title: Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype.
abstract: BACKGROUND
  TAR DNA-binding protein 43 (TDP-43) is one of the major disease proteins in frontotemporal lobar degeneration with ubiquitin immunoreactivity. Approximately one-fourth of subjects with pathologically confirmed Alzheimer disease (AD) have abnormal TDP-43 (abTDP-43) immunoreactivity. The aim of this study was to determine whether subjects with pathologically confirmed AD and abTDP-43 immunoreactivity have distinct clinical, neuropsychological, imaging, or pathologic features compared with subjects with AD without abTDP-43 immunoreactivity.
  
  
  METHODS
  Eighty-four subjects were identified who had a pathologic diagnosis of AD, neuropsychometric testing, and volumetric MRI. Immunohistochemistry for TDP-43 was performed on sections of hippocampus and medial temporal lobe, and positive cases were classified into one of three types. Neuropsychometric data were collated and compared in subjects with and without abTDP-43 immunoreactivity. Voxel-based morphometry was used to assess patterns of gray matter atrophy in subjects with and without abTDP-43 immunoreactivity compared with age- and sex-matched controls.
  
  
  RESULTS
  Twenty-nine (34%) of the 84 AD subjects had abTDP-43 immunoreactivity. Those with abTDP-43 immunoreactivity were older at onset and death and performed worse on the Clinical Dementia Rating scale, Mini-Mental State Examination, and Boston Naming Test than subjects without abTDP-43 immunoreactivity. Subjects with and without abTDP-43 immunoreactivity had medial temporal and temporoparietal gray matter loss compared with controls; however, those with abTDP-43 immunoreactivity showed greater hippocampal atrophy. Multivariate logistic regression adjusting for age at death demonstrated that hippocampal sclerosis was the only pathologic predictor of abTDP-43 immunoreactivity.
  
  
  CONCLUSIONS
  The presence of abnormal TDP-43 immunoreactivity is associated with a modified Alzheimer disease clinicopathologic and radiologic phenotype.
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA. josephs.keith@mayo.edu
authors.forename: K A
authors.initials: KA
authors.lastname: Josephs
authors.forename: J L
authors.initials: JL
authors.lastname: Whitwell
authors.forename: D S
authors.initials: DS
authors.lastname: Knopman
authors.forename: W T
authors.initials: WT
authors.lastname: Hu
authors.forename: D A
authors.initials: DA
authors.lastname: Stroh
authors.forename: M
authors.initials: M
authors.lastname: Baker
authors.forename: R
authors.initials: R
authors.lastname: Rademakers
authors.forename: B F
authors.initials: BF
authors.lastname: Boeve
authors.forename: J E
authors.initials: JE
authors.lastname: Parisi
authors.forename: G E
authors.initials: GE
authors.lastname: Smith
authors.forename: R J
authors.initials: RJ
authors.lastname: Ivnik
authors.forename: R C
authors.initials: RC
authors.lastname: Petersen
authors.forename: C R
authors.initials: CR
authors.lastname: Jack
authors.forename: D W
authors.initials: DW
authors.lastname: Dickson
mesh_terms: D000367:Age Factors; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D001284:Atrophy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D001344:Autopsy; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D009483:Neuropsychological Tests; D011237:Predictive Value of Tests; D011379:Prognosis; D013702:Temporal Lobe / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*
chemical_list: D015415:Biomarkers; D004268:DNA-Binding Proteins