Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review
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TLDR
Recently, a new protein involved in familial ALS, fused in sarcoma (FUS), has been found in FTLD patients with ubiquitin-positive and TDP-43-negative inclusions.Abstract:
Frontotemporal dementia (FTD) is the second most common young-onset dementia and is clinically characterised by progressive behavioural change, executive dysfunction and language difficulties. Three clinical syndromes, behavioural variant FTD, semantic dementia and progressive non-fluent aphasia, form part of a clinicopathological spectrum named frontotemporal lobar degeneration (FTLD). The classical neuropsychological phenotype of FTD has been enriched by tests exploring Theory of Mind, social cognition and emotional processing. Imaging studies have detailed the patterns of atrophy associated with different clinical and pathological subtypes. These patterns offer some diagnostic utility, while measures of progression of atrophy may be of use in future trials. 30e50% of FTD is familial, and mutations in two genes, microtubule associated protein tau and Progranulin (GRN), account for about half of these cases. Rare defects in VCP, CHMP2B, TARDP and FUS genes have been found in a small number of families. Linkage to chromosome 9p13.2e21.3 has been established in familial FTD with motor neuron disease, although the causative gene is yet to be identified. Recent developments in the immunohistochemistry of FTLD, and also in amyotrophic lateral sclerosis (ALS), have led to a new pathological nomenclature. The two major groups are those with tau-positive inclusions (FTLD-tau) and those with ubiquitin-positive and TAR DNA-binding protein of 43 kDa (TDP-43) positive inclusions (FTLD-TDP). Recently, a new protein involved in familial ALS, fused in sarcoma (FUS), has been found in FTLD patients with ubiquitin-positive and TDP-43-negative inclusions. In this review, the authors discuss recent clinical, neuropsychological, imaging, genetic and pathological developments that have changed our understanding of FTD, its classification and criteria. The potential to establish an early diagnosis, predict underlying pathology during life and quantify disease progression will all be required for diseasespecific therapeutic trials in the future.read more
Citations
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Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis
Jonathan D. Rohrer,Jennifer M. Nicholas,Jennifer M. Nicholas,David M. Cash,John C. van Swieten,Elise G.P. Dopper,Lize C. Jiskoot,Rick van Minkelen,Serge A.R.B. Rombouts,M. Jorge Cardoso,Shona Clegg,Miklos Espak,Simon Mead,David L. Thomas,Enrico De Vita,Mario Masellis,Sandra E. Black,Morris Freedman,Ron Keren,Bradley J. MacIntosh,Ekaterina Rogaeva,David F. Tang-Wai,Maria Carmela Tartaglia,Robert Laforce,Fabrizio Tagliavini,Pietro Tiraboschi,Veronica Redaelli,Sara Prioni,Marina Grisoli,Barbara Borroni,Alessandro Padovani,Daniela Galimberti,Elio Scarpini,Andrea Arighi,Giorgio G. Fumagalli,James B. Rowe,Ian Coyle-Gilchrist,Caroline Graff,Caroline Graff,Marie Fallström,Vesna Jelic,Vesna Jelic,Anne Kinhult Ståhlbom,Anne Kinhult Ståhlbom,Christin Andersson,Christin Andersson,Håkan Thonberg,Håkan Thonberg,Lena Lilius,Giovanni B. Frisoni,Giuliano Binetti,Michela Pievani,Martina Bocchetta,Luisa Benussi,Roberta Ghidoni,Elizabeth Finger,Sandro Sorbi,Benedetta Nacmias,Gemma Lombardi,Cristina Polito,Jason D. Warren,Sebastien Ourselin,Nick C. Fox,Martin N. Rossor +63 more
TL;DR: Structural imaging and cognitive changes can be identified 5-10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia, which could help to define biomarkers that can stage presymPTomatic disease and track disease progression.
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Tau imaging: early progress and future directions
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Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features
Colin J. Mahoney,Jon Beck,Jonathan D. Rohrer,Tammaryn Lashley,Kin Y. Mok,Timothy J. Shakespeare,Tom Yeatman,Elizabeth K. Warrington,Jonathan M. Schott,Nick C. Fox,Martin N. Rossor,John Hardy,John Collinge,Tamas Revesz,Simon Mead,Jason D. Warren +15 more
TL;DR: Findings corroborate the clinical importance of the C9ORF72 mutation in frontotemporal lobar degeneration, delineate phenotypic and neuropathological features that could help to guide genetic testing, and suggest hypotheses for elucidating the neurobiology of a culprit subcortical network.
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Journal ArticleDOI
TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis
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TL;DR: The evidence suggests a pathophysiological link between TDP-43 and ALS, and neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases.
Journal ArticleDOI
Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.
Thomas J. Kwiatkowski,D. A. Bosco,D. A. Bosco,A. L. LeClerc,A. L. LeClerc,Eric Tamrazian,Charles R. Vanderburg,Carsten Russ,Carsten Russ,A. Davis,James M. Gilchrist,E. J. Kasarskis,Theodore L. Munsat,Paul N. Valdmanis,Guy A. Rouleau,Betsy A. Hosler,Pietro Cortelli,P. J. De Jong,Yuko Yoshinaga,Jonathan L. Haines,Margaret A. Pericak-Vance,Jianhua Yan,Nicola Ticozzi,Nicola Ticozzi,Nicola Ticozzi,Teepu Siddique,Diane McKenna-Yasek,Peter C. Sapp,Peter C. Sapp,H R Horvitz,John Landers,John Landers,Robert H. Brown,Robert H. Brown +33 more
TL;DR: Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders.
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