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Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review
  1. Harro Seelaar1,
  2. Jonathan D Rohrer2,
  3. Yolande A L Pijnenburg3,
  4. Nick C Fox2,
  5. John C van Swieten1
  1. 1Department of Neurology, Erasmus MC—University Medical Centre Rotterdam, Rotterdam, The Netherlands
  2. 2Dementia Research Centre, UCL Institute of Neurology, London, UK
  3. 3Department of Neurology, VU University Medical Centre Amsterdam, Amsterdam, The Netherlands
  1. Correspondence to Dr John C van Swieten, Erasmus MC—University Medical Center Rotterdam, Department of Neurology, Room Hs 611, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands; j.c.vanswieten{at}erasmusmc.nl

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. 30–50% 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 9p13.2–21.3 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 disease-specific therapeutic trials in the future.

  • Frontotemporal dementia
  • frontotemporal lobar degeneration
  • tau
  • TDP-43
  • fus
  • MAPT
  • progranulin
  • behavioural disorder
  • dementia
  • frontal lobe
  • neurogenetics
  • neuropathology

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Footnotes

  • Funding HS and JCvS are funded by Stichting Dioraphte and Hersenstichting. The Dementia Research Centre is an Alzheimer's Research Trust Co-ordinating centre and receives support from the NIHR Biomedical Research Centres scheme. NCF is funded by the Medical Research Council and is an NIHR Senior Investigator.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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