Defining the spectrum of frontotemporal dementias associated with
            <i>TARDBP</i>
            mutations

Caroppo, Paola; Camuzat, Agnès; Guillot‐Noël, Léna; Thomas‐Antérion, Catherine; Couratier, Philippe; Wong, Tsz Hang; Teichmann, Marc; Golfier, Véronique; Auriacombe, Sophie; Belliard, Serge; Laurent, Bernard; Lattante, Serena; Millecamps, Stéphanie; Clot, Fabienne; Dubois, Bruno; Swieten, John van; Brice, Alexis; Ber, Isabelle Le

doi:10.1212/nxg.0000000000000080

Cited by 55 publications

(49 citation statements)

References 27 publications

(29 reference statements)

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“…VCP mutation cases with FTD present with the unique FTLD-TDP type D with numerous NII and DN in the neocortex ( Figure 2G) [45,46]. TARDBP mutations Mutations in the TARDBP gene encoding TDP-43 are most often associated with clinically pure ALS [92][93][94], but can also result in ALS combined with FTD [95] or even pure FTD [96][97][98]. Descriptions of the neuropathology in cases with FTD are few and the pathogenicity of the reported mutations remains unclear due to current lack of evidence of segregation with the disease.…”

Section: Familial Forms Of Ftld-tdpmentioning

confidence: 99%

Review: Neuropathology of non‐tau frontotemporal lobar degeneration

Neumann

Mackenzie

2019

Neuropathology Appl Neurobio

111

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Frontotemporal dementia (FTD) is a heterogeneous clinical syndrome associated with frontotemporal lobar degeneration (FTLD) as a relatively consistent neuropathological hallmark feature. However, the discoveries in the past decade of many of the relevant pathological proteins aggregating in human FTD brains in addition to several new FTD causing gene mutations underlined that FTD is a diverse condition on the neuropathological and genetic basis. This resulted in a novel molecular classification of these conditions based on the predominant protein abnormality and allows most cases of FTD to be placed now into one of three broad molecular subgroups; FTLD with tau, TAR DNA‐binding protein 43 or FET protein accumulation (FTLD‐tau, FTLD‐TDP and FTLD‐FET respectively). This review will provide an overview of the molecular neuropathology of non‐tau FTLD, insights into disease mechanisms gained from the study of human post mortem tissue as well as discussion of current controversies in the field.

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Section: Familial Forms Of Ftld-tdpmentioning

confidence: 99%

Review: Neuropathology of non‐tau frontotemporal lobar degeneration

Neumann

Mackenzie

2019

Neuropathology Appl Neurobio

111

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“…Other rare mutations include VCP, CHMP2B, UBQLN2 and SQSTM1. It is interesting to note that despite the strong pathological connection with TDP-43 and FUS, mutations in the genes that encoding these proteins are very rare in 'pure' FTD [5][6][7][8] and FTD-ALS [7,9,10], and more frequently associated with ALS [11,12].…”

Section: Introductionmentioning

confidence: 99%

Review: Modelling the pathology and behaviour of frontotemporal dementia

Solomon

Mitchell

Salcher-Konrad

et al. 2019

Neuropathology Appl Neurobio

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Frontotemporal dementia (FTD) encompasses a collection of clinically and pathologically diverse neurological disorders. Clinical features of behavioural and language dysfunction are associated with neurodegeneration, predominantly of frontal and temporal cortices. Over the past decade, there have been significant advances in the understanding of the genetic aetiology and neuropathology of FTD which have led to the creation of various disease models to investigate the molecular pathways that contribute to disease pathogenesis. The generation of in vivo models of FTD involves either targeting genes with known disease‐causative mutations such as GRN and C9orf72 or genes encoding proteins that form the inclusions that characterize the disease pathologically, such as TDP‐43 and FUS. This review provides a comprehensive summary of the different in vivo model systems used to understand pathomechanisms in FTD, with a focus on disease models which reproduce aspects of the wide‐ranging behavioural phenotypes seen in people with FTD. We discuss the emerging disease pathways that have emerged from these in vivo models and how this has shaped our understanding of disease mechanisms underpinning FTD. We also discuss the challenges of modelling the complex clinical symptoms shown by people with FTD, the confounding overlap with features of motor neuron disease, and the drive to make models more disease‐relevant. In summary, in vivo models can replicate many pathological and behavioural aspects of clinical FTD, but robust and thorough investigations utilizing shared features and variability between disease models will improve the disease‐relevance of findings and thus better inform therapeutic development.

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“…Mutations in TARDBP have also been reported in patients with FTD, with and without ALS (Benajiba et al, 2009;Borroni et al, 2009;Kovacs et al, 2009;Pesiridis et al, 2009). The frequency of TARDBP mutations in patients with FTD is estimated at 1%, the majority presenting with bvFTD, though some patients do present with svFTD or nfvFTD at onset (Caroppo et al, 2016).…”

Section: Als10: Tar Dna Binding Protein (Tardbp)mentioning

confidence: 99%