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This article describes the case of a patient who, following herpes simplex encephalitis (HSE), retained the ability to access rich conceptual semantic information for familiar people whom he was no longer able to name. Moreover, this patient presented the very rare combination of name production and name comprehension deficits for different categories of proper names (persons and acronyms). Indeed, besides his difficulty to retrieve proper names, SL presented a severe deficit in understanding and identifying them. However, he was still able to recognize proper names on familiarity decision, demonstrating that name forms themselves were intact. We interpret SL's deficit as a rare form of two-way lexico-semantic disconnection, in which intact lexical knowledge is disconnected from semantic knowledge and face units. We suggest that this disconnection reflects the role of the left anterior temporal lobe in binding together different types of knowledge and supports the classical convergence-zones framework (e.g., Damasio, 1989) rather than the amodal semantic hub theory (e.g., Patterson, Nestor, & Rogers, 2007).

Although it is known that medial temporal lobe (MTL) structures support declarative memory, the fact these structures have different architectonics and circuitry suggests they may also play different functional roles. Selective lesions of MTL structures offer an opportunity to understand these roles. We report, in this study, on JMG, a patient who presents highly unusual lesions that completely affected all MTL structures except for the right hippocampus and parts of neighbouring medial parahippocampal cortex. We first demonstrate that JMG shows preserved recall for visual material on 5 experimental tasks. This finding suggests that his right hippocampus is functional, even though it appears largely disconnected from most of its MTL afferents. In contrast, JMG performed very poorly, as compared to control subjects, on 7 tasks of visual recognition memory for single items. Although he sometimes performed above chance, neither familiarity nor recollection appeared fully preserved. These results indicate that extrahippocampal structures, damaged bilaterally in JMG, perform critical operations for item recognition; and that the hippocampus cannot take over that role, including recollection, when these structures are largely damaged. Finally, in a set of 3 recognition memory tasks with scenes as stimuli, JMG performed at the level of control participants and obtained normal indices of familiarity and recollection. Overall, our findings suggest that the right hippocampus and remnants of parahippocampal cortex can support recognition memory for scenes in the absence of preserved item-recognition memory. The patterns of dissociations, which we report in the present study, provide support for a representational account of the functional organization of MTL structures.

We report the case of a 65-year-old woman, clinically diagnosed with the logopenic variant of primary progressive aphasia (PPA), and carrier of C9ORF72 expansion, despite cerebrospinal fluid biomarkers suggesting Alzheimer's disease (AD). She underwent structural MRI, metabolic PET, and amyloid PET imaging using florbetapir. Comparison with healthy controls revealed widespread hypometabolism, left sided cortical atrophy, and an increased cortical amyloid load. No difference in amyloid binding was found between the patient and predemential AD patients. This case provides evidence of amyloidopathy in a carrier of C9ORF72 expansion exhibiting a clinical profile of the logopenic variant of PPA.

International audience; We report the case of a 37-year-old man suffering from insidious visual agnosia and spastic paraparesis due to a PSEN1 mutation. His mother was diagnosed with Alzheimer disease after a biopsy. He was assessed by multimodal neuroimaging, including new in vivo positron emission tomography amyloid imaging (F-AV45). His data were compared with those from healthy participants and patients with sporadic predemential Alzheimer disease. He exhibited posterior cortical thickness reduction, posterior hypometabolism, and increased amyloid ligand uptake in the posterior cortex and the striatum. We show that F-AV45 positron emission tomography allows visualization of the unusual pattern of amyloid deposits that co-localize with cortical atrophy in this genetic form of Alzheimer disease.

Resume Introduction Le diagnostic de maladie d’Alzheimer (MA) ne peut etre etabli avec certitude que grâce a des preuves anatomopathologiques ou la decouverte de mutations genetiques. Les criteres diagnostiques actuels s’appuient sur des outils d’imagerie et biologiques innovants, afin de detecter les signes de la pathologie des les stades les plus precoces, et ce avec les meilleures sensibilite et specificite possibles. Etat des connaissances Les progres en neuro-imagerie ont permis de developper differents outils d’aide au diagnostique, comme l’evaluation de l’atrophie cerebrale en imagerie par resonance magnetique (IRM), et l’etude du metabolisme cerebral en tomographie par emission de positons (TEP). De plus, l’utilisation des marqueurs biologiques in vivo, combinee aux criteres cliniques, permet de discriminer les patients a des stades de plus en plus precoces. C’est le cas de l’etude des concentrations en proteines tau et beta-amyloide dans le liquide cephalo-rachidien, et de la fixation de radioligands specifiques de l’amyloide. Perspectives, conclusions Les outils d’aide au diagnostic sont de plus en plus nombreux et performants. Au vu de l’heterogeneite clinique des patients, il apparait essentiel d’associer differentes methodes d’investigation pour pouvoir poser un diagnostic le plus precoce et le plus fiable possible.

International audience; We report the case of a 62-year-old asymptomatic carrier of AβPP gene duplication. He was investigated by MRI and the amyloid ligand 18F-AV45, and compared to Alzheimer's disease patients (n = 11) and healthy controls (n = 11). The neuropsychological examination was normal. Cortical thickness and AV45 retention were comparable to Alzheimer's disease patients. AβPP duplication was diagnosed because cerebral amyloid angiopathy and Alzheimer's disease pathology were found on the neuropathological examination of his youngest brother, who died at 42 from intracerebral hemorrhage. This is the first description of a pre-symptomatic AβPP duplication carrier over 60, despite widespread cerebral amyloid angiopathy, "Alzheimer's like" atrophy, and amyloid deposition.

Le TOP 12 examine la memoire collective simplement et rapidement par huit types de question portant sur le souvenir de la vie de 12 celebrites nommement designees. Verifier la correlation entre les scores moyens et le degre de severite de la pathologie ; determiner un seuil permettant de conjecturer sur l’etat de la personne au vu de son score au test. L’echantillon est compose de 145 sujets (91 temoins, 32 patients presentant une maladie d’Alzheimer, 21 patients ayant un trouble cognitif leger de type amnesique ou MCIa, 1 patient ayant une demence semantique). Les proprietes diagnostiques du TOP 12 ont pu etre mises en avant en confrontant deux methodologies : le centilage et la courbe Receiver Operator Characteristic (ROC). L’ordre des moyennes et l’ordre des niveaux de gravite pathologique des groupes sont correles. Le seuil qui optimise le compromis entre la sensibilite (Se) et la specificite (Sp) est donne par la methodologie de la courbe ROC (83 points ; Se = 0,83 ; Sp = 0,70). Le cinquieme centile s’avere non optimal etant donne qu’il majore les omissions. Cette validation externe du TOP 12 montre l’interet de la methodologie de la courbe ROC.

Background: Neuropsychological impairment after stroke when no motor, sensory or language deficits are left remains understudied. The primary aim of this study was to assess neuropsychological outcome in a specific population of patients after a first symptomatic stroke without previous cognitive decline and with a good motor, linguistic, and functional recovery (i.e. 'good outcome'). The secondary aims were to identify the profile of this potential impairment and relations between brain lesions and neuropsychological outcome. Methods: Sixty consecutive patients were evaluated by a comprehensive neuropsychological assessment focusing specifically on executive and attentional functions but also on memory 109 days, on average, after the infarct. Patients were compared with 40 healthy controls matched for age and education. Results: Patients showed lower performance in every cognitive domain compared with controls. Along with an important executive deficit, patients were also impaired on attention and memory. Patients were not more depressed than controls, although they were more apathetic. We also found a significant positive correlation between cognitive impairment and pre-existing white matter brain lesions assessed by MRI. Conclusions: We report the first study examining the impact of a first stroke on cognition but also on psychiatric disorders in patients with good functional outcome. We found that patients considered as asymptomatic were, in fact, exhibiting a multidomain cognitive deficit that could impact return to life as before stroke.

INTRODUCTION: Patient H.M.'s recent death provides the opportunity to highlight the importance of his contribution to a better understanding of the anterograde amnesic syndrome. The thorough study of this patient over five decades largely contributed to shape the unitary model of declarative memory. This model holds that declarative memory is a single system that cannot be fractionated into subcomponents. As a system, it depends mainly on medial temporal lobes structures. The objective of this review is to present the main characteristics of different modular models that have been proposed as alternatives to the unitary model. It is also an opportunity to present different patients, who, although less famous than H.M., helped make signification contribution to the field of memory. STATE OF THE ART: The characteristics of the five main modular models are presented, including the most recent one (the perceptual-mnemonic model). The differences as well as how these models converge are highlighted. PERSPECTIVES: Different possibilities that could help reconcile unitary and modular approaches are considered. CONCLUSION: Although modular models differ significantly in many aspects, all converge to the notion that memory for single items and semantic memory could be dissociated from memory for complex material and context-rich episodes. In addition, these models converge concerning the involvement of critical brain structures for these stages: Item and semantic memory, as well as familiarity, are thought to largely depend on anterior subhippocampal areas, while relational, context-rich memory and recollective experiences are thought to largely depend on the hippocampal formation.

Brain atrophy measured by magnetic resonance structural imaging has been proposed as a surrogate marker for the early diagnosis of Alzheimer's disease. Studies on large samples are still required to determine its practical interest at the individual level, especially with regards to the capacity of anatomical magnetic resonance imaging to disentangle the confounding role of the cognitive reserve in the early diagnosis of Alzheimer's disease. One hundred and thirty healthy controls, 122 subjects with mild cognitive impairment of the amnestic type and 130 Alzheimer's disease patients were included from the ADNI database and followed up for 24 months. After 24 months, 72 amnestic mild cognitive impairment had converted to Alzheimer's disease (referred to as progressive mild cognitive impairment, as opposed to stable mild cognitive impairment). For each subject, cortical thickness was measured on the baseline magnetic resonance imaging volume. The resulting cortical thickness map was parcellated into 22 regions and a normalized thickness index was computed using the subset of regions (right medial temporal, left lateral temporal, right posterior cingulate) that optimally distinguished stable mild cognitive impairment from progressive mild cognitive impairment. We tested the ability of baseline normalized thickness index to predict evolution from amnestic mild cognitive impairment to Alzheimer's disease and compared it to the predictive values of the main cognitive scores at baseline. In addition, we studied the relationship between the normalized thickness index, the education level and the timeline of conversion to Alzheimer's disease. Normalized thickness index at baseline differed significantly among all the four diagnosis groups (P < 0.001) and correctly distinguished Alzheimer's disease patients from healthy controls with an 85% cross-validated accuracy. Normalized thickness index also correctly predicted evolution to Alzheimer's disease for 76% of amnestic mild cognitive impairment subjects after cross-validation, thus showing an advantage over cognitive scores (range 63–72%). Moreover, progressive mild cognitive impairment subjects, who converted later than 1 year after baseline, showed a significantly higher education level than those who converted earlier than 1 year after baseline. Using a normalized thickness index-based criterion may help with early diagnosis of Alzheimer's disease at the individual level, especially for highly educated subjects, up to 24 months before clinical criteria for Alzheimer's disease diagnosis are met.

Frontotemporal dementia (FTD), characterized by behavioural and language disorders, is a clinically, genetically and pathologically heterogeneous group of diseases. The most recently identified of the four known genes is GRN, associated with 17q-linked FTD with ubiquitin-immunoreactive inclusions. GRN was analysed in 502 probands with frontal variant FTD (fvFTD), FTD with motoneuron disease (FTD-MND), primary progressive aphasia (PPA) and corticobasal degeneration syndrome (CBDS). We studied the clinical, neuropsychological and brain perfusion characteristics of mutation carriers. Eighteen mutations, seven novel were found in 24 families including 32 symptomatic mutation carriers. No copy number variation was found. The phenotypes associated with GRN mutations vary greatly: 20/32 (63%) carriers had fvFTD, the other (12/32, 37%) had clinical diagnoses of PPA, CBDS, Lewy body dementia or Alzheimer's disease. Parkinsonism developed in 13/32 (41%), visual hallucinations in 8/32 (25%) and motor apraxia in 5/21 (24%). Constructional disorders were present in 10/21 (48%). Episodic memory disorders were frequent (16/18, 89%), consistent with hippocampal amnestic syndrome in 5/18 (28%). Hypoperfusion was observed in the hippocampus, parietal lobe and posterior cingulate gyrus, as well as the frontotemporal cortices. The frequency of mutations according to phenotype was 5.7% (20/352) in fvFTD, 17.9% (19/106) in familial forms, 4.4% in PPA (3/68), 3.3% in CBDS (1/30). Hallucinations, apraxia and amnestic syndrome may help differentiate GRN mutation carriers from others FTD patients. Variable phenotypes and neuropsychological profiles, as well as brain perfusion profiles associated with GRN mutations may reflect different patterns of neurodegeneration. Since all the mutations cause a progranulin haploinsufficiency, additional factors probably explain the variable clinical presentation of the disease.

There is a large body of research on discourse production in Alzheimer’s disease (AD). Some studies have focused on pause production, revealing that patients make extensive use of pauses during speech. This has been attributed to lexical retrieval difficulties, but pausing may also reflect other forms of cognitive impairment as it increases with cognitive load. The aim of the present study was to analyze autobiographical discourse impairment in AD from a broad perspective, looking at pausing behavior (frequency, duration, and location). Our first objective was to characterize discourse changes in mild cognitive impairment (MCI) due to AD. Our second objective was to determine the cognitive and neuroanatomical correlates of these changes. Fifteen patients with MCI due to AD and 15 matched cognitively normal controls underwent an ecological episodic memory task, a full neuropsychological assessment, and a 3D T1-weighted MRI scans. Autobiographical discourse collected from the ecological episodic memory task was recorded, transcribed, and analyzed, focusing on pausing. Intergroup comparisons showed that although patients did not produce more pauses than controls overall, they did make more between-utterance pauses. The number of these specific pauses was positively correlated with patients’ episodic memory performance. Furthermore, neuroimaging analysis showed that, in the patient group, their use was negatively correlated with frontopolar area (BA 10) grey matter density. This region may therefore play an important role in the planning of autobiographical discourse production. These findings demonstrate that pauses in early AD may reflect a compensatory mechanism for improving mental time travel and memory retrieval.

Background Few patients are reported with dementia with Lewy bodies before fifty years-old, which may partly reflect the difficulty of accurate diagnosis in young population. We report the case of a 44-year-old male with pathologically confirmed sporadic dementia with Lewy bodies, who did not fulfil the revised clinical criteria for this disease. Case presentation We document this atypical case with clinical and cognitive evaluation, imaging, biochemistry, genetics and pathology investigations. Creutzfeldt-Jakob disease was first suspected in this patient with no previous medical history, who developed acute and rapid cognitive impairment, L-dopa-non-responsive parkinsonism, and delusion. Positive 14–3–3 protein was initially detected in cerebrospinal fluid and until the late stages of the disease. Severe atrophy with no diffusion hypersignal was found on structural MRI as well as an extensive hypometabolism on 18F-FDG-PET, in comparison to age-matched healthy volunteers. Genetic investigation found no alpha-synuclein gene mutation. The patient died within 5 years, and post-mortem examination found numerous Lewy bodies and Lewy neurites consistent with pure Lewy body disease. Conclusions This comprehensively described case illustrates that dementia with Lewy bodies can occur in young patients with atypical clinical presentation. Biochemistry and neuroimaging investigations can sometimes be insufficient to allow accurate diagnostic. More specific markers to support such diagnosis are needed. Electronic supplementary material The online version of this article (doi:10.1186/s12883-016-0643-y) contains supplementary material, which is available to authorized users.

TANK1-binding kinase 1 (TBK1) has been recently identified as a new amyotrophic lateral sclerosis (ALS) gene. Loss-of-function (LoF) mutations in TBK1 could be responsible for 0.4%-4% of ALS. Considering the strong genetic overlap existing between frontotemporal dementia (FTD) and ALS, we have evaluated the frequencies of TBK1 mutations in a cohort of French FTD and of ALS patients. We identified 5 LoF mutations, in 4 FTD-ALS and 1 ALS patients. We also identified 5 heterozygous missense variants, predicted to be deleterious, in 1 isolated FTD, 1 FTD-ALS, and 3 ALS cases. Our results demonstrate that TBK1 loss-of-function mutations are more frequent in patients with FTD-ALS (10.8%) than in isolated ALS. TBK1 should thus also be sequenced, after exclusion of C9orf72 mutation, in patients presenting FTD, particularly in cases secondarily associated with ALS.

Background and Purpose— Very few neuroimaging studies have focused on follow-up of subcortical aphasia. Here, overt language production tasks were used to correlate regional cerebral blood flow (rCBF) changes and language performance in patients with vascular subcortical lesions. Methods— Seven aphasic patients were scanned twice with positron emission tomography (PET) at 1-year interval during a word-generation task. Using SPM2, Language-Rest contrast at PET1 was correlated to language performance and to time-lag from stroke. The same contrast was performed at PET2 and session effect (PET2–PET1) was correlated with performance improvement. Results— At PET1, correlation between rCBF and delay from stroke involved mainly ventral regions of the left temporal cortex and mesial frontal cortex. Correlations between rCBF and performance showed predominantly left dorsal regions in the frontal, temporal, and parietal lobes, but also the left ventral temporal cortex. One year apart, language performance improved and rCBF increased in perisylvian regions bilaterally. Best performers at PET2 showed an increase of activity in left ventral temporal cortex as well as in right middle temporal gyrus. Conclusions— On follow-up, expected language improvement and increase of activation in the classical language areas and their counterparts were observed. Moreover, all correlational analyses both at PET1 and on follow-up implicated the anterior part of the left inferior temporal gyrus, suggesting a disconnection between the superior and inferior parts of the left temporal cortex and a specific role for this region in lexical semantic processing.

Background The Alzheimer's Disease Assessment Scale (ADAS) is often used in international multicenter trials. Use across countries presupposes correct translation and adaptation of the scale, and maintenance of its psychometric properties. Objectives To compare the various translations of the ADAS used in Western Europe, to design internationally harmonized translations and to validate these. Setting International cooperative study in eight European countries. Methods An inventory was made of existing versions of the ADAS-Cog used in eight European countries, and adaptations were made. The concurrent validity of the harmonized versions of the ADAS was tested in 283 patients with probable or possible Alzheimer's disease. The Nurses Observation Scale for Geriatrics (NOSGER), CAMCOG-R and MMSE was used to assess concordance between cognitive and behavioral measures. Results Differences between the versions mainly involved object naming, items for verbal memory, such as the number of trials allowed, the imagery value of the words selected as targets or distractors, and the number of parallel versions. These differences were eliminated by adapting and harmonizing the various versions of the ADAS-Cog. Thereafter, only small differences between the different countries were found, and patterns of correlation between ADAS-Cog, and the NOSGER, CAMCOG-R and MMSE were consistent. Conclusions The study underlines the need to use harmonized versions of instruments for rating dementia in multinational studies. The findings indicate that the harmonization of the ADAS-Cog was successful.

Background and Purpose— Follow-up neuroimaging studies of aphasia never addressed a comparison between aphasic and healthy subjects. Investigation of changes over time in healthy subjects during language tasks seems a prerequisite before interpretation of longitudinal changes in aphasic patients. Methods— Six healthy subjects and 8 aphasic patients were PET scanned twice (PET1 and PET2) at a 1-year interval during a word generation task. Using SPM99, language-rest main effect was compared at PET1 and PET2 in each group, whereas group effect was assessed at each session. Correlations were analyzed in each group between performance indexes and changes in regional cerebral flood flow (rCBF) between the 2 sessions. Results— Language performances were improved in both groups. rCBF decreased from PET1 to PET2 in the healthy group and increased in the aphasic group in perisylvian regions bilaterally. Correlations between performance and rCBF changes across sessions were similar in the 2 groups; positive correlations involved superior temporal cortexes bilaterally, and negative correlations concerned superior frontal and medial temporal regions. Conclusions— Increased perisylvian activation over time probably reflects improved performance at the expenses of cognitive effort in aphasic patients. Decreased activation in different neural systems suggests a familiarization effect with reduced emotional load.

This paper investigates face perception in a visual agnosic and prosopagnosic patient (SB). Despite very extensive lesions of visual areas, SB remains capable of some visual processing [Brain 125 (2002) 58]. However, in everyday situations SB does not exhibit signs of specific face recognition. To investigate how SB may process faces, we tested two hypotheses. According to the 'spared module hypothesis,' SBs abilities come from spared modules of implicit face processing. According to the 'general strategy hypothesis,' SB may have developed some deliberate compensatory strategies. A two-session experimental design was constructed. In both sessions, face and non-face pictures were shown to participants. In Session 1 (implicit condition), participants had to decide whether each picture was a vegetable. In Session 2 (explicit condition), participants had to decide whether each picture was a face. Verbal reports showed that SB was not aware of faces in Session 1. However, behavioural results showed that (1). SB could process faces; (2). even when SB was not aware of faces, he processed them differently than non-faces; (3). when knowing the presence of faces, he did not process faces better. In addition, eye-tracking data suggested that SB did not change the nature of his processing from Sessions 1 to 2. Pupil diameters showed that fixated facial features were processed similarly as in control participants. Together, these results are not compatible with a general compensatory strategy hypothesis and suggest sparing of an implicit face processing module in SB.

No definite genetic risk factor of non-monogenic frontotemporal dementia (FTD) has yet been identified. Several groups have examined the potential association of FTD with the apolipoprotein E (APOE) gene, but the results are inconsistent. Our objective was to determine whether APOE is a risk factor of FTD, using the largest series of patients with FTD and controls analysed so far (94 unrelated patients and 392 age and sex-matched controls), and a meta-analysis. Homozygosity for the E2E2 genotype was significantly associated with FTD (odds ratio (OR)=11.3; P=0.033, exact test). After stratification on familial history (FH) for FTD, the OR for E2E2 was still found significant when analysing only patients with a positive FH (OR=23.8; P=0.019). The meta-analysis, using 10 case-control studies with available genotype or allele information, comprising a total of 364 FTD patients and 2671 controls, including the patients of the present study, did not reach statistical significance even if the E2E2 genotype was more frequent in patients than in controls (0.018 vs 0.006, respectively). Because of studies heterogeneity (Mantel-Haenszel statistics: P=0.004), we analysed on one hand the neuropathologically-confirmed studies, and on the other hand the clinical-based studies. In the neuropathologically-confirmed studies (Mantel-Haenszel statistics: P=ns), we found a significant increase of the E2 allele frequency in FTD patients (OR[E2 vs E3]=2.01; 95% CI=1.02-3.98; P=0.04). The same result was found in the clinical-based studies, but studies heterogeneity remained. No result was significant with the E4 allele. The E2 allele seems so to be a risk factor of FTD whereas this allele is associated with the lowest risk in Alzheimer's disease. If this finding was confirmed, it could provide new insights into the mechanisms of differential risk related to APOE in neurodegenerative diseases.

The effect of a language therapy in a group of eight anomic mild patients (the Lexical Therapy group) was assessed by using a 5-month long Lexical Therapy in comparison with an occupational program used in a matched control group (AD; n = 8). The Lexical Therapy group benefited significantly from a language therapy as shown by the naming improvement postintervention. The improvement reached significance only for items that were included in the language therapy protocol and no significant generalization to untreated items was observed. In mild AD patients with anomia and no severe semantic impairment, a reinforcement of the relationship between the form of the object and the corresponding lexical label in episodic long term memory during language therapy may account for the observed lexical improvement.

The low density lipoprotein receptor-related protein gene (LRP) is a good candidate gene for Alzheimer's Disease (AD). Its protein is involved in the physiopathology of AD and has been found in senile plaques; on the other hand, LRP is located in 12q, a region in which genetic linkage to AD was reported. Two common polymorphisms, a tetranucleotide repeat in the 5' untranslated region and a single nucleotide polymorphism at position 766 in exon 3, were found to be associated with AD, but contradictory results were obtained in subsequent association studies. In the absence of clear hypotheses concerning the association of these polymorphisms with AD and their functional role, our objective was to test the association between AD and the two LRP polymorphisms in a large French case-control sample (274 Caucasian AD patients and 290 matched controls) using haplotype analysis. First, the separate study of each polymorphism showed no significant difference in genotype and allele frequencies between AD cases and controls. Second, strong linkage disequilibrium was found between alleles of the two polymorphisms in controls and in cases and the linkage disequilibrium between the 91 bp and C alleles were opposite in cases and in controls. Third, we found that the frequency of the 91-C haplotype was higher in cases than in controls, but the type I error was 0.061, slightly higher than the conventional one of 5%. The haplotype frequencies did not vary significantly as a function of age and APOE epsilon4 status. One interest in this study is the use of the haplotype analysis, which can be used to combine information from several polymorphisms, taking into account their dependence.

Afin d’identifier les patients atteints de maladie d’Alzheimer (MA) a un stade predementiel parmi les patients etiquetes MCI, plusieurs outils sont actuellement developpes : bilan neuropsychologique specifique, biomarqueurs dans le LCR, imagerie morphologique et metabolique. Un diagnostic precoce de MA offrirait la possibilite d’etudier l’effet de nouvelles approches therapeutiques visant a entraver l’evolution du processus pathologique sous-jacent.

International audience; Frontotemporal dementia (FTD) refers to a disease spectrum including the behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy/corticobasal degeneration syndrome (PSP/CBDS), and FTD with amyotrophic lateral sclerosis (FTD-ALS). A GGGGCC expansion in C9ORF72 is a major cause of FTD and ALS. C9ORF72 was analyzed in 833 bvFTD, FTD-ALS, PPA, and PSP/CBDS probands; 202 patients from 151 families carried an expansion. C9ORF72 expansions were much more frequent in the large subgroup of patients with familial FTD-ALS (65.9%) than in those with pure FTD (12.8%); they were even more frequent than in familial pure ALS, according to estimated frequencies in the literature (23-50%). The frequency of carriers in non-familial FTD-ALS (12.7%) indicates that C9ORF72 should be analyzed even when family history is negative. Mutations were detected in 6.8% of PPA patients, and in 3.2% of patients with a clinical phenotype of PSP, thus enlarging the phenotype spectrum of C9ORF72. Onset was later in C9ORF72 (57.4 years, 95%CI: 55.9-56.1) than in MAPT patients (46.8, 95%CI: 43.0-50.6; p = 0.00001) and the same as in PGRN patients (59.6 years; 95%CI: 57.6-61.7; p = 0.4). ALS was more frequent in C9ORF72 than in MAPT and PGRN patients; onset before age 50 and parkinsonism were indicative of MAPT mutations, whereas hallucinations were indicative of PGRN mutations; prioritization of genetic testing is thus possible. Penetrance was age- and gender-dependent: by age 50, 78% of male carriers were symptomatic, but only 52% of females. This can also guide genetic testing and counseling. A flowchart for genetic testing is thus proposed.

We analyzed 12 families with autosomal dominant early-onset Alzheimer's disease (EOAD) for mutations in the coding region of the presenilin I (PSNLI) gene corresponding to the AD3 locus on chromosome 14q24.3. A total of eight missense mutations at codons 82, 115, 139, 163, 231, 264, 392, and 410, including six novel mutations, were identified in eight families. Cosegregation of the mutations with EOAD was confirmed in three families, one including 36 affected individuals. This study underlines the great allelic heterogeneity and the large distribution of the mutations within the PSNLI coding region. Out results support the notion that PSNLI is the major gene involved in autosomal dominant EOAD.

A brain activation study using SPECT and 133Xe in a deep dysphasic patient with left temporal lesion is presented. The activation paradigm consisted of a passive listening to foreign language as baseline, a phoneme monitoring condition and a semantic word monitoring condition. The specific activation of the right middle temporal cortex observed in the semantic condition is congruent with the hypothesis of a compensatory role of the right hemisphere in processing concrete words. This case illustrates the interest of functional imaging for a better understanding of neural mechanisms of functional recovery after brain injury.

International audience; There is an ongoing debate regarding the respective role of anterior subhippocampal structures and the hippocampus in recognition memory. Here, we report a double anatomo-functional dissociation observed in two brain-damaged patients, FRG and JMG. They both suffered from complete destruction of left MTL structures. In the right hemisphere however, FRG sustained extensive lesions to the hippocampus sparing anterior subhippocampal structures, while JMG suffered from the reversed pattern of lesion, i.e., extensive damage to anterior subhippocampal structures but preserved hippocampus. FRG was severely amnesic and failed all recall tasks involving visual material, but exhibited normal performance at a large battery of visual recognition memory tasks. JMG was not amnesic and showed the opposite pattern of performance. These results strongly support the view that right anterior subhippocampal structures are a critical relay for visual recognition memory in the human. © 2010 Wiley-Liss, Inc.

International audience; We tested the efficacy and tolerability of one-year treatment with memantine (10 mg bid) in behavioral variant frontotemporal dementia (bvFTD). BvFTD patients aged 45 to 75 years, with a Mini-Mental Status Examination (MMSE) score ≥19, were enrolled in a national, randomized, double-blind, placebo-controlled (DBPC), Phase II trial. The primary endpoint was the CIBIC-Plus (Clinician's Interview-Based Impression of Change Plus Caregiver Input). The secondary endpoints included: Neuropsychiatric Inventory (NPI), Frontal Behavioral Inventory (FBI), Mattis Dementia Rating Scale (MDRS), MMSE, Disability Assessment for Dementia (DAD), and the Zarit Burden Inventory (ZBI). Forty-nine patients were analyzed. At baseline, mean age was 65.6 years and mean MMSE was 25.0 (range: 19-30). On the CIBIC-Plus, 52 weeks after baseline, there were no significant differences between the memantine group (n = 23) and the placebo group (n = 26); p = 0.4458; however, 10 patients had worsened in the memantine group versus 17 in the placebo group. For the secondary endpoints there were no differences in the evolution of score between the memantine group and the placebo group (MMSE, p = 0.63); (MDRS, p = 0.95); (NPI, p = 0.25); (ZBI, p = 0.43); (DAD, p = 0.10) except for the FBI score, which was lower in the memantine group (p = 0.0417). Memantine was well-tolerated. This is the first DBPC trial in a large group of bvFTD patients involving neuroprotective treatment. A multinational study with a larger number of patients is now needed in order to verify the results of our study. The trial is registered with ClinicalTrials.gov; number NCT 00200538.

This paper presents a correlative study between phonological and semantic verbal fluency performances and SPECT data obtained at rest in a group of dementia of Alzheimer type (DAT) patients. In both verbal fluency tasks, normals were superior to DAT patients, but in the majority of our patients, phonological verbal fluency appeared more resistant than semantic verbal fluency. The only significant result we found was between good performances on semantic verbal fluency and relative preserved left anterior cerebral blood flow. Results are discussed first in terms of cognitive strategies required for verbal fluency and second in terms of predominant lateralized hypoperfusion in relation with both verbal fluency tasks.

Based on a previous work on a large group of aphasics with subcortical lesions, we propose a pathophysiological hypothesis according to which (1) in most cases, subcortical lesions generate a pathological status so that a left perisylvian cortical system, which is involved in the processing of phonological aspects of language, is not affected; (2) two systems are disturbed: (a) a subcortico-frontal system which is implicated in the dynamics of speech production and (b) a complex subcortico-cortical system which processes the lexico-semantic aspects of language production and comprehension; (3) compensatory processes account for the absence of comprehension impairments in many cases; (4) in some cases, non-thalamic subcortical lesions are associated with standard aphasic syndromes including phonemic disorders which correspond to a disturbance of the phonological information processing system. The present SPECT study of regional cerebral blood flow (rCBF) was performed in order to test this hypothesis. The rCBF was assessed in 14 patients with subcortical aphasia at the acute stage, in 11 patients with cortical aphasia and in 23 normal volunteers. Results partly supported our hypothesis. In the subcortical group, the severity aphasia score was correlated with rCBF ratios in three left cortical regions and in a right posterior temporal region. Phonological disorders were associated with a hypoperfusion in some left cortical regions. Auditory comprehension disorders were associated with hypoperfusion in both left and right posterior temporal regions. The rLCR in these homologous regions were highly correlated and this correlation was more marked in the subcortical patient group than in the normal group. We propose that compensatory neural mechanisms in these interconnected homologous posterior temporal areas account for preserved comprehension capacities in many cases of subcortical aphasia, especially the thalamic cases.

International audience; The objective of this study is to identify the cerebral regions that are assessed by the Frontal Assessment Battery (FAB). Using SPM voxel-based analysis, we looked for correlations between FAB performance and brain SPECT perfusion in 47 patients with the frontal variant of frontotemporal dementia (fv-FTD) recruited by the French FTD research network, a multicentre initiative of French University hospitals with expertise in the field of dementia. A significant correlation was found between FAB performance and perfusion in the medial and dorsolateral frontal cortex bilaterally, independently of age, gender and MMSE. No correlations were observed with orbital frontal or parietal perfusion, in spite of the presence of hypoperfusion in these areas, or with perfusion of any other cortical or subcortical region. These findings confirm that the FAB is an adequate tool for assessing functions related to the dorsolateral and medial frontal cortex, and is thus useful for the evaluation of diseases associated with frontal dysfunction.

Objective: To improve diagnosis of early Alzheimer’s disease (AD), i.e., prodromal AD, by an automated quantitative tool combining brain perfusion single-photon emission computed tomography (SPECT) images and memory tests scores in order to be applied in clinical practice. Patients and methods: In this prospective, longitudinal, multi-centric study, a baseline 99m Tc-ECD perfusion SPECT was performed in 83 patients with memory complaint and mild cognitive impairment (MCI). After a 3-year follow-up, 11 patients progressed to Alzheimer’s disease (MCI-AD group), and 72 patients remained stable (MCI-S group), including 1 patient who developed mild vascular cognitive impairment. After comparison between the MCI-S and MCI-AD groups with a voxel-based approach, region masks were extracted from the statistically significant clusters and used alone or in combination with Free and Cued Selective Reminding Test (FCSRT) scores for the subject’s categorization using linear discriminant analysis. Results were validated using the leave-one-out cross-validation method. Results: Right parietal and hippocampal perfusion was significantly (p < 0.05, corrected) decreased in the MCI-AD group as compared to the MCI-S group. The patients’ classification in the MCI group using the mean activity in right and left parietal cortex and hippocampus yielded a sensitivity, specificity, and accuracy of 82%, 90%, and 89%, respectively. Combination of SPECT results and FCSRT free recall scores increased specificity to 93%. Conclusion: The combination of an automated quantitative tool for brain perfusion SPECT images and memory test scores was able to distinguish, in a group of amnestic MCI, patients at an early stage of AD from patients with stable MCI.

Resume Dans l’objectif d’ameliorer l’evaluation des troubles semantiques specifiques dans les phases precoces des maladies cognitives neurodegeneratives, nous proposons un nouvel outil de reconnaissance des personnes celebres, de denomination et d’acces aux connaissances semantiques. La batterie Gretop a ainsi ete developpee en poursuivant les objectifs suivants : etablir un outil facile a manier, realiste dans son temps de passation, informatise, norme sur un grand nombre de sujets temoins, evaluant l’acces semantique sur entree visuelle ou verbale, et permettant un calcul precis de la quantite d’informations semantiques recuperees. Les resultats presentes dans cet article montrent que la batterie possede une bonne coherence interne, que les deux sous-tests visages et noms sont equilibres en termes de difficulte et de familiarite des items, et que les normes ont ete collectees aupres d’un nombre eleve de sujets temoins. De plus, la presentation de huit cas cliniques testes avec la batterie illustre les differents profils cognitifs identifiables et revele le bon degre de specificite de cet outil. Au total, la construction de l’outil, ses normes, ainsi que sa specificite, font donc de Gretop un outil precieux dans le diagnostic precoce de maladies neurodegeneratives

Psychiatric and cognitive disorders were evaluated on an all-inclusive basis in 64 patients with dementia of Alzheimer type and related to regional cerebral blood flow (CBF) measured by SPECT. Isolated affective troubles were found in 22 patients and isolated behavioral changes in 24 cases, whereas only 5 patients presented with both type of disorders. Delirious reactions and hallucinations never occurred alone and were present in only 4 patients. The occurrence and severity of psychiatric disorders were related to the overall severity of dementia and to the magnitude of the instrumental (cortical functions) deficit for most patients, with no difference according to affective versus behavioral disorders. Later onset and higher prevalence of females characterized the group of 14 patients with preponderant psychiatric over instrumental disorders. Left parietotemporal hyperperfusion was associated with prominently decreased instrumental capacities, whereas no peculiar flow defect was associated with either type of psychiatric disorder, while in the 14 patients with preponderant psychiatric impairment, mean CBF was only slightly reduced compared to controls.

We report on a patient with anomic aphasia presenting severe and sometimes unusual word-finding difficulties in noun confrontation naming (i.e. production of Self-Denied Good Responses restricted to the naming to objects). With reference to Warren and Morton's model, which includes picture naming processing (1982), anomic deficits could be the surface manifestations of deficits in (1) the visual identification processing, or (2) the lexical semantic processing, or (3) the lexical phonological processing. However, a neuropsychological assessment indicates that gnosic, semantic and phonological processings seem unimpaired in our patient. Thus, the underlying determinism of his word-finding difficulties could consist in a deficit (1) in the selection and the activation of adequate lexical phonological form and/or (2) in the retroactive control processes in charge of assessing the appropriateness of selected and produced lexical forms. This deficit would exist only in confrontation naming for the lexical forms with concrete reference.

International audience; Frontotemporal dementia (FTD) is the second most frequent type of neurodegenerative dementias. Mutations in the progranulin gene (GRN, PGRN) were recently identified in FTDU-17, an FTD subtype characterized by ubiquitin-immunoreactive inclusions and linkage to chromosome 17q21. We looked for PGRN mutations in a large series of 210 FTD patients (52 familial, 158 sporadic) to accurately evaluate the frequency of PGRN mutations in both sporadic and familial FTD, and FTD with associated motoneuron disease (FTD-MND), as well as to study the clinical phenotype of patients with a PGRN mutation. We identified nine novel PGRN null mutations in 10 index patients. The relative frequency of PGRN null mutations in FTD was 4.8% (10/210) and 12.8% (5/39) in pure familial forms. Interestingly, 5/158 (3.2%) apparently sporadic FTD patients carried a PGRN mutation, suggesting the possibility of de novo mutations or incomplete penetrance. In contrast, none of the 43 patients with FTD-MND had PGRN mutations, supporting that FTDU-17 and FTD-MND are genetically distinct. The clinical phenotype of PGRN mutation carriers was particular because of the wide range in onset age and the frequent occurrence of early apraxia (50%), visual hallucinations (30%), and parkinsonism (30%) during the course of the disease. This study supports that PGRN null mutations represent a more frequent cause of FTD than MAPT mutations (4.8% vs. 2.9%) but are not responsible for FTD-MND. It also demonstrates that half of the patients with a PGRN mutation in our series had no apparent family history of dementia. Taking this into account, genetic testing should be now considered more systematically, even in patients without obvious familial history of FTD.

We conducted a randomized, double-blind, placebo-controlled, single-patient (N = 1) trial to evaluate the efficacy of zolpidem in a 48-year-old woman with an akinetic mutism. Motor and cognitive examinations and functional imaging were performed. Acute administration of zolpidem markedly improved motor performance and neuropsychological status. Cerebral metabolism ((18)F-fluorodeoxyglucose positron emission tomography) increased in postrolandic territories and in frontal cortex. Using the H(2) (15)O positron emission tomography, we found a drug-induced activation in the anterior cingulate and orbitofrontal cortices. Zolpidem induced a transient improvement in motor and cognitive performances. This paradoxical effect could result from an activation of limbic loops modulating motivational processes.

International audience; We conducted a French multicentric cross-sectional study to describe in detail the demographic, neurological and behavioural characteristics of the frontal variant of frontotemporal dementia (fvFTD) and to characterize the pattern of brain perfusion SPECT in comparison to a healthy control group. A total of 68 fvFTD patients had technetium-99m-ECD brain perfusion SPECT at inclusion, 61 of which also underwent an in-depth evaluation including 70 items assessing behaviour, language and affect/emotion at onset and at inclusion. The mean age-at-onset was 60.4 +/- 7.8 years (35-75). Twenty-six per cent of the patients were older than 65 at onset. A positive familial history consistent with an autosomal dominant inheritance was found in 18% of the patients. At onset, the behavioural profile was predominantly inert in 25% of the patients, disinhibited in 18% and mixed in others. The behavioural features progressed to predominantly mixed or inert forms. Although, inertia was associated with predominant medial frontal and cingulate hypoperfusion, and patients with disinhibition exhibited predominant ventromedial prefrontal and temporal hypoperfusion, there were no major clinical differences between disinhibited and inert patients. Forty-five per cent of the deceased patients survived 8 years (long survival). This shows that the final outcome of fvFTD is highly variable. No clinical factors predictive of short or long survival were identified. Unexpected, however, was the finding that brainstem hypoperfusion distinguished patients with a short survival from patients with long survival. In conclusion, this study shows that fvFTD is clinically a rather homogeneous entity. It also provides evidence that different behavioural presentations at onset are related to different anatomical localizations of degenerative damage. Finally, it demonstrates the prognostic value of brainstem hypoperfusion in a subgroup of patients with a short survival.

intensive, long-term caregiver education and support program delays patient nursing home admission. Methods: The AENEAS study is a multicenter, randomized, controlled trial. A total of 292 community-dwelling patients at a mean age of 76 years with moderate (CDR 2, MMSE 18 to 8) probable or possible Alzheimer’s Disease (NINCDS-ADRDA) and their primary caregivers were enrolled in 15 centers in Austria, Germany, and Switzerland. Caregivers in the intervention group participated in a multicomponent, highly standardized, education and support program which had been developed by the German Alzheimer’s Association. It was composed of 7 bi-weekly group sessions (6 to 8 participants, 120 minutes duration) followed by 6 bi-monthly refresher meetings. Caregivers in the control group received one session of standard social worker counseling. Caregivers were re-interviewed 12 months after the initial 7 group meetings to ascertain patient nursing home admission. Raters were blinded to participants’ group allocation. Results: For a preliminary analysis follow-up data were available on 259 participants from 13 centers. In each group, 22 patients had been permanently admitted to a nursing home (p 0.74). The mean time to nursing home admission was approximately 2 months longer in the intervention than in the control group, but this difference did not reach statistical significance. Conclusions: The multi-component, longterm caregiver intervention was associated with a non-significant delay in patient nursing home admissions. These findings will be discussed in terms of caregiver intervention design and targeting. This work was supported by the German Ministry of Education and Research (Grant 01GL0305).

ED, a 83-year-old woman, meets the criteria of pure progressive amnesia, with gradual impairment of episodic and autobiographical memory, sparing of semantic processing and strong working memory (WM) deficit. The dissociation between disturbed WM and spared semantic processing permitted testing the role of WM in processing anaphors like pronouns or repeated names. Results showed a globally normal anaphoric behavior in two experiments requiring anaphoric processing in sentence production and comprehension. We suggest that preserved semantic processing in ED would have compensated for working memory deficit in anaphoric processing.

We conducted an event-related functional magnetic resonance imaging experiment to better understand the potentially compensatory alternative brain networks activated by a clinically relevant face-name association task in Alzheimer's disease (AD) patients and matched control subjects. We recruited 17 healthy subjects and 12 AD patients at an early stage of the disease. They underwent functional magnetic resonance imaging scanning in four sessions. Each of the sessions combined a "study" phase and a "test" phase. Face/name pairs were presented in each study phase, and subjects were asked to associate faces with names. In the test phase, a recognition task, faces seen in the study phase were presented each with four different names. The task required selection of appropriate previously associated names from the study phase. Responses were recorded for post hoc classification into those successfully or unsuccessfully encoded. There were significant differences between the groups in accuracy and reaction time. Comparison of correctly versus incorrectly encoded and recognized pairs in the two groups indicated bilateral hippocampal hypoactivation both when encoding and recognizing in the AD group. Moreover, patients showed bilateral hyperactivation of parts of the parietal and frontal lobes. We discuss whether hyperactivation of a frontoparietal network reflects compensatory strategies for failing associative memory in AD patients.

Background: AD is characterized by cerebral deposition of β-amyloid plaques with amyloid β-peptide (Aβ) 42 as the major peptide constituent, along with neurofibrillary tangles and neuronal loss. In transgenic mice, active immunization against Aβ42 removes these plaques and improves cognitive function. A Phase I study in AD patients demonstrated good safety and tolerability of multiple injections of aggregated Aβ42 (AN1792) with QS-21 as adjuvant. Methods: Three hundred seventy-two patients with mild to moderate AD were randomized to receive IM injections of AN1792 or placebo (4:1) at baseline and at months 1, 3, 6, 9, and 12 in a multicenter Phase II safety, tolerability, and pilot efficacy study. Dosing was terminated after four early reports of meningoencephalitis, but follow-up continued. The study remains blinded, and further results will be reported after its termination. Results: Symptoms and laboratory findings consistent with meningoencephalitis occurred in 18 of 298 (6%) patients treated with AN1792 compared with 0 of 74 on placebo ( p = 0.020). Sixteen of the 18 had received two doses, one had received one dose, and one had received three doses of the study drug before symptoms occurred. The median latency from the first and last injections to symptoms was 75 and 40 days. No case occurred later than 6 months after the first immunization. Anti-Aβ42 antibody titers were not correlated with the occurrence or severity of symptoms or relapses. Twelve patients recovered to or close to baseline within weeks, whereas six remain with disabling cognitive or neurologic sequelae. All 18 patients remain alive to date (December 31, 2002), 6 months to >1 year after symptom onset. Conclusions: Postvaccination meningoencephalitis occurred without clear relation to serum anti-Aβ42 antibody titers. Potential mechanisms such as T-cell and microglial activation may be responsible and are under consideration to develop a safer anti-Aβ immunotherapy for AD.

Background Recent studies have shown an association between an extended tau haplotype (H1) that covers the entire human tau gene and progressive supranuclear palsy or, more inconsistently, other neurodegenerative disorders, such as corticobasal degeneration, Parkinson disease, Alzheimer disease, and frontotemporal dementia (FTD). In addition, disease-causing mutations in the tau gene on chromosome 17 have been detected in some families with autosomal dominant FTD and parkinsonism. In FTD, the pathological accumulation of the microtubule-associated protein tau suggests that the tau gene may be a genetic risk factor for this disorder. Objective To confirm or refute the association between the H1 haplotype or the H1H1 genotype of the tau gene and FTD. Design Case-control study. Setting Neurology departments of 12 French university hospitals. Participants One hundred unrelated patients with FTD and 79 controls. Methods Tau genotype (contiguous polymorphisms in exons 1, 7, and 13 and in intron 9 used to reconstruct the extended haplotypes H1 and H2). Clinical examination, psychometric testing, laboratory tests, computed tomography and magnetic resonance imaging, single-photon emission computed tomography, and electroencephalography for patients with FTD. Results The H1H1 genotype was significantly overrepresented in patients with FTD compared with controls (62% vs 46%; P = .01, 1-sided; odds ratio adjusted for age and sex, 1.95). After stratification according to apolipoprotein E ( APOE ) genotype, we found a significant interaction between APOE and tau genotypes ( P = .03). Conclusions This study of the largest series of patients with FTD confirms the primary role of tau in FTD and establishes that the H1 haplotype of the tau gene and the E2 allele of APOE interact by an unknown mechanism that increases the risk of FTD.

International audience; BACKGROUND: The cognitive consequences of carbon monoxide (CO) poisoning are well described. However, most studies have been carried out without an ad-hoc group of control subjects. The main aim of this study was to evaluate cognitive and psychiatric outcome after CO exposure during the storm Klaus in the South West of France (January 2009) in a homogeneous group of patients compared to a group of 1:1 paired controls. METHODS: Patients and controls were asked to fill out questionnaires about quality of life and cognitive complaints. They then underwent a cognitive assessment derived from the Carbon Monoxide Neuropsychological Screening Battery. Psychiatric assessment was performed using subtests of the Mini International Neuropsychiatric Interview. RESULTS: 38 patients and 38 paired controls were included (mean age 38.8 years) and evaluated 51 days after the poisoning. No difference was found between groups on the cognitive complaint questionnaire but patients had a lower quality of life than controls. Patients showed significantly lower cognitive performance than controls on processing speed, mental flexibility, inhibition and working and verbal episodic memories. Patients were more depressed than controls, and suffered more from post-traumatic stress disorder. CONCLUSIONS: We report the first study investigating cognitive and psychiatric outcome in consecutive patients after CO poisoning during a natural disaster, using a group comparison method. CO poisoning during storms needs to be dealt with adequately and clinicians should be aware of its possible consequences.

The apolipoprotein E (APOE, gene; apoE, protein) isoforms are associated with differential risk of Alzheimer's disease (AD). An additional involvement of APOE promoter polymorphisms in AD risk has recently been suggested by several studies. Indeed, three polymorphisms of the APOE regulatory region (-219 G/T, -427 C/T and -491 A/T) have been found associated with AD even after adjustment on the apoE status. We analysed these three promoter region polymorphisms in a large French case-control study (388 AD cases and 386 controls). We found that the -427 T and -491 A alleles were associated with an increased risk of developing AD, but not the -219 G/T alleles. However, a strong linkage disequilibrium was observed between the alleles of these promoter region polymorphisms and the APOE coding region alleles. We therefore retested association after adjustment on apoE status and found that the sole association which remained significant was the association with the -427 T allele. The alpha level was equal to 0.03 (0.09 after Bonferroni correction for multiple comparisons). Analysis of promoter haplotypes also yielded non-significant results. Thus our study does not reinforce the hypothesis of an independent involvement of the APOE promoter region polymorphisms in AD risk.

SummaryTo determine the prevalence of early-onset Alzheimer disease (EOAD) and of autosomal dominant forms of EOAD (ADEOAD), we performed a population-based study in the city of Rouen (426,710 residents). EOAD was defined as onset of disease at age

To investigate the relationship among risk for Alzheimer disease (AD), familial aggregation of AD, and the apolipoprotein E (apoE) epsilon4 allele in first-degree relatives of probands with AD and known apoE genotype.Two hundred ninety subjects fulfilling the criteria of the National Institute of Neurological Communicative Disease and Stroke-Alzheimer's Disease and Related Disorders Association for probable AD were ascertained from March 1, 1992, to December 31, 1996, through consecutive admissions in several university hospitals.Family data were collected on 1176 first-degree relatives (parents and siblings), aged 40 to 90 years. Most living relatives underwent a clinical examination, whereas we relied on family history for clinical data for deceased or unavailable relatives. First, we conducted standard survival analyses to estimate cumulative lifetime risk (LTR) for AD among relatives and to investigate for sex and apoE genotype effects on LTR. Then, we assessed to what extent clustering of secondary AD could be explained by the apoE epsilon4 allele by deriving the expected proportions of relatives with 0, 1, or 2 apoE epsilon4 alleles conditionally on the proband's genotype.Cumulative LTR for AD among first-degree relatives increased significantly with the number of epsilon4 alleles present in the proband. By 90 years of age, LTRs in relatives of probands with epsilon3/epsilon3, epsilon3/epsilon4, and epsilon4/epsilon4 genotypes were 29.2%, 46.1%, and 61.4%, respectively. Significant sex-by-apoE genotype interaction effects on LTR were observed. Women had about a 2-fold higher risk for AD than men among relatives of epsilon4 carriers but not among relatives of non-epsilon4 carriers. The predicted proportion of epsilon4 carriers in relatives of probands with epsilon3/epsilon3 genotype remains about 50% lower than the corresponding LTR for AD, indicating that familial clustering of AD is largely due to other factors than the apoE epsilon4 allele. Although aggregation of AD in families of probands with the epsilon4 allele is more prominent, we estimated that AD would not develop in about 30% of female and up to 60% of male relatives carrying at least 1 epsilon4 allele, even by 90 years of age.Our results support the hypothesis that the apoE epsilon4 allele enhances AD susceptibility, but putative factors enhancing risk for AD remain to be found.