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Amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD) represents a spectrum of neurodegenerative disease with clinical presentations ranging from progressive paralysis to cognitive impairment. Approximately 15% of ALS-FTD patients initially presenting with motor symptoms also receive a diagnosis of dementia, but a majority of these patients demonstrate some level of cognitive impairment over the course of disease. Identifying molecular pathways that contribute to the development of cognitive deficits in ALS-FTD has thus far been limited by the quality of clinical information and postmortem tissue preservation as well as available technologies. This thesis aims to investigate early stages of cognitive involvement in ALS-FTD using postmortem tissues from a cohort of non-demented ALS patients who have had cognitive and pathological phenotyping. Spatially resolved transcriptome profiling of prefrontal cortex tissues from this cohort identifies dysregulated pathways in non-motor regions, contributing to our understanding of molecular perturbations underlying cognitive impairment in ALS-FTD.

As the most common motor neuron disease, Amyotrophic lateral sclerosis (ALS) affects around 4 in every 100,000 people worldwide with reports of increasing prevalence over the years. Characterized by progressive degeneration of motor neurons, ALS patients suffer impairments of movement and typically die from respiratory failure 2-5 years after diagnosis. Curiously, ALS exists on a disease continuum with Frontotemporal Dementia (FTD) where 30-50% of patients will be diagnosed with both diseases. In FTD, degeneration of cortical neurons results in diverse behavioural changes including deficits in executive and social skills as well as language and memory. A central connection between ALS and FTD is TDP-43 (encoded by TARDBP), an essential DNA/RNA binding protein known to serve critical functions in numerous cellular processes. Despite mutations in TARDBP constituting a small percentage of familial cases, TDP 43 nuclear-to-cytoplasmic mislocalization is a pathological hallmark of most ALS-FTD cases. Therefore, therapeutic targets to rectify pathology and disease may be uncovered by identifying factors that regulate TDP-43. While it is currently established TDP-43 is ubiquitinated and phosphorylated in diseased states, our lab recently found TDP-43 is SUMOylated in response to stress. Of note, perturbations in the stress response are becoming increasingly implicated in neurodegenerations. Furthermore, TDP-43 plays critical roles in the stress response which become perturbed in ALS/FTD. We developed a TDP-43 "SUMO dead" mouse allele to gain an understanding of how disrupting this may contribute to the pathogenesis of ALS-FTD. Longitudinal characterization of the model explored behavioural and histological in vivo consequences following loss of TDP-43 SUMOylation. However, the phenotypes observed in the mutant mice were less robust in comparison to established ALS/FTD mouse models. Mutant mice did not have consistent differences in tests for similar outcomes, trials of the same test, or across age. Female mutant mice presented with early hyperactivity and disinhibition along with altered social grooming behaviour. At later age, these female mice developed impairments in spatial working memory. Male mice developed apathetic behaviour and motor deficits at the middle age timepoint. Histologically, various forms of pathological TDP-43 were observed in the absence of neurodegeneration. These data reveal that TDP-43 SUMOylation may play an important role in ALS/FTD pathogenesis.

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: 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 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: 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

CHMP2B est une sous-unité du complexe ESCRT-III, un complexe cytosolique très conservé, responsable du remodelage des membranes biologique, dans divers processus cellulaires. Des mutations de CHMP2B sont associées à une forme familiale de démence frontotemporale. Une étude précédente a mis en évidence que les mutants pathogènes de CHMP2B altèrent la morphologie des épines dendritiques, un phénomène potentiellement à l'origine de la maladie. Ce travail de recherche a pour objectif de décrire le rôle de CHMP2B, et du complexe ESCRT-III, dans la structure et le fonctionnement des épines dendritiques. Dans des lignées cellulaires, nous avons démontré que CHMP2B a la propriété de s'associer préférentiellement à la membrane plasmique, de se polymériser en filaments hélicoïdaux et de former de longs et fins tubes membranaires. Ce résultat indique que CHMP2B est directement impliqué dans le remodelage de la membrane plasmique. Dans les neurones, CHMP2B se concentre dans des régions sous-membranaires proches de la PSD. Une analyse biochimique a montré que CHMP2B et CHMP4B sont associées à d'autres sous-unités, pour former un complexe ESCRT-III postsynaptique particulièrement stable. Nous avons identifié par spectrométrie de masse que ce complexe interagit également avec des protéines d'échafaudage postsynaptiques et des protéines de remodelage du cytosquelette d'actine. La déplétion de CHMP2B par RNAi, dans des neurones en culture, affecte la complexité de l'arborisation dendritique, la morphologie des épines dendritiques et empêche le gonflement des épines associé à la LTP. Des expériences de récupération, avec des mutants pontuels, indiquent que le rôle de CHMP2B dans le maintien de l'arborisation dendritique est dépendant à la fois de de son association avec ESCRT-III et la bicouche phospholipidique. Nous proposons une nouvelle fonctionnalité pour un complexe ESCRT-III contenant CHMP2B, dans les processus de remodelage de la membrane postsynaptique associés à la maturation et à la plasticité des épines dendritiques. / CHMP2B is a subunit of ESCRT-III, a highly conserved cytosolic protein machinery, responsible for membrane remodeling in diverse cellular mechanisms. Mutations in CHMP2B are responsible for a familial form of frontotemporal dementia. A previous study highlighted that FTD-related mutants of CHMP2B impair the morphological maturation of dendritic spines, a process that may underlie neurodegeneration in this disease. The goal of this research work id directed towards understanding the role of CHMP2B and ESCRT-III in dendritic spines structure and function. In cell lines, we demonstrated that CHMP2B associates preferentially with the plasma membrane, polymerizes in helical filaments and forms long and thin membrane protrusions. This result indicates that CHMP2B is directly involved in plasma membrane remodeling. In neurons, CHMP2B concentrates in specific sub-membrane microdomains close to the PSD. Biochemical analysis revealed that CHMP2B and CHMP4B associate with other subunits to form a remarkably stable postsynaptic ESCRT-III complex. Mass-spectrometry indicated that this complex also interacts with postsynaptic scaffolds and proteins involved in actin cytoskeleton remodelling. RNAi depletion of CHMP2B, in cultured neurons, alters stability of dendrite branching and morphology of dendritic spines, and impairs spine head growth, normally associated with LTP. Rescue experiments, with point mutants, indicated that CHMP2B activity in dendrite branching is dependent on its capacity to both bind phospholipids and oligomerization with ESCRT-III. We propose a novel functionality for an ESCRT-III complex containing CHMP2B, in maturation-dependent and plasticity-dependent processes of dendritic spine morphogenesis.

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.

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.