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Vahram Haroutunian, PhD; Dushyant P. Purohit, MD; Daniel P. Perl, MD; Deborah Marin, MD; Khalid Khan, MD; Melinda Lantz, MD; Kenneth L. Davis, MD; Richard C. Mohs, PhD

Arch Neurol. 1999;56:713-718.

Background  The relationship between neuropathological lesions and mild, "preclinical," cognitive impairments of Alzheimer disease is poorly understood. Identification of the lesions that are most closely associated with the earliest symptoms of Alzheimer disease is crucial to the understanding of the disease process and the development of treatment strategies to affect its progression.

Design and Main Outcome Measures  We examined the extent of neurofibrillary tangles (NFTs) in 4 neocortical regions, the hippocampus, the entorhinal cortex, and the amygdala in 65 elderly subjects with no dementia, questionable dementia, mild dementia, or moderate dementia as assessed using the Clinical Dementia Rating Scale (CDR).

Setting and Patients  Postmortem study of nursing home residents.

Results  Neurofibrillary tangles were present in the entorhinal cortex and the hippocampus of all subjects, including those without cognitive deficits. Neocortical NFTs were mostly absent in the nondemented (CDR score, 0.0) subjects. The density of NFTs in the questionably demented (CDR score, 0.5) subjects was not significantly increased (P>.20) relative to the nondemented group in any of the brain regions studied. Significant increases (P<.04) in NFT density become apparent first in the amygdala and the temporal cortex in subjects rated to be mildly impaired (CDR score, 1.0). By the time that cognitive impairments were judged to be moderately severe (CDR score, 2.0), all regions of the brain examined, except for the occipital cortex, were significantly (P<.05) involved.

Conclusions  Some NFTs are present in the entorhinal cortex and hippocampus of most elderly individuals irrespective of their cognitive status, but the density of NFTs increases as a function of dementia severity.

From the Departments of Psychiatry (Drs Haroutunian, Marin, Khan, Davis, and Mohs) and Pathology (Drs Purohit and Perl), The Mount Sinai School of Medicine, New York, NY; Psychiatry Service, Bronx Veteran Affairs Medical Center, Bronx, NY (Drs Haroutunian, Purohit, Perl, Marin, Khan, Davis, and Mohs) ; and Jewish Home and Hospital, New York (Dr Lantz).

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