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%

Atualmente, as demências tornam-se mais prevalentes e constituem-se como um importante problema de saúde pública mundial. A Degeneração Lobar Frontotemporal (DLFT) e a Doença de Alzheimer (DA) são as de maior incidência. A investigação dos fatores de risco para as demências degenerativas inscreve-se entre os temas mais relevantes das neurociências e a avaliação dos fatores de risco de natureza genética tem produzido contribuições importantes. Na DLFT, mutações no gene TARDBP, codificador da proteína nuclear TDP-43, estão entre as ocorrências genéticas mais descritas, enquanto que para a DA, o alelo 4 do gene da apolipoproteína E (APOE) é o principal fator de risco. Pacientes com diagnóstico clínico de DLFT (n=47) e de DA provável (n=30) recebidos do ambulatório do Grupo de Neurologia Cognitiva e do Comportamento (GNCC) da Clínica Neurológica do HC-FMUSP foram convidados a participar do estudo. Amostras de sangue foram coletadas para a realização da extração de DNA linfocitário. Os éxons de 1-6 do gene TARDBP foram amplificados por PCR e seus produtos foram sequenciados em sequenciador automático. Os polimorfismos do gene APOE foram determinados através da técnica de PCR em tempo real. A análise do gene da TDP-43 em pacientes com DLFT mostrou a presença de uma mutação na região do éxon 6 do TARDBP (g.14935A>G) em um paciente do sexo masculino, com idade de 54 anos e diagnóstico de demência semântica. Na genotipagem dos pacientes de DA, foi observado que a metodologia utilizada, através de PCR em tempo real mostrou-se eficiente em detectar os polimorfismos do gene APOE, fornecendo resultados compatíveis quando comparados aos demais estudos brasileiros publicados anteriormente / Brazil is one of the developing countries that are undergoing a process of demographic transition in which the elderly represents a significant proportion of the total population. Neurodegenerative illnesses most commonly appear at such ages. Frontotemporal lobar degeneration (FTLD) and Alzheimers disease (AD) are the most frequent causes for dementia. The investigation of risk factors for degenerative dementia is a relevant subject of neurosciences and the evaluation of the nature of genetic risk factors has produced the most important contributions. Mutations in TARDBP gene, the encoder of the TDP-43 nuclear protein, appear as the most frequent genetic occurrences for FTLD, whereas, in DA, the 4 allele of the apolipoprotein E (APOE) is the major genetic risk factor. Patients with clinical diagnosis of FTLD types of families and sporadic (n=47) and probable AD (n=30) from the ambulatory of Cognitive Neurology Group and Behavior (CNGB) of Neurological Clinic of HC-FMUSP were invited to participate in this study. Blood samples were collected for lymphocytic DNA extraction. The APOE gene polymorphisms are being determined through the real time PCR technique. The 1-6 exons of TARDBP gene were amplified by PCR and their products were sequenced in automated sequencer. The TDP-43 gene analysis in patients with FTLD showed the presence of one mutation in the region of exon 6 TARDBP gene in a male patient of 54 years old, with diagnoses of semantic dementia. Regarding DA patients genotyping, the real time methodology has been shown as an efficient approach to detect APOE polymorphisms, presenting data similar to those observed in other Brazilian studies

Introdução: No Brasil há carência de instrumentos validados para a análise do curso da Demência Frontotemporal (DFT). Dessa forma, torna-se relevante a validação da Escala de Estadiamento e Progressão da Demência Frontotemporal (FTD-FRS). Em nosso meio, as escalas de estadiamento das demências, como a Clinical Dementia Rating (CDR), foram elaboradas para graduar a doença de Alzheimer (DA) e não incluem os sintomas específicos da DFT. Objetivos: 1. Realizar a tradução, adaptação transcultural e validação da FTD-FRS para o contexto brasileiro. 2. Avaliar a capacidade da FTD-FRS detectar alterações em pacientes com DFTvc, afasia progressiva primária (APP) e DA após 12 meses da avaliação inicial, em comparação com a escala CDR para DLFT, e com a CDR original. Métodos: Participaram do estudo 101 indivíduos com idade igual ou superior a 40 anos, com escolaridade formal acima de dois anos, sendo 31 pacientes com diagnóstico de DFT variante comportamental (DFTvc), doze pacientes com afasia progressiva primária (APP), 28 pacientes com doença de Alzheimer (DA), oito com comprometimento cognitivo leve (CCL) e 22 controles normais (CN). Foram entrevistados os familiares ou cuidadores que tinham contato frequente com o paciente. Os pacientes com DA, e com os subtipos de DFT foram pareados quanto à gravidade da doença, segundo a CDR. Resultados: Foi realizado o processo de adaptação transcultural da FTD-FRS. Consistiu em: tradução, retrotradução (realizadas por tradutores independentes), discussão com especialistas sobre a versão em português e equivalência com a versão original, e desenvolvimento da versão final. A consistência interna da FTD-FRS, estimada pelo alfa de Cronbach foi 0,975, e o coeficiente de correlação intra-classe, para a estabilidade no teste e reteste em seis meses foi de 0,977. A análise fatorial revelou a existência de quatro fatores que se correlacionaram significativamente com os domínios da CDR-DLFT. Os pacientes com DFTvc apresentaram progressão mais rápida em 12 meses do que os demais subtipos de demência na FTD-FRS, na CDR-DLFT e na CDR-original. Considerações finais: A FTD-FRS tem propriedades psicométricas adequadas para seu uso clínico no Brasil. Este instrumento pode auxiliar na caracterização de sintomas clínicos relevantes para o diagnóstico e estadiamento da DFT. Também pode documentar os resultados relacionados à intervenção terapêutica. Este estudo fornece aos clínicos e pesquisadores um instrumento válido para estadiamento e acompanhamentode de pacientes diagnosticados com DFT / Introduction: In Brazil there is a shortage of validated instruments for the analysis of the course of Frontotemporal Dementia (FTD). Thus, the validation of the Frontotemporal Dementia Staging and Progression Scale (FTD-FRS) becomes relevant. In our setting, dementia staging scales, such as the Clinical Dementia Rating (CDR), were designed to stage Alzheimer\'s disease (AD) and did not include the specific symptoms of FTD. Objectives: 1. To perform the translation, cross-cultural adaptation and validation of the FTD-FRS for the Brazilian context. 2. Evaluate the ability of the FTD-FRS to detect changes in patients with bvFTD, primary progressive aphasia (PPA) and AD after 12 months of the initial evaluation, compared to the CDR scale for FTLD, and with the original CDR. Methods: A total of 101 individuals aged 40 years and older, with formal schooling above two years of age, were included in the study. Twenty-one patients were diagnosed with bvFTD, twelve patients with PPA, 28 AD, eight with mild cognitive impairment (MCI) and 22 normal controls (NC). Family members or caregivers who had frequent contact with the patient were interviewed. Patients with AD and with FTD subtypes were matched for disease severity, according to CDR. Results: The process of cross-cultural adaptation of the FTD-FRS was carried out. It consisted of: translation, back-translation (carried out by independent translators), discussion with experts about the Portuguese version and equivalence with the original version, and development of the final version. The internal consistency of the FTD-FRS, estimated by the Cronbach\'s alpha was 0.975, and the intra-class correlation coefficient for the test and retest stability at six months was 0.977. Factor analysis revealed the existence of four factors that correlated significantly with the CDR-DLFT domains. Patients with bvFTD showed faster progression at 12 months than the other dementia subtypes in the FTD-FRS, CDR-DLFT and CDR-original version scales. Final considerations: FTD-FRS has psychometric properties suitable for clinical use in Brazil. This instrument may aid in the characterization of clinical symptoms relevant to the diagnosis and staging of FTD. It can also document the results related to therapeutic interventions. This study provides clinicians and researchers with a valid instrument for staging and follow-up of patients diagnosed with FTD

Atualmente, as demências tornam-se mais prevalentes e constituem-se como um importante problema de saúde pública mundial. A Degeneração Lobar Frontotemporal (DLFT) e a Doença de Alzheimer (DA) são as de maior incidência. A investigação dos fatores de risco para as demências degenerativas inscreve-se entre os temas mais relevantes das neurociências e a avaliação dos fatores de risco de natureza genética tem produzido contribuições importantes. Na DLFT, mutações no gene TARDBP, codificador da proteína nuclear TDP-43, estão entre as ocorrências genéticas mais descritas, enquanto que para a DA, o alelo 4 do gene da apolipoproteína E (APOE) é o principal fator de risco. Pacientes com diagnóstico clínico de DLFT (n=47) e de DA provável (n=30) recebidos do ambulatório do Grupo de Neurologia Cognitiva e do Comportamento (GNCC) da Clínica Neurológica do HC-FMUSP foram convidados a participar do estudo. Amostras de sangue foram coletadas para a realização da extração de DNA linfocitário. Os éxons de 1-6 do gene TARDBP foram amplificados por PCR e seus produtos foram sequenciados em sequenciador automático. Os polimorfismos do gene APOE foram determinados através da técnica de PCR em tempo real. A análise do gene da TDP-43 em pacientes com DLFT mostrou a presença de uma mutação na região do éxon 6 do TARDBP (g.14935A>G) em um paciente do sexo masculino, com idade de 54 anos e diagnóstico de demência semântica. Na genotipagem dos pacientes de DA, foi observado que a metodologia utilizada, através de PCR em tempo real mostrou-se eficiente em detectar os polimorfismos do gene APOE, fornecendo resultados compatíveis quando comparados aos demais estudos brasileiros publicados anteriormente / Brazil is one of the developing countries that are undergoing a process of demographic transition in which the elderly represents a significant proportion of the total population. Neurodegenerative illnesses most commonly appear at such ages. Frontotemporal lobar degeneration (FTLD) and Alzheimers disease (AD) are the most frequent causes for dementia. The investigation of risk factors for degenerative dementia is a relevant subject of neurosciences and the evaluation of the nature of genetic risk factors has produced the most important contributions. Mutations in TARDBP gene, the encoder of the TDP-43 nuclear protein, appear as the most frequent genetic occurrences for FTLD, whereas, in DA, the 4 allele of the apolipoprotein E (APOE) is the major genetic risk factor. Patients with clinical diagnosis of FTLD types of families and sporadic (n=47) and probable AD (n=30) from the ambulatory of Cognitive Neurology Group and Behavior (CNGB) of Neurological Clinic of HC-FMUSP were invited to participate in this study. Blood samples were collected for lymphocytic DNA extraction. The APOE gene polymorphisms are being determined through the real time PCR technique. The 1-6 exons of TARDBP gene were amplified by PCR and their products were sequenced in automated sequencer. The TDP-43 gene analysis in patients with FTLD showed the presence of one mutation in the region of exon 6 TARDBP gene in a male patient of 54 years old, with diagnoses of semantic dementia. Regarding DA patients genotyping, the real time methodology has been shown as an efficient approach to detect APOE polymorphisms, presenting data similar to those observed in other Brazilian studies

Introdução: No Brasil há carência de instrumentos validados para a análise do curso da Demência Frontotemporal (DFT). Dessa forma, torna-se relevante a validação da Escala de Estadiamento e Progressão da Demência Frontotemporal (FTD-FRS). Em nosso meio, as escalas de estadiamento das demências, como a Clinical Dementia Rating (CDR), foram elaboradas para graduar a doença de Alzheimer (DA) e não incluem os sintomas específicos da DFT. Objetivos: 1. Realizar a tradução, adaptação transcultural e validação da FTD-FRS para o contexto brasileiro. 2. Avaliar a capacidade da FTD-FRS detectar alterações em pacientes com DFTvc, afasia progressiva primária (APP) e DA após 12 meses da avaliação inicial, em comparação com a escala CDR para DLFT, e com a CDR original. Métodos: Participaram do estudo 101 indivíduos com idade igual ou superior a 40 anos, com escolaridade formal acima de dois anos, sendo 31 pacientes com diagnóstico de DFT variante comportamental (DFTvc), doze pacientes com afasia progressiva primária (APP), 28 pacientes com doença de Alzheimer (DA), oito com comprometimento cognitivo leve (CCL) e 22 controles normais (CN). Foram entrevistados os familiares ou cuidadores que tinham contato frequente com o paciente. Os pacientes com DA, e com os subtipos de DFT foram pareados quanto à gravidade da doença, segundo a CDR. Resultados: Foi realizado o processo de adaptação transcultural da FTD-FRS. Consistiu em: tradução, retrotradução (realizadas por tradutores independentes), discussão com especialistas sobre a versão em português e equivalência com a versão original, e desenvolvimento da versão final. A consistência interna da FTD-FRS, estimada pelo alfa de Cronbach foi 0,975, e o coeficiente de correlação intra-classe, para a estabilidade no teste e reteste em seis meses foi de 0,977. A análise fatorial revelou a existência de quatro fatores que se correlacionaram significativamente com os domínios da CDR-DLFT. Os pacientes com DFTvc apresentaram progressão mais rápida em 12 meses do que os demais subtipos de demência na FTD-FRS, na CDR-DLFT e na CDR-original. Considerações finais: A FTD-FRS tem propriedades psicométricas adequadas para seu uso clínico no Brasil. Este instrumento pode auxiliar na caracterização de sintomas clínicos relevantes para o diagnóstico e estadiamento da DFT. Também pode documentar os resultados relacionados à intervenção terapêutica. Este estudo fornece aos clínicos e pesquisadores um instrumento válido para estadiamento e acompanhamentode de pacientes diagnosticados com DFT / Introduction: In Brazil there is a shortage of validated instruments for the analysis of the course of Frontotemporal Dementia (FTD). Thus, the validation of the Frontotemporal Dementia Staging and Progression Scale (FTD-FRS) becomes relevant. In our setting, dementia staging scales, such as the Clinical Dementia Rating (CDR), were designed to stage Alzheimer\'s disease (AD) and did not include the specific symptoms of FTD. Objectives: 1. To perform the translation, cross-cultural adaptation and validation of the FTD-FRS for the Brazilian context. 2. Evaluate the ability of the FTD-FRS to detect changes in patients with bvFTD, primary progressive aphasia (PPA) and AD after 12 months of the initial evaluation, compared to the CDR scale for FTLD, and with the original CDR. Methods: A total of 101 individuals aged 40 years and older, with formal schooling above two years of age, were included in the study. Twenty-one patients were diagnosed with bvFTD, twelve patients with PPA, 28 AD, eight with mild cognitive impairment (MCI) and 22 normal controls (NC). Family members or caregivers who had frequent contact with the patient were interviewed. Patients with AD and with FTD subtypes were matched for disease severity, according to CDR. Results: The process of cross-cultural adaptation of the FTD-FRS was carried out. It consisted of: translation, back-translation (carried out by independent translators), discussion with experts about the Portuguese version and equivalence with the original version, and development of the final version. The internal consistency of the FTD-FRS, estimated by the Cronbach\'s alpha was 0.975, and the intra-class correlation coefficient for the test and retest stability at six months was 0.977. Factor analysis revealed the existence of four factors that correlated significantly with the CDR-DLFT domains. Patients with bvFTD showed faster progression at 12 months than the other dementia subtypes in the FTD-FRS, CDR-DLFT and CDR-original version scales. Final considerations: FTD-FRS has psychometric properties suitable for clinical use in Brazil. This instrument may aid in the characterization of clinical symptoms relevant to the diagnosis and staging of FTD. It can also document the results related to therapeutic interventions. This study provides clinicians and researchers with a valid instrument for staging and follow-up of patients diagnosed with FTD

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%

Les dégénérescences lobaires fronto-temporale (DLFT) sont des démences neurodégénératives rares. 30-50% des DLFT a une cause génétique, la plupart sont des mutations des gènes C9orf72 et progranuline (GRN). L'objectif de la thèse a été d'élargir le spectre mutationnel et phénotypique des mutations GRN. Nous avons identifié les premières délétions partielles du gène GRN chez des patients avec progranulinémie baisse (la progranulinémie est abaissée en cas de mutation), mais sans mutation détectée par séquençage. Nous avons contribué à élargir le spectre clinique de la maladie en décrivant un phénotype d'atrophie corticale postérieure et des lésions de la substance blanche cérébrale chez des patients GRN, caractéristique évocatrice de cette forme génétique. Enfin, nous avons étudié la phase présymptomatique de la maladie, alors que se développent les premiers essais thérapeutiques, par une approche longitudinale avec IRM et TEP-FDG. Le métabolisme cérébral est réduit dans le lobe temporal latéral gauche 20 ans avant l'apparition des symptômes et, après 20 mois, dans les régions frontales et l'épaisseur corticale dans les régions temporales gauche. Le lobe temporal latéral pourrait être donc l'"épicentre " de la maladie, et le processus lésionnel pourrait, secondairement, progresser vers les régions frontales. J'ai également contribué à définir les phénotypes associés aux mutations de gènes plus rares de DLFT/DLFT-SLA. TARDBP est associé à un large spectre phénotypique; TBK1 est caractérisé par une démence sémantique ou aphasie non fluent associés à l'atteinte de la corne antérieure. Cette étude importante souligne le rôle de ces mutations dans le spectre clinique des DLFT. / Frontotemporal lobar degeneration (FTLD) are rare neurodegenerative dementias. 30-50% of FTLD has a genetic cause, most are mutations in C9orf72 and in progranulin gene (GRN). The aim of the thesis was to expand the mutational and phenotypic spectrum of GRN mutations. We identified the first partial deletions of GRN gene in patients with low plasmatic progranulin (the plasmatic progranulin is low in case of mutation), but without mutation detected by sequencing. We contributed to expand the clinical spectrum of the disease by describing a posterior cortical atrophy phenotype and lesions of the cerebral white matter in GRN patients, evocative feature of this genetic form. Finally, we studied the presymptomatic stage of the disease, while the first clinical trials develop, for a longitudinal approach with MRI and FDG-PET. The cerebral metabolism is reduced in the left temporal lobe 20 years before clinical onset and, after 20 months, the metabolism is reduced in the frontal regions and the cortical thickness in the left temporal regions. The lateral temporal lobe could thus be the "epicenter" of the disease, and the lesional process could secondarily progress towards the frontal regions. I also contributed to define the phenotypes associated with rare gene mutations in FTLD/FTLD-ALS. TARDBP is associated with a wide phenotypic spectrum; TBK1 is characterized by semantic dementia or not fluent aphasia associated with involvement of the anterior horn. This important study highlights the role of these mutations in the clinical spectrum of FTLD.

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.

Abstract Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are the two most common neurodegenerative diseases leading to early onset dementia (< 65 years). Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes cause a proportion of familial early-onset AD (eoAD), while the microtubule-associated protein tau (MAPT) and progranulin (PGRN) mutations have been identified in FTLD patients. Only a few PSEN1 and APP mutations have previously been found in Finnish AD patients, and one MAPT mutation in a FTLD family, while the role of PGRN in Finnish FTLD patients is unknown. Increasing evidence suggests that mitochondrial dysfunction and oxidative stress also play an important role in neurodegenerative diseases. The aim here was to investigate the genetics of eoAD and FTLD in the population of the province of Northern Ostrobothnia, Finland. Sequencing analysis of the APP, PSEN1 and PSEN2 genes was performed to determine whether mutations in these genes could be detected. The MAPT and PGRN genes were analysed in the FTLD patients by sequencing and MAPT haplotypes were determined. The contributions of mtDNA and its maintenance enzymes to eoAD and FTLD were studied by comparing the frequencies of mtDNA haplogroups and their clusters between the patient groups and controls and by screening for the five common POLG1 mutations (T251I, A467T, P587L, W748S, Y955C), two common mtDNA mutations (m.3243A>G, m.8344A>G) and mutations in the PEO1 and ANT1 genes. This is the first report of a significant association between the mtDNA haplogroup cluster IWX and FTLD. The H2 MAPT haplotype was also associated with FTLD in our cohort. No significant differences in the frequencies of the mtDNA haplogroups were observed between the eoAD patients and controls, nor were there any pathogenic mutations detected in the genes analysed. The findings suggest that possession of the mtDNA haplogroup cluster IWX and the H2 MAPT haplotype may be possible risk factors for FTLD in our cohort. The absence of any pathogenic mutations in the MAPT, PGRN, APP or PSEN genes in our series, together with the previous reports of only a few mutations found in this region, supports a minor role for these genes in the aetiology of eoAD and FTLD in Northern Ostrobothnia and indicates that this population may have its own genetic features. There may be other, still unknown genetic factors to be discovered, that explain familial diseases in the region.

Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of illnesses which can be difficult to diagnose. Modern diagnostic criteria require the presence of imaging abnormalities, but these are not always seen in the early stages of the illness. Hence there is a need to consider the use of more advanced MR techniques. This thesis reports the results of a multimodal MRI study of patients with FTLD, and considers two things: how well data from the different modalities can classify patients, and how well the different modalities can identify affected tissue. FTLD is thought to involve alterations in cerebral blood flow, but it is possible that microvascular changes will alter additional perfusion parameters, such as the time taken for blood to reach the tissue (the arrival time). Multi-time point arterial spin labelling (ASL) measurements have the ability to extract the relevant parameters. I consider the parameters involved in modelling these data, and report the accuracy of cerebral blood flow (CBF) measurement achievable in a clinically acceptable time. FTLD patients have atrophy in the frontal and temporal lobes, regions problematic for MRI because of susceptibility artefacts caused by adjacent air spaces. I consider two ASL MR read-out sequences (gradient-echo and spin-echo)and show that spin-echo images give higher signal in frontal and temporal regions than gradient-echo. ASL, T1-weighted and diffusion-weighted images were collected for a group of 17 FTLD patients and 18 controls. I found decreased CBF in highly atrophied regions of cortical grey matter in patients, but this deficit was not seen when corrected for atrophy. An increased arrival time was seen in regions adjacent to the atrophied regions, but a decreased arrival time was seen in the atrophied regions; this is a novel finding. The diffusion metrics of fractional anisotropy (FA) and particularly mean diffusivity (MD) are found to be highly sensitive to differences in FTLD patients. I speculate that this is an increased sensitivity to atrophy because of the increased signal from cerebrospinal fluid. I combine the regional values of all the modalities in a classification method to distinguish patients from controls, and establish a combination of region and modality that classified 21/22 subjects correctly. This exploratory study is the first time all three modalities have been combined in a study of FTLD patients; it shows that combining MR modalities may lead to improved classification of FTLD patients and better identification of affected tissue.