[Show abstract][Hide abstract] ABSTRACT: We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] Aβ42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it “always/frequently”) followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as “moderate”. Seventy-nine percent of responders felt “very/extremely” comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.
Alzheimer's & dementia: the journal of the Alzheimer's Association 08/2014; · 14.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A large proportion of dementia cases are still undiagnosed. Although early dementia care has been hypothesized to benefit both patients and families, evidence-based benefits are lacking. Thus, investigating the benefits for newly demented persons according to their recourse to care in the "real life" appears critical.
Alzheimer's & dementia: the journal of the Alzheimer's Association 08/2014; · 14.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
The worldwide population is ageing and the proportion of elderly aged 60 and over is expected to
dramatically rise in Low and Middle Income Countries (LMIC). The epidemic of dementia will not spare those
countries, where the largest increases in numbers of people affected are estimated. Besides, dementia is still
understudied in sub-Saharan Africa (SSA) compared to other regions. This paper describes the protocol for the ‘Epidemiology of Dementia in Central Africa'population-based study, which aims at estimating the prevalence of dementia in two countries of Central Africa and investigating possible risk factors.
A multicenter population-based study was carried out in Central African Republic and Republic
of Congo between 2011 and 2012 including both urban and rural sites in each country. Around 2000 participants aged ≥ 65 years old were interviewed in total using the Community Screening Interview for Dementia (CSI-D), the GMS-AGECAT and the CERAD’s 10-word list. Elderly with low performance to the cognitive part of the CSI-D (COGSCORE ≤ 24.5) were then clinically assessed by neurologists and underwent further psychometrical tests. DSM-IV and NINCDS-ADRDA criteria were required for dementia and Alzheimer’s disease (AD) diagnoses respectively. The algorithmic 10/66 dementia diagnosis was also determined. Petersen’s criteria were required for the diagnosis of Mild Cognitive Impairment. Sociodemographic, and environmental factors including vascular, nutritional, biological,
psychosocial and lifestyle factors were collected in each setting in order to investigate factors associated with dementia. Blood sampling was realized to investigate genetic variations that could modify the risk of dementia.
For now, no large epidemiological study has been undertaken to compare the prevalence of dementia in
both rural and urban areas within SSA countries. This programme will provide further evidence regarding the
prevalence of dementia in SSA, and also the possible rural/urban disparities existing with associated factors.
Furthermore, the genetics of AD in those populations will be addressed.
[Show abstract][Hide abstract] ABSTRACT: Semicompeting risks and interval censoring are frequent in medical studies, for instance when a disease may be diagnosed only at times of visit and disease onset is in competition with death. To evaluate the ability of markers to predict disease onset in this context, estimators of discrimination measures must account for these two issues. In recent years, methods for estimating the time-dependent receiver operating characteristic curve and the associated area under the ROC curve have been extended to account for right censored data and competing risks. In this paper, we show how an approximation allows to use the inverse probability of censoring weighting estimator for semicompeting events with interval censored data. Then, using an illness-death model, we propose two model-based estimators allowing to rigorously handle these issues. The first estimator is fully model based whereas the second one only uses the model to impute missing observations due to censoring. A simulation study shows that the bias for inverse probability of censoring weighting remains modest and may be less than the one of the two parametric estimators when the model is misspecified. We finally recommend the nonparametric inverse probability of censoring weighting estimator as main analysis and the imputation estimator based on the illness-death model as sensitivity analysis.
Statistical Methods in Medical Research 05/2014; · 2.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cognitive lifestyle measures such as education, occupation, and social engagement are commonly associated with late-life cognitive ability although their associations with cognitive decline tend to be mixed. However, longitudinal analyses of cognition rarely account for death and dropout, measurement error of the cognitive phenotype, and differing trajectories for different population sub-groups. This paper applies a joint latent class mixed model (and a multi-state model in a sensitivity analysis) that accounts for these issues to a large (n = 3,653), population-based cohort, Paquid, to model the relationship between cognitive lifestyle and cognitive decline. Cognition was assessed over a 20-year period using the Mini-Mental State Examination. Three cognitive lifestyle variables were assessed: education, mid-life occupation, and late-life social engagement. The analysis identified four latent sub-populations with class-specific longitudinal cognitive decline and mortality risk. Irrespective of the cognitive trajectory, increased social engagement was associated with a decreased mortality risk. High education was associated with the most favourable cognitive trajectory, and after adjusting for cognitive decline, with an increased mortality risk. Mid-life occupational complexity was also associated with more favourable trajectories but not with mortality risk. To realistically examine the link between cognitive lifestyle and cognitive decline, complex statistical models are required. This paper applies and compares in a sensitivity analysis two such models, and shows education to be linked to a compression of cognitive morbidity irrespective of cognitive trajectory. Furthermore, a potentially modifiable variable, late-life social engagement is associated with a decreased mortality risk in all of the population sub-groups.
European Journal of Epidemiology 02/2014; · 5.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A better knowledge of long-term trajectories of cognitive decline is a central feature of the study of the process leading to Alzheimer's dementia. Several factors may mitigate such decline, among which is education, a major risk factor for Alzheimer's disease. The aim of our work was to compare the pattern and duration of clinical trajectories before Alzheimer's dementia in individuals with low and high education within the PAQUID cohort involving 20 years of follow-up. The sample comprises 442 participants with incident Alzheimer's disease (27.2% were male)-171 with low education (mean age = 86.2 years; standard deviation = 5.3 years) and 271 with higher education (mean age = 86.5; standard deviation = 5.4)-and 442 control subjects matched according to age, sex and education. At each visit and up to the 20-year follow-up visit, several cognitive and clinical measures were collected and incident cases of Alzheimer's disease clinically diagnosed. The evolution of clinical measures in pre-demented subjects and matched controls was analysed with a semi-parametric extension of the mixed effects linear model. The results show that the first signs of cognitive decline occurred 15 to 16 years before achieving dementia threshold in higher-educated subjects whereas signs occurred at 7 years before dementia in low-educated subjects. There seemed to be two successive periods of decline in higher-educated subjects. Decline started ∼15 to 16 years before dementia with subtle impairment restricted to some cognitive tests and with no impact during the first 7 to 8 years on global cognition, cognitive complaints, or activities of daily living scales. Then, ∼7 years before dementia, global cognitive abilities begin to deteriorate, along with difficulties dealing with complex activities of daily living, the increase in self-perceived difficulties and depressive symptoms. By contrast, lower-educated subjects presented a single period of decline lasting ∼7 years, characterized by decline concomitantly affecting specific and more global cognitive function along with alteration in functional abilities. This study demonstrates how early cognitive symptoms may emerge preceding Alzheimer's dementia particularly in higher-educated individuals, for whom decline occurred up to 16 years before dementia. It also demonstrates the protective role of education in the clinical trajectory preceding Alzheimer's dementia. We suggest that the initial decline in cognition occurs at the onset of comparable Alzheimer's disease pathology in both groups, and is associated with immediate decline to dementia in the lower education group. In contrast, higher education protects against further cognitive decline for ∼7 years until pathology becomes more severe.
[Show abstract][Hide abstract] ABSTRACT: We aimed to investigate the impact of endogenous estradiol (E2) on dementia and to evaluate the contribution of vascular risk factors and inflammatory and blood coagulation markers to this association.
Using data from a French population-based prospective study (the Three-City Study) including 5,644 postmenopausal women aged 65 years or older, we investigated the association of endogenous total-E2 and bioavailable-E2 and total-testosterone with the 4-year incidence of all-cause dementia. We further focused on the role of dementia and cardiovascular risk factors as well as inflammation (C-reactive protein, fibrinogen) and hypercoagulability (fibrin d-dimers, thrombin generation) in these associations. We used a case-cohort design consisting of a random subcohort of 562 women not using hormone therapy and 132 incident dementia cases.
Adjusted Cox proportional hazards models showed a J-shaped relationship between total-E2 and risk of dementia (p = 0.001). Total-E2 values in the lower and upper quartiles were associated with an increased dementia risk (adjusted hazard ratio [HR] [95% confidence interval] = 2.2 [1.1-4.5] and HR = 2.4 [1.2-5.2], respectively). Importantly, the risk associated with higher E2 levels was dramatically increased in women with diabetes compared with nondiabetic women (adjusted HR associated with the upper E2 quartile = 14.2 [1.60-123] and HR = 3.4 [0.1-147], respectively, p interaction <0.05). Similar results were found for bioavailable-E2. Adjustment for inflammatory and blood coagulation markers did not modify our results. No significant association was found for total-testosterone.
High E2 level is an independent predictor of incident dementia, particularly in postmenopausal women with diabetes.
[Show abstract][Hide abstract] ABSTRACT: Structural alterations of a large network characterize Alzheimer's disease (AD), but the time course of these changes remains unclear. The dynamic of these alterations was examined in the AD preclinical phase using data from the 10-year follow-up of a population-based cohort (Bordeaux-3City).
Participants received neuropsychological assessments every 2 years and two identical magnetic resonance imaging (MRI) exams at baseline and 4 years later. Twenty-five incident AD cases were compared with 319 subjects who remained free of dementia. Subjects were free of dementia at baseline and at follow-up MRI. Incident AD occurred after these time points.
At baseline, incident AD already presented smaller volumes only in the left amygdalo-hippocampal complex. Moreover, a higher annual rate of atrophy of the temporoparietal cortices was observed in future AD subjects during the following 4 years.
Incident AD cases present mediotemporal lesions up to 5 years before diagnosis. This neurodegenerative process seems to progressively reach the temporoparietal cortices in the AD preclinical phase.
Alzheimer's & dementia: the journal of the Alzheimer's Association 01/2014; · 14.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Motivation
Diseases that progress slowly are often studied by observing cohorts at different stages of disease for short periods of time. The Alzheimer's Disease Neuroimaging Initiative (ADNI) follows elders with various degrees of cognitive impairment, from normal to impaired. The study includes a rich panel of novel cognitive tests, biomarkers, and brain images collected every 6 months for as long as 6 years. The relative timing of the observations with respect to disease pathology is unknown. We propose a general semiparametric model and iterative estimation procedure to estimate simultaneously the pathological timing and long-term growth curves. The resulting estimates of long-term progression are fine-tuned using cognitive trajectories derived from the long-term “Personnes Agées Quid” study.
We demonstrate with simulations that the method can recover long-term disease trends from short-term observations. The method also estimates temporal ordering of individuals with respect to disease pathology, providing subject-specific prognostic estimates of the time until onset of symptoms. When the method is applied to ADNI data, the estimated growth curves are in general agreement with prevailing theories of the Alzheimer's disease cascade. Other data sets with common outcome measures can be combined using the proposed algorithm.
Software to fit the model and reproduce results with the statistical software R is available as the grace package. ADNI data can be downloaded from the Laboratory of NeuroImaging.
Alzheimer's & dementia: the journal of the Alzheimer's Association 01/2014; · 14.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
The objective of this study is to compare cognitive decline of elderly people after entering an institution with that of elders living in the community with similar clinical conditions.
The Personnes Agées QUID (PAQUID) cohort is a prospective population-based study which included, at baseline, 3777 community-dwelling people aged 65 years and older. Participants were followed-up for 22 years. Among those who were nondemented and living at home at baseline, 2 groups were compared: participants who entered a nursing home during study follow-up (n = 558) and those who remained living at home (n = 3117). Cognitive decline was assessed with Mini-Mental State Examination (MMSE), Benton visual retention test, and verbal fluency Isaacs Set Test.
After controlling for numerous potential confounders, including baseline MMSE and instrumental activities of daily living scores, incident dementia, depressive symptoms, and chronic diseases, nursing home placement was significantly associated with a lower score on MMSE between the last visit before and after institutionalization (difference of 2.8 points, P < .0001) and greater further cognitive decline after institutionalization (difference of 0.7 point per year, P < .0001). Similar results were found for the Benton memory test. In a second series of analysis in which the persons who became demented over the study follow-up were excluded, the results remained unchanged.
The present study suggests that institutionalized elderly people present a greater cognitive decline than persons remaining in the community. The reasons of that decline remain unclear and may be related to physical and psychological effects of institutionalization in elderly people.
Journal of the American Medical Directors Association 01/2014; · 5.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lipid metabolism and particularly high-density lipoprotein (HDL) may be involved in the pathogenic mechanism of age-related macular degeneration (AMD). However, conflicting results have been reported in the associations of AMD with plasma HDL and other lipids, which may be confounded by the recently reported associations of AMD with HDL-related genes. We explored the association of AMD with plasma lipid levels and lipid-lowering medication use, taking into account most of HDL-related genes associated with AMD.
The Alienor study is a population-based study on age-related eye diseases performed in 963 elderly residents of Bordeaux (France). AMD was graded from non mydriatic color retinal photographs in three exclusive stages: no AMD (n = 430 subjects, 938 eyes); large soft distinct drusen and/or large soft indistinct drusen and/or reticular drusen and/or pigmentary abnormalities (early AMD, n = 176, 247); late AMD (n = 40, 61). Associations of AMD with plasma lipids (HDL, total cholesterol (TC), Low-density lipoprotein (LDL), and triglycerides (TG)) were estimated using Generalized Estimating Equation logistic regressions. Statistical analyses included 646 subjects with complete data.
After multivariate adjustment for age, sex, educational level, smoking, BMI, lipid-lowering medication use, cardiovascular disease and diabetes, and for all relevant genetic polymorphisms (ApoE2, ApoE4, CFH Y402H, ARMS2 A69S, LIPC rs10468017, LIPC rs493258, LPL rs12678919, ABCA1 rs1883025 and CETP rs3764261), higher HDL was significantly associated with an increased risk of early (OR = 2.45, 95%CI: 1.54-3.90; P = 0.0002) and any AMD (OR = 2.29, 95%CI: 1.46-3.59; P = 0.0003). Association with late AMD was far from statistical significance (OR = 1.58, 95%CI: 0.48-5.17; p = 0.45). No associations were found for any stage of AMD with TC, LDL and TG levels, statin or fibrate drug use.
This study suggests that elderly patients with high HDL concentration may be at increased risk for AMD and, further, that HDL dysfunction might be implicated in AMD pathogenesis.
PLoS ONE 01/2014; 9(3):e90973. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Knowledge of functional evolution in dementia is crucial for the patients and their families and for clinician. Objective: This review identifies scales and outcomes used to describe the natural history of functional decline and describes the natural history of functional decline in a representative clinical and population sample of published studies of patients with Alzheimer's disease (AD). Methods: A search of three relevant databases was conducted and limited to articles published in English and French between 1998 to March 2012, using the keywords "Dementia", "Activities of Daily Living", "Instrumental Activities of Daily Living", "Functional Impairment", "Prognosis", and "Disease Progression". Results: The search strategy displayed 683 articles, 20 of which were found to be related to the functional evolution of AD. In these studies, different scales were used to describe the evolution of the functional decline, except for the decline of instrumental activities, for which the Lawton scale was used in all studies. Thus, it is difficult to represent the evolution of the functional decline from a clinical point of view. Conclusion: Relatively little data are available to estimate the functional evolution of AD. A consensus with broaden thought is required to know if the progression of the incapacities in these scales is additive or hierarchical.
Journal of Alzheimer's disease: JAD 12/2013; · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To validate a rapid questionnaire as a screening tool, because application of the diagnostic revised criteria of the ICHD-II for medication overuse headache (MOH) requires experience for the physician and is time-consuming.
ICHD-II criteria for probable MOH (pMOH) were transformed in questions formulated in such a way that they could be self-administered, easily understood, and quickly filled out. We compared this questionnaire to the gold standard: the diagnosis made by headache specialists, based on the the ICHD-II criteria. Patients who were consulting for pMOH or migraine for the first time were consecutively included. As validity indicators, we calculated sensitivity, specificity, positive and negative predictive values of the items.
Seventy-nine patients were screened, 77 included, 2 female patients excluded. Forty-two patients have been considered as suffering from pMOH, 35 patients suffered from migraine without medication overuse. The association of the question "do you take a treatment for attacks more than 10 days per month" and the question "is this intake on a regular basis?" had a sensitivity of 95.2% and a specificity of 80%.
This screening tool can detect pMOH with a sensitivity that could be of interest to screen patients in clinical practice and to pre-include patients for research as epidemiological studies.
The Journal of Headache and Pain 10/2013; 14(1):81. · 2.78 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to examine the association of plasma estradiol and testosterone with risk for dementia in elderly men.
Within the population based Three-City study, including 3650 men age 65 years and older, a case-cohort design was set up after 4-years of follow-up. Baseline plasma levels of total 17-β estradiol (Total-E2), total testosterone (total-T) and bioavailable testosterone (bio-T) were measured for all cases of incident dementia (n = 105) and for a random sample of the cohort (n = 413). Cox regression models were used to estimate multivariate steroid sex hormone-associated hazard ratios (HR) and 95% confidence intervals of dementia.
There was a reverse J-shaped relationship between total-T and risk for dementia (P = .007). Compared with the median tertile, the HRs associated with total-T in the lower and upper tertile were increased (HR, 2.33; P = .026; HR, 1.9, P = .126; respectively). Low bio-T was associated with a greater risk for dementia (HR for one standard deviation of decreasing log(bio-T), 1.29; 95% confidence interval, 1.03-1.62). An interaction was found between bio-T and age (P < .0001), and bio-T and education (P = .044). Risk for dementia associated with low bio-T was greater in older men (80 years or older) than in younger men (younger than 80 years; HR, 3.11; P = .011 vs. HR, 1.07, P = .715, respectively) and in men with high level of education compared with those with low level of education (HR, 2.32; P = .0002 vs. HR, 0.95; P = .790, respectively). No significant association was found between Total-E2 and dementia.
Low levels of testosterone are associated with a risk for dementia in elderly men. The association between low bio-T and dementia may be more relevant to men 80 years or older and men with a high level of education.
Alzheimer's & dementia: the journal of the Alzheimer's Association 09/2013; · 14.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The relationship between blood pressure and dementia is incompletely understood in elderly individuals. Blood pressure variability may have a role in the risk of dementia.
This investigation was a cohort study of 6506 elderly individuals followed-up for 8 years (1999-2001 through 2008) with assessments at years 2, 4, and 7-8. Blood pressure was measured by electronic devices at baseline and at 2- and 4-year follow-up examinations. Cox proportional hazard models adjusted for potential confounders were used to estimate the risk of incident dementia according to blood pressure (means and coefficients of variation of the three measures).
During the 40,151 person-years of follow-up 474 participants developed dementia. We observed no association between mean blood pressure and risk of dementia. In contrast, an increase of 1 standard deviation in the coefficient of variation of blood pressure was associated with a 10% increased risk of dementia. Analysis by deciles of the coefficient of variation showed that the higher the variability, the higher the risk of dementia (P < .02 for trend). In the fully adjusted Cox model, the risk of dementia for those in the highest decile of the coefficient of variation of systolic blood pressure was 1.77 (1.17-2.69) compared with the lowest decile.
In this cohort study, variability of blood pressure during follow-up was associated with an increased risk of incident dementia, whereas mean blood pressure was not. Limitation of blood pressure fluctuation may be an important target to preserve cognitive function in the elderly.
Alzheimer's & dementia: the journal of the Alzheimer's Association 08/2013; · 14.48 Impact Factor