title: Pathological tau deposition in Motor Neurone Disease and frontotemporal lobar degeneration associated with TDP-43 proteinopathy.
abstract: It has been suggested that patients with motor neurone disease (MND) and those with MND combined with behavioural variant frontotemporal dementia (bvFTD) (ie FTD + MND) or with FTD alone might exist on a continuum based on commonalities of neuropathology and/or genetic risk. Moreover, it has been reported that both a neuronal and a glial cell tauopathy can accompany the TDP-43 proteinopathy in patients with motor neurone disease (MND) with cognitive changes, and that the tauopathy may be fundamental to disease pathogenesis and clinical phenotype. In the present study, we sought to substantiate these latter findings, and test this concept of a pathological continuum, in a consecutive series of 41 patients with MND, 16 with FTD + MND and 23 with FTD without MND. Paraffin sections of frontal, entorhinal, temporal and occipital cortex and hippocampus were immunostained for tau pathology using anti-tau antibodies, AT8, pThr(175) and pThr(217), and for amyloid β protein (Aβ) using 4G8 antibody. Twenty four (59 %) patients with MND, 7 (44 %) patients with FTD + MND and 10 (43 %) patients with FTD showed 'significant' tau pathology (ie more than just an isolated neurofibrillary tangle or a few neuropil threads in one or more brain regions examined). In most instances, this bore the histological characteristics of an Alzheimer's disease process involving entorhinal cortex, hippocampus, temporal cortex, frontal cortex and occipital cortex in decreasing frequency, accompanied by a deposition of Aβ up to Thal phase 3, though 2 patients with MND, and 1 with FTD did show tau pathology beyond Braak stage III. Four other patients with MND showed novel neuronal tau pathology, within the frontal cortex alone, specifically detected by pThr(175) antibody, which was characterised by a fine granular or more clumped aggregation of tau without neurofibrillary tangles or neuropil threads. However, none of these 4 patients had clinically evident cognitive disorder, and this type of tau pathology was not seen in any of the FTD + MND or FTD patients. Finally, two patients, one with MND and one with FTD, showed a tau pathology consistent with Argyrophilic Grain Disease (AGD). Western blotting and use of 3- and 4-repeat tau antibodies confirmed the histological interpretation of Alzheimer's disease type pathology in all instances except for those patients with accompanying AGD where a banding pattern on western blot, and immunohistochemistry, confirmed 4-repeat tauopathy. In all 3 patient groups, amyloid pathology was more likely to be present in patients dying after 65 years of age, and in the presence of APOE ε4 allele. We conclude that tau pathological changes are equally common amongst patients with MND, FTD + MND and FTD though, in most instances, these are limited in extent. In patients with MND, when cognitive impairment is present this is most likely due to an accompanying/evolving (coincidental) Alzheimer's disease process or, as in a single case, Dementia with Lewy bodies, within the cerebral cortex rather than as a result of TDP-43 proteinopathy. Conversely, in FTD and FTD + MND dementia is more likely to be associated with TDP-43 proteinopathy than tau. Hence, present study shows no progression in severity of (tau) pathology from MND through FTD + MND to FTD, and does not support the concept of these conditions forming a continuum of clinical or pathological change.
authors.affiliation: Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford, M6 8HD, UK.
authors.forename: Roya
authors.initials: R
authors.lastname: Behrouzi
authors.affiliation: Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford, M6 8HD, UK.|Beijing University of Chinese Medicine, Dongzhimen Hospital, 5 Hyancung St, Beijing, 100700, PR China.
authors.forename: Xiawei
authors.initials: X
authors.lastname: Liu
authors.affiliation: Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford, M6 8HD, UK.|Beijing University of Chinese Medicine, Dongzhimen Hospital, 5 Hyancung St, Beijing, 100700, PR China.
authors.forename: Dongyue
authors.initials: D
authors.lastname: Wu
authors.affiliation: Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford, M6 8HD, UK.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Robinson
authors.affiliation: Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, 156-8585, Japan.
authors.forename: Sayuri
authors.initials: S
authors.lastname: Tanaguchi-Watanabe
authors.affiliation: Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, A V Hill Building, M13 9PT, Manchester, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Rollinson
authors.affiliation: Beijing University of Chinese Medicine, Dongzhimen Hospital, 5 Hyancung St, Beijing, 100700, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
authors.affiliation: Beijing University of Chinese Medicine, Dongzhimen Hospital, 5 Hyancung St, Beijing, 100700, PR China.
authors.forename: Jinzhou
authors.initials: J
authors.lastname: Tian
authors.affiliation: Manchester MND Care Centre, Salford Royal Hospital, Stott Lane, Salford, M6 8HD, UK.
authors.forename: Hisham H M
authors.initials: HH
authors.lastname: Hamdalla
authors.affiliation: Manchester MND Care Centre, Salford Royal Hospital, Stott Lane, Salford, M6 8HD, UK.
authors.forename: John
authors.initials: J
authors.lastname: Ealing
authors.affiliation: Cerebral Function Unit, Greater Manchester Neurosciences Centre, Salford Royal Hospital, Stott Lane, Salford, M6 8HD, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Richardson
authors.affiliation: Cerebral Function Unit, Greater Manchester Neurosciences Centre, Salford Royal Hospital, Stott Lane, Salford, M6 8HD, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Jones
authors.affiliation: Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, A V Hill Building, M13 9PT, Manchester, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Pickering-Brown
authors.affiliation: Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford, M6 8HD, UK.
authors.forename: Yvonne S
authors.initials: YS
authors.lastname: Davidson
authors.affiliation: Molecular Brain Research Group, Robarts Research Institute, Western University, Canada, London, ON, N6A 5B7, Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Strong
authors.affiliation: Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, 156-8585, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
authors.affiliation: Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford, M6 8HD, UK.|Cerebral Function Unit, Greater Manchester Neurosciences Centre, Salford Royal Hospital, Stott Lane, Salford, M6 8HD, UK.
authors.forename: Julie S
authors.initials: JS
authors.lastname: Snowden
authors.affiliation: Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford, M6 8HD, UK. david.mann@manchester.ac.uk.
authors.forename: David M A
authors.initials: DM
authors.lastname: Mann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000682:Amyloid / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D002540:Cerebral Cortex / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D000682:Amyloid; D001057:Apolipoproteins E; D004268:DNA-Binding Proteins; D020033:Protein Isoforms; C000598624:TARDBP protein, human; D016875:tau Proteins