Alzheimer Disease: Barberger-Gateau P

Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P. · INSERM U610, Hôpital de la Salpêtrière, Paris, France. · Lancet Neurol. · Pubmed #17616482 No free full text.

Abstract: The NINCDS-ADRDA and the DSM-IV-TR criteria for Alzheimer's disease (AD) are the prevailing diagnostic standards in research; however, they have now fallen behind the unprecedented growth of scientific knowledge. Distinctive and reliable biomarkers of AD are now available through structural MRI, molecular neuroimaging with PET, and cerebrospinal fluid analyses. This progress provides the impetus for our proposal of revised diagnostic criteria for AD. Our framework was developed to capture both the earliest stages, before full-blown dementia, as well as the full spectrum of the illness. These new criteria are centred on a clinical core of early and significant episodic memory impairment. They stipulate that there must also be at least one or more abnormal biomarkers among structural neuroimaging with MRI, molecular neuroimaging with PET, and cerebrospinal fluid analysis of amyloid beta or tau proteins. The timeliness of these criteria is highlighted by the many drugs in development that are directed at changing pathogenesis, particularly at the production and clearance of amyloid beta as well as at the hyperphosphorylation state of tau. Validation studies in existing and prospective cohorts are needed to advance these criteria and optimise their sensitivity, specificity, and accuracy.

Letenneur L, Larrieu S, Barberger-Gateau P. · Inserm U 593, case 11, Université Victor Segalen Bordeaux 2, 146, rue Léo Saignat, 33076 Bordeaux cedex, France. · Biomed Pharmacother. · Pubmed #14992790 No free full text.

Abstract: The association between dementia and smoking or alcohol use has been examined in several epidemiological studies. In many case-control studies, a decreased risk of dementia or Alzheimer's disease (AD) was observed among smokers. However, when this association was analysed in prospective studies, an increased risk of AD was observed. In addition, in the PAQUID study, we showed that the decreased risk disappeared after adjustment for educational level and occupation. These factors are strong confounders in the association between dementia and tobacco use. We also showed that moderate consumption of wine was associated with a lower risk of developing AD. This result remains unchanged after adjustment for many potential confounders. The association between moderate alcohol consumption and risk of developing a dementia or AD was recently confirmed by prospective studies. In some studies, wine consumption was more specifically associated with a decreased risk, whereas beer or spirit consumption was not associated. These results suggest that tobacco consumption is not associated with a lower risk of dementia and that moderate alcohol intake does not increase the risk of developing dementia.

Deschamps V, Barberger-Gateau P, Peuchant E, Orgogozo JM. · INSERM U330, Université Victor Ségalen, Bordeaux, France. · Neuroepidemiology. · Pubmed #11174040 No free full text.

Abstract: There is increasing evidence that oxidative stress is involved in cerebral aging and dementia. The objective of this review is to give a progress report on the more recent results of the various epidemiologic cohorts studied for the association between nutrition of older people, the evolution of cognitive performances and the risk of later occurrence of dementia or stroke. The oxidative theory of pathological brain ageing is supported by animal laboratory experiments. Furthermore, experimental research has consistently suggested that diet-related factors play an important role in cognitive functions in ageing. In humans, a number of epidemiological case-control and prospective studies analyzed the association between nutrition, particularly fatty acids and antioxidant molecules (vitamins A, E, C, beta-carotene and polyphenols) and cognition. In the context of evidence already available, further studies are needed to identify the specific role of various nutrients, their interactions and the influence of genetic factors and living habits on cerebral aging and dementia. Vascular dementia and Alzheimer's disease, that share several risk factors, might be targets for primary prevention through nutritional recommendations and/or supplementation.

Dartigues JF, Goulley F, Bourdeix I, Péré JJ, Barberger-Gateau P. · INSERM U 330. Université de Bordeaux II. France. · Rev Neurol (Paris). · Pubmed #12386525 No free full text.

Abstract: Six hundred and sixty nine out patients with mild to moderate Alzheimer's disease were enrolled by 193 French neurologists, psychiatrists and gerontologists. The patients, 38p.cent males and 62p.cent females with a mean age of 75 years were progressively titrated from 3 to 12mg by day of rivastigmine, Exelon((R)), a day, and treated for 6 months. Mean Mini-Mental State (MMS) at baseline was 18.6. Concomitant pathologies and treatments were present in 89p.cent of the patients. Safety was good though 86p.cent reported an adverse event which was mild in most of the cases. The premature drop out rate was 29p.cent. Seventy-five patients showed no change or an improvement in their 4 Instrumental Activities of Daily Living (IADL) score with no change in the MMS at the end of treatment (18.8). Four items of the Neuro-Psychiatric Inventory (NPI): delusions, anxiety, apathy, and irritability were significantly improved at week 12 and the improvement in anxiety was still significant at the end of treatment. The total score frequency X severity showed a tendency to improvement. The correlations between the sum of the 4 IADL, MMS and NPI scores were strongly significant.

Amieva H, Le Goff M, Millet X, Orgogozo JM, Pérès K, Barberger-Gateau P, Jacqmin-Gadda H, Dartigues JF. · Institut National de la Sante et de la Recherche Médicale, U897, France. · Ann Neurol. · Pubmed #19067364 No free full text.

Abstract: OBJECTIVE: Whereas cognitive deficits are known to be detectable long before the typical symptoms of Alzheimer's disease (AD) are evident, previous studies have failed to determine when cognitive functioning actually begins to decline before dementia. Utilizing the long follow-up of the PAQUID study, we examined the emergence of the first clinical symptoms over a 14-year period of follow-up before the dementia phase of AD. METHODS: This study relies on a case-control sample selected from the PAQUID cohort. Of the 3,777 initial subjects of the cohort, 350 subjects experienced development of AD during the 14 years of follow-up. The cases were matched to 350 elderly control subjects. The evolution of scores on cognitive, functional, and depression scales was described throughout the 14-year follow-up using a semiparametric extension of the mixed-effects linear model. RESULTS: The first decline in cognitive performances appeared as early as 12 years before dementia in measures of semantic memory and conceptual formation. Then, more global deficits appeared that were concomitant with an increase in memory complaints and depressive symptoms. About 2 years later, as a consequence of cognitive dysfunction, the subjects started to become slightly dependent in their activities of daily living. In the last 3 years, the impairment significantly worsened until the subjects reached the dementia phase. INTERPRETATION: This approach, describing the 14 years preceding dementia, provides a clear illustration of the particularly long and progressive prodromal phase of AD, and shows the successive emergence of cognitive deficits, depressive symptoms, and functional impairment during this phase.

Letenneur L, Pérès K, Fleury H, Garrigue I, Barberger-Gateau P, Helmer C, Orgogozo JM, Gauthier S, Dartigues JF. · INSERM, U897, Bordeaux, France. · PLoS One. · Pubmed #18982063 links to  free full text

Abstract: BACKGROUND: Herpes Simplex Virus (HSV) infection has been proposed as a possible risk factor of Alzheimer's Disease (AD) notably because it is neurotropic, ubiquitous in the general population and able to establish lifelong latency in the host. The fact that HSV was present in elderly subjects with AD suggests that the virus could be a co-factor of the disease. We investigated the risk of developing AD in anti-HSV immunoglobulin G (IgG) positive subjects (indicator of a lifelong infection to HSV) and IgM-positive subjects (indicator of primary infection or reactivation of the virus) in a longitudinal population-based cohort of elderly subjects living in the community. METHODS: Cox proportional hazard models were used to study the risk of developing AD according to the presence or not of anti-HSV IgG and IgM antibodies, assessed in the sera of 512 elderly initially free of dementia followed for 14 years. RESULTS: During the follow-up, 77 incident AD cases were diagnosed. Controlled for age, gender, educational level and Apolipoprotein E4 (APOE4) status, IgM-positive subjects showed a significant higher risk of developing AD (HR = 2.55; 95% CI [1.38-4.72]), although no significant increased risk was observed in IgG-positive subjects (HR = 1.67; 95%CI [0.75-3.73]). No modification effect with APOE4 status was found. CONCLUSION: Reactivation of HSV seropositivity is highly correlated with incident AD. HSV chronic infection may therefore be contributive to the progressive brain damage characteristic of AD.

Samieri C, Féart C, Letenneur L, Dartigues JF, Pérès K, Auriacombe S, Peuchant E, Delcourt C, Barberger-Gateau P. · Inserm, U897, Equipe Epidémiologie de Nutrition et des Comportements Alimentaires, Bordeaux, France. · Am J Clin Nutr. · Pubmed #18779288 No free full text.

Abstract: BACKGROUND: The potential preventive role of polyunsaturated fatty acids (PUFAs) in Alzheimer disease has aroused increasing interest. Plasma n-3 PUFAs have been shown to be inversely related to the risk of dementia and to depression, which is frequently associated with dementia. OBJECTIVE: The objective was to ascertain whether plasma PUFAs predict the risk of incident dementia in a cohort of older persons, independently of their depressive status. DESIGN: Of 1214 nondemented participants in the Three-City Study from Bordeaux (France) who were followed up for 4 y, 65 developed dementia. The association between the proportion of plasma fatty acids at baseline and the risk of incident dementia was assessed by multivariate proportional hazard models, taking into account depressive status assessed on the basis of the Center for Epidemiologic Studies Depression scale. RESULTS: A higher plasma eicosapentaenoic acid (EPA) concentration was associated with a lower incidence of dementia [hazard ratio (HR) for 1 SD = 0.69; 95% CI: 0.48, 0.98], independently of depressive status and after adjustment for age, education, apolipoprotein E epsilon4 allele, diabetes, and baseline plasma vitamin E and triacylglycerol. The relations between docosahexaenoic acid (DHA), total n-3 PUFAs, and incident dementia did not remain significant in multivariate models. Higher ratios of arachidonic acid (AA) to DHA and of n-6 to n-3 fatty acids were related to an increased risk of dementia, particularly in depressive subjects (n = 90): ratio of AA to DHA (HR: 2.65; 95% CI: 1.07, 6.56) and ratio of n-6 to n-3 (HR: 1.61; 95% CI: 1.04, 2.47). CONCLUSIONS: A high plasma EPA concentration may decrease the risk of dementia, whereas high ratios of n-6 to n-3 fatty acids and of AA to DHA may increase the risk of dementia, especially in depressed older persons. The role of EPA in dementia warrants further research.

Barberger-Gateau P, Raffaitin C, Letenneur L, Berr C, Tzourio C, Dartigues JF, Alpérovitch A. · INSERM, U593, University Victor Segalen Bordeaux 2, case 11, 146 rue Léo-Saignat, F-33076 Bordeaux cedex, France. · Neurology. · Pubmed #17998483 No free full text.

Abstract: BACKGROUND: Dietary fatty acids and antioxidants may contribute to decrease dementia risk, but epidemiologic data remain controversial. The aim of our study was to analyze the relationship between dietary patterns and risk of dementia or Alzheimer disease (AD), adjusting for sociodemographic and vascular risk factors, and taking into account the ApoE genotype. METHODS: A total of 8,085 nondemented participants aged 65 and over were included in the Three-City cohort study in Bordeaux, Dijon, and Montpellier (France) in 1999-2000 and had at least one re-examination over 4 years (rate of follow-up 89.1%). An independent committee of neurologists validated 281 incident cases of dementia (including 183 AD). RESULTS: Daily consumption of fruits and vegetables was associated with a decreased risk of all cause dementia (hazard ratio [HR] 0.72, 95% CI 0.53 to 0.97) in fully adjusted models. Weekly consumption of fish was associated with a reduced risk of AD (HR 0.65, 95% CI 0.43 to 0.994) and all cause dementia but only among ApoE epsilon 4 noncarriers (HR 0.60, 95% CI 0.40 to 0.90). Regular use of omega-3 rich oils was associated with a decreased risk of borderline significance for all cause dementia (HR 0.46, 95% CI 0.19 to 1.11). Regular consumption of omega-6 rich oils not compensated by consumption of omega-3 rich oils or fish was associated with an increased risk of dementia (HR 2.12, 95% CI 1.30 to 3.46) among ApoE epsilon 4 noncarriers. CONCLUSION: Frequent consumption of fruits and vegetables, fish, and omega-3 rich oils may decrease the risk of dementia and Alzheimer disease, especially among ApoE epsilon 4 noncarriers.

Pérès K, Chrysostome V, Fabrigoule C, Orgogozo JM, Dartigues JF, Barberger-Gateau P. · INSERM U593 the French Institute of Health and Medical Research, University Victor Segalen, France. · Neurology. · Pubmed #16894108 No free full text.

Abstract: OBJECTIVE: To describe the restriction in instrumental activities of daily living (IADL) in mild cognitive impairment (MCI) and to assess the impact of IADL restriction on the progression to dementia and on MCI reversibility. METHODS: The study sample included 1,517 participants of the PAQUID cohort, visited at 8- and 10-year follow-ups. Subjects classified as having MCI had no dementia but a cognitive deficit according to five neuropsychological tests. Four IADL (telephone, transports, medication, finances) were assessed and considered restricted if at least two of them were not performed at the highest level of performance. Cross-sectional and longitudinal analyses were conducted. RESULTS: A total of 285 subjects were classified as having MCI at baseline, and 15.2% developed dementia within 2 years. MCI subjects were more frequently IADL restricted (34.3%) than controls (5.4%) but less than those with dementia (91.1%). The IADL-restricted MCI subjects were more likely to develop dementia over 2 years (30.7%) than the nonrestricted ones (7.8%). In multivariate analyses, the odds ratio for dementia was 7.4 (CI: 3.3 to 16.5) in the IADL-restricted MCI and 2.8 (CI: 1.3 to 6.0) in the non-IADL-restricted MCI compared with the non-IADL-restricted controls. IADL restriction also lowered the chance of reversibility to normal, observed in 10.7% of the restricted MCI and 34.7% of the nonrestricted MCI. CONCLUSIONS: Inclusion of instrumental activities of daily living restriction in the criteria of mild cognitive impairment improves the prediction of dementia and the stability of this status over time. Conversely, its exclusion results in inappropriate selection of subjects with a low probability of short-term progression to dementia.

Amieva H, Jacqmin-Gadda H, Orgogozo JM, Le Carret N, Helmer C, Letenneur L, Barberger-Gateau P, Fabrigoule C, Dartigues JF. · INSERM (Institut National de la Santé et de la Recherche Médicale) Unit 593, Bordeaux, France. · Brain. · Pubmed #15774508 links to  free full text

Abstract: Better knowledge of the preclinical phase of Alzheimer's disease would be an important advance to allow earlier treatment of this ominous disease. This prodromal period was investigated in the Paquid cohort by analysing change in cognitive performances at five time points over a 9 year period. Neuropsychological measures including global cognitive functioning (Mini-Mental State Examination), visuo-spatial memory (Benton Visual Retention Test), verbal fluency (Isaacs Set Test) and abstract thinking (Wechsler Similarities Test) were assessed in 215 future Alzheimer's disease subjects and 1050 individuals without dementia. The results showed that cognitive performances of the pre-morbid subjects at baseline were already lower than those of individuals without dementia (1.4 points less on the Mini-Mental State Examination; 1.8 points less on the Benton Visual Retention Test; 4 points less on the Isaacs Set Test and 0.8 points less on the Wechsler Similarities Test). For some neuropsychological tests, an acceleration of the decline occurred approximately 3 years before the diagnosis and, for each test, the course of decline was modulated by education level. These findings show that abnormally low performances can be evidenced 9 years before the clinical diagnosis of Alzheimer's disease in several domains of cognition beyond memory and that cognitive change over time can be influenced by education.

Ramaroson H, Helmer C, Barberger-Gateau P, Letenneur L, Dartigues JF, Anonymous00037. · Unité INSERM 330, Université Victor Segalen Bordeaux II. · Rev Neurol (Paris). · Pubmed #12773869 No free full text.

Abstract: The progression of the prevalence of dementia in developed countries will increase the difficulties of medical and psycho-social management of demented patients and their family. The aim of this study was to estimate the prevalence of dementia among subjects aged 75 years and over. These subjects have been followed-up ten years after the baseline examination of the PAQUID study, a prospective population-based cohort study on normal and pathological aging after 65 years. A total of 1,461 subjects, aged 75 years and over, have been visited. The prevalence of dementia was estimated to be at 17.8 p.cent. About 38.5 p.cent of these demented subjects ware living in an institution, which leads to the fact that more than the two thirds of the subjects living in an institution were demented persons. Alzheimer's disease was the main etiology of dementia (79.6 p.cent). Based on the French population census, currently there would be about 769,000 demented people aged 75 years or over in France. Dementia accounts for 72 p.cent of the potential need for the French subvention for dependent persons, called Allocation Personnalisee d'Autonomie P. These results point out the importance of regarding dementia as a Public Health priority and of developing necessary measures for caring for these subjects, whether residing in their home or an institution.

Larrieu S, Letenneur L, Orgogozo JM, Fabrigoule C, Amieva H, Le Carret N, Barberger-Gateau P, Dartigues JF. · Epidemiology Research Unit, Institut National de la Santé et de la Recherche Médicale (INSERM) U 330, France. · Neurology. · Pubmed #12451203 No free full text.

Abstract: OBJECTIVE: To estimate the age-specific incidence rate of mild cognitive impairment (MCI) according to sex and educational level and to explore the course of MCI, particularly its progression to AD, in a population-based cohort. METHODS: A community-based cohort of nondemented elderly people (Personnes Agées QUID [PAQUID]) was followed longitudinally for 5 years. MCI was defined as memory complaints with objective memory impairment, without dementia, impairment of general cognitive functioning, or disability in activities of daily living. Incidence rates were calculated using the person-years method. A descriptive analysis at the different follow-up times was performed to study the course of MCI. RESULTS: At baseline, there were 58 prevalent cases of MCI (2.8% of the sample). During a 5-year follow-up, 40 incident cases of MCI occurred in 1,265 subjects at risk. The global incidence rate of MCI was 9.9/1,000 person-years. MCI was a good predictor of AD with an annual conversion rate of 8.3% and a good specificity, but it was very unstable over time: Within 2 to 3 years, only 6% of the subjects continued to have MCI, whereas >40% reverted to normal. CONCLUSIONS: Conventionally defined MCI has reasonable predictive value and specificity for AD. However, MCI was very unstable across time in this study. Furthermore, the definition of MCI seems to be too restrictive and should probably be extended to other categories of individuals also at high risk of developing AD.

Helmer C, Letenneur L, Rouch I, Richard-Harston S, Barberger-Gateau P, Fabrigoule C, Orgogozo JM, Dartigues JF. · INSERM U 330, Université de Bordeaux II, 146 Rue Léo Saignat, 33076 Bordeaux cedex, France. · J Neurol Neurosurg Psychiatry. · Pubmed #11511701 links to  free full text

Abstract: OBJECTIVE: To determine whether principal occupation during life is a risk factor for incident Alzheimer's disease, vascular dementia, or dementia with parkinsonism. METHODS: This study was carried out from the PAQUID (Personnes Agées QUID) cohort, an epidemiological study on normal and pathological aging after 65 years in the south west of France. At baseline, 2950 non-demented people living at home were identified and re-examined 1, 3, 5, 8, and 10 years later with identical standardised neurological and neuropsychological measures. Cox proportional hazards models with delayed entry were used, taking age as the time scale and adjusting for sex, education, tobacco, and wine consumption to estimate the risk ratio (RR) of incident dementia, Alzheimer's disease, vascular dementia, and dementia with parkinsonism associated with occupational category. RESULTS: Of the 2950 subjects, 393 became demented, of whom 251 had Alzheimer's disease, 112 had vascular dementia, and 27 had dementia with parkinsonism. The risk of Alzheimer's disease was not related to a given occupation. However the risk of dementia with parkinsonism seemed to be increased in farmers in comparison with professionals and managerials, particularly among women (RR 7.47; 95%CI, 1.80-31.07). CONCLUSION: The data suggest that occupation does not change the risk of Alzheimer's disease, which seems to be more influenced by cognitive abilities in childhood and adolescence than by occupation in adult life. However, being a farmer may increase the risk of dementia with parkinsonism among women; occupation could act by the way of differences in health behaviour or in exposure to environmental factors.

Commenges D, Scotet V, Renaud S, Jacqmin-Gadda H, Barberger-Gateau P, Dartigues JF. · Institut National de la Santé et de la Recherche Médicale U330, Bordeaux, France. · Eur J Epidemiol. · Pubmed #10959944 No free full text.

Abstract: It has been postulated that oxidative stress may play a key role in dementia. This is substantiated by the recent discovery of the protective effect of wine. In wine, the flavonoids--powerful antioxidant substances also contained in tea, fruits and vegetables--have been thought to offer such protection. We investigated whether flavonoid intake could be associated with a lower incidence of dementia in a cohort of 1367 subjects above 65 years of age (Paquid). A questionnaire was used to evaluate their intake of flavonoids and subjects were followed-up for 5 years between 1991 and 1996: 66 incident cases of dementia were observed. We estimated the relative risk (RR) of dementia according to tertiles of flavonoid intake using a Cox model. The age-adjusted RR of dementia was 0.55 for the two highest tertiles compared to the lowest (95% CI: 0.34-0.90; p = 0.02). After additional adjustment for gender, education, weight and vitamin C intake, the RR was 0.49 (95% CI: 0.26-0.92; p = 0.04). We conclude that the intake of antioxidant flavonoids is inversely related to the risk of incident dementia.

Helmer C, Damon D, Letenneur L, Fabrigoule C, Barberger-Gateau P, Lafont S, Fuhrer R, Antonucci T, Commenges D, Orgogozo JM, Dartigues JF. · INSERM U 330, Université de Bordeaux II, France. · Neurology. · Pubmed #10599764 No free full text.

Abstract: OBJECTIVE: To analyze the relationship between marital status and risk of AD or dementia. METHODS: This study was carried out from the Personnes Agées QUID (PAQUID) cohort, an epidemiologic study on normal and pathologic aging after age 65 years. The PAQUID cohort began in 1988. Individuals were followed up at 1, 3, and 5 years, with an active detection of dementia. Marital status was divided into four categories: widowed, never married, divorced or separated, and the reference category, married or cohabitant. The longitudinal relationship between marital status and risk of incident AD or dementia was analyzed by a Cox model with delayed entry. RESULTS: Among the 3,675 individuals initially not demented, 2,106 were married or cohabitants, 1,287 were widowers, 179 were never married, and 103 were divorced or separated. Among the 2,881 individuals reevaluated at least once for the risk of dementia during the 5-year follow-up, 190 incident cases of dementia were identified, including 140 with AD. The relative risks (RRs) of dementia (RR = 1.91, p = 0.018) and of AD (RR = 2.68, p<0.001) were increased for the never-married individuals compared with those who were married or cohabitants. This excess of risk was specifically associated with AD. Adjustment for other risk factors of dementia (education, wine consumption), or for factors reflecting social environment, leisure activities, and depression, did not modify the risk of AD for never-married individuals (RR = 2.31, p = 0.02). CONCLUSIONS: We confirmed an association between marital status and AD, with an excess risk observed among never-married individuals. This association may provide clues about the pathogenesis of AD.