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Semantic Dementia (semantic + dementia)
Selected AbstractsMolecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia,HUMAN MUTATION, Issue 4 2008Odity Mukherjee Abstract Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by the presence of two major phenotypes: 1) behavioral and personality disorder, and 2) language disorder, which includes primary progressive aphasia and semantic dementia. Recently, the gene for familial frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) linked to chromosome 17 was cloned. In the present study, 62 unrelated patients from the Washington University Alzheimer's Disease Research Center and the Midwest Consortium for FTD with clinically diagnosed FTD and/or neuropathologically characterized cases of FTLD-U with or without motor neuron disease (MND) were screened for mutations in the progranulin gene (GRN; also PGRN). We discovered two pathogenic mutations in four families: 1) a single-base substitution within the 3, splice acceptor site of intron 6/exon 7 (g.5913A>G [IVS6,2A>G]) causing skipping of exon 7 and premature termination of the coding sequence (PTC); and 2) a missense mutation in exon 1 (g.4068C>A) introducing a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (p.A9D). Functional analysis in mutation carriers for the splice acceptor site mutation revealed a 50% decrease in GRN mRNA and protein levels, supporting haploinsufficiency. In contrast, there was no significant difference in the total GRN mRNA between cases and controls carrying the p.A9D mutation. Further, subcellular fractionation and confocal microscopy indicate that although the mutant protein is expressed, it is not secreted, and appears to be trapped within an intracellular compartment, possibly resulting in a functional haploinsufficiency. Hum Mutat 29(4), 512,521, 2008. © 2008 Wiley-Liss, Inc. [source] Language Processing in Frontotemporal Dementia: A Brief ReviewLINGUISTICS & LANGUAGE COMPASS (ELECTRONIC), Issue 1 2008Jonathan E. Peelle Frontotemporal dementia (FTD) is a neurodegenerative condition that presents with a number of distinct behavioral phenotypes. Here we review language-processing deficits in three subgroups of FTD patients: progressive nonfluent aphasia (PNFA), semantic dementia (SD), and nonaphasic FTD patients with a disorder of social and executive functioning (SOC/EXEC). These three clinical subgroups have contrasting patterns of regional cortical atrophy that can be linked to their language impairments. PNFA patients' disease includes left ventral inferior frontal cortex, resulting in impaired grammatical processing. SD patients demonstrate a profound impairment for semantic knowledge related to atrophy of the left temporal lobe. SOC/EXEC patients' frontal atrophy tends to be more right lateralized and is associated with declines in executive functioning. SOC/EXEC patients' limited executive resources impact language processing in a variety of ways, including slowed grammatical processing and impaired narrative discourse. FTD patients therefore provide converging evidence regarding dissociable components of language processing and their neuroanatomical bases. [source] Clinical concept of frontotemporal dementiaNEUROPATHOLOGY, Issue 1 2000Hirotaka Tanabe The clinical concept of frontotemporal dementia is reviewed by discussing its relationships to several related concepts. These include dementia of the frontal lobe type, slowly progressive aphasia without dementia or primary progressive aphasia, semantic dementia and frontotemporal lobar degeneration. A number of examples of confusion in the terminology are also examined. [source] The neuropathology of frontotemporal lobar degeneration with respect to the cytological and biochemical characteristics of tau proteinNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 1 2004S. Taniguchi Pathological examinations, using a panel of tau and other antibodies, were performed on the brains from 55 consecutively acquired cases of frontotemporal lobar degeneration (FTLD). Clinically, these comprised 31 cases of frontotemporal dementia (FTD), 10 cases of motor neurone disease inclusion dementia (MNDID), seven cases of progressive aphasia (PA), four cases of semantic dementia (SD) and three cases of progressive apraxia (PAX). Tau pathology, in the form of neurofibrillary tangles (NFTs) and glial cell tangles, was present in six cases of FTD with parkinsonism linked to chromosome 17, five of these cases resulting from +16 splice-site mutation and one from +13 mutation in the tau gene. The insoluble tau proteins were comprised mostly of four-repeat (4-R) isoforms. Eight other cases of FTD, one of PA and all three cases of PAX showed tau-positive inclusions (Pick bodies) and swollen cells (Pick cells), characteristic of Pick's disease. In these cases, the insoluble tau proteins were present in most instances as three-repeat (3-R) tau isoforms, although two cases with a mixture of 3-R and 4-R isoforms were seen. One other case of FTD showed an unusual pathology characterized by massive extracellular deposition of tau protein, composed of 4-R tau isoforms, within white matter without neuronal or glial cell inclusions. However, 33 (60%) of 55 FTLD cases showed no tau pathology in the brain, except for the rare NFTs, composed of a mix of 3-R and 4-R isoforms, in some of the more elderly cases. Of these 33 cases, 13 had FTD, 10 had MNDID, six had PA and four had SD. The pathological changes present were those of a superficial cortical laminar microvacuolation with mild subpial and subcortical gliosis; the 10 MNDID cases had ubiquitin-positive inclusions in the cerebral cortex and hippocampus. These 33 nontau FTLD cases, along with five Alzheimer's disease (AD) and six Huntington's disease (HD) cases with severe pathology, showed a variable loss of soluble tau proteins, broadly comparable with the extent of neuronal loss from the cortex and loss of the intracortical perikaryal marker, NeuN, but unrelated to proteins within afferent projection fibres such as neurofilament and ,-synuclein. Levels of tau mRNA were decreased in parallel in the tau-negative FTLD cases and in the severe AD and HD cases. Hence, the loss of tau from these 33 nontau FTLD cases is just one aspect of a neurodegenerative process that destroys many components of the nerve cell machinery and does not represent a specific disordering of the cell's ability to form tau proteins or incorporate these into microtubules. [source] TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration,ANNALS OF NEUROLOGY, Issue 4 2009Lina Benajiba MS TDP-43 (TAR-DNA binding protein) aggregates in neuronal inclusions in motoneuron disease (MND), as well as in frontotemporal lobar degeneration (FTLD) and FTLD associated with MND (FTLD-MND). Mutations in TARDBP gene, coding for TDP-43, were found in patients with pure MND. We now describe TARDBP mutations in two patients with FTLD-MND, presenting with a behavioral variant of FTLD and semantic dementia, suggesting that TDP-43 may also have a direct pathogenic role in FTLD disorders. Ann Neurol 2009;65:470,474 [source] A, amyloid and glucose metabolism in three variants of primary progressive aphasiaANNALS OF NEUROLOGY, Issue 4 2008Gil D. Rabinovici MD Objective Alzheimer's disease (AD) is found at autopsy in up to one third of patients with primary progressive aphasia (PPA), but clinical features that predict AD pathology in PPA are not well defined. We studied the relationships between language presentation, A, amyloidosis, and glucose metabolism in three PPA variants using [11C]-Pittsburgh compound B ([11C]PIB) and [18F]-labeled fluorodeoxyglucose positron emission tomography ([18F]FDG-PET). Methods Patients meeting PPA criteria (N = 15) were classified as logopenic aphasia (LPA), progressive nonfluent aphasia (PNFA), or semantic dementia (SD) based on language testing. [11C]PIB distribution volume ratios were calculated using Logan graphical analysis (cerebellar reference). [18F]FDG images were normalized to pons. Partial volume correction was applied. Results Elevated cortical PIB (by visual inspection) was more common in LPA (4/4 patients) than in PNFA (1/6) and SD (1/5) (p < 0.02). In PIB-positive PPA, PIB uptake was diffuse and indistinguishable from the pattern in matched AD patients (n = 10). FDG patterns were focal and varied by PPA subtype, with left temporoparietal hypometabolism in LPA, left frontal hypometabolism in PNFA, and left anterior temporal hypometabolism in SD. FDG uptake was significant asymmetric (favoring left hypometabolism) in PPA (p < 0.005) but not in AD. Interpretation LPA is associated with A, amyloidosis, suggesting that subclassification of PPA based on language features can help predict the likelihood of AD pathology. Language phenotype in PPA is closely related to metabolic changes that are focal and anatomically distinct between subtypes, but not to amyloid deposition patterns that are diffuse and similar to AD. Ann Neurol 2008 [source] | ||||||||||