YNIMG-05176; No. of pages: 6; 4C:

www.elsevier.com/locate/ynimg

ARTICLE IN PRESS

NeuroImage xx (2008) xxx–xxx

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

L. Truchot,a,b,c,d,⁎,1 N. Costes,b,c L. Zimmer,a,b,c B. Laurent,e,f D. Le Bars,a,b

C. Thomas-Antérion,e,f B. Mercier,a,d M. Hermier,a A. Vighetto,a,c,d and P. Krolak-Salmona,c,d

aUniversity Lyon 1 and Hospices Civils de Lyon, Hôpital Neurologique, 69677 Bron cedex, FrancebCERMEP-Imagerie du vivant, 59 boulevard Pinel, 69003 Lyon, FrancecInstitut Fédératif des Neurosciences de Lyon, 59 boulevard Pinel, 69394 Lyon Cedex 03, FrancedMemory Research Resource Centre for Alzheimer's Disease of Lyon, FranceeHôpital Bellevue, Service de Neurologie, 25 boulevard Pasteur, 42100 Saint Etienne, FrancefMemory Research Resource Centre for Alzheimer's Disease of Saint Etienne, France

Received 14 May 2007; revised 18 November 2007; accepted 8 January 2008

To date, two positron emission tomography (PET) studies haveexplored 5-HT1A receptor density in the hippocampus of Alzheimer'sdisease (AD) patients. They showed early changes of 5-HT1A receptorsin this brain region, known to have a dense serotonergic innervation.These studies only reported measurements in hippocampus. In thepresent PET study, we used an antagonist of 5-HT1A receptors, the[18F]MPPF (1) to explore 5-HT1A receptor density in the whole brainof AD patients at a mild stage of dementia and amnestic mild cognitiveimpairment (aMCI) patients compared to a control population; (2) toexplore more precisely the 5-HT1A receptor density in the limbic brainregions 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 patientscompared to controls. Analyses of whole-brain [18F]MPPF BP showeda global decrease in AD brains in contrast with a global increase inaMCI brains. In AD brains, a significant decrease of BP was detectedin hippocampus and parahippocampal gyrus, whereas a significantincrease of BP was observed in the inferior occipital gyrus in aMCIbrains. These whole brain results are in accordance to hippocampaldata reported in a previous study, showing an increase of [18F]MPPFbinding in the aMCI group contrasting with a decrease in the ADgroup. Altogether, these results suggest the implication of a compen-satory mechanism illustrated by an up regulation of serotonergicmetabolism at the aMCI stage before a breakdown of this mechanismat the AD stage. This difference of serotonergic receptor labeling

⁎ Corresponding author. Hôpital Neurologique PierreWertheimer, Service deNeurologie du Pr Vighetto, 59 boulevard Pinel 69677 Bron cedex, France.Fax: +33 472688610.

E-mail address: lydie.truchot@free.fr (L. Truchot).1 Current address: Forenap Pharma, 27 Rue du 4ème RSM, 68250

Roufach, France.Available online on ScienceDirect (www.sciencedirect.com).

1053-8119/$ - see front matter © 2008 Published by Elsevier Inc.doi:10.1016/j.neuroimage.2008.01.030

Please cite this article as: Truchot, L., et al., A distinct [18F]MPPF PET profildisease, NeuroImage (2008), doi:10.1016/j.neuroimage.2008.01.030

allows to distinguish the groups of aMCI patients from mild ADpatients with specific [18F]MPPF PET profiles for each patient group.© 2008 Published by Elsevier Inc.

Introduction

The earliest and most severe cognitive deficit in Alzheimer'sdisease (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 (Braakand Braak, 1991; Delacourte et al., 1999). The recent development ofselective PET ligands for 5-HT1A receptors, including [18F]MPPF,allows the in vivo exploration of the serotonergic system in humanbrain (Passchier et al., 2000; Aznavour and Zimmer, 2007, for areview). These serotonergic receptors are known to be numerous inthe hippocampus. To date, only two studies with PET [18F]MPPFhave been performed in AD patients, focusing only on thehippocampus (Kepe et al., 2006; Truchot et al., 2007). These studieshave shown major decreases of 5-HT1A receptor density in thehippocampus of AD patients, but divergent results in aMCI patients.Thus the first study (Kepe et al., 2006) demonstrated a slight decreaseof 5-HT1A receptor binding in the hippocampus of aMCI patients anda dramatic decrease in AD patients compared to controls. The secondstudy (Truchot et al., 2007) showed a large increase of 5-HT1A

receptor binding in the hippocampus of aMCI patients and a dramaticdecrease in AD patients compared to controls. A likely explanationfor the divergent result was based upon the fact that the second studyused partial volume effect correction to compensate for hippocampusatrophy. A compensatory mechanism with an up regulation ofserotonergic metabolism manifesting during the aMCI stage, a pre-dementia stage of AD, in contrast with a breakdown during the mild

e in amnestic mild cognitive impairment compared to mild Alzheimer's

Table 1

Group Age (years) Gender (F:M) MMSE CDR

Control±SD 66±7.6 12:9 29.8±0.4 0aMCI±SD 73.2±10.8 6:5 25.8±3 0.5Mild AD±SD 70±8.7 6:4 24±3.8 1

2 L. Truchot et al. / NeuroImage xx (2008) xxx–xxx

ARTICLE IN PRESS

dementia AD stage, has been suggested (Truchot et al., 2007). Thisdifference of hippocampus serotonergic receptor binding has alloweddistinguishing the groups of aMCI patients from mild AD patientsand from controls.

In this present study, we explored the serotonergic system in thewhole brain of aMCI and AD patients compared to controls. Theaim was to investigate whether the changes in serotonergictransmission seen in the hippocampus (Truchot et al., 2007) arealso found in the whole brain and whether it is possible to obtainselective [18F]MPPF PET profiles at the different stages of AD. Weused 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 alternativeto ROI analyses and provides a comprehensive assessment of theentire brain, also allowing localization of the areas concerned. We

Fig. 1.

Please cite this article as: Truchot, L., et al., A distinct [18F]MPPF PET profildisease, NeuroImage (2008), doi:10.1016/j.neuroimage.2008.01.030

subsequently explored limbic structures with a standard maskusing voxel-based techniques in order to test whether an increaseof [18F]MPPF binding potential on 5-HT1A is observed in brainstructures known to be affected in aMCI patients.

Materials and methods

Subjects and evaluation

A total of 11 aMCI patients, 10 mild AD patients and 21controls older than 55 years were included in the study at theNeurological Hospital of Lyon, France, according to consensusdiagnosis criteria (McKhann et al., 1984; Petersen et al., 2001).Patients with a history of other neurological or psychiatriccondition and patients with depression were excluded. All subjectshad been free from medication with a known effect on serotoninmetabolism (Bantick et al., 2004) for at least 3 months. After allprocedures had been explained, all subjects gave informed consentfor the protocol, which was approved by the local ethics committee(Centre Léon Bérard, Lyon, France) in accordance with theHelsinki Declaration and French rules protecting persons.

Neuropsychological evaluation explored global cognition withMMSE (Folstein et al., 1975), episodic memory with the RL-RI-16

e in amnestic mild cognitive impairment compared to mild Alzheimer's

Table 2

Cluster no. MNI coordinates Extend Peak Side Lobe Covered regions % surface covered

x y z (voxels) Z score

1 −46 −28 −20 1056 4.02 Left Temporal Parahippocampal gyrus 14.3Uncus 24.0Hippocampus 25.9

Temporal Inferior temporal gyrus 9.22 32 −14 −36 550 4 Right Temporal Parahippocampal gyrus 8.8

Uncus 24.9Hippocampus 24.1

3 −40 −60 44 282 3.7 Left Parietal Inferior parietal lobule 8.6Superior parietal lobule 2.1

4 44 16 52 169 3.58 Right Frontal Middle frontal gyrus 1.6Precentral gyrus 0.8

3L. Truchot et al. / NeuroImage xx (2008) xxx–xxx

ARTICLE IN PRESS

test (French adaptation of the Grober and Buschke Test) (Van DerLinden, 2004) controlling encoding, free and cued recall, executivefunctions with the Trail Making Test (Reitan and Wolfson 1985),verbal fluencies (Cardebat et al., 1990), working memory with thedirect and reverse digit spans from the Wechsler Memory Scale(Wechsler 1987) and language with the 36 picture naming task(Bachy-Langedock, 1989). The Clinical Dementia Rating (CDR)scale was used for staging the severity of the functional impairment(Morris, 1993). Mood was evaluated with the Beck's scale (Becket al., 1974). Characteristics of subjects are reported in Table 1.

[18F]MPPF synthesis

The [18F]MPPF was obtained by nucleophilic fluoration on anitro precursor with a radiochemical yield of 20% to 25% EOS andspecific activity of 37 to 111 GBq/μmol (Le Bars et al., 1998).

PET scan acquisition and processing

PET sessions were performed on a CTI-SIEMENS HR+(Knoxville, TN, USA). For tracer injections, an intravenous catheterwas placed in the radial vein of the left arm. Before emissionacquisition, a 10-min transmission scan was performed using three68Ge rod sources for the measurement of tissue and head supportattenuation. After intravenous injection of a bolus of 130–237 MBq[18F]MPPF (mean±SD, 191.8±29.9 MBq), the dynamic PET scanof emission consisting of 35 frames of increasing duration (20 s to5 min) was acquired to evaluate the local radiotracer concentrationduring 60 min post-injection. The PET scanner was operating in 3Dmode. Images were corrected for scatter and attenuation andreconstructed using a filtered back projection (Hamming filter ofcut-off 0.5 cycles/pixels) to provide a 3D volume of 128×128×63voxels with a voxel size of 2.04×2.04×2.42 mm3.

Table 3

Cluster no. MNI coordinates Extend Peak Hemis

x y z (voxels) Z score

1 38 −82 −6 440 4.08 Right

2 −36 −84 −4 325 3.73 Left

Please cite this article as: Truchot, L., et al., A distinct [18F]MPPF PET profildisease, NeuroImage (2008), doi:10.1016/j.neuroimage.2008.01.030

The binding of the tracer was characterized according to the3-compartmental simplified reference tissuemodel (Gunn et al., 1997)previously applied to other [18F]MPPF studies (Costes et al., 2005).This model is based on the analytic solution of the compartmentmodel that is used to estimate 3 indexes without the use of an arterialsampling input function: R1 (ratio of plasma to brain transport con-stant in the ROI and in the reference region), k2 (tracer's efflux in thevascular system), and BP (binding potential, ratio of available thereceptor density to the dissociation constant, BP=Bmax/Kd). Cere-bellum was used as reference region, known to be devoid of 5-HT1Areceptors (Costes et al., 2002). Individual parametric images of BPwere computed with this model. Spatial normalization transformwascomputed from 0 to 60 min average image and applied to parametricimage. Our homemade template of summed MPPF created fromhealthy subject database was used for normalization in the MNIICBM space. Finally, normalized BP images were smoothed with an8 mm FWHM isotropic Gaussian filter.

Statistical analysis

Whole-brain exploration analysisThe BP of [18F]MPPF were handled with SPM2 (statistical

parametric mapping) as detailed elsewhere (Merlet et al., 2004).The aMCI patients, mild AD patients and controls were comparedusing the “compare-populations one scan/subject” routine, whichcarries out a fixed-effects analysis variance ANOVA for eachvoxel. No normalization of the voxel values was applied.Hippocampal volume was incorporated as covariate in the linearmodel (Mevel et al., 2007). Individual BP images were thresholdedat an absolute level of 0.1. After ANOVA, post-hoc SPM t-mapswere thresholded at individual voxel t-score of pb0.001 and onlyclusters with spatial extend superior to 150 voxels ( pb0.05) werereported and considered as significant.

phere Lobe Covered regions % surface covered

Occipital Middle occipital gyrus 4.8Lingual gyrus 3.0Inferior occipital gyrus 6.3

Occipital Inferior occipital gyrus 20.8Middle occipital gyrus 5.9Lingual gyrus 2.3

e in amnestic mild cognitive impairment compared to mild Alzheimer's

Fig. 2.

4 L. Truchot et al. / NeuroImage xx (2008) xxx–xxx

ARTICLE IN PRESS

Regional limbic structures analysisThe mean of individual regional BP values was extracted by

applying a standard atlas (Collins et al., 1999) of the followingcerebral regions: hippocampus, parahippocampus, inferior temporalgyrus, inferior occipital gyrus, cingulum, insula and amygdala.

Comparison of group regional BP values was realized with aKruskal–Wallis non parametric test.

Results

Global brain analysis

A significant decrease of [18F]MPPF binding was observed inthe brains of mild AD patients compared to controls (Fig. 1a),mainly located in right and left hippocampus, uncus, parahippo-campus and inferior temporal gyrus and, less extensively, in the leftinferior 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 wasobserved in mild AD patient brains compared to controls, whereasa significant increase of [18F]MPPF binding was observed in theleft and right inferior and middle occipital gyrus and the lingualgyrus in aMCI patient (Fig. 1b; Table 3).

Table 4

Hippocampus Inferior temporal gyrus Inferior occ

Controls 1.09 0.74 0.37aMCI/Controls NS NS ↑⁎⁎

Mild AD/Controls ↓ ⁎⁎⁎⁎ ↓⁎⁎ ↓⁎

Please cite this article as: Truchot, L., et al., A distinct [18F]MPPF PET profildisease, NeuroImage (2008), doi:10.1016/j.neuroimage.2008.01.030

Limbic regions analysis

The details of [18F]MPPF BP values in right and left limbicregions are shown in Fig. 2. The BP values of [18F]MPPF weresymmetrical in all brain regions. So, left and right BP values of eachbrain region were pooled for statistical results analysis. The Kruskal–Wallis test revealed a group effect on the regional BP value (pb0.05).Post-hoc tests of are summarized in Table 4 show variations of [18F]MPPF BP in patient populations compared to control.

Mild AD patients vs controlsIn all AD brain regions, the [18F]MPPF binding was decreased

compared to controls. A significant decrease was observed in ADpatients' hippocampus compared to controls (pb10−4). A signifi-cant decrease was also observed in the inferior temporal gyrus(pb10−2), in the parahippocampus and in the inferior occipitalgyrus (pb0.05).

aMCI patients vs controlsIn aMCI patients, the [18F]MPPF binding was significantly

increased in the inferior occipital gyrus compared to controls(pb10−2), and there was a non-significant increase in the inferiortemporal gyrus.

ipital gyrus Cingulum Insula Parahippocampus Amygdala

0.49 0.66 0.66 1.01NS NS NS NSNS NS ↓⁎ NS

e in amnestic mild cognitive impairment compared to mild Alzheimer's

5L. Truchot et al. / NeuroImage xx (2008) xxx–xxx

ARTICLE IN PRESS

Mild AD patients vs aMCI patientsA significant difference of [18F]MPPF binding was observed in

mild AD patients compared to aMCI patients, in the hippocampus(pb10−3), the parahippocampus (pb0.05), the inferior temporalgyrus (pb0.05) and in the inferior occipital gyrus (pb10−4). Par-ticularly, a significant decrease (pb10−4) of [18F]MPPF binding wasobserved in the inferior occipital gyrus in mild AD compared toaMCI.

Discussion

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

In the aMCI group, an increase of MPPF binding potential wasdisclosed in non-atrophic brain structures, especially the inferioroccipital gyrus, the lingual gyrus and the median occipital gyrus. Inthe mild AD dementia group, in accordance with the literature (Kepeet al., 2006; Truchot et al., 2007), voxel-based and region of interestanalyses disclosed a significant decrease of [18F]MPPF bindingpotential focused in the hippocampus and in the parahippocampus.These results confirm our previous observation of an up regulation ofserotonergic metabolism in brain at the stage of aMCI before abreakdown at the stage of mild AD dementia (Truchot et al., 2007).Indeed, in our previous study, the same mirror-like MPPF bindingprofile between aMCI and mild AD groups has been disclosed in thehippocampus (Truchot et al., 2007). These results reinforce thehypothesis of the existence of compensatory mechanisms at the pre-dementia stage of AD, in particular at the stage of aMCI (Bookheimeret al., 2000; Dickerson et al., 2004; Dickerson et al., 2005). Increasedhippocampal neurogenesis in early AD disclosed recently by neuro-pathology is consistent with such a functional transient compensationpathophysiological mechanisms of which remain to be determined(Jin et al., 2004). Some hemodynamic modification secondary toearly neuropathological changes observed in AD may be discussed,as well as multiplication of selective receptors or recruitment of newneuron networks.

In the present study, voxel-based analyses disclosed a [18F]MPPFBP increase in some cortical regions in the aMCI group, but not in thehippocampus, which contrasts with our previous ROI study (Truchotet al., 2007). This discrepancy underlines the critical role of partialvolume correction for studying small structures like hippocampus.Correction of partial volume effect is essential to study [18F]MPPFbinding in atrophic small brain region like hippocampus in AD toavoid any confusion between serotonergic metabolism and volumechanges related to neurodegeneration (Truchot et al., 2007). Partialvolume effect correction may thus avoid false interpretation ofbinding decrease (Costes and Reilhac, 2006; Samuraki et al., 2006).Emerging voxel-based partial volume effect correction methodsbased on resolution recovery by iterative process may be used in thefuture (Teo et al., 2007 and Boussion et al., 2006).

In the present study, a simple method applicable in a clinicalcontext was used, excluding manual drawing of brain regions orautomatic segmentation. Brain atrophy was taken into accountfollowing a recently reported method (Mevel et al., 2007). Thismethod consists in taking the hippocampal volume as an index ofglobal atrophy and then including it in the SPM analysis as

Please cite this article as: Truchot, L., et al., A distinct [18F]MPPF PET profildisease, NeuroImage (2008), doi:10.1016/j.neuroimage.2008.01.030

covariate. This analysis revealed that hippocampal volume losscould not explain important differences in [18F]MPPF bindingfound between controls and mild AD dementia patients. Functionalimages showed indeed a decrease of [18F]MPPF binding superiorto the decrease of signal potentially due to partial volume effectinduced by atrophy. The introduction of hippocampal volume inthe model allowed to show, in the aMCI group, a BP increasetendency in the hippocampus that did not reach significance.

Thus, our study confirms that the serotonergic system is earlyaffected in AD (Chen and Penington, 1996; Chen et al., 1996; Kepeet al., 2006; Truchot et al., 2007; Lanctôt et al., 2007). Beside thatlack of an exhaustive detection, automated methods computedwithout any human intervention confirm an increase of [18F]MPPFbinding potential in aMCI and a decrease at the mild dementia stageof AD. Further neuropathological and functional imaging studies areneeded to help in understanding earliest serotonergic metabolismchanges in AD.

Acknowledgment

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

References

Aznavour, N., Zimmer, L., 2007. 18F-MPPF as a tool for the in vivo imagingof 5-HT1A receptor in animal and human brain. Neuropharmacology 52,695–707.

Bachy-Langedock, N., 1989. Batterie d'examen des troubles en denomina-tion. Editest, Bruxelles.

Bantick, R.A., Rabiner, E.A., Hirani, E., de Vries, M.H., Hume, S.P.,Grasby, P.M., 2004. Occupancy of agonist drugs at the 5-HT1A receptor.Neuropsychopharmacology 29, 847–859.

Braak, H., Braak, E., 1991. Morphological changes in the human cerebralcortex in dementia. J. Hirnforsch. 32, 277–282.

Beck, A.T., Weissman, A., Lester, D., Trexler, L., 1974. The measurementof pessimism: the hopelessness scale. J. Consult. Clin. Psychol. 42, 861–865.

Bookheimer, S.Y., Strojwas, M.H., Cohen, M.S., Saunders, A.M., Pericak-Vance, M.A., Mazziotta, J.C., Small, G.W., 2000. Patterns of brainactivation in people at risk for Alzheimer's disease. N. Engl. J. Med.343, 450–456.

Boussion, N., Hatt, M., Lamare, F., Bizais, Y., Turzo, A., Cheze-Le Rest, C.,Visvikis, D., 2006. A multiresolution image based approach forcorrection of partial volume effects in emission tomography. Phys.Med. Biol. 51 (7), 1857–1876.

Cardebat, D., Doyon, B., Puel, M., Goulet, P., Joanette, Y., 1990. Formal andsemantic lexical evocation in normal subjects. Performance anddynamics of production as a function of sex, age and educationallevel. Acta Neurol. Belg. 90, 207–217.

Chen, Y., Penington, N.J., 1996. Differential effects of protein kinase Cactivation on 5-HT1A receptor coupling to Ca2+ and K+ currents in ratserotonergic neurones. J. Physiol. 496 (Pt 1), 129–137.

Chen, C.P., Alder, J.T., Bowen, D.M., Esiri, M.M., McDonald, B., Hope, T.,Jobst, K.A., Francis, P.T., 1996. Presynaptic serotonergic markers incommunity-acquired cases of Alzheimer's disease: correlations withdepression and neuroleptic medication. J. Neurochem. 66, 1592–1598.

Collins, D., Zijdenbos, A., Baar, W., Evans, A., 1999. ANIMAL+INSECT:improved cortical structure segmentation. In: Kuba, A.S.M., Todd-Pokropek, A. (Eds.), Proceedings of the Annual Symposium onInformation Processing in Medical Imaging, pp. 210–223.

e in amnestic mild cognitive impairment compared to mild Alzheimer's

6 L. Truchot et al. / NeuroImage xx (2008) xxx–xxx

ARTICLE IN PRESS

Costes, N., Merlet, I., Zimmer, L., Lavenne, F., Cinotti, L., Delforge, J.,Luxen, A., Pujol, J.-F., Le Bars, D., 2002. Modeling [18F]MPPF PETkinetics for the determination of 5-HT1A concentration with multi-injection. J. Cereb. Blood Flow Metab. 22 (6), 753–763.

Costes, N., Merlet, I., Ostrowsky, K., Faillenot, I., Lavenne, F., Zimmer, L.,Ryvlin, P., Le Bars, D., 2005. A 18F-MPPF PET normative database of5-HT1A receptor binding in men and women over aging. J. Nucl. Med.46, 1980–1989.

Costes, N., Reilhac, A., 2006. Evaluation of PET tracer binding recoveredby partial volume correction technique in case of hippocampic atrophy.IEEE Nuclear Science Symposium & Medical Imaging Conference.

Delacourte, A., David, J.P., Sergeant, N., Buée, L., Waltez, A., Vermersch,P., 1999. The biochemical pathways of neurofibrillary degeneration inaging and Alzheimer's disease. Neurology 52, 1158–1165.

Dickerson, B.C., Salat, D.H., Bates, J.F., Atiya,M., Killiany, R.J., Greve, D.N.,Dale, A.M., Stern, C.E., Blacker, D., Albert, M.S., Sperling, R.A., 2004.Medial temporal lobe function and structure in mild cognitive impairment.Ann. Neurol. 56, 27–35.

Dickerson, B.C., Salat, D.H., Greve, D.N., Chua, E.F., Rand-Giovannetti, E.,Rentz, D.M., Bertram, L., Mullin, K., Tanzi, R.E., Blacker, D., Albert, M.S.,Sperling, M.D., 2005. Increased hippocampal activation in mild cognitiveimpairment compared to normal aging and AD. Neurology 65, 404–411.

Dubois, B., Feldman, H.H., Jacova, C., Dekosky, S.T., Barberger-Gateau, P.,Cummings, J., Delacourte, A., Galasko, D., Gauthier, S., Jicha, G.,Meguro, K., O'Brien, J., Pasquier, F., Robert, P., Rossor, M., Salloway,S., Stern, Y., Visser, P.J., Scheltens, P., 2007. Research criteria for thediagnosis of Alzheimer's disease: revising the NINCDS-ADRDAcriteria. Lancet Neurol. 8, 667–669.

Folstein, M.F., Folstein, S.E., McHugh, P.R., 1975. “Mini-mental state”. Apractical method for grading the cognitive state of patients for theclinician. J. Psychiatr. Res. 12, 189–198.

Gunn, R.N., Lammertsma, A.A., Hume, S.P., Cunningham, V.J., 1997.Parametric imaging of ligand-receptor binding in PET using a simplifiedreference region model. NeuroImage 6, 279–287.

Jin, K., Peel, A.L., Mao, X.O., Xie, L., Cottrell, B.A., Henshall, D.C.,Greenberg, D.A., 2004. Increased hippocampal neurogenesis inAlzheimer's disease. Proc. Natl. Acad. Sci. U. S. A. 101, 343–347.

Kepe, V., Barrio, J.R., Huang, S.C., Ercoli, L., Siddarth, P., Shoghi-Jadid,K., Cole, G.M., Satyamurthy, N., Cummings, J.L., Small, G.W., Phelps,M.E., 2006. Serotonin 1A receptors in the living brain of Alzheimer'sdisease patients. Proc. Natl. Acad. Sci. U. S. A. 103, 702–707.

Lanctôt, K.L., Hussey, D.F., Herrmann, N., Black, S.E., Rusjan, P.M.,Wilson, A.A., Houle, S., Kozloff, N., Verhoeff, N.P., Kapur, S., 2007. Apositron emission tomography study of 5-hydroxytryptamine-1Areceptors in Alzheimer disease. Am. J. Geriatr. Psychiatry 15, 888–898.

Please cite this article as: Truchot, L., et al., A distinct [18F]MPPF PET profildisease, NeuroImage (2008), doi:10.1016/j.neuroimage.2008.01.030

Le Bars, D., Lemaire, C., Ginovart, N., Plenevaux, A., Aerts, J., Brihaye, C.,Hassoun, W., Leviel, V., Mekhsian, P., Weissmann, D., Pujol, J.F.,Luxen, A., Comar, D., 1998. High-yield radiosynthesis and preliminaryin vivo evaluation of p-[18F]MPPF, a fluoro analog of WAY-100635.Nucl. Med. Biol. 25, 343–350.

McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., Stadlan,E.M., 1984. Clinical diagnosis of Alzheimer's disease: report of theNINCDS-ADRDA Work Group under the auspices of Department ofHealth and Human Services Task Force on Alzheimer's Disease.Neurology 34, 939–944.

Mevel, K., Desgranges, B., Baron, J.C., Landeau, B., De la Sayette, V.,Viader, F., Eustache, F., Chételat, G., 2007. Detecting hippocampalhypometabolism in mild cognitive impairment using automatic voxel-based approaches. NeuroImage 37 (1), 18–25.

Merlet, I., Ryvlin, P., Costes, N., Dufournel, D., Isnard, J., Faillenot, I.,Ostrowsky, K., Lavenne, F., Le Bars, D., Mauguiere, F., 2004. Statisticalparametric mapping of 5-HT1A receptor binding in temporal lobeepilepsy with hippocampal ictal onset on intracranial EEG. NeuroImage22 (2), 886–896.

Morris, J.C., 1993. The Clinical Dementia Rating (CDR): current versionand scoring rules. Neurology 43, 2412–2414.

Passchier, J., van Waarde, A., Pieterman, R.M., Elsinga, P.H., Pruim, J.,Hendrikse, H.N., Willemsen, A.T., Vaalburg, W., 2000. Quantitativeimaging of 5-HT1A receptor binding in healthy volunteers with [18F]p-MPPF. Nucl. Med. Biol. 27, 473–476.

Petersen, R.C., Doody, R., Kurz, A., Mohs, R.C., Morris, J.C., Rabins, P.V.,Ritchie, K., Rossor, M., Thal, L., Winblad, B., 2001. Current concepts inmild cognitive impairment. Arch. Neurol. 58, 1985–1992.

Reitan, R.M., Wolfson, D., 1985. The Halstead–Reitan Neuropsychologicaltests Battery. Tucson, Neuropsychology Press.

Samuraki, M., Ichiro, M., Wei-Ping, C., et al., 2006. FDG PET in patientswith mild Alzheimer's disease before and after correction for corticalatrophy. J. Nucl. Med. 47, 118P.

Teo, B.K., Seo, Y., Bacharach, S.L., Carrasquillo, J.A., Libutti, S.K.,Shukla, H., Hasegawa, B.H., Hawkins, R.A., Franc, B.L., 2007.Partial-volume correction in PET: validation of an iterative postcon-struction method with phantom and patient data. J. Nucl. Med. 48 (5),802–810.

Truchot, L., Costes, N., Zimmer, L., Laurent, B., Le Bars, D., Thomas-Antérion, C., Croisile, B., Mercier, B., Hermier, M., Vighetto, A.,Krolak-Salmon, P., 2007. Up regulation of hippocampal serotoninmetabolism in Mild Cognitive Impairment. Neurology 69, 1012–1017.

Van Der Linden, M., 2004. Evaluation des troubles de la mémoire. Solal.Wechsler, D., 1987. Wechsler Memory Scale-revised. the Psychological

Corporation, San Antonio, Tx.

e in amnestic mild cognitive impairment compared to mild Alzheimer's