title: TDP-43 pathology and neuronal loss in amyotrophic lateral sclerosis spinal cord.
abstract: We examined the phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) inclusions as well as neuronal loss in full-length spinal cords and five selected regions of the central nervous system from 36 patients with amyotrophic lateral sclerosis (ALS) and 10 age-matched normal controls. The most severe neuronal loss and pTDP-43 lesions were seen in lamina IX motor nuclei columns 4, 6, and 8 of lower cervical segments and in columns 9-11 of lumbosacral segments. Severity of pTDP-43 pathology and neuronal loss correlated closely with gray and white matter oligodendroglial involvement and was linked to onset of disease, with severe involvement of columns 4, 6, and 8 of upper extremity onset cases and severe involvement of columns of 9, 10, and 11 in cases with lower extremity onset. Severe TDP-43 lesions and neuronal loss were observed in stage 4 cases and sometimes included Onuf's nucleus. Notably, three cases displayed pTDP-43 aggregates in the midbrain oculomotor nucleus, which we had not seen previously even in cases with advanced (i.e., stage 4) pathology. pTDP-43 aggregates were observed in neurons of Clarke's column in 30.6 % of cases but rarely in the intermediolateral nucleus (IML). Gray matter oligodendroglial pTDP-43 inclusions were present in areas devoid of neuronal pTDP-43 aggregates and neuronal loss. Taken together, our findings indicate that (1) the dorsolateral motor nuclei columns of the cervical and lumbosacral anterior horn may be the earliest foci of pTDP-43 pathology in the spinal cord, (2) gray matter oligodendroglial involvement is an early event in the ALS disease process that possibly heralds subsequent involvement of neurons by pTDP-43 pathology, and (3) in some very advanced cases, there is oculomotor nucleus involvement, which may constitute an additional neuropathological stage (designated here as stage 5) of pTDP-43 pathology in ALS.
authors.affiliation: Center for Neurodegenerative Disease Research (CNDR), University of Pennsylvania School of Medicine, 3rd Floor Maloney Building, 3600 Spruce Street, Philadelphia, PA, 19104, USA, jbre@mail.med.upenn.edu.
authors.forename: Johannes
authors.initials: J
authors.lastname: Brettschneider
authors.forename: Kimihito
authors.initials: K
authors.lastname: Arai
authors.forename: Kelly
authors.initials: K
authors.lastname: Del Tredici
authors.forename: Jon B
authors.initials: JB
authors.lastname: Toledo
authors.forename: John L
authors.initials: JL
authors.lastname: Robinson
authors.forename: Edward B
authors.initials: EB
authors.lastname: Lee
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kuwabara
authors.forename: Kazumoto
authors.initials: K
authors.lastname: Shibuya
authors.forename: David J
authors.initials: DJ
authors.lastname: Irwin
authors.forename: Lubin
authors.initials: L
authors.lastname: Fang
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.forename: Lauren
authors.initials: L
authors.lastname: Elman
authors.forename: Leo
authors.initials: L
authors.lastname: McCluskey
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: Heiko
authors.initials: H
authors.lastname: Braak
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D016022:Case-Control Studies; D016923:Cell Death / Q000502:physiology; D057167:Claudins / Q000378:metabolism; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000473:pathology*; D000076104:Oligodendrocyte Transcription Factor 2; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology*; D018709:Statistics, Nonparametric; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D057167:Claudins; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D051844:alpha-Synuclein; D016875:tau Proteins; C120453:CLDN11 protein, human; C405708:OLIG2 protein, human