Bernadette Mercier

Impaired social cognition in mild Alzheimer disease

Abnormal decoding of social information has been associated with the conversion from prodromal Alzheimers disease (AD) to dementia. Since the distributed neural networks involved in face processing are differentially affected in prodromal and dementia states of AD and in Fronto-Temporal Dementia (FTD), we hypothezed a differential impairment in face processing in these populations. Facial expression, gender and gaze direction decoding abilities were examined in patients with probable amnesic Mild Cognitive Impairment (aMCI, N = 10) fulfilling criteria for prodromal AD, in patients with mild and moderate AD (N = 10) as well as in FTD patients (N = 10) and in a group of age- and sex-matched healthy comparison subjects (N = 10). Gender recognition was preserved in all groups. Compared to controls, patients with mild or moderate AD were impaired in expression recognition and FTD patients were impaired in expression and gaze direction determination, whereas MCI patients were not impaired at all.

Up-regulation of hippocampal serotonin metabolism in mild cognitive impairment.

Objective: Recent studies have suggested modifications of serotonin cerebral metabolism and of 5-HT1A receptors density in Alzheimer disease (AD). This study aims at exploring hippocampus 5-HT1A 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-HT1A antagonist, 2′-methoxyphenyl-(N-2′-pyridinyl)-p-[18F]fluoro-benzamidoethylpiperazine ([18F]MPPF), the hippocampus 5-HT1A 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 (BPc). 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 BPc 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 BPc 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-HT1A 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.

In vivo demonstration of amyloid burden in posterior cortical atrophy: a case series with PET and CSF findings

Our objective was to evaluate amyloid deposition in posterior cortical atrophy (PCA), using both cerebrospinal fluid (CSF) biomarker analysis and amyloid imaging. Five PCA patients, selected based on their neuropsychological profile and atrophic changes in posterior regions on MRI, underwent CSF analysis. CSF amyloid-beta 1–42, total tau, and phosphorylated tau at threonine 181 levels were determined. They also had positron emission tomography (PET) with Pittsburgh Compound B ([11C]PIB). [11C]PIB ratio images were assessed with visual, regional and voxel-based analyses and compared to eight typical Alzheimers disease (AD) patients and eight controls. The biological profile in the five PCA patients, resulting from CSF and [11C]PIB images analysis, was consistent with AD. Individual comparisons of PCA patients’ [11C]PIB images with the AD group with Statistical Parametric Mapping (SPM) revealed a distinctive posterior uptake in four out of the five patients showing increased amyloid deposition in occipital, temporal, and/or parietal regions. ROI group analysis showed a tendency for higher amyloid deposition in occipital and temporal regions. However, this pattern was not found with SPM group analysis when the global level of [11C]PIB uptake was used as a covariate. Our results indicate that amyloid burden can be demonstrated in vivo in PCA suggesting a diagnosis of AD. PCA patients may present a higher global amyloid load than AD that was not related to age at onset, disease severity, disease duration, or educational level in our study. Combined CSF and PET biomarkers seem helpful for in vivo diagnosis of this focal syndrome with underlying AD pathology.

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

To date, two positron emission tomography (PET) studies have explored 5-HT(1A) receptor density in the hippocampus of Alzheimers disease (AD) patients. They showed early changes of 5-HT(1A) 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-HT(1A) receptors, the [(18)F]MPPF (1) to explore 5-HT(1A) 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-HT(1A) 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 [(18)F]MPPF binding potential (BP) between AD patients and aMCI patients compared to controls. Analyses of whole-brain [(18)F]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 [(18)F]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 [(18)F]MPPF PET profiles for each patient group.

Initial Memory Deficit Profiles in Patients with a Cerebrospinal Fluid Alzheimer's Disease Signature

BACKGROUND Alzheimers disease (AD) clinical onset is usually characterized by a memory complaint and a progressive memory deficit. The proportion of typical medial-temporal amnesia revealing AD remains unknown. OBJECTIVE The present study explores the episodic memory impairment profiles by the Free and Cued Selective Recall Reminding Test (FCSRT) in patients with initial memory complaint and a cerebrospinal fluid (CSF) biomarker signature of AD. METHODS Seventy-three patients referred for memory complaint to the Centers for Memory, Resource and Research of Lyon and Montpellier (France) were included consecutively. All patients underwent an extensive neuropsychological examination and had a Mini-Mental State Examination (MMSE) score ≥20 and a positive CSF AD signature. The patients were classified as having mild dementia or prodromal AD. Verbal episodic memory was assessed using the French version of the FCSRT exploring encoding, storage/consolidation, and cued delayed retrieval phases of memorization. Three different memory profiles were identified according to the results of FCSRT. RESULTS The median age was 72 year-old [interquartiles: 65-76]. The median MMSE score was 23 [interquartiles: 21-25]. 88% of the patients (n = 64) presented with a medial temporal amnesia profile. The dysexecutive amnesia and normal verbal episodic memory profiles represented respectively 5% (n = 4) and 7% (n = 5). There were no significant differences in term of age, gender, and MMSE score between the three profile groups. CONCLUSION In a population initially presenting with memory complaints and depicting a CSF AD signature, a high proportion of medial temporal amnesia is disclosed as expected, but also a proportion of dysexecutive amnesia and normal FCSRT.

Initial memory deficit in patients with a CSF Alzheimer's disease signature

Aline Dorey, Armand Perret-Liaudet, Floriane Delphin-Combe, Bernadette Mercier, Isabelle Roullet-Solignac, Alain Vighetto, Pierre Krolak-Salmon, Memory Center of Lyon Hospices Civils de Lyon Universit e Lyon 1 Inserm Unite 1048, Villeurbanne, France; 2 Memory Center of Lyon Hospices Civils de Lyon Universit e Lyon 1, Bron Cedex, France; Hospices Civils de Lyon Universit e Lyon 1, Villeurbanne, France; Memory Center of Lyon Hospices Civils de Lyon Universit e Lyon 1, Bron, France; 5 Memory Center of Lyon -Lyon Hospices Civils de Lyon Universit e Lyon 1, Bron, France; 6 Memory Center of Lyon Hospices Civils de Lyon Universit e Lyon 1, Lyon, France.

P2a-6 Atrophie corticale postérieure, LCR et imagerie amyloïde : A propos de 2 cas

Introduction L’atrophie corticale posterieure (ACP) est un syndrome clinico-radiologique caracterise par un deficit progressif des fonctions visuelles et gestuelles superieures en lien avec un dysfonctionnement cortical de la partie posterieure des hemispheres. Elle est dans certains cas consideree comme la variante visuelle de la maladie d’Alzheimer (MA), les depots amyloides et les degenerescences neurofibrillaires ayant alors une predilection pour les regions posterieures. Le dosage des biomarqueurs du LCR et l’imagerie amyloide avec le Pittsburgh compound B (PIB) en tomographie par emission de positons (TEP) permettent d’etudier ces processus neuropathologiques du vivant des patients. Materiel Nous rapportons l’observation de deux patients ayant consulte pour une gene visuelle ou une maladresse gestuelle ayant conduit au diagnostic d’ACP. Une evaluation neuropsychologique, un bilan ophtalmologique furent realises ainsi qu’une imagerie anatomique et/ou metabolique, un dosage des proteines amyloides et tau du LCR par ponction lombaire et une mesure de la charge amyloide cerebrale en TEP au 11C-PIB. Resultats Le premier patient presentait des difficultes de lecture secondaires a une alexie et une simultagnosie, le deuxieme, une gene visuelle et une maladresse gestuelle du membre superieur gauche revelatrices d’un syndrome parkinsonien akineto-hypertonique et d’une apraxie ideo-motrice asymetriques associes a des troubles visuo-spatiaux. Le bilan neuropsychologique confirmait les troubles visuo-spatiaux et/ou praxiques et la relative preservation des fonctions mnesiques et executives. Des anomalies campimetriques etaient observees au champ visuel. L’IRM cerebrale retrouvait une atrophie corticale parieto-occipitale ou plus diffuse. L’analyse du LCR a mis en evidence une diminution du peptide Aβ et une augmentation des proteines Tau et Phospho-Tau compatible avec le diagnostic de MA. La TEP au PIB a retrouve une augmentation de la charge amyloide corticale par rapport aux sujets temoins, comparable a celle des sujets MA remplissant les criteres diagnostiques cliniques de MA. Conclusion Ces ACP revelees par des troubles visuo-spatiaux ou praxiques ont des capacites mnesiques preservees et ne remplissent pas les criteres NINCDS-ADRDA pour le diagnostic de MA probable. L’analyse du LCR et l’imagerie amyloide suggerent cependant l’implication des pathologies amyloide et neurofibrillaire caracteristiques de la MA dans ce tableau, soulignant ainsi l’interet de ces biomarqueurs dans le bilan etiologique des atrophies corticales focales.

E - 8 Biomarqueurs du LCR et mémoire hippocampique dans la maladie d’Alzheimer (MA)

Introduction Le test de Grober et Buschke oriente le diagnostic vers une MA lorsqu’il revele un deficit hippocampique. Les taux anormaux de biomarqueurs proteiques du LCR ont ete recemment associes aux lesions degeneratives de la maladie. Objectifs Tester l’hypothese d’une correlation entre biomarqueurs du LCR, et en particulier les proteines tau, et le deficit mnesique « hippocampique » mesure par le test de Grober et Buschke chez les patients Alzheimer. Methodes Dans le cadre d’une etude prospective mise en place dans la region Rhone-Alpes en 2004 (protocole de recherche clinique : Demences et biomarqueurs du LCR), 49 patients presentant un MCI ou un syndrome dementiel ont beneficie d’une expertise clinique et neuropsychologique comprenant une epreuve de Grober et Buschke. Ils ont subi une ponction lombaire. Les proteines beta-amyloide 1-42, tau totale et phospho-tau181 ont ete dosees par methode ELISA dans le LCR obtenu par ponction lombaire. Resultats Les sous-scores du Grober et Buschke differaient significativement entre les etiologies dementielles. La somme des rappels totaux SRT et le rappel total differe RTD, ainsi que la somme des rappels libres SRL, etaient plus basses chez les patients diagnostiques comme MA probable que dans les autres etiologies dementielles (p Chez les patients MA, le taux dans le LCR de la proteine tau etait inversement correle a la SRT et au RTD (Spearman : respectivement p = 0,03 et p = 0,02). Discussion Cette correlation conforte la validite du biomarqueur tau refletant la degenerescence neurofibrillaire s’accumulant initialement dans les regions hippocampiques. Ces resultats incriminent la tauopathie affectant precocement les structures temporales internes dans l’alteration mnesique qui est revelee par le test de memorisation verbale de Grober-Buschke par un profil dit « hippocampique » : rappel libre differe effondre sans efficacite de l’indicage. Conclusion Ces resultats preliminaires etablissent pour la premiere fois une correlation entre les resultats d’un test neuropsychologique explorant la memoire hippocampique et le biomarqueur tau du LCR dans la maladie d’Alzheimer.