title: TAR DNA-binding protein 43 and pathological subtype of Alzheimer's disease impact clinical features.
abstract: OBJECTIVE
  The aim of this study was to determine whether the frequency of TAR DNA-binding protein 43 (TDP-43) deposition in Alzheimer's disease (AD) differs across pathologically defined AD subtypes (hippocampal sparing [HpSp]; typical and limbic) and further examine the relationship between TDP-43, pathological subtype, and clinical features in AD.
  
  
  METHODS
  We identified all cases with pathologically confirmed AD (NIA-Reagan intermediate-high probability, Braak stage IV-VI) independent of cognitive status (n = 188). Neurofibrillary tangle counts were performed using thioflavin-S microscopy in hippocampus and three neocortical regions, and all cases were subtyped: HpSp AD pathology (n = 19); typical AD pathology (n = 136); and limbic AD pathology (n = 33). TDP-43 immunoreactivity was performed in multiple brain regions to assess for the presence of TDP-43 and TDP-43 stage. All cases were clinically subclassified at presentation as amnestic AD dementia versus atypical AD dementia. Statistical analysis was performed using linear and penalized logistic regression to assess associations with pathological subtype, and the effects of TDP-43, accounting for possible interactions between pathological subtype and TDP-43.
  
  
  RESULTS
  TDP-43 deposition was frequent in typical (59%) and limbic AD pathologies (67%), but not HpSp AD pathology (21%; p = 0.003). The observed associations of TDP-43 with greater memory loss, naming and functional decline, and smaller hippocampal volumes, closest to death, did not differ across AD pathological subtype. Clinical presentation was associated with pathological subtype (p = 0.01), but not TDP-43 (p = 0.69).
  
  
  CONCLUSIONS
  Although the frequency of TDP-43 deposition in AD varies by pathological subtype, the observed effects of TDP-43 on clinical/magnetic resonance imaging features are consistent across pathological subtypes. Clinical presentation in AD is driven by pathological subtype, not by TDP-43.
authors.affiliation: Departments of Neurology (Behavioral Neurology).
authors.forename: Keith A
authors.initials: KA
authors.lastname: Josephs
authors.affiliation: Radiology (Radiology Research).
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Whitwell
authors.affiliation: Health Science Research (Biostatistics).
authors.forename: Nirubol
authors.initials: N
authors.lastname: Tosakulwong
authors.affiliation: Health Science Research (Biostatistics).
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Weigand
authors.affiliation: Mayo Clinic Rochester, MN and Department of Neuroscience (Neuropathology).
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Murray
authors.affiliation: Mayo Clinic Rochester, MN and Department of Neuroscience (Neuropathology).
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Liesinger
authors.affiliation: (Molecular Neuroscience) Mayo Clinic, Jacksonville, FL.
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
authors.affiliation: Radiology (Radiology Research).|Information Technology.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Senjem
authors.affiliation: Neuropsychiatry (Neuropsychology).
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ivnik
authors.affiliation: Laboratory Medicine and Pathology (Neuropathology).
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parisi
authors.affiliation: Departments of Neurology (Behavioral Neurology).
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.affiliation: Mayo Clinic Rochester, MN and Department of Neuroscience (Neuropathology).
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 / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D003071:Cognition; D004268:DNA-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008032:Limbic System / Q000473:pathology; D008297:Male; D008569:Memory Disorders / Q000209:etiology / Q000235:genetics; D008875:Middle Aged; D019579:Neocortex / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000473:pathology; D009483:Neuropsychological Tests; D011597:Psychomotor Performance; D057177:TDP-43 Proteinopathies / Q000235:genetics* / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human