Elsevier

NeuroImage

Volume 40, Issue 3, 15 April 2008, Pages 1251-1256
NeuroImage

A distinct [18F]MPPF PET profile in amnestic mild cognitive impairment compared to mild Alzheimer's disease

https://doi.org/10.1016/j.neuroimage.2008.01.030Get rights and content

Abstract

To date, two positron emission tomography (PET) studies have explored 5-HT1A receptor density in the hippocampus of Alzheimer's disease (AD) patients. They showed early changes of 5-HT1A receptors in this brain region, known to have a dense serotonergic innervation. These studies only reported measurements in hippocampus. In the present PET study, we used an antagonist of 5-HT1A receptors, the [18F]MPPF (1) to explore 5-HT1A receptor density in the whole brain of AD patients at a mild stage of dementia and amnestic mild cognitive impairment (aMCI) patients compared to a control population; (2) to explore more precisely the 5-HT1A receptor density in the limbic brain regions of AD patients and aMCI patients compared to controls. Voxel-based analyses were performed to assess differences in the [18F]MPPF binding potential (BP) between AD patients and aMCI patients compared to controls. Analyses of whole-brain [18F]MPPF BP showed a global decrease in AD brains in contrast with a global increase in aMCI brains. In AD brains, a significant decrease of BP was detected in hippocampus and parahippocampal gyrus, whereas a significant increase of BP was observed in the inferior occipital gyrus in aMCI brains. These whole brain results are in accordance to hippocampal data reported in a previous study, showing an increase of [18F]MPPF binding in the aMCI group contrasting with a decrease in the AD group. Altogether, these results suggest the implication of a compensatory mechanism illustrated by an up regulation of serotonergic metabolism at the aMCI stage before a breakdown of this mechanism at the AD stage. This difference of serotonergic receptor labeling allows to distinguish the groups of aMCI patients from mild AD patients with specific [18F]MPPF PET profiles for each patient group.

Introduction

The earliest and most severe cognitive deficit in Alzheimer's disease (AD) concerns episodic memory (Dubois et al., 2007). Pathologically, neurofibrillary tangles first appear in the rhinal cortex, then in the hippocampus and finally spread into the neocortex (Braak and Braak, 1991, Delacourte et al., 1999). The recent development of selective PET ligands for 5-HT1A receptors, including [18F]MPPF, allows the in vivo exploration of the serotonergic system in human brain (Passchier et al., 2000, Aznavour and Zimmer, 2007, for a review). These serotonergic receptors are known to be numerous in the hippocampus. To date, only two studies with PET [18F]MPPF have been performed in AD patients, focusing only on the hippocampus (Kepe et al., 2006, Truchot et al., 2007). These studies have shown major decreases of 5-HT1A receptor density in the hippocampus of AD patients, but divergent results in aMCI patients. Thus the first study (Kepe et al., 2006) demonstrated a slight decrease of 5-HT1A receptor binding in the hippocampus of aMCI patients and a dramatic decrease in AD patients compared to controls. The second study (Truchot et al., 2007) showed a large increase of 5-HT1A receptor binding in the hippocampus of aMCI patients and a dramatic decrease in AD patients compared to controls. A likely explanation for the divergent result was based upon the fact that the second study used partial volume effect correction to compensate for hippocampus atrophy. A compensatory mechanism with an up regulation of serotonergic metabolism manifesting during the aMCI stage, a pre-dementia stage of AD, in contrast with a breakdown during the mild dementia AD stage, has been suggested (Truchot et al., 2007). This difference of hippocampus serotonergic receptor binding has allowed distinguishing the groups of aMCI patients from mild AD patients and from controls.

In this present study, we explored the serotonergic system in the whole brain of aMCI and AD patients compared to controls. The aim was to investigate whether the changes in serotonergic transmission seen in the hippocampus (Truchot et al., 2007) are also found in the whole brain and whether it is possible to obtain selective [18F]MPPF PET profiles at the different stages of AD. We used a voxel-by-voxel analysis (statistical parametric mapping, SPM; Welcome Trust Centre for Neuroimaging, UCL, London, http://www.fil.ion.ucl.ac.uk/spm) which is an accurate alternative to ROI analyses and provides a comprehensive assessment of the entire brain, also allowing localization of the areas concerned. We subsequently explored limbic structures with a standard mask using voxel-based techniques in order to test whether an increase of [18F]MPPF binding potential on 5-HT1A is observed in brain structures known to be affected in aMCI patients.

Section snippets

Subjects and evaluation

A total of 11 aMCI patients, 10 mild AD patients and 21 controls older than 55 years were included in the study at the Neurological Hospital of Lyon, France, according to consensus diagnosis criteria (McKhann et al., 1984, Petersen et al., 2001). Patients with a history of other neurological or psychiatric condition and patients with depression were excluded. All subjects had been free from medication with a known effect on serotonin metabolism (Bantick et al., 2004) for at least 3 months.

Global brain analysis

A significant decrease of [18F]MPPF binding was observed in the brains of mild AD patients compared to controls (Fig. 1a), mainly located in right and left hippocampus, uncus, parahippocampus and inferior temporal gyrus and, less extensively, in the left inferior and superior parietal lobule, the right middle frontal gyrus (Table 2). In contrast, MCI patients showed no decrease of [18F]MPPF binding in the brain. No increase of [18F]MPPF binding was observed in mild AD patient brains compared to

Discussion

Our study using voxel-based analyses highlights different [18F]MPPF PET profiles (1) in the aMCI group disclosing a binding increase in the inferior occipital gyrus, in the lingual gyrus and in the median occipital gyrus, (2) in the AD group showing a decrease of MPPF binding in the hippocampus and in the parahippocampus. These results were confirmed by the regions of interest analyses from a standard brain atlas.

In the aMCI group, an increase of MPPF binding potential was disclosed in

Acknowledgments

The authors thank the control subjects and the patients who took part in the study. We wish to thank the chemistry, medical and neuropsychological teams for their help in this study. This work was financially supported by the “Association France Alzheimer” and by the “Fédération pour la Recherche sur le Cerveau”.

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