Serotonin 1A receptors in the living brain of Alzheimer's disease patients

doi:10.1073/pnas.0510237103

Serotonin 1A receptors in the living brain of Alzheimer's disease patients

Departments of ^*Molecular and Medical Pharmacology, ^‡Psychiatry and Biobehavioral Sciences, and ^¶Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and ^§VA Greater Los Angeles Healthcare System and Geriatric Research Education and Clinical Center, North Hills, CA 91343

Contributed by Michael E. Phelps, November 26, 2005

Abstract

4-[F-18]fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)benzamide, a selective serotonin 1A (5-HT_1A) molecular imaging probe, was used in conjunction with positron emission tomography (PET) for quantification of 5-HT_1A receptor densities in the living brains of Alzheimer's disease patients (ADs) (n = 8), subjects with mild cognitive impairment (n = 6), and controls (n = 5). ADs had receptor densities significantly decreased in both hippocampi (binding potential: controls 1.62 ± 0.07; ADs 1.18 ± 0.26) and also in raphe nuclei (controls 0.63 ± 0.09; ADs 0.37 ± 0.20). When volume losses are included, 5-HT_1A losses are even more severe (i.e., average mean decreases of 24% in mild cognitive impairment patients and 49% in ADs). A strong correlation of 5-HT_1A receptor decreases in hippocampus with worsening of clinical symptoms (Mini Mental State Exam scores) was also found. Moreover, these decreases in 5-HT_1A receptor measures correlate with decreased glucose utilization as measured with 2-deoxy-2-[F-18]fluoro-d-glucose PET in the brains of ADs (standardized uptake values; globally: controls 0.89 ± 0.04, ADs 0.72 ± 0.04; posterior cingulate gyrus: controls 1.05 ± 0.09, ADs 0.79 ± 0.11). They also inversely correlate with increased neuropathological loads measured with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile PET in several neocortical regions in the same subjects. The in vivo observations were confirmed independently by in vitro digital autoradiography with 4-[F-18]fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)benzamide and 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}-ethylidene)malononitrile on brain tissue specimens from two ADs and three nondemented subjects.

Footnotes

↵ † To whom correspondence may be addressed. E-mail: jbarrio{at}mednet.ucla.edu or mphelps{at}mednet.ucla.edu.
Conflict of interest statement: No conflicts declared.
Abbreviations: AD, Alzheimer's disease; ADs, AD patients; BP, binding potential; BPT, total binding potential; DVR, distribution volume ratio; [F-18]FDDNP, 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile; [F-18]FDG, 2-deoxy-2-[F-18]-fluoro-d-glucose; [F-18]MPPF, 4-[F-18]fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl}-N-(2-pyridinyl)benzamide; 5-HT^1A, serotonin 1A; LTL, lateral temporal lobe; MCI, mild cognitive impairment; MCI, MCI patients; MMSE, Mini Mental State Exam; MTL, medial temporal lobe; NFT, neurofibrillary tangle; PCG, posterior cingulate gyrus; PET, positron emission tomography; ROI, region of interest; SUVR, relative standardized uptake value.