompi AT:a sairastavilla. Myös CERAD-tehtäväsarjassa AT-potilaat suoriutuivat heikommin viivästetyn mieleenpalautuksen tehtävissä, mutta kokonaisuutena tehtäväsarjan kyky erotella otsa-ohimolohkorappeumaa ja AT:a sairastavat oli rajallinen. C9ORF72-mutaation kantajilla toiminnanohjauksen ongelmat olivat vaikeampia kuin ei-kantajilla. Lisäksi havaittiin, että C9ORF72-mutaatioon liittyvä sairaus voi edetä hyvin hitaasti. FBI-mod erotteli hyvin otsalohkodementiaa sairastavat AT- ja MCI-potilaista sekä otsa-ohimolohkorappeumien kielellistä muotoa sairastavista. Tulokset korostavat laajan neuropsykologisen tutkimuksen merkitystä otsa-ohimolohkorappeumien diagnostiikassa. Vaikka C9ORF72-mutaation kliininen kuva on vaihteleva, ovat toiminnanohjauksen ongelmat keskeinen osa taudinkuvaa. FBI-mod -kyselyn käyttö on suositeltavaa otsalohkodementiaan liittyvien käytösoireiden strukturoidussa arvioinnissa.