Effects of Age, Level of Education and HIV Status on Cognitive Performance in West African Older Adults: The West Africa IeDEA Cohort Collaboration.

An in-depth understanding of the impact of aging, cognitive reserve, and HIV status on cognitive function is needed in older West African adults. Ninety-nine HIV-negative and 334 HIV-positive adults aged ≥ 50 years were enrolled in three clinics (Senegal and Côte d'Ivoire) participating in the IeDEA West Africa collaboration. All subjects underwent the Free and Cued Selective Reminding Test (FCSRT) and the Isaacs Set Test (IST). Age (both linear and quadratic), education level, and HIV status effects on Z-scores were assessed using multivariate linear regression models. Interactions between HIV status and age or educational level were tested. In the present cohort of older West African adults, the role of age and educational level on episodic memory and verbal fluency was observed without revealing an interaction between HIV status and age effect. As age had quadratic effects, older HIV-positive adults should not be considered as a unique group irrespective of their age. Low-educated HIV-positive patients had the lowest verbal fluency performance compared to others. Further studies are needed to duplicate these results. In clinical settings, screening and adapted programs focusing on improving cognition in those patients are needed.

Important oral care needs of older French people: A cross-sectional study.

BACKGROUND: Older persons comprise a growing proportion of the European population and may have a distinct epidemiological oral profile requiring specific preventive and curative care poorly documented. The objectives of this study were to assess the oral health status of people ≥90 years of age in France, to compare their perceived and observed oral care needs and to investigate the oral problems associated with a low oral health-related quality-of-life (OHRQoL). METHODS: An oral cross-sectional study was performed during the 25th follow-up of a cohort of older persons being followed up prospectively for screening of dementia over a 15-year period in Gironde and Dordogne, France. Clinical oral indices were determined by oral examinations conducted at the participants' place of living. Cohen's Kappa coefficient was used to assess the agreement between perceived and observed oral care needs. Oral problems associated with a low OHRQoL, measured with the Geriatric Oral Health Assessment Index (GOHAI<50) were investigated with logistic regression. Odds ratios (OR) were estimated with their 95% confidence intervals (CI). RESULTS: Data from 90 persons were analysed (76% female; median age=93 years; 20% living in an institution). Plaque and calculus were present in 93% and 58% respectively, of the 74 dentate participants. The mean number of decayed, missing, and filled teeth was 26.5 (±5.3); 66% of the participants had at least one untreated decayed tooth. Among the 85 participants with tooth loss not replaced by a fixed denture, two thirds had a removable dental prosthesis; 84% of these prostheses were considered to be maladapted. Among the 39 participants who felt unable to consult a dentist (43%), lack of transportation was the most frequently cited reason. Although 88% of the participants needed oral care, only 26% perceived that they had such a need (Kappa=0.06). Oral problems associated with a GOHAI<50 were the absence of posterior occluding teeth (OR=7.15; 95%CI=1.53-33.35; P=0.012), feeling of dry mouth (OR=11.94; 95%CI=3.21-44.39; P=0.0002) and oral pain (OR=9.06; 95%CI=1.91-69.00; P=0.033). CONCLUSIONS: Persons ≥90 years of age have considerable preventive and curative dental care needs that impact their quality-of-life but they are rarely aware and lack transportation. NCT04065828.

17q21.31 duplication causes prominent tau-related dementia with increased MAPT expression.

To assess the role of rare copy number variations in Alzheimer's disease (AD), we conducted a case-control study using whole-exome sequencing data from 522 early-onset cases and 584 controls. The most recurrent rearrangement was a 17q21.31 microduplication, overlapping the CRHR1, MAPT, STH and KANSL1 genes that was found in four cases, including one de novo rearrangement, and was absent in controls. The increased MAPT gene dosage led to a 1.6-1.9-fold expression of the MAPT messenger RNA. Clinical signs, neuroimaging and cerebrospinal fluid biomarker profiles were consistent with an AD diagnosis in MAPT duplication carriers. However, amyloid positon emission tomography (PET) imaging, performed in three patients, was negative. Analysis of an additional case with neuropathological examination confirmed that the MAPT duplication causes a complex tauopathy, including prominent neurofibrillary tangle pathology in the medial temporal lobe without amyloid-ß deposits. 17q21.31 duplication is the genetic basis of a novel entity marked by prominent tauopathy, leading to early-onset dementia with an AD clinical phenotype. This entity could account for a proportion of probable AD cases with negative amyloid PET imaging recently identified in large clinical series.

SORL1 rare variants: a major risk factor for familial early-onset Alzheimer's disease.

The SORL1 protein plays a protective role against the secretion of the amyloid ß peptide, a key event in the pathogeny of Alzheimer's disease. We assessed the impact of SORL1 rare variants in early-onset Alzheimer's disease (EOAD) in a case-control setting. We conducted a whole exome analysis among 484 French EOAD patients and 498 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of disruptive and predicted damaging missense SORL1 variants in cases (odds radio (OR)=5.03, 95% confidence interval (CI)=(2.02-14.99), P=7.49.10(-5)). This enrichment was even stronger when restricting the analysis to the 205 cases with a positive family history (OR=8.86, 95% CI=(3.35-27.31), P=3.82.10(-7)). We conclude that predicted damaging rare SORL1 variants are a strong risk factor for EOAD and that the association signal is mainly driven by cases with positive family history.

The impact of chronic psychiatric disorders on cognitive decline.

OBJECTIVES: Based on seemingly contradictory results in the existing literature, the objective of our study was to investigate whether older individuals suffering from chronic psychiatric disorders show a more rapid decline in cognitive performances than their non-psychiatric counterparts, or if the pattern of decline through older age is similar in both groups. METHOD: A total of 820 older adults were selected from the Ageing Multidisciplinary Investigation (AMI) cohort study, which studies health-related issues of people over 65 years old living in rural areas. Among them, 30 suffer from chronic psychiatric disorders. Cognition was assessed with four neuropsychological tests: the Mini-Mental State Examination, the Digit Symbol Substitution Test, the Free and Cued Selective Reminding test and the Isaacs Set Test. Linear mixed models were used to compare the evolution of cognitive performances in the two groups between baseline and the four-year follow-up. RESULTS: Despite lower performances at baseline, the pattern of cognitive decline of the psychiatric group is similar to that of the control group. CONCLUSION: As suggested by this study conducted in rural communities, community-dwelling people suffering from chronic psychiatric disorders should not be considered at greater risk of age-related accelerated cognitive decline than the non-psychiatric older population.

Effect size for the main cognitive function determinants in a large cross-sectional study.

BACKGROUND AND PURPOSE: The aim of our study was to examine the effect sizes of different cognitive function determinants in middle and early old age. METHODS: Cognitive functions were assessed in 11 711 volunteers (45 to 75 years old), included in the French CONSTANCES cohort between January 2012 and May 2014, using the free and cued selective reminding test (FCSRT), verbal fluency tasks, digit-symbol substitution test (DSST) and trail making test (TMT), parts A and B. The effect sizes of socio-demographic (age, sex, education), lifestyle (alcohol, tobacco, physical activity), cardiovascular (diabetes, blood pressure) and psychological (depressive symptomatology) variables were computed as omega-squared coefficients (ω2 ; part of the variation of a neuropsychological score that is independently explained by a given variable). RESULTS: These sets of variables explained from R2 = 10% (semantic fluency) to R2 = 26% (DSST) of the total variance. In all tests, socio-demographic variables accounted for the greatest part of the explained variance. Age explained from ω2 = 0.5% (semantic fluency) to ω2 = 7.5% (DSST) of the total score variance, gender from ω2 = 5.2% (FCSRT) to a negligible part (semantic fluency or TMT) and education from ω2 = 7.2% (DSST) to ω2 = 1.4% (TMT-A). Behavioral, cardiovascular and psychological variables only slightly influenced the cognitive test results (all ω2 < 0.8%, most ω2 < 0.1%). CONCLUSION: Socio-demographic variables (age, gender and education) are the main variables associated with cognitive performance variations between 45 and 75 years of age in the general population.

A genome-wide association meta-analysis of plasma Aß peptides concentrations in the elderly.

Amyloid beta (Aß) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aß peptides' functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aß peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aß-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aß1-40 and Aß1-42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10(-)(5)). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aß1-42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aß1-42 secretion. In conclusion, our study results suggest that plasma Aß peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites.

Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease.

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 × 10(-10)). We finally searched for association between SNPs within the FRMD4A locus and Aß plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aß42/Aß40 ratio (best signal, P=5.4 × 10(-7)). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.

Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology.

Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer's disease (AD) after APOE. We report that BIN1 transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ∼28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14-1.26) (P=3.8 × 10(-11))). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology.

High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease.

Performing exome sequencing in 14 autosomal dominant early-onset Alzheimer disease (ADEOAD) index cases without mutation on known genes (amyloid precursor protein (APP), presenilin1 (PSEN1) and presenilin2 (PSEN2)), we found that in five patients, the SORL1 gene harbored unknown nonsense (n=1) or missense (n=4) mutations. These mutations were not retrieved in 1500 controls of same ethnic origin. In a replication sample, including 15 ADEOAD cases, 2 unknown non-synonymous mutations (1 missense, 1 nonsense) were retrieved, thus yielding to a total of 7/29 unknown mutations in the combined sample. Using in silico predictions, we conclude that these seven private mutations are likely to have a pathogenic effect. SORL1 encodes the Sortilin-related receptor LR11/SorLA, a protein involved in the control of amyloid beta peptide production. Our results suggest that besides the involvement of the APP and PSEN genes, further genetic heterogeneity, involving another gene of the same pathway is present in ADEOAD.

A simple score to predict survival with dementia in the general population.

BACKGROUND/AIMS: This study was designed to develop a practical risk score for predicting 5-year survival after the diagnosis of dementia. METHODS: Using the Paquid Study (prospective, population-based, long-term cohort study), we created a prognosis score with incident cases of dementia and validated it in another prospective, population-based, long-term cohort study, the Three City Study. - RESULTS: Among the 3,777 subjects enrolled in the Paquid Study, 454 incident cases of dementia were included in this study. After a 5-year follow-up period, 319 (70.3%) were deceased. The score was constructed from three independent prognostic variables (gender, age at diagnosis and number of ADL restricted). The discriminant ability of the score was good with a c index of 0.754. Sensitivity was 64.7% and specificity 76.3%. In the validation cohort, the discriminant ability of the prognostic score with c statistics was 0.700. Sensitivity was 26.3% and specificity 95.4%. CONCLUSIONS: The prognostic factors selected in the predictive model are easily assessable, so this simple score could provide helpful information for the management of dementia, particularly to identify patients with duration of the disease greater than 5 years.

Prevalence of word retrieval complaint and prediction of dementia in a population-based study of elderly subjects.

There is agreement that elderly people complain about word finding difficulties, particularly proper names. However, few studies have focused on the prevalence of this complaint in the general population, nor is it clearly known whether it is predictive of dementia. The aim of this study was to fill this gap using the PAQUID cohort. 1,838 people aged 65 or more completed questionnaires and neuropsychological evaluation regularly during 13 years. Results show that the complaint about proper name retrieval concerns 64% of people aged above 65 years, and the complaint about common names 30%. The complaint was not associated with enhanced risk of dementia, whereas short naming tests were. Only a marginal relation was found between these naming tests and word retrieval complaint. This study emphasizes the importance of proper name retrieval complaint in the general population and suggests that elderly subjects can be reassured in the absence of other symptoms.

[Relationship between educational level and dementia: social factor and age-related chronic disease]. / Relation entre facteur social et maladie chronique liée à l'âge: l'exemple du niveau d'études et des démences.

Dementia is an age-related chronic syndrome, whose the first cause is a neurodegenerative disease: Alzheimer's disease (AD). In spite of some controversies, educational level is now considered as a major risk factor for dementia and AD. The protective effect of a high level of education could be related to a preservation of cognitive reserve and a reinforcement of brain reserve. Moreover, subjects with a high level of education have a better access to health care and a better management of vascular risk factors. With the general improvement of the educational level, the age-related incidence of AD and dementia should decrease in the future.

ETNA3, a clinical randomized study assessing three cognitive-oriented therapies in dementia: rationale and general design.

Despite the popularity of cognitive-oriented therapies in dementia, very few data gathered from scientific literature provide a clear demonstration of the genuine efficacy of these techniques. Most of the results published have issued from studies suffering from important methodological limitations such as: absence of control group to compare clinical courses, very small size of study samples, absence of group randomization, absence of blind assessment of efficacy criteria or absence of long-term efficacy assessment. Randomized clinical trials are rare or even absent for some techniques and generally report more modest benefits. In this context, the ETNA3 study has been implemented. The ETNA3 study is a French nationwide prospective simple-blinded randomized clinical trial conducted to evaluate the impact of cognitive training, reminiscence therapy and an individualized cognitive rehabilitation program on the progression rate of dementia. The study was conducted in 653 outpatients with mild to moderate Alzheimer's disease followed up for 2 years (MMSE score 16 and 26). The main objective was to determine whether any or several of these non-pharmacological treatments could delay the severe stage of dementia during a 2-year follow-up compared to a usual care group without non-pharmacological treatment. The secondary outcomes assessed cognitive abilities, functional abilities in activities of daily living, behavioral disturbance, apathy, quality of life, depression, caregiver's burden and resource utilization. This article presents the rationale and methodology of the study.

[The Goblets test: Norms in the elderly population and properties in the detection of cognitive impairment in elderly individuals selected from the general population]. / Le test des gobelets : normes et propriétés de détection d'un trouble cognitif chez des sujets sélectionnés en population générale.

INTRODUCTION: Most current tools exploring visuospatial memory abilities are poorly adapted to the elderly population. The Goblets test allows a brief evaluation of visuospatial memory abilities through an encoding phase in which the participant has to learn a particular sequence and a further delayed recall phase. The aim of the present work was to produce normative scores for this test and to study its properties in the detection of dementia. METHODS: Data were collected in a sample of 1002 agricultural retirees aged 65 years and over included in the AMI study, a population-based cohort study conducted in Gironde (southwestern France). The sample analyzed to establish normative data included 795 non-institutionalized and non-demented participants. Regarding the validity study, the sample analyzed included 912 participants of whom 76 subjects with a diagnosis of Alzheimer's disease. RESULTS: Normative scores were calculated according to age (65-74 years and 75 years and over) and educational level (primary school level not validated by a diploma, primary school level validated by a diploma and more than a primary school level). The normative scores of the learning phase were described using the percentiles while rates of success were reported for the delayed recall. Regarding the properties of the test, the Goblets test seemed to be more specific than sensitive and presented high negative predictive values. The Youden index showed that the better cut-off score was two trials (with 75.0% sensitivity and 83.0% specificity). CONCLUSION: The Goblets test can be a helpful tool in screening for dementia. Nevertheless, like many other simple and quick cognitive tests, it cannot be used alone to establish the diagnosis of dementia. This test has the advantage to be easy to administer in clinical situations; the normative scores presented in this study could be used as an aid to interpret a patient's performance.

Ten Years after the National Alzheimer's Plan: Dementia Remains a Hidden Syndrome in France.

Ten years after the implementation of the French Plan on Alzheimer's Disease (2008-2012), the present study aimed at describing the situation of the persons living with dementia in terms of diagnosis and high-risk situations (living alone, continuing driving, inability to handle budget and to manage medication). Among the 115 dementia cases followed-up in the AMI population-based cohort on aging in 2018 (i.e. ten years after the launch of the Plan), the prevalence of under-diagnosis was similar to the one estimated ten years earlier (53.0% vs. 55.6%). Almost all cases (95.3%) were concerned by high-risk situations (61.2% were unable to handle finances, 48.2% were living alone, 27.1% continued driving). Being diagnosed as demented was not associated with a lower frequency of high-risk situations, excepting for driving (16.7% vs. 37.2%). Ten years after the beginning of the French Alzheimer's Plan, dementia remains a hidden syndrome, with a frequent inadequate management of high-risk situations.

Joint model with latent state for longitudinal and multistate data.

In many chronic diseases, the patient's health status is followed up by quantitative markers. The evolution is often characterized by a 2-phase degradation process, that is, a normal phase followed by a pathological degradation phase preceding the disease diagnosis. We propose a joint multistate model with latent state for the joint modeling of repeated measures of a quantitative marker, time-to-illness and time-to-death. Using data from the PAQUID cohort on cognitive aging, we jointly studied cognitive decline, dementia risk, and death risk. We estimated the mean evolution of cognitive scores given age at dementia for subjects alive and demented, the mean evolution of cognitive scores for subjects alive and nondemented, in addition to age at acceleration of cognitive decline and duration of the pre-dementia phase.

APOE and Alzheimer disease: a major gene with semi-dominant inheritance.

Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.

[Needs and expectations of Alzheimer's disease family caregivers]. / Attentes et besoins des aidants de personnes souffrant de maladie d'Alzheimer.

BACKGROUND: Family members of people suffering from Alzheimer's disease play a major role in providing daily life care for their relatives. Compared to non-caregivers, they present increased risks of mortality as well as psychological and physical co-morbidity. Altered relationships between caregivers and medical staff and dissatisfaction with the quality of help provided tend to increase the risk of depression and anxiety disorders among caregivers. The present study aimed at exploring the needs and expectations of family caregivers of patients with Alzheimer's disease who request medical assistance for their relatives. METHODS: The present analysis is an ancillary study of a large multicentric controlled randomized study designed to assess the efficacy of three non-pharmacological treatments in Alzheimer's disease, in which 645 mild-to-moderate Alzheimer patients were enrolled. Needs and expectations of the caregivers were assessed with a French scale of patient expectations for medical consultation, the échelle d'attentes en matière de consultations (EAC), completed by caregivers during the inclusion visit. This scale consists in a self-administered 28-item questionnaire concerning four main needs: learning skills to improve daily life management of their relatives; information regarding the disease; improving caregivers' self-confidence; support to improve communication with their relatives. RESULTS: The ten items for which more than 40% of caregivers reported high or very high expectations referred to two main needs: information regarding the disease (treatment, prognosis…) and learning skills in order to improve daily life management of their relative. The predominance of such needs was observed whatever the relationship between the caregiver and the cared relative but seemed to be more pronounced in female spouses and children of patients with Alzheimer's disease. CONCLUSIONS: Needs and expectations of Alzheimer's disease family caregivers involve two major aspects: first, information regarding the disease (treatment, prognosis…) and second, learning skills for improving daily life management of their relative. These results suggest that among the various available family caregivers support programs, programs providing information, education, and practical advice to improve daily life assistance seem to be adequate.

[Epidemiology of dementia in elderly living in the 3rd borough of Bangui (Central African Republic)]. / Épidémiologie des démences chez les personnes âgées dans le troisième arrondissement de la ville de Bangui (République Centrafricaine).

Given the gradual improvement of living conditions and aging, dementia and related syndromes are becoming serious problems in the developing countries. A cross-sectional door to door type study in neighbourhood, was conducted from October 2008 to January 2009, in the general population in Bangui, order to help get a better understanding of the prevalence and risk factors of dementia among people over 65 living in the Central African capital. Of the 496 elderly respondents, 188 had cognitive disorders. After a neuropsychological examination, 40 of these subjects were diagnosed with dementia. The prevalence of dementia was 8.1% (IC 95% = [5.7-10.5]). The average age of subjects with dementia, ranging from 65 to 90 years, was 76.0 ± 7.1 years. There was a significant risk of developing dementia for an increase of ten years old (OR = 2.6, 95% CI [1.5 to 4.5]). The sex-ratio was 6/34. 82.5% of the demented had never attended school. 70.0% showed a state of malnutrition (BMI ≤ 18,5 kg/m(2)), significantly associated with dementia (OR = 3.3; IC 95% = [1.5-7.3]). The blood pressure was high in 67.5% of demented which is significantly associated with dementia (OR = 2.4; IC 95% = [1.1-5.4]). A recent change in financial status was a factor significantly associated with dementia (OR = 6.4; IC 95% = [1.8-22.5]). These results support the existence of dementia in urban Africa. The observed prevalence is close to those found in high-income countries. Further studies should be conducted which includes both the rural and urban Africa, to better understand the problem and solutions consider to comprehensive care and prevention axes adapted to our context.