title: Spread of pathology in amyotrophic lateral sclerosis: assessment of phosphorylated TDP-43 along axonal pathways.
abstract: BACKGROUND
  The progression of amyotrophic lateral sclerosis (ALS) through the brain has recently been staged using independent neuropathological and neuroimaging modalities. The two schemes tie into the concept of pathological spread through corticofugal axonal transmission that stems from observation of oligodendrocyte pTDP-43 aggregates along with neuronal inclusions. Here, we aimed to assess evidence of transmission along axonal pathways by looking for pTDP-43 oligodendrocyte pathology in involved white matter tracts, and to present a first validation of the neuropathological staging scheme. pTDP-43 immunohistochemistry was performed in select white matter tracts and grey matter regions from the staging scheme in postmortem-confirmed ALS cases (N = 34). Double-labelling immunofluorescence was performed to confirm co-localisation of pTDP-43 immunoreactivity to oligodendrocytes.
  
  
  RESULTS
  While pTDP-43 immunoreactive oligodendrocytes were frequent in the white matter under the motor and sensory cortices, similar assessment of the white matter along the corticospinal tract and in the corpus callosum and cingulum bundle of the same cases revealed no pTDP-43 pathology, questioning the involvement of oligodendrocytes in pathological propagation. The assessment of Betz cell loss revealed that the lack of deep white matter pTDP-43 oligodendrocyte pathology was not due to an absence of motor axons. Assessment of the propagation of pathology to different grey matter regions validated that all cases could be allocated to one of four neuropathological stages, although Stage 4 cases were found to differ significantly in age of onset (~10 years older) and disease duration (shorter duration than Stage 3 and similar to Stage 2).
  
  
  CONCLUSIONS
  Four stages of ALS neuropathology can be consistently identified, although evidence of sequential clinical progression requires further assessment. As limited pTDP-43 oligodendrocyte pathology in deep corticospinal and other white matter tracts from the motor cortex was observed, the propagation of pathology between neurons may not involve oligodendrocytes and the interpretation of the changes observed on neuroimaging should be modified accordingly.
authors.affiliation: Discipline of Pathology, University of Sydney, Level 6 W Charles Perkins Centre D17, Sydney, 2006, Australia.|School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, 2052, Australia.
authors.forename: Manaal
authors.initials: M
authors.lastname: Fatima
authors.affiliation: Neuroscience Research Australia, Sydney, 2031, Australia.
authors.forename: Rachel
authors.initials: R
authors.lastname: Tan
authors.affiliation: School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, 2052, Australia.|Neuroscience Research Australia, Sydney, 2031, Australia.
authors.forename: Glenda M
authors.initials: GM
authors.lastname: Halliday
authors.affiliation: Discipline of Pathology, University of Sydney, Level 6 W Charles Perkins Centre D17, Sydney, 2006, Australia. jillian.kril@sydney.edu.au.|Discipline of Medicine, University of Sydney, Sydney, 2006, Australia. jillian.kril@sydney.edu.au.
authors.forename: Jillian J
authors.initials: JJ
authors.lastname: Kril
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D001369:Axons / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D016009:Chi-Square Distribution; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D066128:Gray Matter / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018709:Statistics, Nonparametric
chemical_list: D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; C118136:TPPP protein, human