title: Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD).
abstract: We examined regional distribution patterns of phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) intraneuronal inclusions in frontotemporal lobar degeneration (FTLD). Immunohistochemistry was performed on 70 μm sections from FTLD-TDP autopsy cases (n = 39) presenting with behavioral variant frontotemporal dementia. Two main types of cortical pTDP-43 pathology emerged, characterized by either predominantly perikaryal pTDP-43 inclusions (cytoplasmic type, cFTLD) or long aggregates in dendrites (neuritic type, nFTLD). Cortical involvement in nFTLD was extensive and frequently reached occipital areas, whereas cases with cFTLD often involved bulbar somatomotor neurons and the spinal cord. We observed four patterns indicative of potentially sequential dissemination of pTDP-43: cases with the lowest burden of pathology (pattern I) were characterized by widespread pTDP-43 lesions in the orbital gyri, gyrus rectus, and amygdala. With increasing burden of pathology (pattern II) pTDP-43 lesions emerged in the middle frontal and anterior cingulate gyrus as well as in anteromedial temporal lobe areas, the superior and medial temporal gyri, striatum, red nucleus, thalamus, and precerebellar nuclei. More advanced cases showed a third pattern (III) with involvement of the motor cortex, bulbar somatomotor neurons, and the spinal cord anterior horn, whereas cases with the highest burden of pathology (pattern IV) were characterized by pTDP-43 lesions in the visual cortex. We interpret the four neuropathological patterns in bvFTD to be consistent with the hypothesis that pTDP-43 pathology can spread sequentially and may propagate along axonal pathways.
authors.affiliation: Center for Neurodegenerative Disease research (CNDR), Perelman School of Medicine at the University of Pennsylvania, 3rd Floor Maloney Building, 3600 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: Johannes
authors.initials: J
authors.lastname: Brettschneider
authors.affiliation: Clinical Neuroanatomy Section, Department of Neurology, Center for Biomedical research, University of Ulm, Helmholtzstrasse 8/1, 89081 Ulm, Germany.
authors.forename: Kelly
authors.initials: K
authors.lastname: Del Tredici
authors.affiliation: Center for Neurodegenerative Disease research (CNDR), Perelman School of Medicine at the University of Pennsylvania, 3rd Floor Maloney Building, 3600 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Irwin
authors.affiliation: Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, 3 W Gates, 3400 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: Murray
authors.initials: M
authors.lastname: Grossman
authors.affiliation: Center for Neurodegenerative Disease research (CNDR), Perelman School of Medicine at the University of Pennsylvania, 3rd Floor Maloney Building, 3600 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Robinson
authors.affiliation: Center for Neurodegenerative Disease research (CNDR), Perelman School of Medicine at the University of Pennsylvania, 3rd Floor Maloney Building, 3600 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: Jon B
authors.initials: JB
authors.lastname: Toledo
authors.affiliation: Clinical Neuroanatomy Section, Department of Neurology, Center for Biomedical research, University of Ulm, Helmholtzstrasse 8/1, 89081 Ulm, Germany.
authors.forename: Lubin
authors.initials: L
authors.lastname: Fang
authors.affiliation: Center for Neurodegenerative Disease research (CNDR), Perelman School of Medicine at the University of Pennsylvania, 3rd Floor Maloney Building, 3600 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.affiliation: Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.affiliation: Center for Neurodegenerative Disease research (CNDR), Perelman School of Medicine at the University of Pennsylvania, 3rd Floor Maloney Building, 3600 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.affiliation: Clinical Neuroanatomy Section, Department of Neurology, Center for Biomedical research, University of Ulm, Helmholtzstrasse 8/1, 89081 Ulm, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Braak
authors.affiliation: Center for Neurodegenerative Disease research (CNDR), Perelman School of Medicine at the University of Pennsylvania, 3rd Floor Maloney Building, 3600 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D000368:Aged; D001921:Brain / Q000378:metabolism / Q000473:pathology; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005820:Genetic Testing; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D011506:Proteins