Cited by 147Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis Research

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TAR DNA‐binding protein 43 and pathological subtype of Alzheimer's disease impact clinical features

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Josephs, Keith A., Whitwell, Jennifer L., Tosakulwong, Nirubol, Weigand, Stephen D., Murray, Melissa E., Liesinger, Amanda M., Petrucelli, Leonard, Senjem, Matthew L., Ivnik, Robert J., Parisi, Joseph E., Petersen, Ronald C., Dickson, Dennis W.·2015·Annals of Neurology

DOI 10.1002/ana.24493PMC PMC4623932

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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). INTERPRETATION: 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.

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Authors: Josephs, K. A., Whitwell, J. L., Tosakulwong, N., Weigand, S. D., Murray, M. E., Liesinger, A. M., Petrucelli, L., Senjem, M. L., Ivnik, R. J., Parisi, J. E., Petersen, R. C., & Dickson, D. W.
Affiliations: Departments of Neurology (Behavioral Neurology)
Radiology (Radiology Research)
Health Science Research (Biostatistics)
Mayo Clinic (US)
Neuropsychiatry (Neuropsychology)
Laboratory Medicine and Pathology (Neuropathology)
Corresponding author: Josephs, Keith A.
ORCID: Josephs, Keith A.
Whitwell, Jennifer L.
Tosakulwong, Nirubol
Weigand, Stephen D.
Murray, Melissa E.
Petrucelli, Leonard
Senjem, Matthew L.
Petersen, Ronald C.
Dickson, Dennis W.
Venue: Annals of Neurology
Publisher: Wiley
Published: 2015-09-16
Volume: 78
Issue: 5
Pages: 697-709
ISSN: 0364-5134 (ISSN-L)
1531-8249
DOI: 10.1002/ana.24493
PMC: PMC4623932
OpenAlex: W1921675910
Cited by: 147
References: 39
Citations by year: 2026: 20 · 2025: 15 · 2024: 20 · 2023: 7 · 2022: 16 · 2021: 10 · 2020: 26 · 2019: 12 · 2018: 5 · 2017: 9 · 2016: 7
FWCI: 5.69
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Annals of Neurology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (R01 AG037491 [K.A.J.], R21-AG038736 [J.L.W.], and P50-AG016574 [R.C.P.])
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
Keywords: TDP-43, Alzheimer's disease, pathological subtypes, hippocampal sparing, typical Alzheimer's disease, neurofibrillary tangles, clinical features, hippocampal volume, memory loss, functional decline
MeSH terms: Aged, Aged, 80 and over, Alzheimer Disease, Cognition, DNA-Binding Proteins, Female, Gene Frequency, Hippocampus, Humans, Limbic System, Male, Memory Disorders, Middle Aged, Neuropsychological Tests, Psychomotor Performance, Neurofibrillary Tangles, Age of Onset, Disease Progression, Neocortex, TDP-43 Proteinopathies

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TAR DNA‐binding protein 43 and pathological subtype of Alzheimer's disease impact clinical features

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