Serotonin 1A receptors in the living brain of Alzheimer's disease patients.
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.
Kepe
Vladimir
V
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Barrio
Jorge R
JR
Huang
Sung-Cheng
SC
Ercoli
Linda
L
Siddarth
Prabha
P
Shoghi-Jadid
Kooresh
K
Cole
Gregory M
GM
Satyamurthy
Nagichettiar
N
Cummings
Jeffrey L
JL
Small
Gary W
GW
Phelps
Michael E
ME
D000544:Alzheimer Disease / Q000378:metabolism*; D001345:Autoradiography; D001921:Brain / Q000378:metabolism*; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008297:Male; D009570:Nitriles; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding / Q000502:physiology; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*
C444520:2-(1-(6-((2-fluoroethyl)(methyl)amino)-2-naphthyl)ethylidene)malononitrile; D009570:Nitriles; D019788:Fluorodeoxyglucose F18; D044282:Receptor, Serotonin, 5-HT1A