Cited by 1,118Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease

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Giannakopoulos, P., Herrmann, F. R., Bussière, T., Bouras, C., Kövari, E., Perl, D. P., Morrison, J. H., Gold, G. +1 more·2003·Neurology

Abstract

OBJECTIVE: To examine the relationship between stereologic estimates of AD-related pathology and severity of cognitive deficits in brain aging. BACKGROUND: Previous studies reported substantial contributions of neurofibrillary tangles (NFT), amyloid deposits, and neuronal loss to the development of dementia. However, the prediction of cognitive status based on nonstereologic quantification of these measures has led to conflicting results. Such studies have measured densities, rather than absolute numbers, and most do not take into account the potential interaction between the above pathologic hallmarks in a global multivariate analysis. METHODS: Clinicopathologic study in 22 elderly cases. Cognitive status assessed prospectively using the Mini-Mental State Examination (MMSE); stereologic assessment of NFT, unaffected neurons, and total amyloid volume in the CA1 field of the hippocampus, entorhinal cortex, and area 9. Statistical analysis was performed using both univariate and multivariate linear regression models. RESULTS: High total NFT counts but not amyloid volume were strongly associated with a lower number of unaffected neurons in all areas studied. A high proportion of variability in MMSE scores was explained by NFT and neuronal counts in the CA1 field (83% and 85.4%), entorhinal cortex (87.8% and 83.7%), and area 9 (87% and 79%); amyloid volume in the entorhinal cortex, but not in the CA1 field and area 9, accounted for 58.5% of MMSE variability. Multivariate analyses showed that total NFT counts in the entorhinal cortex and area 9 as well as neuron numbers in the CA1 field were the best predictors of MMSE score. CONCLUSIONS: These new stereologic data indicate that neuronal pathology in hippocampal formation and frontal cortex closely reflects the progression of cognitive deficits in brain aging and AD. They also demonstrate that amyloid volume has no additional predictive value, in terms of clinicopathologic correlations, beyond its interaction with NFT.

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Crossref · 10.1212/01.wnl.0000063311.58879.01

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  • Extracellular amyloid plaque deposits have a poor correlation with disease status.

    “Even though extracellular amyloid plaque deposits had long been considered the principal players in the development and progression of AD, this association has been challenged by a poor correlation with the disease status [11]”
  • Loss of neurons in the CA1 region of the hippocampus and in the entorhinal cortex seems to correlate with the severity of memory deficits.

    “In particular, loss of neurons in the CA1 region of the hippocampus [22,23] and in the entorhinal cortex seems to correlate with the severity of memory deficits [11].”
  • Cognitive impairment correlates with the number of neurofibrillary tangles.

    “Cognitive impairment correlates with the number of neurofibrillary tangles137, which selectively affect highly connected pyramidal cells in association cortex but not in primary sensory cortex6,138,139.”
  • Occurrence of Tau deposits correlates with the loss of cognitive functions in Alzheimer's disease.

    “Occurrence of Tau deposits correlates with the loss of cognitive functions in AD, suggesting a connection between Tau and synaptic transmission20.”
  • Pathological tau aggregates, in the absence of amyloid plaques, can induce neurotoxicity, chronic brain inflammation, and subsequent cognitive impairment in primary human tauopathies including Pick's disease, progressive supranuclear palsy, and corticobasal degeneration.

    “pathological tau aggregates, in the absence of amyloid plaques, can induce neurotoxicity, chronic brain inflammation, and subsequent cognitive impairment in many primary human tauopathies, including Pick's disease (PiD), progressive supranuclear palsy (PSP), and corticobasal degeneration. 4 , 5 , 6”

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Authors
Giannakopoulos, P., Herrmann, F. R., Bussière, T., Bouras, C., Kövari, E., Perl, D. P., Morrison, J. H., Gold, G., & Hof, P. R.
Affiliations
  • University of Geneva (CH)
  • From the Departments of Psychiatry (Drs. Giannakopoulos, Bouras, and Kövari) and Geriatrics (Drs. Herrmann and Gold), HUG Belle-Idée, University of Geneva School of Medicine; Department of Psychogeriatrics (Dr. Giannakopoulos), University of Lausanne School of Medicine, Switzerland; Kastor Neurobiology of Aging Laboratories and Fishberg Research Center for Neurobiology (Drs. Bussière, Bouras, Perl, Morrison, and Hof) and Departments of Geriatrics and Adult Development (Drs. Morrison and Hof),...
Venue
Neurology
Published
2003-05-13
Volume
60
Issue
9
Pages
1495-1500
ISSN
  • 0028-3878 (ISSN-L)
  • 1526-632X
OpenAlex
W2066792703
Cited by
1,118
References
49
Citations by year
2026: 27 · 2025: 52 · 2024: 57 · 2023: 60 · 2022: 64 · 2021: 72 · 2020: 87 · 2019: 64 · 2018: 65 · 2017: 54 · 2016: 62 · 2015: 56 · 2014: 56 · 2013: 45 · 2012: 51
FWCI
11.66
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • IRIS (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion)
Funders
National Institute on Aging (AG-02219, AG 05138, P50AG005138, P01AG002219)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
Alzheimer's disease, neurofibrillary tangles, amyloid plaques, neuronal loss, cognitive decline, stereology, hippocampal CA1, entorhinal cortex, frontal cortex, amygdala, Mini-Mental State Examination, dementia prediction, clinicopathological correlation
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Cognition, Female, Frontal Lobe, Hippocampus, Humans, Male, Middle Aged, Neuropsychological Tests, Peptide Fragments, Severity of Illness Index, Single-Blind Method, Amyloid beta-Peptides, Neurofibrillary Tangles, tau Proteins, Entorhinal Cortex

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