title: Updated TDP-43 in Alzheimer's disease staging scheme.
abstract: In this study, we update the TDP-43 in Alzheimer's disease staging scheme by assessing the topography of TDP-43 in 193 cases of Alzheimer's disease, in 14 different brain regions (eight previously described plus six newly reported) and use conditional probability to model the spread of TDP-43 across the 14 brain regions. We show that in addition to the eight original regions we previously reported [amygdala, entorhinal cortex, subiculum, dentate gyrus of the hippocampus, occipitotemporal cortex, inferior temporal cortex, middle frontal cortex and basal ganglia (putamen/globus pallidum)] that TDP-43 is also deposited in the insular cortex, ventral striatum, basal forebrain, substantia nigra, midbrain tectum, and the inferior olive of the medulla oblongata, in Alzheimer's disease. The conditional probability analysis produced six significantly different stages (P < 0.01), and suggests that TDP-43 deposition begins in the amygdala (stage 1), then moves to entorhinal cortex and subiculum (stage 2); to the dentate gyrus of the hippocampus and occipitotemporal cortex (stage 3); insular cortex, ventral striatum, basal forebrain and inferior temporal cortex (stage 4); substantia nigra, inferior olive and midbrain tectum (stage 5); and finally to basal ganglia and middle frontal cortex (stage 6). This updated staging scheme is superior to our previous staging scheme, classifying 100% of the cases (versus 94% in the old scheme), based on criteria provided, and shows clinical significance with some regions and with increasing stage. We discuss the relevance of the updated staging scheme, as well as its impact on the prion-like hypothesis of protein spread in neurodegenerative disease. We also address the issue of whether frontotemporal lobar degeneration with TDP-43 could be the primary pathology in stage 6.
authors.affiliation: Department of Neurology, Division of Behavioral Neurology, Mayo Clinic, Rochester, 55905, MN, USA. josephs.keith@mayo.edu.|Department of Neurology, Division of Movement Disorders, Mayo Clinic, Rochester, MN, 55905, USA. josephs.keith@mayo.edu.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Josephs
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, 32224, FL, USA.
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Murray
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, 55905, MN, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Whitwell
authors.affiliation: Department of Health Sciences Research, Division of Biostatistics, Mayo Clinic, Rochester, 55905, MN, USA.
authors.forename: Nirubol
authors.initials: N
authors.lastname: Tosakulwong
authors.affiliation: Department of Health Sciences Research, Division of Biostatistics, Mayo Clinic, Rochester, 55905, MN, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Weigand
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, 32224, FL, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, 32224, FL, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Liesinger
authors.affiliation: Department of Neurology, Division of Behavioral Neurology, Mayo Clinic, Rochester, 55905, MN, USA.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.affiliation: Laboratory Medicine and Pathology, Mayo Clinic, Rochester, 55905, MN, USA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parisi
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, 32224, FL, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000473:pathology*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008609:Mental Status Schedule; D008875:Middle Aged; D011336:Probability
chemical_list: D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human
keywords: Alzheimer’s disease; Brainstem; Insular cortex; Limbic; Staging; TDP-43
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