title: Expansion of the classification of FTLD-TDP: distinct pathology associated with rapidly progressive frontotemporal degeneration.
abstract: Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) can typically be categorized into one of four distinct histopathologic patterns of TDP-43 pathology, types A to D. The strength of this histopathologic classification lies in the association between FTLD-TDP subtypes and various clinical and genetic features of disease. Seven cases of FTLD-TDP were identified here which were difficult to classify based on existing pathologic criteria. Distinct features common to these cases included TDP-43 aggregates over a wide neuroanatomic distribution comprised of granulofilamentous neuronal inclusions, abundant grains, and oligodendroglial inclusions. TDP-43 aggregates were phosphorylated and associated with loss of normal nuclear TDP-43 protein (nuclear clearance) but were negative for ubiquitin. Biochemical analysis confirmed the presence of insoluble and phosphorylated TDP-43 and also revealed a distinct pattern of TDP-43 C-terminal fragments relative to other FTLD-TDP subtypes. Finally, these cases were uniformly associated with a very rapid clinical course culminating in death within ~3 years of disease onset. We suggest that these cases may represent a unique clinicopathologic subtype of FTLD-TDP which we provisionally call "type E." The immature appearance of TDP-43 aggregates, widespread distribution, uniform biochemical profile and rapid clinical course highlights the clinical and pathologic variability within FTLD-TDP, and raises the possibility that type E neuropathology is the sequelae of a particularly virulent strain of TDP-43 proteinopathy.
authors.affiliation: Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 613A Stellar Chance Laboratories, 422 Curie Blvd, Philadelphia, PA, 19104, USA. edward.lee@uphs.upenn.edu.|Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA. edward.lee@uphs.upenn.edu.|Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. edward.lee@uphs.upenn.edu.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Lee
authors.affiliation: Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA.|Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Porta
authors.affiliation: Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Michael Baer
authors.affiliation: Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA.|Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA.|Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: EunRan
authors.initials: E
authors.lastname: Suh
authors.affiliation: Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA.|Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Linda K
authors.initials: LK
authors.lastname: Kwong
authors.affiliation: Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Elman
authors.affiliation: Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Murray
authors.initials: M
authors.lastname: Grossman
authors.affiliation: Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA.|Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.affiliation: Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Irwin
authors.affiliation: Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA.|Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.affiliation: Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA.|Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D004268:DNA-Binding Proteins / Q000378:metabolism; D018450:Disease Progression; D005455:Fluorescent Antibody Technique; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D057174:Frontotemporal Lobar Degeneration / Q000145:classification* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008875:Middle Aged; D010641:Phenotype; D012044:Regression Analysis
chemical_list: D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human