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.

The aim of this thesis was to identify genetic factors involved in frontotemporal lobar degeneration (FTLD), a neurodegenerative disorder clinically characterised by a progressive change in personality, behaviour and language. FTLD is a genetically complex disorder and a positive family history is found in up to 40% of the cases. In 10-20% of the familial cases the disease can be explained by mutations in the gene encoding the microtubule associated protein tau (MAPT). In the first study we describe the clinical and neuropathological features of a Finnish family with FTLD caused by a mutation in MAPT. We also provide evidence that the pathogenic mechanism of this mutation is through altered splicing of MAPT transcripts. Recently, mutations in the gene encoding progranulin (PGRN) were identified as a major cause of FTLD. In the second study we describe a Swedish family with FTLD caused by a frameshift mutation in PGRN. We provide a clinical and neuropathological description of the family, as well as evidence that the pathogenicity of this mutation is through nonsense-mediated decay of the mutant mRNA transcripts and PGRN haploinsufficiency. In the third study we describe a novel PGRN splice site mutation and a previously described PGRN frameshift mutation, found in a mutation screen of 51 FTLD patients. We describe the clinical and neuropathological characteristics of the mutation carriers and demonstrate that haploinsufficiency is the pathogenic mechanism of the two mutations. In the fourth study we investigate the prevalence of PGRN and MAPT gene dosage alterations in 39 patients with FTLD. No gene dosage alterations were identified, indicating that variations in copy number of the PGRN and MAPT genes are not a common cause of disease, at least not in this FTLD patient collection.

The aim of this thesis was to identify genetic factors involved in frontotemporal lobar degeneration (FTLD), a neurodegenerative disorder clinically characterised by a progressive change in personality, behaviour and language. FTLD is a genetically complex disorder and a positive family history is found in up to 40% of the cases. In 10-20% of the familial cases the disease can be explained by mutations in the gene encoding the microtubule associated protein tau (MAPT). In the first study we describe the clinical and neuropathological features of a Finnish family with FTLD caused by a mutation in MAPT. We also provide evidence that the pathogenic mechanism of this mutation is through altered splicing of MAPT transcripts. Recently, mutations in the gene encoding progranulin (PGRN) were identified as a major cause of FTLD. In the second study we describe a Swedish family with FTLD caused by a frameshift mutation in PGRN. We provide a clinical and neuropathological description of the family, as well as evidence that the pathogenicity of this mutation is through nonsense-mediated decay of the mutant mRNA transcripts and PGRN haploinsufficiency. In the third study we describe a novel PGRN splice site mutation and a previously described PGRN frameshift mutation, found in a mutation screen of 51 FTLD patients. We describe the clinical and neuropathological characteristics of the mutation carriers and demonstrate that haploinsufficiency is the pathogenic mechanism of the two mutations. In the fourth study we investigate the prevalence of PGRN and MAPT gene dosage alterations in 39 patients with FTLD. No gene dosage alterations were identified, indicating that variations in copy number of the PGRN and MAPT genes are not a common cause of disease, at least not in this FTLD patient collection.

The 43 kDa TAR DNA binding protein (TDP-43) has been identified as one of the major proteins that accumulates in the cytoplasm of brain and spinal cord from the patients affected with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Under basal conditions, TDP-43 localizes in nucleus functioning as an RNA binding protein to regulate different aspects of RNA metabolism, such as alternative splicing of messenger RNA. In ALS/FTLD brains and spinal cords, TDP-43 forms well-defined cytoplasmic granules, the behavior very similar to stress granule (SG) proteins, but the mechanisms are poorly understood. To investigate the mechanism of TDP-43 granule formation and to identify potential therapeutic targets by inhibiting the granule formation, our laboratory screened a chemical library of 75,000 compounds using the inducible PC12 cells that express EGFP-tagged wild-type human TDP-43. We used the biological effect of cycloheximide on SGs as a basis for the screen, since it is known to prevent the formation of SGs and TDP-43 granules, pointing to a novel biological pathway that regulates TDP-43 granule formation. One of the candidate compounds, Compound 8 (C8) and its analog C8j dose- dependently decreased the arsenite-induced TDP-43 granules without cytotoxicity, and reduced the protein levels of full-length, truncated, high molecular weight and phosphorylated TDP-43. In addition, we found C8j reduced the phosphorylation at novel, previously unknown Thr103-Ser104 amino acid residues of human TDP-43 under arsenite stress. The phospho-mimetic mutations at these sites induced spontaneous intracellular TDP-43 granules, indicating their regulatory role in TDP-43 granule formation. We also performed a series of gene expression analysis combined with the systems biology algorithm, mode of action by network identification (MNI), to identify the mode of action of C8, and found C8 potentially targets protein metabolism and modification processes to reduce the TDP-43 granules. Our study identified a family of non-cytotoxic chemical compounds that reduces the formation of arsenite-induced TDP-43 granules and their potential mode of action. Furthermore, we identified previously unknown TDP-43 phosphorylation sites Thr103- Ser104 that are involved in the TDP-43 granule formation. We anticipate this study will elucidate the biological pathways regulating TDP-43 aggregation and potential therapeutics for ALS/FTLD-U.

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.

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.

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.

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.

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