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Beta-amyloid deposition and other measures of neuropathology predict cognitive status in Alzheimer's disease.

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 beta-amyloid immunoreactivity (A beta 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 dysfunction on all three cognitive measures was the relative area of entorhinal cortex occupied by beta-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.

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  • Authors+Show Affiliations

    ,

    Laboratory for Molecular Neuroscience, McLean Hospital/Harvard Medical School, Belmont, MA 02178, USA. cummings@helix.mgh.harvard.edu

    , ,

    Source

    Neurobiology of aging 17:6 pg 921-33

    MeSH

    Aged
    Aged, 80 and over
    Alzheimer Disease
    Amyloid beta-Peptides
    Brain
    Cell Count
    Entorhinal Cortex
    Female
    Fluorescent Dyes
    Humans
    Image Processing, Computer-Assisted
    Immunohistochemistry
    Male
    Neurobehavioral Manifestations
    Neurofibrillary Tangles
    Plaque, Amyloid
    Thiazoles

    Pub Type(s)

    Journal Article
    Research Support, U.S. Gov't, P.H.S.

    Language

    eng

    PubMed ID

    9363804

    Citation

    Cummings, B J., et al. "Beta-amyloid Deposition and Other Measures of Neuropathology Predict Cognitive Status in Alzheimer's Disease." Neurobiology of Aging, vol. 17, no. 6, 1996, pp. 921-33.
    Cummings BJ, Pike CJ, Shankle R, et al. Beta-amyloid deposition and other measures of neuropathology predict cognitive status in Alzheimer's disease. Neurobiol Aging. 1996;17(6):921-33.
    Cummings, B. J., Pike, C. J., Shankle, R., & Cotman, C. W. (1996). Beta-amyloid deposition and other measures of neuropathology predict cognitive status in Alzheimer's disease. Neurobiology of Aging, 17(6), pp. 921-33.
    Cummings BJ, et al. Beta-amyloid Deposition and Other Measures of Neuropathology Predict Cognitive Status in Alzheimer's Disease. Neurobiol Aging. 1996;17(6):921-33. PubMed PMID: 9363804.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Beta-amyloid deposition and other measures of neuropathology predict cognitive status in Alzheimer's disease. AU - Cummings,B J, AU - Pike,C J, AU - Shankle,R, AU - Cotman,C W, PY - 1996/11/1/pubmed PY - 1997/11/18/medline PY - 1996/11/1/entrez SP - 921 EP - 33 JF - Neurobiology of aging JO - Neurobiol. Aging VL - 17 IS - 6 N2 - 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 beta-amyloid immunoreactivity (A beta 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 dysfunction on all three cognitive measures was the relative area of entorhinal cortex occupied by beta-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. SN - 0197-4580 UR - https://www.unboundmedicine.com/medline/citation/9363804/Beta_amyloid_deposition_and_other_measures_of_neuropathology_predict_cognitive_status_in_Alzheimer's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0197458096001704 DB - PRIME DP - Unbound Medicine ER -