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Up-regulation of hippocampal serotonin metabolism in mild cognitive impairment

From the Service de Neurologie D (L.T., B.C., B.M., M.H., A.V., P.K.-S.), Hôpital Neurologique, University Lyon 1 and Hospices Civils de Lyon, Institut Fédératif des Neurosciences de Lyon (L.T., S.N.C., L.Z., B.L., C.T.-A., M.H., A.V., P.K.-S.), and Memory Research Resource Center for Alzheimer’s Disease of Lyon (L.T., B.C., B.M., A.V., P.K.-S.), CERMEP (L.T., S.N.C., L.Z., D.L.B.), Bron, and Service de Neurologie (B.L., C.T.-A.), Hôpital Bellevue, and Memory Research Resource Center for Alzheimer’s Disease of Saint Etienne (B.L., C.T.-A.), France.

Address correspondence and reprint requests to Dr. L. Truchot, Service de Neurologie du Pr Vighetto, Hôpital Neurologique Pierre Wertheimer, 59 boulevard, Pinel 69677, Bron cedex lydie.truchot{at}free.fr

Objective: Recent studies have suggested modifications of serotonin cerebral metabolism and of 5-HT_1A receptors density in Alzheimer disease (AD). This study aims at exploring hippocampus 5-HT_1A receptor density in patients at the amnesic mild cognitive impairment (aMCI) and mild AD dementia stages.

Methods: With use of PET with a selective 5-HT_1A antagonist, 2'-methoxyphenyl-(N-2'-pyridinyl)-p-[¹⁸F]fluoro-benzamidoethylpiperazine ([¹⁸F]MPPF), the hippocampus 5-HT_1A binding potential (BP) was quantified in 10 patients with mild AD, in 11 patients with aMCI, and in 21 aged paired control subjects. To take into account hippocampal atrophy, a partial volume correction was applied to the [¹⁸F]MPPF data, leading to the calculation of a corrected BP (BP_c). Comparison of hippocampus BP over populations was performed using Kruskal–Wallis rank analysis.

Results: Hippocampus serotonergic receptor binding distinguishes patients from controls and patients with aMCI from patients with AD. In aMCI patients, the mean hippocampus BP_c was 59% higher than the controls’ (p < 0.005), and it was conversely 35% lower in patients with mild AD (p < 0.01). The difference in BP_c values between patients with aMCI and mild AD was large, resulting in a p value of <0.0005. These differences were not related to hippocampus atrophy.

Conclusion: A compensatory mechanism illustrated by an up-regulation of serotonergic metabolism has been shown at the stage of amnesic mild cognitive impairment (aMCI) in contrast with a dramatic decrease at later stages of Alzheimer disease (AD). This difference of hippocampus serotonergic receptor labeling allows distinguishing of patients with aMCI from those with mild AD. Exploring 5-HT_1A receptors with 2'-methoxyphenyl-(N-2'-pyridinyl)-p-¹⁸F-fluoro-benzamidoethylpiperazine PET seems to be of interest for better understanding pathophysiologic changes at early stages of AD.

Supported by the "Association France Alzheimer," the "Fédération pour la Recherche sur le Cerveau."

Disclosure: The authors report no conflicts of interest.

Received November 21, 2006. Accepted in final form April 6, 2007.