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Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine

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Abstract

Frontotemporal lobar degeneration (FTLD) comprises two main classes of neurodegenerative diseases characterized by neuronal/glial proteinaceous inclusions (i.e., proteinopathies) including tauopathies (i.e., FTLD-Tau) and TDP-43 proteinopathies (i.e., FTLD-TDP) while other very rare forms of FTLD are known such as FTLD with FUS pathology (FTLD-FUS). This review focuses mainly on FTLD-Tau and FLTD-TDP, which may present as several clinical syndromes: a behavioral/dysexecutive syndrome (behavioral variant frontotemporal dementia); language disorders (primary progressive aphasia variants); and motor disorders (amyotrophic lateral sclerosis, corticobasal syndrome, progressive supranuclear palsy syndrome). There is considerable heterogeneity in clinical presentations of underlying neuropathology and current clinical criteria do not reliably predict underlying proteinopathies ante-mortem. In contrast, molecular etiologies of hereditary FTLD are consistently associated with specific proteinopathies. These include MAPT mutations with FTLD-Tau and GRN, C9orf72, VCP and TARDBP with FTLD-TDP. The last decade has seen a rapid expansion in our knowledge of the molecular pathologies associated with this clinically and neuropathologically heterogeneous group of FTLD diseases. Moreover, in view of current limitations to reliably diagnose specific FTLD neuropathologies prior to autopsy, we summarize the current state of the science in FTLD biomarker research including neuroimaging, biofluid and genetic analyses. We propose that combining several of these biomarker modalities will improve diagnostic specificity in FTLD through a personalized medicine approach. The goals of these efforts are to enhance power for clinical trials focused on slowing or preventing progression of spread of tau, TDP-43 and other FTLD-associated pathologies and work toward the goal of defining clinical endophenotypes of FTD.

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Acknowledgments

Support for this work was provided by grants from the National Institute on Aging of the National Institutes of Health (PO1-AG03991 and P50-AG05681) and from the Alzheimer’s Drug Discovery Foundation to NJC and P30-AG10124 (JQT and VMV), PO1-AG17586 (JQT, VMV, and VM-YL), PO1-AG032953 (JQT, VMV, and VM-YL) and NS088341 (DJI). We would also like to thank the members of the Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO, and the Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, who contributed to the work, and the many patients studied and their families, for making the research reviewed here possible.

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  1. Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Institute on Ageing, University of Pennsylvania School of Medicine, HUP Maloney 3rd Floor, 36th and Spruce Streets, Philadelphia, PA, 19104-4283, USA

    David J. Irwin, Vivianna M. Van Deerlin, Virginia M.-Y. Lee & John Q. Trojanowski

  2. Department of Neurology, Penn Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia, PA, 19104, USA

    David J. Irwin, Murray Grossman & Corey T. McMillan

  3. Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Edward B. Lee

  4. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Nigel J. Cairns

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  1. David J. Irwin
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Irwin, D.J., Cairns, N.J., Grossman, M. et al. Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine. Acta Neuropathol 129, 469–491 (2015). https://doi.org/10.1007/s00401-014-1380-1

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