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The Neuropathological Diagnosis of Alzheimer’s Disease: Clinical-Pathological Studies

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Abstract

The neuropathological diagnosis of Alzheimer’s disease currently relies on quantitative or semiquantitative criteria of senile or neuritic plaques that are adjusted for age and for the presence or absence of a clinical history of dementia. Based on clinical-pathological correlation studies, I will argue that neuropathological assessment should stand independently of clinical history and instead should describe brain lesions in the context of the topography and natural history of the disease. Only probabalistic estimates about the presence or absence of dementia can be made from a neuropathological examination, especially in the setting of Alzheimer disease lesions plus other pathological alterations such as Lewy bodies or infarcts. Moreover, I will argue that any neurofibrillary tangles or senile plaques are inherently pathological entities, even if clinically silent and so “incidental” neuropathological findings. Because the intensity and location of neurofibrillary tangles, rather than senile plaques, appears to correlate most closely with clinical symptoms, I suggest using a staging system that highlights this information rather than using absolute numerical cut-offs for diagnostic purposes.

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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