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Brains With Medial Temporal Lobe Neurofibrillary Tangles But No Neuritic Amyloid Plaques Are a Diagnostic Dilemma But May Have Pathogenetic Aspects Distinct From Alzheimer Disease
Open accessAbstract
Brains that have many neurofibrillary tangles (NFTs) in medial temporal lobe structures (Braak stage III or IV) but no cortical neuritic plaques (NPs) may be a diagnostic dilemma; they also raise questions about the amyloid cascade hypothesis of Alzheimer disease (AD) in which NFT development is thought to occur downstream of the development of amyloid plaques. To determine the clinical, demographic, and biological factors related to NFT+/NP- cases, we analyzed 26 NFT+/NP- patient brains identified from the University of Kentucky AD Center autopsy cohort (n=502); most of these patients were at least 85 years old and lacked profound antemortem cognitive impairment. A subset of the cases had NFTs in the medulla oblongata. Aberrant trans-activator regulatory DNA-binding protein 43 immunohistochemical staining was seen in 5 of the 26 cases with the clinical diagnoses of AD or mild cognitive impairment. We also queried cases in the National Alzheimer's Coordinating Center Registry (n=5,108) and found 219 NFT+/NP- cases. Those patients had a relatively high likelihood of belonging to a birth cohort with the highest incidence of influenza infection during the 1918 to 1919 pandemic. This observation may link the pathogenesis in NFT+/NP- cases to encephalitis during childhood. We conclude that NFT+/NP- cases comprise approximately 5% of aged individuals in multiple data sets; these cases are not necessarily within the spectrum of AD.
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“In addition, mesial temporal lobe NFTs in the absence of substantial Aβ or neuritic plaque can occur in older individuals without cognitive impairment, those with mild impairment, or those with cognitive impairment associated with other causes than AD.”
From Positron Emission Tomography Imaging With [ 18 F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes (2020) · cites this paper as [46]
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“Recently, it has been reported that NFTs are also very common in certain brainstem nuclei in subjects without dementia (39-44).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [41]
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Metadata
- Authors
- Nelson, P. T., Abner, E. L., Schmitt, F. A., Kryscio, R. J., Jicha, G. A., Santacruz, K., Smith, C. D., Patel, E., & Markesbery, W. R.
- Affiliations
- University of Kentucky (US)
- Corresponding author
- Nelson, Peter T.
- ORCID
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-07
- Volume
- 68
- Issue
- 7
- Pages
- 774-784
- ISSN
- 0022-3069 (ISSN-L)
- 1554-6578
- PMC
- PMC2725359
- OpenAlex
- W2040124543
- Cited by
- 115
- References
- 74
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 7 · 2023: 6 · 2022: 7 · 2021: 10 · 2020: 6 · 2019: 2 · 2018: 3 · 2017: 9 · 2016: 5 · 2015: 6 · 2014: 5 · 2013: 11 · 2012: 6
- FWCI
- 4.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (AG028 383, NS061933)
- National Institute on Aging (P30AG028383, U01AG016976)
- National Institute of Neurological Disorders and Stroke (R01NS061933, K08NS050110)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- neurofibrillary tangles, neuritic plaques, Alzheimer's disease, medial temporal lobe, amyloid hypothesis, tau protein, medulla oblongata, pediatric encephalitis, mild cognitive impairment, differential diagnosis, Braak staging
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Brain, Cerebral Cortex, Cognition Disorders, Female, Humans, Immunohistochemistry, Influenza, Human, Male, Neurons, Temporal Lobe, Cohort Studies, Incidence, Neurofibrillary Tangles, Plaque, Amyloid
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