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.
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: S M Sawrie; R C Martin; F G Gilliam; R E Faught; B Maton; J W Hugg; N Bush; K Sinclair; R I Kuzniecky Journal: Brain Date: 2000-04 Impact factor: 13.501
Authors: Jennifer L Whitwell; Stephen D Weigand; Maria M Shiung; Bradley F Boeve; Tanis J Ferman; Glenn E Smith; David S Knopman; Ronald C Petersen; Eduardo E Benarroch; Keith A Josephs; Clifford R Jack Journal: Brain Date: 2007-01-31 Impact factor: 13.501
Authors: Nigel J Cairns; Manuela Neumann; Eileen H Bigio; Ida E Holm; Dirk Troost; Kimmo J Hatanpaa; Chan Foong; Charles L White; Julie A Schneider; Hans A Kretzschmar; Deborah Carter; Lisa Taylor-Reinwald; Katherine Paulsmeyer; Jeffrey Strider; Michael Gitcho; Alison M Goate; John C Morris; Manjari Mishra; Linda K Kwong; Anna Stieber; Yan Xu; Mark S Forman; John Q Trojanowski; Virginia M-Y Lee; Ian R A Mackenzie Journal: Am J Pathol Date: 2007-07 Impact factor: 4.307
Authors: Catalina Amador-Ortiz; Wen-Lang Lin; Zeshan Ahmed; David Personett; Peter Davies; Ranjan Duara; Neill R Graff-Radford; Michael L Hutton; Dennis W Dickson Journal: Ann Neurol Date: 2007-05 Impact factor: 10.422
Authors: Hanae Nakashima-Yasuda; Kunihiro Uryu; John Robinson; Sharon X Xie; Howard Hurtig; John E Duda; Steven E Arnold; Andrew Siderowf; Murray Grossman; James B Leverenz; Randy Woltjer; Oscar L Lopez; Ronald Hamilton; Debby W Tsuang; Douglas Galasko; Eliezer Masliah; Jeffrey Kaye; Christopher M Clark; Thomas J Montine; Virginia M-Y Lee; John Q Trojanowski Journal: Acta Neuropathol Date: 2007-07-25 Impact factor: 17.088
Authors: E Cavedo; S Lista; Z Khachaturian; P Aisen; P Amouyel; K Herholz; C R Jack; R Sperling; J Cummings; K Blennow; S O'Bryant; G B Frisoni; A Khachaturian; M Kivipelto; W Klunk; K Broich; S Andrieu; M Thiebaut de Schotten; J-F Mangin; A A Lammertsma; K Johnson; S Teipel; A Drzezga; A Bokde; O Colliot; H Bakardjian; H Zetterberg; B Dubois; B Vellas; L S Schneider; H Hampel Journal: J Prev Alzheimers Dis Date: 2014-12
Authors: Keith A Josephs; Jennifer L Whitwell; Stephen D Weigand; Melissa E Murray; Nirubol Tosakulwong; Amanda M Liesinger; Leonard Petrucelli; Matthew L Senjem; David S Knopman; Bradley F Boeve; Robert J Ivnik; Glenn E Smith; Clifford R Jack; Joseph E Parisi; Ronald C Petersen; Dennis W Dickson Journal: Acta Neuropathol Date: 2014-03-23 Impact factor: 17.088
Authors: William T Hu; Keith A Josephs; David S Knopman; Bradley F Boeve; Dennis W Dickson; Ronald C Petersen; Joseph E Parisi Journal: Acta Neuropathol Date: 2008-07-01 Impact factor: 17.088
Authors: Keith A Josephs; Melissa E Murray; Nirubol Tosakulwong; Stephen D Weigand; Amanda M Serie; Ralph B Perkerson; Billie J Matchett; Clifford R Jack; David S Knopman; Ronald C Petersen; Joseph E Parisi; Leonard Petrucelli; Matthew Baker; Rosa Rademakers; Jennifer L Whitwell; Dennis W Dickson Journal: Acta Neuropathol Date: 2019-01-02 Impact factor: 17.088
Authors: Anil Varma V Vatsavayi; Julia Kofler; Mary Ann A Demichele-Sweet; Patrick S Murray; Oscar L Lopez; Robert A Sweet Journal: Int Psychogeriatr Date: 2014-03-04 Impact factor: 3.878
Authors: Bryan D James; Robert S Wilson; Patricia A Boyle; John Q Trojanowski; David A Bennett; Julie A Schneider Journal: Brain Date: 2016-11-01 Impact factor: 13.501
Authors: Margaret E Flanagan; Brenna Cholerton; Caitlin S Latimer; Laura S Hemmy; Steven D Edland; Kathleen S Montine; Lon R White; Thomas J Montine Journal: J Alzheimers Dis Date: 2018 Impact factor: 4.472