Orbitofrontal metabolic impairment is characteristic of the frontal variant of frontotemporal dementia (fv-FTD), as are early changes in emotional and social conduct. Two main types of behavioral disturbances have been distinguished in fv-FTD patients: apathetic and disinhibited manifestations. In this study, we searched for relationships between brain metabolism and presence of apathetic or disinhibited behavior. Metabolic activity and behavioral data were collected in 41 fv-FTD patients from European PET centers. A conjunction analysis of the PET data showed an expected impairment of metabolic activity in the anterior cingulate, ventromedial and orbital prefrontal cortex, the dorsolateral prefrontal cortex and the left anterior insula in fv-FTD subjects compared to matched controls. A correlation was observed between disinhibition scores on the Neuropsychiatric Inventory scale and a cluster of voxels located in the posterior orbitofrontal cortex (6, 28, –24). Comparison of brain activity between apathetic and nonapathetic fv-FTD patients from two centers also revealed a specific involvement of the posterior orbitofrontal cortex in apathetic subjects (4, 22, –22). The results confirm that the main cerebral metabolic impairment in fv-FTD patients affects areas specializing in emotional evaluation and demonstrate that decreased orbitofrontal activity is related to both disinhibited and apathetic syndromes in fv-FTD. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Doctor of Clinical Psychology / Obsessive-compulsive (OC) symptoms occur in a variety of clinical conditions, but the underlying pathogenesis of these symptoms remains elusive. Few neuropsychological investigations have compared idiopathic Obsessive-Compulsive Disorder (OCD) with patient groups where OC symptoms are acquired. The present study investigated the neuropsychological correlates of OC symptoms in OCD and frontotemporal dementia (FTD), a neurodegenerative illness in which OC symptoms are often acquired. Neuroimaging in OCD has consistently implicated the frontal-striatal-thalamic circuit, particularly the orbitofrontal cortex and basal ganglia. These areas overlap considerably with the sites of cerebral pathology found in FTD. OCD has been associated with a number of neuropsychological deficits, with most consistent findings pointing towards impaired executive function (EF), and less commonly reported deficits in visual memory and visuospatial ability. The neuropsychological hallmark of FTD is deficits in EF. However in both OCD and FTD, the relationship between cognitive deficits and OC symptoms remains unclear. Further, the extent to which OC symptoms are comparable between the groups is ambiguous. Part I of the present study compared 19 OCD subjects to 20 age, education and IQ-matched healthy controls on a battery of neuropsychological tests of all major cognitive domains with emphasis on EF. A measure of Theory of Mind (ToM) thought to be sensitive to orbitofrontal function was also administered. OCD subjects performed worse than controls on a measure of visual memory, visuospatial reasoning and on only one measure of EF. OCD symptom subtypes, as measured by the Obsessive-Compulsive Inventory (OCI), were not correlated with any cognitive deficits. No group differences in ToM were found. It is suggested that prior research has overestimated the severity and significance of EF deficits in OCD. Part II of the study compared 9 FTD participants with 10 matched healthy controls on the same neuropsychological test battery and OC symptom measures. In addition, a measure of compulsive behaviours used in neurological populations was administered to carers. While the incidence of OC symptoms was comparable to reports in previous studies (78%), the OCI was not sensitive in the detection of OC symptoms in FTD. The similarities and differences in OC symptoms between the two patient groups are discussed.

Submitted by Cláudia Bueno (claudiamoura18@gmail.com) on 2015-11-18T18:39:05Z No. of bitstreams: 2 Dissertação - Cândida Dias Soares - 2010.pdf: 1198463 bytes, checksum: acc22e0252670b4f6969e526efca18eb (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2015-11-19T14:26:37Z (GMT) No. of bitstreams: 2 Dissertação - Cândida Dias Soares - 2010.pdf: 1198463 bytes, checksum: acc22e0252670b4f6969e526efca18eb (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2015-11-19T14:26:37Z (GMT). No. of bitstreams: 2 Dissertação - Cândida Dias Soares - 2010.pdf: 1198463 bytes, checksum: acc22e0252670b4f6969e526efca18eb (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2010-09-14 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The national surveys of dementia and its implications for language, although in small numbers, line up with the international literature in the early trends of research. The articles presented were intended to draw a profile comparison between the differential Neurolinguistics degenerative dementia of Alzheimer type and non-Alzheimer's and dementia compare the two groups with a control group. The study was conducted from March 2008 to December 2009 were evaluated in 90 participants in the Dementia Clinic of the Hospital das Clinicas, Federal University of Goias The sample consisted of 30 patients with frontotemporal lobar degeneration (DLF), 30 patients with AD and 30 subjects with no dementia. We applied the following tests neurolinguistic: Boston Diagnostic Aphasia Examination (BDAE), Boston Naming Test (Boston Naming Test - BNT), Verbal Fluency Category for Semantics and Semantic and Phonemic Fluency (FAS), Token Test, subtest of Vocabulary / WAIS-R Similarities subtest of and / WAIS-R. To compare the performance of the group used the Mann-Whitney. All groups showed substantial linguistic differences. The APP group stood out from the other groups when compared to DA, showing that fluency, vocabulary, abstraction of ideas, understanding, reading and writing are more impaired. The FTD group reinforced the presence of dysfunction in semantic and phonemic verbal fluency DS group showed a statistically significant abstractive capacity with respect to the AD group. The DLF group is the group where the oral expression was shown to be noticeably compromised compared to the AD group. The language is therefore an indispensable tool to aid in the differential diagnosis of dementia. / As investigações nacionais das demências e suas implicações na linguagem, embora ainda em pequeno número, alinham-se com a literatura internacional, nas primeiras tendências de investigação. Os artigos apresentados tiveram como objetivo traçar um perfil diferencial neurolinguístico comparativo entre as demências degenerativas do tipo Alzheimer e não Alzheimer e comparar os dois grupos demenciais com um grupo controle. Foi realizado o estudo no período de março de 2008 a dezembro de 2009 em que foram avaliados 90 participantes do Ambulatório de Demências do Hospital das Clínicas da Universidade Federal de Goiás. A amostra foi constituída por 30 pacientes com Degenerações Lobares Frontotemporais (DLF); 30 pacientes com DA e 30 indivíduos com ausência de demência. Foram aplicados os seguintes testes neurolinguísticos: Teste de Boston para Diagnóstico da Afasia (BDAE), Teste de Nomeação de Boston (Boston Naming Test – BNT), Fluência Verbal por Categoria Semântica e Fluência Fonêmica e Semântica (F.A.S.),Token Test, Subteste de Vocabulário / WAIS-R e Subteste de Semelhanças / WAIS-R. Para comparar o desempenho dos grupo utilizou-se o teste de Mann-Whitney. Todos os grupos avaliados mostraram diferenças lingüísticas significativas. O grupo APP destacou-se dos demais grupos quando comparado ao grupo DA, demonstrando que a fluência, o vocabulário, a abstração de idéias, a compreensão, a leitura e a escrita encontram-se mais comprometidas. O grupo DFT reforçou a presença da disfunção na fluência verbal fonêmica semântica e o grupo DS demonstrou significância estatística na capacidade abstrativa com relação ao grupo DA. O grupo DLF foi o grupo em que a expressão oral mostrou-se visivelmente mais comprometida comparada ao grupo DA. A linguagem é, portanto, um instrumento indispensável para auxiliar no diagnóstico diferencial das demências.

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2017-03-27T13:27:24Z No. of bitstreams: 2 Dissertação - Marilda Aparecida do Nascimento Souza - 2016.pdf: 2356436 bytes, checksum: a957e23bb1a3bdd13c4601abcd76f854 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2017-03-27T13:28:08Z (GMT) No. of bitstreams: 2 Dissertação - Marilda Aparecida do Nascimento Souza - 2016.pdf: 2356436 bytes, checksum: a957e23bb1a3bdd13c4601abcd76f854 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-03-27T13:28:08Z (GMT). No. of bitstreams: 2 Dissertação - Marilda Aparecida do Nascimento Souza - 2016.pdf: 2356436 bytes, checksum: a957e23bb1a3bdd13c4601abcd76f854 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2016-08-12 / INTRODUCTION: The main risks factors of dementia are: aging, medical comorbidities and genetic risk. Genetic factors are very important in the investigation of dementia. A positive family history and genetic factors associated can influence the age of onset of the disease. OBJECTIVES: To investigate the prevalence of family history in dementiating degenerative syndromes. To analyze the cognitive and functional performance of these patients to determine whether the positive FH is related to the early onset of the disease, to assess the prevalence of positive FH by dementia subtype, to compare the profile sociodemographic patients with degenerative dementia with family history and no family history and observe which group had more severe dementia. METHODS: This is a cross-sectional study, conducted in the memory clinic of a university hospital in Central Brazil . Were assigned 483 patients with a diagnosis of dementia, from May 2015 to May 2016. This study evaluated the sociodemographic variables, pre- existing diseases and FH of dementia, through a semi-structured interview. To analyze the cognitive level and functional capacity was used the Mini-mental state examination - MMSE and Pfeffer Questionnaire. The Clinical Dementia Rating - CDR was used to assess the severity of dementia. RESULTS: Of the 483 selected participants, 63.8% were women; the average age at evaluation was 74 years, most with low education (32.7%). We found that 45.5% of patients have an affected relative, mostly among simblings, and the age of onset of dementia is lower in people who have positive HF. Positive FH was greater in Huntington's disease 88.8%, followed by Semantic Dementia (66.7%) and primary progressive aphasia (66.7%). CONCLUSION: Family history proved very common in all types of dementia in our sample, mainly in Huntington's disease, followed by frontotemporal lobar degenerations. / INTRODUÇÃO: Entre os riscos para o surgimento das demências estão o envelhecimento, as comorbidades médicas e o risco genético. Fatores genéticos são muito relevantes na investigação das síndromes demenciais. História familiar (HF) positiva e fatores genéticos associados podem influenciar a idade de início da demência. OBJETIVOS: Investigar a prevalência de história familiar em síndromes degenerativas demenciantes; analisar o desempenho cognitivo e funcional desses pacientes; verificar se a HF positiva está relacionada com o inicio precoce da doença; avaliar a prevalência de HF positiva por subtipo de demência; comparar o perfil sociodemográfico de pacientes com demência degenerativa com HF e sem HF e verificar em qual grupo a demência foi mais grave. MÉTODOS: Trata-se de um estudo transversal, realizado no ambulatório de transtornos cognitivos de um hospital universitário, no Brasil Central, realizado em 483 pacientes com o diagnóstico de Demência, no período de maio de 2015 a maio de 2016. Foram avaliadas as variáveis sociodemográficas, as doenças pré-existentes e HF de demência, através de uma entrevista semiestruturada. Para análise do estado cognitivo e da capacidade funcional foram utilizados o Mini Exame do Estado Mental – MEEM e o questionário de atividades funcionais de Pfeffer. O Clinical Dementia Rating – CDR foi utilizado para verificar a gravidade da demência. RESULTADOS: Dos 483 participantes selecionados, 63,8% eram mulheres, com aproximadamente 74 anos, a maioria (32,7%) com baixíssima escolaridade. Do total de pacientes entrevistados, 45,5% possuem um familiar com a mesma doença, sendo o irmão o que mais apresentou alterações cognitivas semelhantes às do entrevistado. A idade de início da demência é menor em pessoas que possuem HF positiva. Entre os tipos de demências mais prevalentes, relacionadas à HF, foram identificadas a doença de Huntington (88,8%), seguida pela Demência Semântica (66,7%) e Afasia Primária Progressiva (66,7%). CONCLUSÃO: A HF positiva mostrou-se frequente nos casos de demência nesta amostra. O tipo de demência que mais apresentou essa herdabilidade foi a Doença de Huntington, seguida pelas degenerações lobares frontotemporais.

No description available.

Le terme dégénérescence lobaire frontotemporale ou FTLD définit un groupe hétérogène de maladies neurodégénératives caractérisé par des troubles du langage, du comportement et/ou moteurs qui résultent principalement d’une dégénérescence du cortex frontal et temporal. Cette hétérogénéité tant au niveau clinique, génétique que neuropathologique rend cette pathologie très complexe et il existe aujourd’hui un véritable problème de diagnostic différentiel des FTLD. Le diagnostic final des FTLD repose ainsi sur l’examen neuropathologique, la nature des lésions observées et leurs constituants moléculaires. La caractérisation de ces lésions a permis d’établir une classification des FTLD qui ne cesse d’évoluer avec la découverte de nouveaux acteurs moléculaires. À l’instar de nombreuses maladies neurodégénératives, les FTLD sont caractérisées par la présence de protéines agrégées dans les régions cérébrales affectées. Cependant, contrairement à la maladie d’Alzheimer (MA), ces agrégats ne sont pas toujours constitués des mêmes protéines. Ainsi, approximativement 40% des cas de FTLD présentent des agrégats composés de protéines Tau hyper et anormalement phosphorylées, et forment le groupe FTLD-Tau. Lorsqu’aucune pathologie Tau n’est détectée, les patients présentent généralement des inclusions neuronales cytoplasmiques ou intranucléaires immunoréactives pour la protéine TDP-43 (transactive response DNA binding protein 43), et constituent la sous-classe FTLD-TDP. Plus rarement, la protéine FUS (Fused in Sarcoma, FTLD-FUS) ou des protéines liées au système ubiquitine protéasome peuvent également s’agréger (FTLD-UPS). La génétique représente également une composante majeure des FTLD avec 10 à 15% des cas correspondant à des formes héréditaires dominantes. Les premières mutations furent découvertes sur le gène MAPT. Le gène de la progranuline (GRN) fut ensuite identifié comme fréquemment associé aux FTLD. Plus récemment, une répétition anormale d’héxanucléotides GGGGCC au sein du gène C9ORF72 (chromosome 9 open reading frame 72) a été montrée comme étant responsable d’un grand nombre de cas familiaux de FTLD. De manière moins fréquente, d’autres gènes tels que VCP (valosin containing protein) ou CHMP2B (charged multivesicular body protein 2B) peuvent aussi être associés à des cas familiaux de FTLD. Des années avant la découverte des principaux acteurs moléculaires des FTLD, des études ont décrit une perte partielle ou totale des protéines Tau physiologiques dans le tissu cérébral. A l’origine, ce phénomène fut observé dans un groupe de démences appelées DLDH pour démences sans signe histopathologique distinctif (plus tard appelé FTLD-ni pour no inclusion). En 2006, la majorité de ces cas a été reclassée en tant que FTLD-U (présence de lésions immunoréactives pour l’ubiquitine). En revanche, aucune étude ne s’est intéressée à cette perte de Tau depuis celle de Zhukareva et collègues en 2003. Au regard des récentes avancées sur la compréhension de la base moléculaire et génétique des FTLD, la pertinence de cette perte de Tau reste ainsi encore à déterminer. Dans ce contexte, ce travail de recherche a pour principal objectif d’étudier l’expression des protéines Tau au sein du tissu cérébral d’individus sains ou atteints de différents troubles neurodégénératifs (MA, FTLD-Tau, FTLD-TDP-GRN, FTLD-TDP-C9ORF72, FTLD-TDP et FTLD-FUS sporadiques) en utilisant la technique d’immunoempreinte. De manière remarquable, nous avons mis en évidence une réduction significative de Tau, et ce, spécifiquement chez les patients FTLD-TDP-GRN. Ainsi, nos résultats démontrent que ces cas, appelés FTLD-TDP-GRNltau (pour low Tau protein level), caractérisés par une altération synaptique et une astrogliose très importante, pourraient constituer un groupe distinct dans la classification des FTLD [...] / FTLD is a clinical syndrome mainly characterized by progressive deterioration in behavior, personality and/or language resulting from progressive frontal and temporal degeneration. In addition, movement disorder can also be frequently observed. Given this phenotype variability, FTLD clinical diagnosis remains difficult and uneasy to establish with certainty.The final diagnosis relies on neuropathological examination of the brain, the characteristics of these brain lesions and their molecular basis. Indeed, as many neurodegenerative diseases, FTLD are characterized by the presence of protein aggregates in the affected brain regions. However, in contrast to the well-characterized nature of protein inclusions in Alzheimer’s disease (AD), proteinaceous aggregates in FTLD can be composed of different proteins. Thus, approximatively 40% of FTLD cases display aggregates made of abnormally and hyperphosphorylated Tau proteins and constitute the FTLD-Tau subclass. However, most of FTLD brains are negative for Tau inclusions and exhibit neuronal cytoplasmic and/or nuclear inclusions immunoreactive for transactive response DNA binding protein 43 (TDP-43) and constitute the FTLD-TDP subclass). To a lesser extent, another protein called FUS (Fused in Sarcoma protein) is found in aggregates that are Tau and TDP-43 negative. This subclass is thus named FTLD-FUS. Finally, inclusions negative for Tau, TDP-43 or FUS are observed in rare cases of FTLD and associated with ubiquitin-proteasome system related proteins (FTLD-UPS).Gene mutations also play an important role in FTLD with 30 to 50% of patients reporting a positive family history of FTD and 10 to 15% of patients corresponding to dominantly inherited form. Firstly described are the MAPT mutations. Mutations in the progranulin gene GRN were then found to be the most frequent mutations associated with FTLD. More recently, two studies demonstrated that expanded hexanucleotide GGGGCC repeats in a noncoding region of the chromosome 9 open reading frame 72 (C9ORF72) gene was responsible for a large proportion of FTLD. Less frequently mutations in the valosin containing protein (VCP) gene or charged multivesicular body protein 2B (CHMP2B) gene are also found associated with FTLD.Prior to the discovery of the main molecular actors of FTLD, studies described a partial or total loss of soluble or physiological Tau protein expression in both grey and white matter. This loss of Tau was originally found in a subset of dementia called DLDH for Dementia Lacking Distinctive Histopathology (renamed later FTLD-ni for FTLD with no inclusion). In 2006, most of these cases were reclassified as FTLD-U (presenting with ubiquitin positive inclusions). However, additional investigation with specific regards to this loss of Tau expression has not been reported since Zhukareva et al. in 2003. With the progress in genetics and neuropathology of FTLD, the question of whether this reduction of Tau expression is seldom remains ill-defined.This work takes place in this context whose primary goal was to investigate human brain Tau protein expression in Control, AD, FTLD-Tau, FTLD-TDP-GRN, FTLD-TDP-C9ORF72, sporadic FTLD-TDP and sporadic FTLD-FUS brains using western blot analysis. Remarkably, we demonstrated a huge reduction of all six human brain Tau isoforms only in a subset of FTLD-TDP brains with mutation on the GRN gene. Thus, our data clearly suggest that these specific cases, referred to as FTLD-TDP-GRNltau (for low levels of Tau protein), could be part of the current classification as a distinct entity with more severe synaptic dysfunction and astrogliosis. Beside this, we also performed a comparative proteomic study between the different FTLD sub-classes in order to find common physiopathological mechanisms.

Abstract Frontotemporal lobar degeneration (FTLD) is the second most common neurodegenerative disease leading to early-onset dementia with an estimated worldwide prevalence of 10 to 30 cases per 100000 individuals in the age group of 46 to 65 years. Behavioral variant frontotemporal dementia (bvFTD) is the most common FTLD subtype. It is characterized by a progressive deterioration of behavior and personality as well as executive dysfunction. In Finland, almost 50 % of familial FTLD cases are attributable to the C9ORF72 mutation. bvFTD is associated with a characteristic pattern of brain atrophy detectable in structural MRI. However, these changes are typically not visible in the early stages of the disease. Resting-state functional MRI (RS-fMRI) is being increasingly used to evaluate changes in functional connectivity within neuronal networks in the brain but only a few RS-fMRI investigations of bvFTD patients have been published with inconsistent results. The object of this thesis was to investigate functional connectivity changes detected in the salience (SLN) and default mode networks (DMN) in bvFTD. Another aim was to clarify the role of other cognitive resting-state networks in this disease. A cohort of 26 bvFTD patients was studied, with 8 of these patients carrying the C9ORF72 expansion. Connectivity changes were detected in multiple clinically relevant cognitive networks. Decreased functional connectivity was observed in the SLN, which is associated with guiding of behavior. Increased activity was present in the DMN and the dorsal attention network (DAN). In C9ORF72 associated bvFTD, there was an abnormal linkage detected between the DMN and the thalamus. Currently, fMRI is generally used as a research tool and in a group setting. Different study methods have been used in the literature and also in the studies of this thesis, the analysis procedures differed to some extent. The variety of analysis methods may explain the heterogeneity in fMRI findings in bvFTD patients. There is a need for standardization of the fMRI methodology, larger study groups and also in the future the methodology should be improved so that single patient analysis would provide results to allow a confident diagnosis of this disease. / Tiivistelmä Otsa-ohimolohkorappeuma (Frontotemporal lobar degeneration, FTLD) on toiseksi yleisin etenevä dementiaan johtava sairaus, joka ilmaantuu usein jo työikäisenä. Otsalohkodementia on otsa-ohimolohkorappeuman yleisin alamuoto, jonka oireisto painottuu persoonan ja käyttäytymisen muutoksiin sekä toiminnan ohjauksen ongelmiin. Suomessa C9ORF72-toistojaksomutaatio selittää lähes 50 % perinnöllisistä otsa-ohimolohkorappeumista. Aivojen rakenteellisella magneettikuvauksella (MK) voidaan havaita rakenteellisia muutoksia, jotka ilmaantuvat kuitenkin vasta taudin edettyä vaikeampaan vaiheeseen. Aivojen lepotilan toiminnallinen magneettikuvaus (TMK) mahdollistaa aivojen hermoverkkojen toiminnan eli konnektiviteetin kartoituksen. Aiemmin TMK:a on tutkittu esim. Alzheimerin taudissa. Otsalohkodementiassa TMK:sta on julkaistu ainoastaan yksittäisiä tutkimuksia ja tulokset ovat olleet osin ristiriitaisia. Väitöskirjatutkimuksen tarkoituksena on ollut selvittää valve-lepotilan hermoverkossa ja olennaisen tunnistavassa hermoverkossa tapahtuvia muutoksia otsalohkodementiaa sairastavilla potilailla. Toisena tavoitteena on ollut tutkia muissa kognitiivisissa hermoverkoissa tapahtuvia muutoksia. Otsalohkodementiaa sairastaville potilaille (n= 26) sekä ikä- ja sukupuolivakioiduille kontrolleille on tehty kliininen tutkimus ja rakenteellinen sekä toiminnallinen aivojen magneettikuvaus. Kahdeksalla potilaalla todettiin C9ORF72-toistojaksomutaatio. Useiden kognitiivisten hermoverkkojen toiminnassa havaittiin muutoksia, jotka korreloivat potilaiden kliinisiin oireisiin. Alentunutta konnektiviteettia todettiin olennaisen tunnistavassa hermoverkossa, joka osallistuu käyttäytymisen säätelyyn. Lisääntynyttä konnektiviteettia esiintyi valve-lepotilan hermoverkossa ja tarkkaavaisuus hermoverkossa. Potilailla, joilla on C9ORF72-mutaatio, havaittiin epänormaali yhteys valve-lepotilan hermoverkon ja talamuksen välillä. TMK:ta käytetään tällä hetkellä lähinnä tutkimustyökaluna. Analyysityökaluissa on ollut vaihtelevuutta eri julkaisuissa ja osin myös tämän väitöskirjan osatöissä. Julkaistut TMK-löydökset otsalohkodementiassa ovat osin ristiriitaisia ja se saattaa selittyä erilaisilla analyysimenetelmillä. Metodologiaa tulisi standardisoida ja lisäksi tarvitaan suurempia potilasryhmiä ja menetelmien kehittämistä, jotta TMK:n käyttö yksilötason kliinisessä diagnostiikassa olisi jatkossa mahdollista.

Orbitofrontal metabolic impairment is characteristic of the frontal variant of frontotemporal dementia (fv-FTD), as are early changes in emotional and social conduct. Two main types of behavioral disturbances have been distinguished in fv-FTD patients: apathetic and disinhibited manifestations. In this study, we searched for relationships between brain metabolism and presence of apathetic or disinhibited behavior. Metabolic activity and behavioral data were collected in 41 fv-FTD patients from European PET centers. A conjunction analysis of the PET data showed an expected impairment of metabolic activity in the anterior cingulate, ventromedial and orbital prefrontal cortex, the dorsolateral prefrontal cortex and the left anterior insula in fv-FTD subjects compared to matched controls. A correlation was observed between disinhibition scores on the Neuropsychiatric Inventory scale and a cluster of voxels located in the posterior orbitofrontal cortex (6, 28, –24). Comparison of brain activity between apathetic and nonapathetic fv-FTD patients from two centers also revealed a specific involvement of the posterior orbitofrontal cortex in apathetic subjects (4, 22, –22). The results confirm that the main cerebral metabolic impairment in fv-FTD patients affects areas specializing in emotional evaluation and demonstrate that decreased orbitofrontal activity is related to both disinhibited and apathetic syndromes in fv-FTD. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Frontotemporal dementia (FTD) is the second most common early-onset dementia. A rare mutation in CHMP2B gene was found to be associated with FTD linked to chromosome 3. Previous studies have shown that mutant CHMP2B could lead to impaired autophagy pathway and altered RNA metabolism. However, it is still unknown what genes mediate the crosstalk between different pathways affected by mutant CHMP2B. Genetic screens designed to identify genes interacting with mutant CHMP2B represents a key approach in solving the puzzle. Expression of mutant CHMP2B (CHMP2Bintron5) in Drosophila eyes leads to a neurodegenerative phenotype including melanin deposition and disrupted internal structure of ommatidia. The phenotype is easily quantified by estimating the percentage of black dots on the surface of the eyes. Using this established Drosophila model, I searched for genes encoding RNA binding proteins that genetically modify CHMP2Bintron5 toxicity. I found that partial loss of Pumilio, a translation repressor, mitigates CHMP2Bintron5 induced toxicity in the fly eyes. Western blot analysis showed that down regulation of Pumilio does not significantly decrease CHMP2Bintron5 protein level, indicating indirect regulation involved in suppression of the phenotype. The molecular targets regulated by Pumilio and the mechanism underlying CHMP2Bintron5 toxicity suppression by Pumilio down-regulation requires further investigation.

The aim of this study is to investigate the neural mechanisms underlying the drawing of inferences based on a reader s knowledge during reading. Previous research studies have investigated this topic by using different types of text materials varying in coherence (e.g. Kuperberg et al., 2006), complexity (e.g. Xu et al., 2005), comprehensibility (e.g. Vandenberghe et al., 2002) or acceptability (e.g. Hagoort et al., 2004). Instead of using different types of text materials, we used a less explored method that manipulated the reader s reading goals to vary the level of engagement of inference processes. Cognitive psychologists have shown that the reader s reading goals have considerable influence on the cognitive processes of comprehension and on the content of the resulting representation of the text (Graesser et al., 1994). Here, two functional magnetic resonance imaging (fMRI) experiments were conducted to investigate the neural mechanisms of drawing strategic and routine inferences. The experimental data were analysed using two complementary approaches, namely conventional fMRI data analysis and effective connectivity analysis. Combined with an anatomical model developed in this study, the latter approach enabled us to quantify the interregional interactions modulated by the experimental conditions and to discriminate between several plausible hypotheses regarding how inferences are drawn. The results of both fMRI experiments show that the left inferior frontal gyrus (IFG) in Brodmann area (BA) 45/47 is involved in inference processes, regardless of whether inferences are drawn strategically or routinely, while the left anterior prefrontal cortex in BA 9/10 is only involved in retrieving strategic inferences. The effective connectivity analyses show that the retrieval of strategic and routine inferences consistently enhances the connectivity between the left posterior superior temporal sulcus and the left dorsal lateral IFG.