Methodological aspects of clinical trials for the prevention and treatment of Alzheimer's disease

La prévention et le traitement de la maladie d'Alzheimer (MA), maladie neurodégénérative chronique liée à l'âge, devient un enjeu majeur de santé publique étant donné le poids de la maladie et le vieillissement de la population. Aujourd'hui, seuls des traitements symptomatiques existent; le développement de nouveaux traitements capables de ralentir l'évolution de la maladie est donc une priorité. L'efficacité des nouveaux traitements doit être démontrée dans des essais randomisés, mais ces essais incluant des personnes âgées atteintes ou à risque d'une MA soulèvent de nombreux problèmes méthodologiques, par exemple le choix de la population cible, la durée de suivi et du critère de jugement principal et un taux de données manquantes élevé. Les données manquantes étant une source potentiellement majeure de biais dans les essais cliniques sur la MA, nous avons analysé les déterminants de l'attrition (sorties d'étude), une source majeure de données manquantes, dan une étude longitudinale de la MA. Nous avons également montré l'importance du choix de la méthode statistique de gestion des données manquantes lors de l'analyse d'un essai longitudinal. La définition du critère de jugement principal est aussi un choix important. Les essais pour les patients présentant des symptômes cliniques de la MA doivent être positifs sur deux types de critères (cognition, fonction). Une analyse a donc été réalisée pour étudier la possibilité d'utiliser un seul critère global, la CDR-SB. Aussi, dans les essais de prévention, étant donné la difficulté d'utiliser la conversion au stade de démence comme critère de jugement principal, l'alternative d'utiliser le déclin cognitif a été étudiée.The prevention and treatment of Alzheimer's disease (AD), a chronic progressive neurodegenerative disorder primarily affecting older people, is a growing public health concern given the burden of the disease, and the aging of the global population. Currently only symptomatic treatments are available, so the development of new treatments able to slow or stop the disease process is a research priority. Randomised trials are therefore required to demonstrate the efficacy (or lack thereof) of new treatments, but trials involving older people diagnosed with or at risk for AD raise numerous methodological challenges, including the definition of the target population, primary endpoint, and duration of follow-up, as well as the problems of a high level of dropouts, the burden of cognitive evaluations, and the increasing dependency of the trial participants. As missing data are a major potential source of bias in AD trials, the determinants of attrition, a major cause of missing data, were analysed in a longitudinal AD study. The impact of using different methods for handling missing data in statistical analyses of AD trials was also investigated. The choice of the primary endpoint is another important choice during the design of AD trials. Trials for symptomatic patients must demonstrate positive effects on two types of criteria (cognition and function). The suitability of using a single global primary endpoint, the CDR-SB, for such trials was therefore evaluated. Also, for prevention trials, given the difficulties of measuring conversion to dementia as the primary endpoint, the alternative of using cognitive decline as a surrogate endpoint was assessed

Effectiveness of a specific care plan in patients with Alzheimer’s disease: cluster randomised trial (PLASA study)

Objective To test the effectiveness of a comprehensive specific care plan in decreasing the rate of functional decline in patients with mild to moderate Alzheimer’s disease compared with usual care in memory clinics

Adherence to multidomain interventions for dementia prevention : Data from the FINGER and MAPT trials

Introduction: Multidomain interventions, targeting multiple risk factors simultaneously, could be effective dementia prevention strategies, but may be burdensome and not universally acceptable. Methods: We studied adherence rates and predictors in the Finnish Geriatric Intervevntion Study to Prevent Cognitive Impairment and Disability and Multidomain Alzheimer Preventive Trial prevention trials, for all intervention components (separately and simultaneously). Finnish Geriatric Intervevntion Study to Prevent Cognitive Impairment and Disability participants received a 2-year multidomain lifestyle intervention (physical training, cognitive training, nutritional counseling, and cardiovascular monitoring). Multidomain Alzheimer Preventive Trial participants received a 3-year multidomain lifestyle intervention (cognitive training, physical activity counseling, and nutritional counseling) with either an omega-3 supplement or placebo. Results: Adherence decreased with increasing intervention complexity and intensity: it was highest for cardiovascular monitoring, nutritional counseling, and the omega-3 supplement, and lowest for unsupervised computer-based cognitive training. The most consistent baseline predictors of adherence were smoking and depressive symptoms. Discussion: Reducing participant burden, while ensuring that technological tools are suitable for older individuals, maintaining face-to-face contacts, and taking into account participant characteristics may increase adherence in future trials. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.Peer reviewe

The effect of adherence on cognition in a multidomain lifestyle intervention (FINGER)

Publisher Copyright: Alzheimer's & Dementia© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.Introduction: Lifestyle interventions may prevent cognitive decline, but the sufficient dose of intervention activities and lifestyle changes is unknown. We investigated how intervention adherence affects cognition in the FINGER trial (pre-specified subgroup analyses). Methods: FINGER is a multicenter randomized controlled trial examining the efficacy of multidomain lifestyle intervention (ClinicalTrials.gov NCT01041989). A total of 1260 participants aged 60 to 77 with increased dementia risk were randomized to a lifestyle intervention and control groups. Percentage of completed intervention sessions, and change in multidomain lifestyle score (self-reported diet; physical, cognitive, and social activity; vascular risk) were examined in relation to change in Neuropsychological Test Battery (NTB) scores. Results: Active participation was associated with better trajectories in NTB total and all cognitive subdomains. Improvement in lifestyle was associated with improvement in NTB total and executive function. Discussion: Multidomain lifestyle changes are beneficial for cognitive functioning, but future interventions should be intensive enough, and supporting adherence is essential.Peer reviewe

Cross-sectional Associations of Fatigue with Cerebral β-Amyloid in Older Adults at Risk of Dementia

Fatigue is a common symptom in the elderly and has also been associated with impaired cognition in older adults. Hence, we sought to explore the cross-sectional relationship between fatigue and cerebral \u3b2-amyloid (A\u3b2) in 269 elderly individuals reporting subjective memory complaints from the Multidomain Alzheimer Preventive Trial. Standard uptake value ratios (SUVRs) were generated by [18F] florbetapir positron emission tomography (PET) using the cerebellum as a reference. Cortical-to-cerebellar SUVRs (cortical-SUVRs) were obtained using the mean signal from the frontal cortex, temporal cortex, parietal cortex, precuneus, anterior cingulate, and posterior cingulate. Other brain regions independently assessed were the anterior cingulate, anterior putamen, caudate, hippocampus, medial orbitofrontal cortex, occipital cortex, parietal cortex, pons, posterior cingulate, posterior putamen, precuneus, semioval center, and temporal cortex. Fatigue was defined according to two questions retrieved from the Center for Epidemiological Studies-Depression scale. Chronic fatigue was defined as meeting fatigue criteria at two consecutive clinical visits 6 months apart between study baseline and 1 year (visits were performed at baseline, 6 months and 1 year then annually). Cross-sectional associations between fatigue variables and cerebral A\u3b2 were explored using fully adjusted multiple linear regression models. We found no statistically significant cross-sectional associations between fatigue assessed at the clinical visit closest to PET and A\u3b2 in any brain region. Similarly, chronic fatigue was not significantly associated with A\u3b2 load. Sensitivity analysis in subjects with a Clinical Dementia Rating of 0.5 showed that fatigue reported at the clinical visit closest to PET was, however, weakly associated with increased A\u3b2 in the hippocampus (B-coefficient: 0.07, 95% CI: 0.01, 0.12, p\u2009=\u20090.016). These preliminary results suggest that fatigue might be associated with A\u3b2 in brain regions associated with Alzheimer's disease in subjects in the early stages of disease

Experiences of dementia and attitude towards prevention: a qualitative study among older adults participating in a prevention trial

Background A better insight into older adults’ understanding of and attitude towards cognitive disorders and their prevention, as well as expectations and reasons for participation in prevention trials, would help design, conduct, and implement effective preventive interventions. This qualitative study aimed at exploring the knowledge and perceptions of cognitive disorders and their prevention among participants in a prevention trial. Methods Semi-structured interviews were conducted among the participants of a multinational randomised controlled trial testing the efficacy of a lifestyle-based eHealth intervention in preventing cardiovascular disease or cognitive decline in community dwellers aged 65+. Participants were probed on their reasons for participation in the trial and their views on general health, cardiovascular disease, ageing, and prevention. The subset of data focusing on cognitive disorders (15 interviewees; all in Finland) was considered for this study. Data were analysed using content analysis. Results Participants’ knowledge of the cause and risk factors of cognitive disorders and prevention was limited and superficial, and a need for up-to-date, reliable, and practical information and advice was expressed. Cognitive disorders evoked fear and concern, and feelings of hopelessness and misery were frequently expressed, indicating a stigma. Strong heredity of cognitive disorders was a commonly held belief, and opinions on the possibility of prevention were doubtful, particularly in relation to primary prevention. Family history and/or indirect experiences of cognitive disorders was a recurrent theme and it showed to be linked to both the knowledge of and feelings associated with cognitive disorders, as well as attitude towards prevention. Indirect experiences were linked to increased awareness and knowledge, but also uncertainty about risk factors and possibility of prevention. Distinct fear and concerns, particularly over one’s own cognition/risk, and high motivation towards engaging in prevention and participating in a prevention trial were also identified in connection to this theme. Conclusions Family history and/or indirect experiences of cognitive disorders were linked to sensitivity and receptiveness to brain health and prevention potential. Our findings may be helpful in addressing older adults’ expectations in future prevention trials to improve recruitment, maximise adherence, and facilitate the successful implementation of interventions

Designing an Internet-Based Multidomain Intervention for the Prevention of Cardiovascular Disease and Cognitive Impairment in Older Adults: The HATICE Trial.

BACKGROUND: Many dementia and cardiovascular disease (CVD) cases in older adults are attributable to modifiable vascular and lifestyle-related risk factors, providing opportunities for prevention. In the Healthy Aging Through Internet Counselling in the Elderly (HATICE) randomized controlled trial, an internet-based multidomain intervention is being tested to improve the cardiovascular risk (CVR) profile of older adults. OBJECTIVE: To design a multidomain intervention to improve CVR, based on the guidelines for CVR management, and administered through a coach-supported, interactive, platform to over 2500 community-dwellers aged 65+ in three European countries. METHODS: A comparative analysis of national and European guidelines for primary and secondary CVD prevention was performed. Results were used to define the content of the intervention. RESULTS: The intervention design focused on promoting awareness and self-management of hypertension, dyslipidemia, diabetes mellitus, and overweight, and supporting smoking cessation, physical activity, and healthy diet. Overall, available guidelines lacked specific recommendations for CVR management in older adults. The comparative analysis of the guidelines showed general consistency for lifestyle-related recommendations. Key differences, identified mostly in methods used to assess the overall CVR, did not hamper the intervention design. Minor country-specific adaptations were implemented to maximize the intervention feasibility in each country. CONCLUSION: Despite differences in CVR management within the countries considered, it was possible to design and implement the HATICE multidomain intervention. The study can help define preventative strategies for dementia and CVD that are applicable internationally.The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 305374. The study has also been funded by the “Multimodal preventive trials for Alzheimer’s Disease: towards multinational strategies-programme: MIND-AD”, Academy of Finland (291803) and VTR, Kuopio University Hospital (5772815), Swedish Research Council (529-2014-7503), The Stockholms Sjukhem foundation, the Netherlands Organization for Health Research and Development, (733051041), and the French National Research Agency (ANR-14-JPPS-0001-02)

Prevention of dementia using mobile phone applications (PRODEMOS): A multinational, randomised, controlled effectiveness–implementation trial

Background: The expected increase of dementia prevalence in the coming decades will mainly be in low-income and middle-income countries and in people with low socioeconomic status in high-income countries. This study aims to reduce dementia risk factors in underserved populations at high-risk using a coach-supported mobile health (mHealth) intervention. Methods: This open-label, blinded endpoint, hybrid effectiveness–implementation randomised controlled trial (RCT) investigated whether a coach-supported mHealth intervention can reduce dementia risk in people aged 55–75 years of low socioeconomic status in the UK or from the general population in China with at least two dementia risk factors. The primary effectiveness outcome was change in cardiovascular risk factors, ageing, and incidence of dementia (CAIDE) risk score from baseline to after 12–18 months of intervention. Implementation outcomes were coverage, adoption, sustainability, appropriateness, acceptability, fidelity, feasibility, and costs assessed using a mixed-methods approach. All participants with complete data on the primary outcome, without imputation of missing outcomes were included in the analysis (intention-to-treat principle). This trial is registered with ISRCTN, ISRCTN15986016, and is completed. Findings: Between Jan 15, 2021, and April 18, 2023, 1488 people (601 male and 887 female) were randomly assigned (734 to intervention and 754 to control), with 1229 (83%) of 1488 available for analysis of the primary effectiveness outcome. After a mean follow-up of 16 months (SD 2·5), the mean CAIDE score improved 0·16 points in the intervention group versus 0·01 in the control group (mean difference –0·16, 95% CI –0·29 to –0·03). 1533 (10%) invited individuals responded; of the intervention participants, 593 (81%) of 734 adopted the intervention and 367 (50%) of 734 continued active participation throughout the study. Perceived appropriateness (85%), acceptability (81%), and fidelity (79%) were good, with fair overall feasibility (53% of intervention participants and 58% of coaches), at low cost. No differences in adverse events between study arms were found. Interpretation: A coach-supported mHealth intervention is modestly effective in reducing dementia risk factors in those with low socioeconomic status in the UK and any socioeconomic status in China. Implementation is challenging in these populations, but those reached actively participated. Whether this intervention will result in less cognitive decline and dementia requires a larger RCT with long follow-up. Funding: EU Horizon 2020 Research and Innovation Programme and the National Key R&D Programmes of China. Translation: For the Mandarin translation of the abstract see Supplementary Materials section

Prevention of dementia using mobile phone applications (PRODEMOS): protocol for an international randomised controlled trial.

IntroductionProfiles of high risk for future dementia are well understood and are likely to concern mostly those in low-income and middle-income countries and people at greater disadvantage in high-income countries. Approximately 30%-40% of dementia cases have been estimated to be attributed to modifiable risk factors, including hypertension, smoking and sedentary lifestyle. Tailored interventions targeting these risk factors can potentially prevent or delay the onset of dementia. Mobile health (mHealth) improves accessibility of such prevention strategies in hard-to-reach populations while at the same time tailoring such approaches. In the current study, we will investigate the effectiveness and implementation of a coach-supported mHealth intervention, targeting dementia risk factors, to reduce dementia risk.Methods and analysisThe prevention of dementia using mobile phone applications (PRODEMOS) randomised controlled trial will follow an effectiveness-implementation hybrid design, taking place in the UK and China. People are eligible if they are 55-75 years old, of low socioeconomic status (UK) or from the general population (China); have ≥2 dementia risk factors; and own a smartphone. 2400 participants will be randomised to either a coach-supported, interactive mHealth platform, facilitating self-management of dementia risk factors, or a static control platform. The intervention and follow-up period will be 18 months. The primary effectiveness outcome is change in the previously validated Cardiovascular Risk Factors, Ageing and Incidence of Dementia dementia risk score. The main secondary outcomes include improvement of individual risk factors and cost-effectiveness. Implementation outcomes include acceptability, adoption, feasibility and sustainability of the intervention.Ethics and disseminationThe PRODEMOS trial is sponsored in the UK by the University of Cambridge and is granted ethical approval by the London-Brighton and Sussex Research Ethics Committee (reference: 20/LO/01440). In China, the trial is approved by the medical ethics committees of Capital Medical University, Beijing Tiantan Hospital, Beijing Geriatric Hospital, Chinese People's Liberation Army General Hospital, Taishan Medical University and Xuanwu Hospital. Results will be published in a peer-reviewed journal.Trial registration numberISRCTN15986016