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

Arch Neurol. 1998;55:1185-1191.

Background  Identification of the neuropathological lesions that are most closely associated with the earliest symptoms of Alzheimer disease (AD) is crucial to the understanding of the disease process and the development of treatment strategies to affect its progress. Do the classical neuropathological lesions of AD precede, follow, or occur in synchrony with the earliest signs of cognitive deterioration?

Design and Outcome Measures  We examined the extent of neuritic plaque (NP) formation in 5 neocortical regions and the hippocampus, entorhinal cortex, and amygdala in 66 elderly subjects with no dementia, questionable dementia, or mild dementia as assessed using the Clinical Dementia Rating Scale (CDR).

Setting and Patients  Postmortem study of nursing home residents.

Results  Even questionable dementia (CDR, 0.5) was associated with a significant (P=.04) increase in neocortical NP density. The density of NPs increased further with increasing dementia severity in all brain regions examined. However, subjects with questionable dementia or definite but mild dementia did not differ significantly from each other. Density of NPs was nearly maximal in subjects with moderate dementia (CDR=2.0), suggesting that other neuropathological changes may be responsible for cognitive deficits beyond this level. Dementia severity correlated significantly with the density of NPs in all brain regions examined (r range, 0.47-0.56; P <.001), even when subjects with a CDR of 0 were excluded.

Conclusions  These findings are consistent with the hypothesis that NPs are among the earliest neuropathological lesions in AD. Even very mild or questionable dementia is associated with increased density of neocortical NPs that do not distinguish between clinically questionable vs definite dementia.

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

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