Alzheimer Disease: Puel M

Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, Jouanny P, Dubois B, Eisner L, Flitman S, Michel BF, Boada M, Frank A, Hock C. · Federation of Neurology, CHU Pellegrin, Bordeaux, France. · Neurology. · Pubmed #12847155 No free full text.

Abstract: BACKGROUND: AD is characterized by cerebral deposition of beta-amyloid plaques with amyloid beta-peptide (Abeta) 42 as the major peptide constituent, along with neurofibrillary tangles and neuronal loss. In transgenic mice, active immunization against Abeta42 removes these plaques and improves cognitive function. A Phase I study in AD patients demonstrated good safety and tolerability of multiple injections of aggregated Abeta42 (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-Abeta42 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-Abeta42 antibody titers. Potential mechanisms such as T-cell and microglial activation may be responsible and are under consideration to develop a safer anti-Abeta immunotherapy for AD.

Sarazin M, Berr C, De Rotrou J, Fabrigoule C, Pasquier F, Legrain S, Michel B, Puel M, Volteau M, Touchon J, Verny M, Dubois B. · INSERM U 610 and Centre des Maladies Cognitives et Comportementales, Hôpital de la Salpêtrière, Paris, France. · Neurology. · Pubmed #17984454 No free full text.

Abstract: OBJECTIVE: To compare the power of tests assessing different cognitive domains for the identification of prodromal Alzheimer disease (AD) among patients with mild cognitive impairment (MCI). BACKGROUND: Given the early involvement of the medial temporal lobe, a precocious and specific pattern of memory disorders might be expected for the identification of prodromal AD. METHODS: A total of 251 patients with MCI were tested at baseline by a standardized neuropsychological battery, which included the Free and Cued Selective Recall Reminding Test (FCSRT) for verbal episodic memory; the Benton Visual Retention Test for visual memory; the Deno 100 and verbal fluency for language; a serial digit learning test and the double task of Baddeley for working memory; Wechsler Adult Intelligence Scale (WAIS) similarities for conceptual elaboration; and the Stroop test, the Trail Making test, and the WAIS digit symbol test for executive functions. The patients were followed at 6-month intervals for up to 3 years in order to identify those who converted to AD vs those who remained stable over time. Statistical analyses were based on receiver operating characteristic curve and Cox proportional hazards models. RESULTS: A total of 59 subjects converted to AD dementia. The most sensitive and specific test for diagnosis of prodromal AD was the FCSRT. Significant cutoff for the diagnosis was 17/48 for free recall, 40/48 for total recall, and below 71% for index of sensitivity of cueing (% of efficacy of semantic cues for retrieval). CONCLUSIONS: The amnestic syndrome of the medial temporal type, defined by the Free and Cued Selective Recall Reminding Test, is able to distinguish patients at an early stage of Alzheimer disease from mild cognitive impairment non-converters.

Pariente J, Cole S, Henson R, Clare L, Kennedy A, Rossor M, Cipoloti L, Puel M, Demonet JF, Chollet F, Frackowiak RS. · Wellcome Department of Imaging Neuroscience, London, United Kingdom. · Ann Neurol. · Pubmed #16315273 No free full text.

Abstract: 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.

Verhey FR, Houx P, Van Lang N, Huppert F, Stoppe G, Saerens J, Böhm P, De Vreese L, Nordlund A, DeDeyn PP, Neri M, Peña-Casanova J, Wallin A, Bollen E, Middelkoop H, Nargeot MC, Puel M, Fleischmann UM, Jolles J. · Department of Psychiatry and Neuropsychology, University of Maastricht, The Netherlands. · Int J Geriatr Psychiatry. · Pubmed #14716698 No free full text.

Abstract: 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.

Verpillat P, Camuzat A, Hannequin D, Thomas-Anterion C, Puel M, Belliard S, Dubois B, Didic M, Michel BF, Lacomblez L, Moreaud O, Sellal F, Golfier V, Campion D, Clerget-Darpoux F, Brice A. · Département d'Epidémiologie, de Biostatistique, et de Recherche Clinique, Hôpital Bichat-Claude Bernard, 46 rue Henri Huchard, 75877 Paris CEDEX 18, France. · Arch Neurol. · Pubmed #12056929 links to  free full text

Abstract: 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.

Ousset PJ, Viallard G, Puel M, Celsis P, Démonet JF, Cardebat D. · Department of Gerontology, CHU Purpan, 31059 Toulouse Cedex 3, France. · Brain Lang. · Pubmed #11817887 No free full text.

Abstract: 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.

Verpillat P, Bouley S, Campion D, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Antérion C, Agid Y, Brice A, Clerget-Darpoux F. · INSERM U535, Le Kremlin Bicêtre, France, and INSERM U289, Paris, France. · Eur J Hum Genet. · Pubmed #11436129 links to  free full text

Abstract: 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.

Zurutuza L, Verpillat P, Raux G, Hannequin D, Puel M, Belliard S, Michon A, Pothin Y, Camuzat A, Penet C, Martin C, Brice A, Campion D, Clerget-Darpoux F, Frebourg T. · Faculté de Médecine et de Pharmacie, INSERM EPI 9906, IFRMP, Rouen. · Eur J Hum Genet. · Pubmed #10980578 links to  free full text

Abstract: 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.

Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T. · INSERM EPI 9906, Faculté de Médecine, 76183 Rouen, France. · Am J Hum Genet. · Pubmed #10441572 links to  free full text

Abstract: To 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 <61 years, and ADEOAD was defined as the occurrence of at least three EOAD cases in three generations. Using these stringent criteria, we calculated that the EOAD and ADEOAD prevalences per 100,000 persons at risk were 41.2 and 5.3, respectively. We then performed a mutational analysis of the genes for amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) in 34 families with ADEOAD ascertained in France. In 19 (56%) of these families, we identified 16 distinct PSEN1 missense mutations, including 4 (Thr147Ile, Trp165Cys, Leu173Trp, and Ser390Ile) not reported elsewhere. APP mutations, including a novel mutation located at codon 715, were identified in 5 (15%) of the families. In the 10 remaining ADEOAD families and in 9 additional autosomal dominant Alzheimer disease families that did not fulfill the strict criteria for ADEOAD, no PSEN1, PSEN2, or APP mutation was identified. These results show that (1) PSEN1 and APP mutations account for 71% of ADEOAD families and (2) nonpenetrance at age <61 years is probably infrequent for PSEN1 or APP mutations.

Verpillat P, Bouley S, Hannequin D, Belliard S, Puel M, Thomas-Anterion C, Dubois B, Agid Y, Campion D, Clerget-Darpoux F, Brice A. · No affiliation provided · Ann Neurol. · Pubmed #10976654 No free full text.

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