Regular Article
Localization of Neurofibrillary Tangles and Beta-Amyloid Plaques in the Brains of Living Patients With Alzheimer Disease

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The authors used 2-(1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([18F]FDDNP), a hydrophobic radiofluorinated derivative of 2-{1-[6-(dimethylamino)-2-naphthyl]ethylidene}malononitrile (DDNP), in conjunction with positron emission tomography to determine the localization and load of neurofibrillary tangles (NFTs) and β-amyloid senile plaques (APs) in the brains of living Alzheimer disease (AD) patients. Previous work illustrated the in vitro binding characteristics of [18F]FDDNP to synthetic β-amyloid(1–40) fibrils and to NFTs and APs in human AD brain specimens. In the present study, greater accumulation and slower clearance was observed in AP- and NFT-dense brain areas and correlated with lower memory performance scores. The relative residence time of the probe in brain regions affected by AD was significantly greater in patients with AD (n=9) than in control subjects (n=7; p=0.0007). This noninvasive technique for monitoring AP and NFT development is expected to facilitate diagnostic assessment of patients with AD and assist in response-monitoring during experimental treatments.

Section snippets

Preparation of 2-(1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2 naphthyl}ethylidene)malononitrile ([18F]FDDNP)

1-(6-methoxy-2-naphthyl)ethanone was subjected to demethylation in boiling hydrochloric acid to give 1-(6-hydroxy-2-naphthyl)ethanone. The Bucherer reaction with 2-(methylamino)ethanol gave 1-{6-[(2-hydroxyethyl)(methyl)amino]-2-naphthyl}ethanone, which, when reacted with malononitrile under the conditions of the Knoevenagel reaction, yielded 2-(1-{6-[(2-hydroxyethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (Figure 1: 3). Reaction of the compound (Figure 1: 3) with

RESULTS

Table 1 summarizes the clinical and demographic information on the two subject groups. Although, on average, patients with AD (n=9) were older and had fewer years of education than control subjects (n=7), these differences were not statistically significant (Age: Wilcoxon-Mann-Whitney statistic=50; exact p=0.33; Education: Wilcoxon Mann-Whitney statistic=71.5; exact p=0.22).

[18F]FDDNP crosses the blood–brain barrier very rapidly in proportion to blood flow, as can be seen in Figure 2, where ROI

DISCUSSION

This work demonstrates, for the first time, the in vivo detection of pathological deposition (i.e., NFTs and APs) in the brain of living AD patients. Earlier attempts to use monoclonal antibodies as probes for in vivo imaging of APs were hampered by their limited ability to cross the blood–brain barrier.33 Congo red, widely used in vitro to label AP, is a charged molecule and lacks sufficient hydrophobicity for diffusion through the blood–brain barrier.34 Chrysamine G enters the blood–brain

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    We thank R. Sumida, L. Pan, F. Aguilar (tomographic determinations), D. Dorsey, A. Kaplan, J.L. Cummings and his staff (patient management), B. Amarasekera (cyclotron), D. Stout, and R. Yee (biochemistry). We also thank Dr. Donald Guthrie for his invaluable statistical insight.

    This work is supported in part by Department of Energy Grant DE-FC0387-ER60615, the Charles A. Dana Foundation, the Alzheimer's Association Zenith Award, and The Institute for the Study of Aging, Inc.

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