ArticlesThe Neuropathological Diagnosis of Alzheimer’s Disease: Clinical-Pathological Studies
Section snippets
What Is the Definition of Alzheimer’s Disease?
Alzheimer’s disease is a clinical-pathological syndrome in which clinical dementia is due to Alzheimer’s disease-type neuropathological lesions. Current neuropathological criteria specify different numbers of plaques necessary for the diagnosis based on whether a clinical history of dementia is available and on age [27]. I believe that linking neuropathological diagnosis to clinical information is a conceptual mistake and will argue for a formal separation of pathological evaluation from
What Lesions Should the Neuropathologist Report As “Abnormal”?
From a practical perspective, there are two robust positive phenomenon (i.e., things that can be seen) and two negative phenomenon (i.e., things that can be inferred) clearly associated with Alzheimer’s disease. The two positive phenomenon, neurofibrillary tangles and senile plaques, are most useful for diagnosis. The two negative phenomenon, loss of synapses (as judged by electron microscopy or confocal microscopy of synaptophysin immunostaining) and loss of neurons (as assessed with
Staging of Alzheimer’s Disease Lesions
Braak and Braak [7]have taken advantage of this consistent pattern of hierarchical vulnerability that is evident in detailed topographical maps of Alzheimer’s disease lesions 1, 8to propose a “staging” scheme for Alzheimer’s disease. Because of the lack of correlations of plaques with clinical symptoms and the variability in plaque numbers, the staging scheme is entirely dependent on tangle formation and does not rely on plaque formation at all. The staging scheme enumerates six stages, moving
Relationship of Alzheimer’s Disease Lesions to Aging
A related issue to the question of “what lesions should a neuropathologist report” is whether any observed neurofibrillary tangles or senile plaques represent a disease process or are a nonspecific age-related phenomenon. The occurrence of both these lesions is strongly age-related, and age is unquestionably the strongest risk factor for developing neurofibrillary tangles or senile plaques (e.g., see [3]). There are frequently some tangles in the entorhinal cortex and related medial temporal
Clinical-Pathological Correlations
In the last section, I highlighted work from our laboratory and that of several other groups that are for the most part mutually reinforcing. Quantitative assessment of lesions is a worthwhile goal for research protocols within a laboratory, but standardization among laboratories is difficult. Such quantitative studies now often use computerized image analysis systems and sensitive immunostains or modified silver stains, apply stereological principles 13, 39, 40to counting, and take into
Summary and Recommendations
Current criteria for Alzheimer’s disease are based on numbers of senile plaques in a scale that is modified by clinical history and age. My laboratory’s experience in studying clinical-pathological correlations argues for a separation of the description of neuropathological changes from the clinical history. Whether or not specific lesions are symptomatic (and what is meant by symptomatic) should not be the primary focus of the neuropathologist’s task. I suggest instead that the
Acknowledgements
The work presented in this paper was supported through the NIA (AG08487), an award to the Massachusetts Alzheimer Disease Research Center (P50AG05134), and an award from the Alzheimer’s Association.
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