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

By P. Giannakopoulos, F. Herrmann, T. Bussiere, C. Bouras, E. Kovari, D. Perl, John H. Morrison, Gabriel Gold, Patrick R. Hof. Neurology, 2003

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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.

Subfields: Applied Mathematics, Physiology, Psychiatry and Mental health

View Paper: https://www.semanticscholar.org/paper/d3ebfb6453280593d07d7faa8138a89ffe4bd19b

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Citations in the corpus

Classification and basic pathology of Alzheimer disease (2009, background): “This said, tau pathology has been almost invariably found to be the most reliable correlate of the cognitive deficit in the numerous correlative studies that have been published [31, 35, 37, 98, 122, 128, 243].”
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019, positive): “Unlike Aβ, the stage of tau pathology correlates well with progression of cognitive impairment (Giannakopoulos et al., 2003; Nelson et al., 2012).”
β-amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer's disease (2007, background): “While a strong relationship is evident between neurofibrillary tangles and cognition, consensus has not been reached on the relationship between Ab burden and cognition (Cummings, et al., 1996; Nagy et al., 1996; Bartoo et al., 1997; Kanne et al., 1998; Mufson et al., 1999; Bussière et al., 2002; Gi”
Tau and Aβ imaging, CSF measures, and cognition in Alzheimer's disease (2016, positive): “Consistent with this proposal, markers of tau pathology correlate more closely with changes in cognition compared to Ab measures (12).”