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Cited by 366Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchAmyotrophic Lateral Sclerosis Research

Staging TDP-43 pathology in Alzheimer’s disease

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Josephs, Keith A., Murray, Melissa E., Whitwell, Jennifer L., Parisi, Joseph E., Petrucelli, Leonard, Jack, Clifford R., Petersen, Ronald C., Dickson, Dennis W.·2014·Acta Neuropathologica
DOI 10.1007/s00401-013-1211-9PMC PMC3944799
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Abstract

TDP-43 immunoreactivity occurs in 19-57 % of Alzheimer's disease (AD) cases. Two patterns of TDP-43 deposition in AD have been described involving hippocampus (limbic) or hippocampus and neocortex (diffuse), although focal amygdala involvement has been observed. In 195 AD cases with TDP-43, we investigated regional TDP-43 immunoreactivity with the aim of developing a TDP-43 in AD staging scheme. TDP-43 immunoreactivity was assessed in amygdala, entorhinal cortex, subiculum, hippocampal dentate gyrus, occipitotemporal, inferior temporal and frontal cortices, and basal ganglia. Clinical, neuroimaging, genetic and pathological characteristics were assessed across stages. Five stages were identified: stage I showed scant-sparse TDP-43 in the amygdala only (17 %); stage II showed moderate-frequent amygdala TDP-43 with spread into entorhinal and subiculum (25 %); stage III showed further spread into dentate gyrus and occipitotemporal cortex (31 %); stage IV showed further spread into inferior temporal cortex (20 %); and stage V showed involvement of frontal cortex and basal ganglia (7 %). Cognition and medial temporal volumes differed across all stages and progression across stages correlated with worsening cognition and medial temporal volume loss. Compared to 147 AD patients without TDP-43, only the Boston Naming Test showed abnormalities in stage I. The findings demonstrate that TDP-43 deposition in AD progresses in a stereotypic manner that can be divided into five distinct topographic stages which are supported by correlations with clinical and neuroimaging features. Given these findings, we recommend sequential regional TDP-43 screening in AD beginning with the amygdala.

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  • Data from multiple reports suggest that between 19 and 75% of AD have TDP-43 neuronal inclusions.

    “Data from multiple reports suggest that between 19 and 75% of AD have TDP-43 neuronal inclusions [132].”

    From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [132]

    The Introduction (page unavailable) reviews multiple studies and reports TDP-43 in 19–57% of AD patients, supporting the lower bound but not the claimed 75% upper bound. The paper describes TDP-43 immunoreactivity, which its Materials and methods defines to include neuronal inclusions and dystrophic neurites. (LLM, conf=0.91)

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  • As TDP-43 distribution increases from limbic regions to other parts of the brain, it is associated with worsening cognition and medial temporal atrophy on antemortem brain imaging.

    “As the distribution of TDP-43 increases from limbic regions to other parts of the brain, it is associated with worsening cognition and with medial temporal atrophy on antemortem brain imaging [130, 132, 133].”

    From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [132]

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Cited by

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Authors
Josephs, K. A., Murray, M. E., Whitwell, J. L., Parisi, J. E., Petrucelli, L., Jack, C. R., Petersen, R. C., & Dickson, D. W.
Affiliations
Mayo Clinic (US)
Corresponding author
Josephs, Keith A.
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2013-11-16
Volume
127
Issue
3
Pages
441-450
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-013-1211-9
PMC
PMC3944799
OpenAlex
W2027177575
Cited by
366
References
2
Citations by year
2026: 31 · 2025: 42 · 2024: 30 · 2023: 37 · 2022: 18 · 2021: 30 · 2020: 38 · 2019: 28 · 2018: 30 · 2017: 27 · 2016: 21 · 2015: 23 · 2014: 11
FWCI
11.39
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Acta Neuropathologica (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (P01AG003949, R21AG038736, R01AG011378, R01AG037491, P50AG016574)
  • National Cancer Institute
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
TDP-43, Alzheimer's disease, amygdala, entorhinal cortex, subiculum, dentate gyrus, occipitotemporal cortex, inferior temporal cortex, frontal cortex, basal ganglia, cognitive decline, Boston Naming Test
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Brain, Cognition, DNA-Binding Proteins, Female, Humans, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Organ Size, Psychiatric Status Rating Scales, Severity of Illness Index, Disease Progression

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