title: TDP-43 proteinopathies: pathological identification of brain regions differentiating clinical phenotypes.
abstract: The pathological sequestration of TAR DNA-binding protein 43 (TDP-43, encoded by TARDBP) into cytoplasmic pathological inclusions characterizes the distinct clinical syndromes of amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia, while also co-occurring in a proportion of patients with Alzheimer's disease, suggesting that the regional concentration of TDP-43 pathology has most relevance to specific clinical phenotypes. This has been reflected in the three different pathological staging schemes for TDP-43 pathology in these different clinical syndromes, with none of these staging schemes including a preclinical phase similar to that which has proven beneficial in other neurodegenerative diseases. To apply each of these three staging schemes for TDP-43 pathology, the clinical phenotype must be known undermining the potential predictive value of the pathological examination. The present study set out to test whether a more unified approach could accurately predict clinical phenotypes based solely on the regional presence and severity of TDP-43 pathology. The selection of brain regions of interest was based on key regions routinely sampled for neuropathological assessment under current consensus criteria that have also been used in the three TDP-43 staging schemes. The severity of TDP-43 pathology in these regions of interest was assessed in four clinicopathological phenotypes: amyotrophic lateral sclerosis (n = 27, 47-78 years, 15 males), behavioural variant frontotemporal dementia (n = 15, 49-82 years, seven males), Alzheimer's disease (n = 26, 51-90 years, 11 males) and cognitively normal elderly individuals (n = 17, 80-103 years, nine males). Our results demonstrate that the presence of TDP-43 in the hypoglossal nucleus discriminates patients with amyotrophic lateral sclerosis with an accuracy of 98%. The severity of TDP-43 deposited in the anterior cingulate cortex identifies patients with behavioural variant frontotemporal dementia with an accuracy of 99%. This identification of regional pathology associated with distinct clinical phenotypes suggests key regions on which probabilistic pathological criteria, similar to those currently available for Alzheimer's disease and dementia with Lewy bodies, can be developed for TDP-43 proteinopathies. We propose and validate a simplified probabilistic statement that involves grading the presence of TDP-43 in the hypoglossal nucleus and the severity of TDP-43 in the anterior cingulate for the pathological identification of TDP-43 proteinopathy cases with clinical amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia.
authors.affiliation: 1 Neuroscience Research Australia, Sydney, Australia 2 UNSW Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Tan
authors.affiliation: 3 Discipline of Pathology, Sydney Medical School, The University of Sydney, Australia 4 Discipline of Medicine, Sydney Medical School, The University of Sydney, Australia.
authors.forename: Jillian J
authors.initials: JJ
authors.lastname: Kril
authors.affiliation: 1 Neuroscience Research Australia, Sydney, Australia 2 UNSW Medicine, University of New South Wales, Sydney, Australia 3 Discipline of Pathology, Sydney Medical School, The University of Sydney, Australia.
authors.forename: Manaal
authors.initials: M
authors.lastname: Fatima
authors.affiliation: 1 Neuroscience Research Australia, Sydney, Australia 2 UNSW Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: McGeachie
authors.affiliation: 1 Neuroscience Research Australia, Sydney, Australia.
authors.forename: Heather
authors.initials: H
authors.lastname: McCann
authors.affiliation: 1 Neuroscience Research Australia, Sydney, Australia 2 UNSW Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Claire
authors.initials: C
authors.lastname: Shepherd
authors.affiliation: 3 Discipline of Pathology, Sydney Medical School, The University of Sydney, Australia.
authors.forename: Shelley L
authors.initials: SL
authors.lastname: Forrest
authors.affiliation: 1 Neuroscience Research Australia, Sydney, Australia 2 UNSW Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Affleck
authors.affiliation: 1 Neuroscience Research Australia, Sydney, Australia 2 UNSW Medicine, University of New South Wales, Sydney, Australia.
authors.forename: John B J
authors.initials: JB
authors.lastname: Kwok
authors.affiliation: 1 Neuroscience Research Australia, Sydney, Australia 2 UNSW Medicine, University of New South Wales, Sydney, Australia 5 ARC Centre of Excellence in Cognition and its Disorders, Sydney, Australia.
authors.forename: John R
authors.initials: JR
authors.lastname: Hodges
authors.affiliation: 6 Brain and Mind Research Institute, Sydney Medical School, The University of Sydney, Australia.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Kiernan
authors.affiliation: 1 Neuroscience Research Australia, Sydney, Australia 2 UNSW Medicine, University of New South Wales, Sydney, Australia g.halliday@neura.edu.au.
authors.forename: Glenda M
authors.initials: GM
authors.lastname: Halliday
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology; D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology; D001921:Brain / Q000473:pathology*; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011237:Predictive Value of Tests; D057177:TDP-43 Proteinopathies / Q000473:pathology*
chemical_list: D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human
keywords: Alzheimer’s disease; TDP-43 proteinopathies; amyotrophic lateral sclerosis; behavioural variant frontotemporal dementia