This research involves an examination of the olfactory ability of individuals with Frontotemporal Dementia, Alzheimer's disease, and geriatric individuals with cognitive complaints owing to Major Depressive Disorder or Generalized Anxiety Disorder. The purpose of this study was to determine if olfactory differences were useful in differentiating between demented and non-demented individuals. Due to the pathway of the olfactory tract, it can be expected that there would be equal olfactory deficits in those diagnosed with Frontotemporal Dementia and Alzheimer's disease, and that these deficits would be worse than those found in geriatric individuals with Major Depressive Disorder or Generalized Anxiety Disorder. Five hypotheses were investigated. The first utilized an ANCOVA and found that the olfaction of the demented group was worse than that of the non-demented, psychiatric group. The second utilized a series of Discriminant Function Analyses and F-tests and determined that olfaction best classified demented and non-demented individuals. The third implemented a Mixed Model ANOVA to assess for lateralized smell deficits within the demented group and between the demented and non-demented groups and found no main effects of lateralization or interaction effects. The fourth hypothesis investigated the relationship between smell and commonly used neuropsychological tests in a Frontotemporal Dementia sample, and found that there was no difference between the relationship of tests measuring the frontal and temporal lobes to those measuring other cerebral areas. The fifth hypothesis replicated Hypothesis 4 in an Alzheimer's disease sample and found that there was a significant difference between the relationship of tests measuring the frontal and temporal lobes to those measuring other cerebral areas. Primarily, this study demonstrated that dementia patients present with significantly more olfactory deficits than a psychiatric sample with subjective cognitive complaints. Additionally, olfaction correctly distinguished the Dementia Group from the Psychiatric Group with 81.6% accuracy, 90.2% sensitivity and 67.6% specificity. Alone, these classification statistics are quite impressive, appearing equivalent, or possibly superior to the classification statistics of commonly used neuropsychological tests of memory, executive functioning, and visuospatial ability. This study concluded that adding an olfactory measure to an assessment battery provides clinically relevant data, and enhances the diagnostic accuracy of the battery. However, though this study found the Alberta Smell Test was a valuable addition to a test battery, the absence of lateralized findings demonstrated the unirhinal format, by which the Alberta Smell Test is administered, does not provide diagnostically relevant information above and beyond the information a clinician will gain from birhinal assessment.

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

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

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

Lima-Silva TB. Funcionalidade e desempenho cognitivo na demência frontotemporal variante comportamental. [Dissertação]. São Paulo: Faculdade de Medicina, Universidade de São Paulo, 2012. Resumo Introdução: Existem poucos estudos sobre alterações funcionais na Demência Frontotemporal variante comportamental (DFTvc). Subtipos de demência menos estudados, como a DFTvc, vêm ganhando destaque, por também apresentarem importância epidemiológica. Objetivou-se no presente estudo: 1. Caracterizar o desempenho funcional e cognitivo de pacientes com diagnóstico prévio de DFTvc, atendidos em ambulatórios de Neurologia e Psiquiatria e compará-los a pacientes com Doença de Alzheimer (DA) e controles saudáveis; 2. Examinar a correlação entre o desempenho em escalas funcionais (DAFS-BR, DAD e PFAQ) e o desempenho cognitivo; 3. Avaliar a acurácia diagnóstica da DAFS-BR para a detecção da DFTvc e da DA. Métodos: Participaram 96 indivíduos com idade igual ou superior a 45 anos, com escolaridade formal acima de dois anos. Destes, 31 haviam recebido o diagnóstico de DFTvc, 31 de DA e 34 eram adultos saudáveis pareados aos pacientes com DFTvc e DA para idade e escolaridade. Foram aplicados: questionário sociodemográfico e de variáveis clínicas; Escala de Depressão Geriátrica (Geriatric Depression Scale - GDS) de 15 itens, Escala de Ansiedade Geriátrica (Geriatric Anxiety Inventory - GAI), Addenbrooke Cognitive Examination-Revised (ACE-R) que engloba as questões do Mini Exame do Estado Mental (MEEM), Executive Interview (EXIT-25), Direct Assessment of Functional Status (DAFS-BR). O protocolo dos acompanhantes conteve a Escala Cornell de Depressão em Demência, Pfeffer Functional Activities Questionnaire (PFAQ), Disability Assessment for Dementia (DAD), Inventário Neuropsiquiátrico (NPI) e a Escala de Avaliação Clínica da Demência (CDR). Resultados: Pôde-se observar que o grupo com DFTvc apresentou pior desempenho em Alimentação na DAFS-BR e nos domínios de Iniciação e Planejamento/Organização na DAD, comparado aos idosos com DA, sugerindo que a dependência na DFTvc é mais acentuada. A pontuação mais elevada na PFAQ, sugeriu que a dependência na DFTvc é mais acentuada. Foram encontradas correlações significativas entre o desempenho cognitivo e funcional. Os dados de acurácia para a DAFS-BR sugeriram que a escala pode auxiliar na identificação das demências, apresentando limitações no diagnóstico diferencial entre os subtipos. Considerações finais: Os resultados apresentados sugerem que indivíduos com DFTvc apresentam maior prejuízo funcional, quando comparados com participantes com DA e adultos saudáveis. Os resultados apresentados destacaram a importância da avaliação funcional de pacientes com suspeita de DFTvc, devido à relevância destas alterações para o diagnóstico e manejo clínico deste subtipo de demência. / Summary Introduction: There are but a few research studies on functional impairment in behavioral variant Frontotemporal Dementia. Less studied dementia subtypes, such as bvFTD, have been gaining prominence due to their epidemiological significance. The objectives of the present research were to: 1. Characterize the functional and cognitive performance of patients previously diagnosed with bvFTD treated at outpatient clinics of Neurology and Psychiatry, and compare their performance with that of patients with AD and normal controls; 2. Examine the correlation between performance in the functional scales (DAFS-BR, DAD e PFAQ) and cognitive performance; and 3. Evaluate the diagnostic accuracy of the DAFS-BR for detecting bvFTD and AD. Methodology: The sample consisted of 96 individuals aged 45 or older, with at least two years of formal education. Of these, 31 had been diagnosed with bvFTD, 31 with AD, and 34 were healthy adults paired with the patients with bvFTD and AD for age and education. The following instruments were used: sociodemographic and clinical questionnaire; 15-item Geriatric Depression Scale (GDS); Geriatric Anxiety Inventory (GAI); Addenbrooke Cognitive Examination-Revised (ACE-R), which includes the questions of the Mini Mental State Examination (MMSE); Executive Interview (EXIT-25); and the Direct Assessment of Functional Status Revised (DAFS-BR). The protocol for caregivers included the Cornell Scale for Depression in Dementia, Pfeffer Functional Activities Questionnaire (PFAQ), Disability Assessment for Dementia (DAD), Neuropsychiatric Inventory (NPI) and the Clinical Dementia Rating scale (CDR). Results: Individuals in the bvFTD group had lower performance in the ´Eating skills´ item of the DAFS-BR, and in ´Initiation´ and in ´Planning/Organization´ in the DAD, suggesting a higher level of dependence in bvFTD, and Higher scores in the PFAQ suggested that dependence in bvFTD is more pronounced. Significant correlations were found between cognitive and functional performances. The accuracy data for the DAFS-BR indicated that the scale can help identify dementia however, it has limitations in the differential diagnosis among subtypes. Final Considerations: The results suggest that individuals with bvFTD display greater functional impairment when compared to individuals with AD and to healthy adults. These results highlight the importance of assessing functionality status among patients suspected to have bvFTD. These deficits are relevant for the diagnosis and clinical management of this subtype of dementia.

Lima-Silva TB. Funcionalidade e desempenho cognitivo na demência frontotemporal variante comportamental. [Dissertação]. São Paulo: Faculdade de Medicina, Universidade de São Paulo, 2012. Resumo Introdução: Existem poucos estudos sobre alterações funcionais na Demência Frontotemporal variante comportamental (DFTvc). Subtipos de demência menos estudados, como a DFTvc, vêm ganhando destaque, por também apresentarem importância epidemiológica. Objetivou-se no presente estudo: 1. Caracterizar o desempenho funcional e cognitivo de pacientes com diagnóstico prévio de DFTvc, atendidos em ambulatórios de Neurologia e Psiquiatria e compará-los a pacientes com Doença de Alzheimer (DA) e controles saudáveis; 2. Examinar a correlação entre o desempenho em escalas funcionais (DAFS-BR, DAD e PFAQ) e o desempenho cognitivo; 3. Avaliar a acurácia diagnóstica da DAFS-BR para a detecção da DFTvc e da DA. Métodos: Participaram 96 indivíduos com idade igual ou superior a 45 anos, com escolaridade formal acima de dois anos. Destes, 31 haviam recebido o diagnóstico de DFTvc, 31 de DA e 34 eram adultos saudáveis pareados aos pacientes com DFTvc e DA para idade e escolaridade. Foram aplicados: questionário sociodemográfico e de variáveis clínicas; Escala de Depressão Geriátrica (Geriatric Depression Scale - GDS) de 15 itens, Escala de Ansiedade Geriátrica (Geriatric Anxiety Inventory - GAI), Addenbrooke Cognitive Examination-Revised (ACE-R) que engloba as questões do Mini Exame do Estado Mental (MEEM), Executive Interview (EXIT-25), Direct Assessment of Functional Status (DAFS-BR). O protocolo dos acompanhantes conteve a Escala Cornell de Depressão em Demência, Pfeffer Functional Activities Questionnaire (PFAQ), Disability Assessment for Dementia (DAD), Inventário Neuropsiquiátrico (NPI) e a Escala de Avaliação Clínica da Demência (CDR). Resultados: Pôde-se observar que o grupo com DFTvc apresentou pior desempenho em Alimentação na DAFS-BR e nos domínios de Iniciação e Planejamento/Organização na DAD, comparado aos idosos com DA, sugerindo que a dependência na DFTvc é mais acentuada. A pontuação mais elevada na PFAQ, sugeriu que a dependência na DFTvc é mais acentuada. Foram encontradas correlações significativas entre o desempenho cognitivo e funcional. Os dados de acurácia para a DAFS-BR sugeriram que a escala pode auxiliar na identificação das demências, apresentando limitações no diagnóstico diferencial entre os subtipos. Considerações finais: Os resultados apresentados sugerem que indivíduos com DFTvc apresentam maior prejuízo funcional, quando comparados com participantes com DA e adultos saudáveis. Os resultados apresentados destacaram a importância da avaliação funcional de pacientes com suspeita de DFTvc, devido à relevância destas alterações para o diagnóstico e manejo clínico deste subtipo de demência. / Summary Introduction: There are but a few research studies on functional impairment in behavioral variant Frontotemporal Dementia. Less studied dementia subtypes, such as bvFTD, have been gaining prominence due to their epidemiological significance. The objectives of the present research were to: 1. Characterize the functional and cognitive performance of patients previously diagnosed with bvFTD treated at outpatient clinics of Neurology and Psychiatry, and compare their performance with that of patients with AD and normal controls; 2. Examine the correlation between performance in the functional scales (DAFS-BR, DAD e PFAQ) and cognitive performance; and 3. Evaluate the diagnostic accuracy of the DAFS-BR for detecting bvFTD and AD. Methodology: The sample consisted of 96 individuals aged 45 or older, with at least two years of formal education. Of these, 31 had been diagnosed with bvFTD, 31 with AD, and 34 were healthy adults paired with the patients with bvFTD and AD for age and education. The following instruments were used: sociodemographic and clinical questionnaire; 15-item Geriatric Depression Scale (GDS); Geriatric Anxiety Inventory (GAI); Addenbrooke Cognitive Examination-Revised (ACE-R), which includes the questions of the Mini Mental State Examination (MMSE); Executive Interview (EXIT-25); and the Direct Assessment of Functional Status Revised (DAFS-BR). The protocol for caregivers included the Cornell Scale for Depression in Dementia, Pfeffer Functional Activities Questionnaire (PFAQ), Disability Assessment for Dementia (DAD), Neuropsychiatric Inventory (NPI) and the Clinical Dementia Rating scale (CDR). Results: Individuals in the bvFTD group had lower performance in the ´Eating skills´ item of the DAFS-BR, and in ´Initiation´ and in ´Planning/Organization´ in the DAD, suggesting a higher level of dependence in bvFTD, and Higher scores in the PFAQ suggested that dependence in bvFTD is more pronounced. Significant correlations were found between cognitive and functional performances. The accuracy data for the DAFS-BR indicated that the scale can help identify dementia however, it has limitations in the differential diagnosis among subtypes. Final Considerations: The results suggest that individuals with bvFTD display greater functional impairment when compared to individuals with AD and to healthy adults. These results highlight the importance of assessing functionality status among patients suspected to have bvFTD. These deficits are relevant for the diagnosis and clinical management of this subtype of dementia.

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.

Dementia causes an increasing social and economic burden worldwide, demanding action regarding its diagnosis, treatment and everyday management. Recent years have seen many advances in neurodegeneration research, but the search for new truly disease modifying therapies for Alzheimer's disease (AD) and frontotemporal dementia (FTD) has so far not been successful. This is mainly due to a lack of understanding of the precise intracellular events that lead up to neuronal dysfunction in early and in late stages of the disease. This thesis describes the approaches taken to extend the current knowledge about the intracellular effects of neuronal amyloid-beta and the signalling pathways causing neuronal death or disturbed synaptic function in dementia. Endophilin-1(Ep-1), amyloid-binding alcohol dehydrogenase (ABAD), peroxiredoxin-2 (Prx-2) and the EF-hand domain family, member D2 (EFHD2) have been found to be elevated in the human brain with dementia and in mouse models for frontotemporal lobar degeneration (FTLD) or AD. The expression of these proteins as well as the expression of c-Jun N-terminal kinase (JNK), c-Jun and APP were analysed by western blotting and real-time PCR in human brains affected by AD or FTLD as well as in mouse models for AD. This provided a new insight into the regulation of these proteins in relation to each other in the ageing brain and uncovered a new potential link between elevated levels of EFHD2, Prx-2 and APP in FTLD. By studying the effects of the overexpression of Ep-1 in neurons, this research has led to a better understanding of its role in JNK-activation. It furthermore verified a protective role for Prx-2 against neurotoxicity and pointed towards a new function for Prx-2 in the regulation of JNK-signalling. The analysis of the effect of increased levels of EFHD2 uncovered for the first time its involvement in the PI3K-signalling cascade in neuronal cells. The current work has therefore contributed to the knowledge about the cellular processes that are affected by Ep-1, Prx-2 and EFHD2 in different types of dementia and will greatly benefit future research into their actions in the neuronal network.

Le diagnostic différentiel de Démence Fronto-Temporale (DFT) vs Maladie d’Alzheimer (MA) n’est pas toujours facile à établir, et peuvent être confondus avec ceux de l’Aphasie Primaire Progressive (APP) » (Snowden et al. 2011) puisque l’anomie est présente dans les deux pathologies (Assal et al. 2009, Barkat-Defadas et al. 2008, Léger et al. 2007). La MA peut se décrire comme une démence dégénérative, avec une perte de tissu neuronal plutôt dans les lobes pariétal et temporal, résultant dans des difficultés dans les domaines de l’attention, les fonctions exécutives, la mémoire, les compétences pour apprendre, le langage, le calcul, et les fonctions viso-spatiales (Robin et al. 2003). De l’autre coté, la DFT est une démence qui atteint plutôt les lobes frontal et temporal elle peut se classifier d’après trois variantes: variante comportementale (DFTbf), Aphasie primaire progressive (APP) et démence sémantique (DS) (Kertesz et al 2003). Dans les deux cas nous pouvons trouver des troubles communs du à la perte du tissu dans les régions temporales, dans les étapes initiales de la maladie. L’analyse du langage chez des patients avec DFT et MA, et la corrélation de celui-ci avec le profil psycholinguistique permettra l’isolement des caractéristiques cliniques propres du profil des patients, a fin de proposer des critères plus spécifiques pour disjoindre le profil clinique de langage entre la DFT et la MA.La présente thèse sera réalisée en co-tutelle entre l’hôpital San Ignacio / Pontificia Universidad Javeriana et l’Université Lumière-Lyon2. Ce projet poursuit trois objectifs : (i) recueillir des données psycholinguistiques et de langage (tenant compte des années de scolarité et la sévérité du cours de la maladie), (ii) étudier et isoler les variantes linguistiques, qui peuvent influencer erronément la différence des critères de diagnostique entre la DFT et MA; (iii) raffiner les critères de diagnostique de la DFT et MA. 75 sujets ont été évalués (FTD n = 63, AD = 12, 22 sujets contrôles). Le test d'afastie (BAT) (Paradis 1989) a été utilisé pour identifier la discrimination auditive, la compréhension des structures syntaxiques (auditive et lecture), la production de phrases, la compréhension des narrations, la lecture de phrases, ainsi qu'une analyse des erreurs selon la structure syntaxique. En outre, nous évaluons les fonctions exécutives et les tests cognitifs de base. Les échantillons de parole spontanée ont été transcrits en utilisant le format CHAT et analysés à l'aide des programmes CLAN. En adition aux analyses descriptives, une analyse de proximité des distances euclidiennes au carré a été effectuée ainsi que des corrélations et régréssions.Les résultats montrent que patients atteints de PPA ont eu la pire performance dans la plupart des tâches langagières. Les DFTvf montrent une bonne peormance pour les tâches standardisées, mais montrent des difficultées isolées pour la compréhension de structures syntaxiques de type négatif qui peut s’associer à l'incapacité de représenter une séquence temporelle de la phrase. Les résultats démontrent que le discours spontané nous permet de différencier tous les groupes de patients. Le discours de ces patients peut être distinctif et reflète non seulement les capacités linguistiques du sujet, mais aussi les autres fonctions cognitives. Même si la théorie différencie les groupes PPA selon leur fluence, les résultats montrent qu’avec les variables qui portent sur la fluence de la parole qu'il n'est pas possible de différencier la variante non fluente et la logopénique. D'autres variables telles que les erreurs et la grammaire doivent être incluses dans les analyses pour obtenir le diagnostic différentiel des variantes de la APP. La parole spontanée démontre être un outil inestimable dans la pratique quotidienne du clinicien pour les diagnostics précoces et les critères pour un diagnostic différentiel entre la MA et la DFT – et ces trois variantes-. / Even though the large majority of cortical dementia is of the Alzheimer’s disease type, there are differential diagnosis limitations of current diagnostic criteria for early-onset Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD, all three variants: behavioural variant frontotemporal –FTDbv-, Primary progressive aphasia –PPA- and semantic dementia –SD-). Initially, either AD and FTD share cognitive declines and first complain includes memory and no language in FTLD or language and no memory in AD. For instance, word retrieval deficits are common in AD and are thought to reflect a degradation of semantic memory. Yet, the nature of semantic deterioration in AD and the underlying neural correlates of these semantic memory changes remain largely unknown (Wierenga, 2011). On the other hand, PPA, FTDbv and SD have, as well, common behavioural features: PPA, prior to word loss, may show apathy and semantic dementia patients have, long before, the pure meaning loss, a great decline on emotional and conduct process. Since new guidelines for the differential diagnosis of behavioural FTD (Raskovsky, 2011) and selective language features –nonfluent/agrammatic, semantic, syntax, narrative - of the language variants are being revised (Gorno-Tempini, 2011) the present project present a novel way to define criteria regarding cognition profile through language analysis in all: AD and FTDL all variants. In sum, isolation of pure clinical characteristics in order to enriched the clinic profile and subtract the pure linguistic features will facilitate better common clinical compromise besides language differences (Zanini et al. 2011, Hernández et al. 2011, Ardila& Ramos, 2008). The present study aims to study through the Javeriana University Memory Clinic (PUJMC) at the San Ignacio Hospital in Colombia, based on the experience in the last 14 years where almost 3000 patients have been studied, language semiology between AD, FDT – all three variants. This project has three objectives: (i) to collect psycholinguistic and language data (taking into account the years of schooling and the severity of the course of the disease), (ii) study and isolate linguistic variants that may erroneously influence the difference in diagnostic criteria between DFT and MA; (iii) refining the diagnostic criteria for FTD and MA. 75 subjects were assessed (FTD n= 63, AD= 12, 22 control sample subjects). Bilingual Aphasia Test (BAT) (Paradis 1989) was used in order to identify auditory discrimination, syntactic structures comprehension (auditory and by reading), sentences production, auditory and by reading, comprehension of narrative structures, sentences reading, as well as an analysis of errors according to the syntactic structure. Additionally, we assess executive functions and basic cognition battery. Spontaneous speech samples were transcribed using the CHAT format, and analysed using the CLAN programs Besides a descriptive analysis, a hierarchical clustering through a squared Euclidean distances was done, where patients groups were formed by similar clinical neighbors regardless the FTD variant. Results show that deep language analysis is useful when heterogeneity w/groups is present and depends (in all groups) on the disease stage. PPA patients had the worse performance. bvFTD executive passive structure difficulty is associated with executive functions: The inability to represent a temporal sequence of the phrase –not understanding if.. Then). Results demonstrate that spontaneous speech allow us to differentiate between all groups of patients. Discourse of these patients can be distinctive and it reflects not only the subject's linguistic abilities but other cognitive functions as well....

abstract: Alzheimer’s Disease (AD) and Frontotemporal Dementia (FTD) are the leading causes of early onset dementia. There are currently no ways to slow down progression, to prevent or cure AD and FTD. Both AD and FTD share a lot of the symptoms and pathology. Initial symptoms such as confusion, memory loss, mood swings and behavioral changes are common in both these dementia subtypes. Neurofibrillary tau tangles and intraneuronal aggregates of TAR DNA Binding Protein 43 (TDP-43) are also observed in both AD and FTD. Hence, FTD cases are often misdiagnosed as AD due to a lack of accurate diagnostics. Prior to the formation of tau tangles and TDP-43 aggregates, tau and TDP-43 exist as intermediate protein variants which correlate with cognitive decline and progression of these neurodegenerative diseases. Effective diagnostic and therapeutic agents would selectively recognize these toxic, disease-specific variants. Antibodies or antibody fragments such as single chain antibody variable domain fragments (scFvs), with their diverse binding capabilities, can aid in developing reagents that can selectively bind these protein variants. A combination of phage display library and Atomic Force Microscopy (AFM)-based panning was employed to identify antibody fragments against immunoprecipitated tau and immunoprecipitated TDP-43 from human postmortem AD and FTD brain tissue respectively. Five anti-TDP scFvs and five anti-tau scFvs were selected for characterization by Enzyme Linked Immunosorbent Assays (ELISAs) and Immunohistochemistry (IHC). The panel of scFvs, together, were able to identify distinct protein variants present in AD but not in FTD, and vice versa. Generating protein variant profiles for individuals, using the panel of scFvs, aids in developing targeted diagnostic and therapeutic plans, gearing towards personalized medicine. / Dissertation/Thesis / Doctoral Dissertation Neuroscience 2018