Elsevier

Neurobiology of Aging

Volume 17, Issue 6, November–December 1996, Pages 921-933
Neurobiology of Aging

Open peer commentary
β-amyloid deposition and other measures of neuropathology predict cognitive status in Alzheimer's disease

https://doi.org/10.1016/S0197-4580(96)00170-4Get rights and content

Abstract

The relationship between progressive cognitive decline and underlying neuropathology associated with Alzheimer s disease (AD) is a key issue in defining the mechanisms responsible for functional loss. This has been a subject of much controversy, with separate studies comparing various clinical and neuropathological indices in AD. Further, it is difficult to compare studies with differences in histochemical staining protocols, brain regions examined, and data quantification criteria. There are many difficulties in designing a clinical-pathological correlative study involving AD patients. It is necessary to control for several key parameters. For example, a broad range of cognitively impaired subjects is needed, as well as short postmortem delays, brief intervals between cognitive testing and death, and the most sensitive detection and quantification techniques. In this study, we carefully controlled for each of these parameters to determine if there is a relationship between global cognitive dysfunction and multiple neuropathological indices. We selected 20 individuals representing a broad range of cognitive ability from normal to severely impaired based on the MMSE, Blessed IMC, and CDR. We counted plaque number, NFT number, dystrophic neurite number, and the relative extent of thioflavine positive plaques and neuritic involvement within plaques. We also quantified cortical area occupied by β-amyloid immunoreactivity (Aβ Load) and PHF-1 positive neuropil threads and tangles (PHF Load) using computer-based image analysis. Interestingly, we found that most pathologic measures correlated highly with the severity of dementia. However, the strongest predictor of premortem cognitive dysfun of entorhinal cortex occupied by β-amyloid deposition. In conclusion, our data show that in a carefully controlled correlative study, a variety of neuropathological variables are strongly correlated with cognitive impairment. Plaque related variables may be as strongly related to cognitive dysfunction as other established measures, including synapse loss, cell death and tau hyperphosphorylation, although no correlative study can demonstrate causality.

References (90)

  • C. Duyckaerts et al.

    Rating of the lesions in senile dementia of the Alzheimer type: Concordance between laboratories

    J. Neurol. Sci.

    (1990)
  • C. Duyckaerts et al.

    Does amyloid precede paired helical filaments in the senile plaque? A study of 15 cases with graded intellectual status in aging and Alzheimer disease

    Neurosci. Lett.

    (1988)
  • S.L. Eastwood et al.

    Synaptophysin gene expression in human brain: A quantitative in situ hybridization and immunocytochemical study

    Neuroscience

    (1994)
  • M.F. Folstein et al.

    Mini-mental state. A practical method for grading the cognitive state of patients for the clinician

    J. Psychiatr. Res.

    (1975)
  • K. Furukawa et al.

    Flow cytometric analysis on cytotoxic action of amyloid beta protein fragment 25–35 on brain neurons dissociated from the rats

    Brain Res.

    (1994)
  • Z. Galdzicki et al.

    βeta-Amyloid increases choline conductance of PC12 cells: Possible mechanism of toxicity in Alzheimer's disease

    Brain Res.

    (1994)
  • J.W. Geddes et al.

    Senile plaques as aberrant sprout-stimulating structures

    Exp. Neurol.

    (1986)
  • S.G. Greenberg et al.

    Hydrofluoric acid-treated tau PHF proteins display the same biochemical properties as normal tau

    J. Biol. Chem.

    (1992)
  • O. Heinonen et al.

    Loss of synaptophysin-like immunoreactivity in the hippocampal formation is an early phenomenon in Alzheimer's disease

    Neuroscience

    (1995)
  • J.Y. Koh et al.

    β-Amyloid protein increases the vulnerability of cultured cortical neurons to excitotoxic damage

    Brain Res.

    (1990)
  • W.E. Muller et al.

    Beta-Amyloid peptide decreases membrane fluidity

    Brain Res.

    (1995)
  • C.J. Pike et al.

    β-Amyloid-induced changes in cultured astrocytes parallel reactive astrocytosis associated with senile plaques in Alzheimer's disease

    Neuroscience

    (1994)
  • J.H. Su et al.

    Subpopulations of dystrophic neurites in Alzheimer's brain with distinct immunocytochemical and argentophilic characteristics

    Brain Res.

    (1994)
  • G.K. Wilcock et al.

    Plaques, tangles and dementia

    J. Neurol. Sci.

    (1982)
  • A. Yang et al.

    Intracellular Aβ1–42 aggregates stimulate the accumulation of stable, insoluble amyloidogenic fragments of the amyloid precursor protein in transfected cells

    J. Biol. Chem.

    (1995)
  • M.F. Alford et al.

    A simple dot-immunobinding assay for quantification of synaptophysin-like immunoreactivity in human brain

    J. Histochem. Cytochem.

    (1994)
  • P.V. Arriagada et al.

    Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease

    Neurology

    (1992)
  • L. Berg et al.

    Neuropathological indexes of Alzheimer's disease in demented and nondemented persons aged 80 years and older

    Arch. Neurol.

    (1993)
  • L.M. Bierer et al.

    Neocortical neurofibrillary tangles correlate with dementia severity in Alzheimer's disease

    Arch. Neurol.

    (1995)
  • G. Blessed et al.

    The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects

    Br. J. Psychiatry

    (1968)
  • H. Braak et al.

    Neuropathological stageing of Alzheimer-related changes

    Acta Neuropathol.

    (1991)
  • J.R. Brorson et al.

    The Ca2+ influx induced by beta-amyloid peptide 25–35 in cultured hippocampal neurons results from network excitation

    J. Neurobiol.

    (1995)
  • M. Citron et al.

    Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production

    Nature

    (1992)
  • C.W. Cotman et al.

    β-amyloid and its contributions to neurodegeneration in Alzheimer's disease

  • C.W. Cotman et al.

    Molecular cascades in adaptive vs. pathologic plasticity

  • S.T. DeKosky et al.

    Synapse loss in frontal cortex biopsies in Alzheimer's disease: Correlation with cognitive severity

    Ann. Neurol.

    (1990)
  • P. Delaère et al.

    Tau, paried helical filaments and amyloid in the neocortex: A morphometric study of 15 cases with graded intellectual status in aging and senile dementia of Alzheimer type

    Acta Neuropathol.

    (1989)
  • D.W. Dickson et al.

    Correlations of synaptic and pathologic markers with cognition of the elderly

    Neurobiol. Aging

    (1995)
  • P. Fuld

    Psychological testing in the differential diagnosis of dementias

  • P.A. Fuld et al.

    Primitive plaques and memory dysfunction in normal and impaired elderly persons

    N. Engl. J. Med.

    (1987)
  • K. Furukawa et al.

    Amyloid beta protein-induced irreversible current in rat cortical neurones

    Neuroreport

    (1994)
  • D. Games et al.

    Alzheimer-type neurophatology in transgenic mice overexpressing V717F beta-amyloid precursor protein

    Nature

    (1995)
  • S.G. Greenberg et al.

    A preparation of Alzheimer paired helical filaments that displays distinct tau proteins by polyacrylamide gel electrophoresis

  • Y. He et al.

    Two distinct ubiquitin immunoreactive senile plaques in Alzheimer's disease: Relationship with the intellectual status in 29 cases

    Acta Neuropathol. (Berl.)

    (1993)
  • Y. He et al.

    Alzheimer's lesions labelled by anti-ubiquitin antibodies: Comparison with other staining techniques. A study of 15 cases with graded intellectual status in ageing and Alzheimer's disease

    Neuropathol. Appl. Neurobiol.

    (1993)
  • Cited by (279)

    • Relationship between frailty and Alzheimer's disease biomarkers: A scoping review

      2018, Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring
    • Protein and Peptides for Elderly Health

      2018, Advances in Protein Chemistry and Structural Biology
    View all citing articles on Scopus
    View full text