Abstract
Frontotemporal lobar degeneration (FTLD) is one of the most common causes of early-onset dementia and presents with early social–emotional–behavioural and/or language changes that can be accompanied by a pyramidal or extrapyramidal motor disorder. About 20–25% of individuals with FTLD are estimated to carry a mutation associated with a specific FTLD pathology. The discovery of these mutations has led to important advances in potentially disease-modifying treatments that aim to slow progression or delay disease onset and has improved understanding of brain functioning. In both mutation carriers and those with sporadic disease, the most common underlying diagnoses are linked to neuronal and glial inclusions containing tau (FTLD-tau) or TDP-43 (FTLD-TDP), although 5–10% of patients may have inclusions containing proteins from the FUS–Ewing sarcoma–TAF15 family (FTLD-FET). Biomarkers definitively identifying specific pathological entities in sporadic disease have been elusive, which has impeded development of disease-modifying treatments. Nevertheless, disease-monitoring biofluid and imaging biomarkers are becoming increasingly sophisticated and are likely to serve as useful measures of treatment response during trials of disease-modifying treatments. Symptomatic trials using novel approaches such as transcranial direct current stimulation are also beginning to show promise.
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Acknowledgements
M.G. is supported by AG066597. J.L.W. is supported by R01-DC12519, R01-DC14942, R01-NS89757 and RF1-NS112153. O.P. is supported by a National Health and Medical Research Council of Australia Leadership Fellowship (GNT2008020). H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (2022-01018 and 2019-02397), the European Union’s Horizon Europe Research and Innovation Programme under grant agreement no. 101053962, and Swedish State Support for Clinical Research (ALFGBG-71320).
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Introduction (M.G. and B.M.); Epidemiology (D.S.K.); Mechanisms/pathophysiology (W.W.S. and R.R.); Diagnosis, screening and prevention (M.G., J.L.W. and H.Z.); Management (A.L.B., A.E.H. and P.A.L.); Quality of life (O.P.); Outlook (M.G. and J.C.v.S.); Overview of Primer (M.G. and W.W.S.).
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H.Z. has served on scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside the submitted work). A.L.B. has received financial support from NIH, the Association for Frontotemporal Degeneration, the Bluefield Project, the Rainwater Charitable Foundation, Regeneron, Eisai and Biogen; and has served as a paid consultant for AGTC, Alector, Amylyx, AviadoBio, Arkuda, Arrowhead, Arvinas, Eli Lilly, Genentech, LifeEdit, Merck, Modalis, Oligomerix, Oscotec, Transposon and Wave. D.S.K. serves on a Data Safety Monitoring Board for the Dominantly Inherited Alzheimer Network Treatment Unit study; served on a Data Safety monitoring Board for a tau therapeutic for Biogen (until 2021) but received no personal compensation; is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals and the University of Southern California; has served as a consultant for Roche, Samus Therapeutics, Magellan Health, Biovie and Alzeca Biosciences but receives no personal compensation; attended an Eisai advisory board meeting for lecanemab on December 2, 2022, but received no compensation; and is an unpaid coinvestigator in an Alector trial for persons with GRN mutations. R.R. received financial support from NIH; is a member of the Scientific Advisory Board of Arkuda Therapeutics; and receives invention royalties from a patent related to progranulin. W.W.S. serves as a paid consultant to Biogen Idec and has received grant support from NIH, the Association for Frontotemporal Degeneration, the Bluefield Project, the Rainwater Charitable Foundation, and the Chan-Zuckerberg Initiative. J.L.W. and A.E.H. received grant support from the NIH. B.M. has received grant support from NIH, the Bluefield Project, and the Rainwater Charitable Foundation; has received royalties from books published by Cambridge University Press, Elsevier, Inc., Guilford Publications, Inc., Johns Hopkins Press, Oxford University Press and Taylor & Francis Group; has received honorarium for serving as a member of the Scientific Advisory Board of the Alzheimer’s Disease Research Center (ADRC) at Massachusetts General Hospital, Stanford University, and the University of Washington; and has received consulting fees from Genworth. P.A.L. receives research search support from NIH/NIA and the Alzheimer’s Association Part the Cloud Partnership; is the FDA IND sponsor for a clinical trial of a drug supplied by Biohaven; has served as a clinical site primary investigator for trials sponsored by Woolsey, Alector, Transposon, and AbbVie; and currently serves as a clinical site sub-investigator for clinical trials sponsored by Lilly, Eisai and Biogen.
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Nature Reviews Disease Primers thanks E. Huey, I. Le Ber, I. Mackenzie and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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We dedicate this work to the late Murray Grossman, who passed away on 4 April 2023. Murray was a dear friend to us all and to a worldwide community of neurologists and neuroscientists. He combined an acute interest in cognitive neuroscience that began as a graduate student with his clinical acumen as a behavioural neurologist to advance our knowledge of the frontotemporal degenerations. We will remember Murray, who was the driving force behind this review, for his wisdom and grace.
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Grossman, M., Seeley, W.W., Boxer, A.L. et al. Frontotemporal lobar degeneration. Nat Rev Dis Primers 9, 40 (2023). https://doi.org/10.1038/s41572-023-00447-0
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DOI: https://doi.org/10.1038/s41572-023-00447-0
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