Methods

Item Response Theory (IRT) models have received growing interest in health science for analyzing latent constructs such as depression, anxiety, quality of life or cognitive functioning from the information provided by each individual’s items responses. However, in the presence of repeated item measures, IRT methods usually assume that the measurement occasions are made at the exact same time for all patients. In this paper, we show how the IRT methodology can be combined with the mixed model theory to provide a longitudinal IRT model which exploits the information of a measurement scale provided at the item level while simultaneously handling observation times that may vary across individuals and items. The latent construct is a latent process defined in continuous time that is linked to the observed item responses through a measurement model at each individual- and occasion-specific observation time; we focus here on a Graded Response Model for binary and ordinal items. The Maximum Likelihood Estimation procedure of the model is available in the R package lcmm. The proposed approach is contextualized in a clinical example in end-stage renal disease, the PREDIALA study. The objective is to study the trajectories of depressive symptomatology (as measured by 7 items of the Hospital Anxiety and Depression scale) according to the time from registration on the renal transplant waiting list and the renal replacement therapy. We also illustrate how the method can be used to assess Differential Item Functioning and lack of measurement invariance over time.Modèles Dynamiques pour les Etudes Epidémiologiques Longitudinales sur les Maladies Chronique

Social activity, cognitive decline and dementia risk: a 20-year prospective cohort study.

BACKGROUND: Identifying modifiable lifestyle correlates of cognitive decline and risk of dementia is complex, particularly as few population-based longitudinal studies jointly model these interlinked processes. Recent methodological developments allow us to examine statistically defined sub-populations with separate cognitive trajectories and dementia risks. METHODS: Engagement in social, physical, or intellectual pursuits, social network size, self-perception of feeling well understood, and degree of satisfaction with social relationships were assessed in 2854 participants from the Paquid cohort (mean baseline age 77 years) and related to incident dementia and cognitive change over 20-years of follow-up. Multivariate repeated cognitive information was exploited by defining the global cognitive functioning as the latent common factor underlying the tests. In addition, three latent homogeneous sub-populations of cognitive change and dementia were identified and contrasted according to social environment variables. RESULTS: In the whole population, we found associations between increased engagement in social, physical, or intellectual pursuits and increased cognitive ability (but not decline) and decreased risk of incident dementia, and between feeling understood and slower cognitive decline. There was evidence for three sub-populations of cognitive aging: fast, medium, and no cognitive decline. The social-environment measures at baseline did not help explain the heterogeneity of cognitive decline and incident dementia diagnosis between these sub-populations. CONCLUSIONS: We observed a complex series of relationships between social-environment variables and cognitive decline and dementia. In the whole population, factors such as increased engagement in social, physical, or intellectual pursuits were related to a decreased risk of dementia. However, in a sub-population analysis, the social-environment variables were not linked to the heterogeneous patterns of cognitive decline and dementia risk that defined the sub-groups

Dynamic reciprocal relationships between cognitive and functional declines along the Alzheimer's disease continuum in the prospective COGICARE study

BACKGROUND: Thoroughly understanding the temporal associations between cognitive and functional dimensions along the dementia process is fundamental to define preventive measures likely to delay the disease's onset. This work aimed to finely describe the trajectories of cognitive and functional declines, and assess their dynamic bidirectional relationships among subjects at different stages of the dementia process. METHODS: We leveraged extensive repeated data of cognition and functional dependency from the French prospective COGICARE study, designed to better characterize the natural history of cognitive and functional declines around dementia diagnosis. Cognition was measured by the Mini-Mental State Examination, the Isaacs Set Test for verbal fluency, the Benton Visual Retention Test for visuo-spatial memory, and Trail Making Test Part B for executive functioning. Functional dependency was measured by basic and instrumental activities of daily living. The study included 102 cognitively normal, 123 mildly cognitively impaired, and 72 dementia cases with a median of 5 repeated visits over up to 57 months. We used a dynamic causal model which addresses the two essential issues in temporal associations assessment: focusing on intra-individual change and accounting for time. RESULTS: Better cognitive abilities were associated with lower subsequent decline of the functional level among the three clinical stages with an intensification over time but no reciprocity of the association whatever the clinical status. CONCLUSION: This work confirms that the progressive functional dependency could be induced by cognitive impairment. Subjects identified as early as possible with clinically significant cognitive impairments could benefit from preventive measures before the deterioration of activities of daily living and the appearance of dementia clinical signs.Modèles statistiques pour la maladie d'Alzheimer et le vieillissementHistoire naturelle du déclin cognitif et du besoin de soins chez le sujet âg

Monitoring of SARS-CoV-2 in wastewater: what normalisation for improved understanding of epidemic trends?

SARS-CoV-2 RNA quantification in wastewater has emerged as a relevant additional means to monitor the COVID-19 pandemic. However, the concentration can be affected by black water dilution factors or movements of the sewer shed population, leading to misinterpretation of measurement results. The aim of this study was to evaluate the performance of different indicators to accurately interpret SARS-CoV-2 in wastewater. Weekly/bi-weekly measurements from three cities in France were analysed from February to September 2021. The concentrations of SARS-CoV-2 gene copies were normalised to the faecal-contributing population using simple sewage component indicators. To reduce the measurement error, a composite index was created to combine simultaneously the information carried by the simple indicators. The results showed that the regularity (mean absolute difference between observation and the smoothed curve) of the simple indicators substantially varied across sampling points. The composite index consistently showed better regularity compared to the other indicators and was associated to the lowest variation in correlation coefficient across sampling points. These findings suggest the recommendation for the use of a composite index in wastewater-based epidemiology to compensate for variability in measurement results

Analysis of the 24-Hour Activity Cycle: An illustration examining the association with cognitive function in the Adult Changes in Thought (ACT) Study

The 24-hour activity cycle (24HAC) is a new paradigm for studying activity behaviors in relation to health outcomes. This approach captures the interrelatedness of the daily time spent in physical activity (PA), sedentary behavior (SB), and sleep. We illustrate and compare the use of three popular approaches, namely isotemporal substitution model (ISM), compositional data analysis (CoDA), and latent profile analysis (LPA) for modeling outcome associations with the 24HAC. We apply these approaches to assess an association with a cognitive outcome, measured by CASI item response theory (IRT) score, in a cohort of 1034 older adults (mean [range] age = 77 [65-100]; 55.8% female; 90% White) who were part of the Adult Changes in Thought (ACT) Activity Monitoring (ACT-AM) sub-study. PA and SB were assessed with thigh-worn activPAL accelerometers for 7 days. We highlight differences in assumptions between the three approaches, discuss statistical challenges, and provide guidance on interpretation and selecting an appropriate approach. ISM is easiest to apply and interpret; however, the typical ISM model assumes a linear association. CoDA specifies a non-linear association through isometric logratio transformations that are more challenging to apply and interpret. LPA can classify individuals into groups with similar time-use patterns. Inference on associations of latent profiles with health outcomes need to account for the uncertainty of the LPA classifications which is often ignored. The selection of the most appropriate method should be guided by the scientific questions of interest and the applicability of each model's assumptions. The analytic results did not suggest that less time spent on SB and more in PA was associated with better cognitive function. Further research is needed into the health implications of the distinct 24HAC patterns identified in this cohort.Comment: 51 pages, 11 tables, 8 figure

Front Psychol

The 24-h activity cycle (24HAC) is a new paradigm for studying activity behaviors in relation to health outcomes. This approach inherently captures the interrelatedness of the daily time spent in physical activity (PA), sedentary behavior (SB), and sleep. We describe three popular approaches for modeling outcome associations with the 24HAC exposure. We apply these approaches to assess an association with a cognitive outcome in a cohort of older adults, discuss statistical challenges, and provide guidance on interpretation and selecting an appropriate approach. We compare the use of the isotemporal substitution model (ISM), compositional data analysis (CoDA), and latent profile analysis (LPA) to analyze 24HAC. We illustrate each method by exploring cross-sectional associations with cognition in 1,034 older adults (Mean age = 77; Age range = 65-100; 55.8% female; 90% White) who were part of the Adult Changes in Thought (ACT) Activity Monitoring (ACT-AM) sub-study. PA and SB were assessed with thigh-worn activPAL accelerometers for 7-days. For each method, we fit a multivariable regression model to examine the cross-sectional association between the 24HAC and Cognitive Abilities Screening Instrument item response theory (CASI-IRT) score, adjusting for baseline characteristics. We highlight differences in assumptions and the scientific questions addressable by each approach. ISM is easiest to apply and interpret; however, the typical ISM assumes a linear association. CoDA uses an isometric log-ratio transformation to directly model the compositional exposure but can be more challenging to apply and interpret. LPA can serve as an exploratory analysis tool to classify individuals into groups with similar time-use patterns. Inference on associations of latent profiles with health outcomes need to account for the uncertainty of the LPA classifications, which is often ignored. Analyses using the three methods did not suggest that less time spent on SB and more in PA was associated with better cognitive function. The three standard analytical approaches for 24HAC each have advantages and limitations, and selection of the most appropriate method should be guided by the scientific questions of interest and applicability of each model's assumptions. Further research is needed into the health implications of the distinct 24HAC patterns identified in this cohort

The serum metabolome mediates the concert of diet, exercise, and neurogenesis, determining the risk for cognitive decline and dementia

INTRODUCTION: Diet and exercise influence the risk of cognitive decline (CD) and dementia through the food metabolome and exercise-triggered endogenous factors, which use the blood as a vehicle to communicate with the brain. These factors might act in concert with hippocampal neurogenesis (HN) to shape CD and dementia. METHODS: Using an in vitro neurogenesis assay, we examined the effects of serum samples from a longitudinal cohort (n = 418) on proxy HN readouts and their association with future CD and dementia across a 12-year period. RESULTS: Altered apoptosis and reduced hippocampal progenitor cell integrity were associated with exercise and diet and predicted subsequent CD and dementia. The effects of exercise and diet on CD specifically were mediated by apoptosis. DISCUSSION: Diet and exercise might influence neurogenesis long before the onset of CD and dementia. Alterations in HN could signify the start of the pathological process and potentially represent biomarkers for CD and dementia.Identification of dietary modulators of cognitive ageing and brain plasticity and proof of concept of efficacy for preventing-reversing cognitive declin

EBioMedicine

BACKGROUND: Brain lipid metabolism appears critical for cognitive aging, but whether alterations in the lipidome relate to cognitive decline remains unclear at the system level. METHODS: We studied participants from the Three-City study, a multicentric cohort of older persons, free of dementia at time of blood sampling, and who provided repeated measures of cognition over 12 subsequent years. We measured 189 serum lipids from 13 lipid classes using shotgun lipidomics in a case-control sample on cognitive decline (matched on age, sex and level of education) nested within the Bordeaux study center (discovery, n = 418). Associations with cognitive decline were investigated using bootstrapped penalized regression, and tested for validation in the Dijon study center (validation, n = 314). FINDINGS: Among 17 lipids identified in the discovery stage, lower levels of the triglyceride TAG50:5, and of four membrane lipids (sphingomyelin SM40:2,2, phosphatidylethanolamine PE38:5(18:1/20:4), ether-phosphatidylethanolamine PEO34:3(16:1/18:2), and ether-phosphatidylcholine PCO34:1(16:1/18:0)), and higher levels of PCO32:0(16:0/16:0), were associated with greater odds of cognitive decline, and replicated in our validation sample. INTERPRETATION: These findings indicate that in the blood lipidome of non-demented older persons, a specific profile of lipids involved in membrane fluidity, myelination, and lipid rafts, is associated with subsequent cognitive decline. FUNDING: The complete list of funders is available at the end of the manuscript, in the Acknowledgement section

Associations among hypertension, dementia biomarkers, and cognition: The MEMENTO cohort

Introduction Approximately 40% of dementia cases could be delayed or prevented acting on modifiable risk factors including hypertension. However, the mechanisms underlying the hypertension–dementia association are still poorly understood. Methods We conducted a cross-sectional analysis in 2048 patients from the MEMENTO cohort, a French multicenter clinic-based study of outpatients with either isolated cognitive complaints or mild cognitive impairment. Exposure to hypertension was defined as a combination of high blood pressure (BP) status and antihypertensive treatment intake. Pathway associations were examined through structural equation modeling integrating extensive collection of neuroimaging biomarkers and clinical data. Results Participants treated with high BP had significantly lower cognition compared to the others. This association was mediated by higher neurodegeneration and higher white matter hyperintensities load but not by Alzheimer's disease (AD) biomarkers. Discussion These results highlight the importance of controlling hypertension for prevention of cognitive decline and offer new insights on mechanisms underlying the hypertension–dementia association. Highlights Paths of hypertension–cognition association were assessed by structural equation models. The hypertension–cognition association is not mediated by Alzheimer's disease biomarkers. The hypertension–cognition association is mediated by neurodegeneration and leukoaraiosis. Lower cognition was limited to participants treated with uncontrolled blood pressure. Blood pressure control could contribute to promote healthier brain aging.Stopping cognitive decline and dementia by fighting covert cerebral small vessel diseas