title: Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine.
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.
authors.affiliation: 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.
authors.forename: David J
authors.initials: DJ
authors.lastname: Irwin
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Cairns
authors.forename: Murray
authors.initials: M
authors.lastname: Grossman
authors.forename: Corey T
authors.initials: CT
authors.lastname: McMillan
authors.forename: Edward B
authors.initials: EB
authors.lastname: Lee
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D000073885:C9orf72 Protein; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D057174:Frontotemporal Lobar Degeneration / Q000145:classification / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D057285:Precision Medicine; D000077153:Progranulins; D011506:Proteins / Q000235:genetics; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; C054369:MAPT protein, human; D000077153:Progranulins; D011506:Proteins; C000598624:TARDBP protein, human; D016875:tau Proteins