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European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (EPAD LCS): study protocol.

ABSTRACT: INTRODUCTION:The European Prevention of Alzheimer's Dementia (EPAD) project is funded initially by the Innovative Medicines Initiative and has been established to overcome the major hurdles hampering drug development for secondary prevention of Alzheimer's dementia, by conducting the EPAD Longitudinal Cohort Study (LCS) in alignment with the Bayesian adaptive designed EPAD Proof-of-Concept (PoC) trial. METHODS AND ANALYSIS:EPAD LCS is an ongoing prospective, multicentre, pan-European longitudinal cohort study. Participants are recruited mainly from existing parent cohorts across Europe to form a 'probability-spectrum' population covering the entire continuum of anticipated probability for Alzheimer's dementia development. The primary objective of the EPAD LCS is to be a readiness cohort for the EPAD PoC trial though a second major objective is to generate a comprehensive and large data set for disease modelling of preclinical and prodromal Alzheimer's disease. This characterisation of cognitive, biomarker and risk factor (genetic and environmental) status of research participants over time will provide the necessary well-phenotyped population for developing accurate longitudinal models for Alzheimer's disease covering the entire disease course and concurrently create a pool of highly characterised individuals for the EPAD PoC trial. ETHICS AND DISSEMINATION:The study has received the relevant approvals from numerous Institutional Review Boards across Europe. Findings will be disseminated to several target audiences, including the scientific community, research participants, patient community, general public, industry, regulatory authorities and policy-makers. Regular and coordinated releases of EPAD LCS data will be made available for analysis to help researchers improve their understanding of early Alzheimer's disease stages and facilitate collaborations. TRIAL REGISTRATION NUMBER:NCT02804789.

SUBMITTER: Solomon A

PROVIDER: S-EPMC6318591 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (EPAD LCS): study protocol.

Solomon Alina A Kivipelto Miia M Molinuevo José Luis JL Tom Brian B Ritchie Craig W CW

BMJ open 20190219 12

<h4>Introduction</h4>The European Prevention of Alzheimer's Dementia (EPAD) project is funded initially by the Innovative Medicines Initiative and has been established to overcome the major hurdles hampering drug development for secondary prevention of Alzheimer's dementia, by conducting the EPAD Longitudinal Cohort Study (LCS) in alignment with the Bayesian adaptive designed EPAD Proof-of-Concept (PoC) trial.<h4>Methods and analysis</h4>EPAD LCS is an ongoing prospective, multicentre, pan-Europ ...[more]

PMID: 30782589

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Project description:BackgroundRecruitment is often a bottleneck in secondary prevention trials in Alzheimer disease (AD). Furthermore, screen-failure rates in these trials are typically high due to relatively low prevalence of AD pathology in individuals without dementia, especially among cognitively unimpaired. Prescreening on AD risk factors may facilitate recruitment, but the efficiency will depend on how these factors link to participation rates and AD pathology. We investigated whether common AD-related factors predict trial-ready cohort participation and amyloid status across different prescreen settings.MethodsWe monitored the prescreening in four cohorts linked to the European Prevention of Alzheimer Dementia (EPAD) Registry (n = 16,877; mean ± SD age = 64 ± 8 years). These included a clinical cohort, a research in-person cohort, a research online cohort, and a population-based cohort. Individuals were asked to participate in the EPAD longitudinal cohort study (EPAD-LCS), which serves as a trial-ready cohort for secondary prevention trials. Amyloid positivity was measured in cerebrospinal fluid as part of the EPAD-LCS assessment. We calculated participation rates and numbers needed to prescreen (NNPS) per participant that was amyloid-positive. We tested if age, sex, education level, APOE status, family history for dementia, memory complaints or memory scores, previously collected in these cohorts, could predict participation and amyloid status.ResultsA total of 2595 participants were contacted for participation in the EPAD-LCS. Participation rates varied by setting between 3 and 59%. The NNPS were 6.9 (clinical cohort), 7.5 (research in-person cohort), 8.4 (research online cohort), and 88.5 (population-based cohort). Participation in the EPAD-LCS (n = 413 (16%)) was associated with lower age (odds ratio (OR) age = 0.97 [0.95-0.99]), high education (OR = 1.64 [1.23-2.17]), male sex (OR = 1.56 [1.19-2.04]), and positive family history of dementia (OR = 1.66 [1.19-2.31]). Among participants in the EPAD-LCS, amyloid positivity (33%) was associated with higher age (OR = 1.06 [1.02-1.10]) and APOE ɛ4 allele carriership (OR = 2.99 [1.81-4.94]). These results were similar across prescreen settings.ConclusionsNumbers needed to prescreen varied greatly between settings. Understanding how common AD risk factors link to study participation and amyloid positivity is informative for recruitment strategy of studies on secondary prevention of AD.

Project description:IntroductionApproximately 40% of late-life dementia may be prevented by addressing modifiable risk factors, including physical activity and diet. Yet, it is currently unknown how multiple lifestyle factors interact to influence cognition. The ACTIVate Study aims to (1) explore associations between 24-hour time-use and diet compositions with changes in cognition and brain function; and (2) identify duration of time-use behaviours and the dietary compositions to optimise cognition and brain function.Methods and analysisThis 3-year prospective longitudinal cohort study will recruit 448 adults aged 60-70 years across Adelaide and Newcastle, Australia. Time-use data will be collected through wrist-worn activity monitors and the Multimedia Activity Recall for Children and Adults. Dietary intake will be assessed using the Australian Eating Survey food frequency questionnaire. The primary outcome will be cognitive function, assessed using the Addenbrooke's Cognitive Examination-III. Secondary outcomes include structural and functional brain measures using MRI, cerebral arterial pulse measured with diffuse optical tomography, neuroplasticity using simultaneous transcranial magnetic stimulation and electroencephalography, and electrophysiological markers of cognitive control using event-related potential and time frequency analyses. Compositional data analysis, testing for interactions between time point and compositions, will assess longitudinal associations between dependent (cognition, brain function) and independent (time-use and diet compositions) variables.ConclusionsThe ACTIVate Study will be the first to examine associations between time-use and diet compositions, cognition and brain function. Our findings will inform new avenues for multidomain interventions that may more effectively account for the co-dependence between activity and diet behaviours for dementia prevention.Ethics and disseminationEthics approval has been obtained from the University of South Australia's Human Research Ethics committee (202639). Findings will be disseminated through peer-reviewed manuscripts, conference presentations, targeted media releases and community engagement events.Trial registration numberAustralia New Zealand Clinical Trials Registry (ACTRN12619001659190).

Project description:IntroductionWith the pressing need to develop treatments that slow or stop the progression of Alzheimer's disease, new tools are needed to reduce clinical trial duration and validate new targets for human therapeutics. Such tools could be derived from neurophysiological measurements of disease.Methods and analysisThe New Therapeutics in Alzheimer's Disease study (NTAD) aims to identify a biomarker set from magneto/electroencephalography that is sensitive to disease and progression over 1 year. The study will recruit 100 people with amyloid-positive mild cognitive impairment or early-stage Alzheimer's disease and 30 healthy controls aged between 50 and 85 years. Measurements of the clinical, cognitive and imaging data (magnetoencephalography, electroencephalography and MRI) of all participants will be taken at baseline. These measurements will be repeated after approximately 1 year on participants with Alzheimer's disease or mild cognitive impairment, and clinical and cognitive assessment of these participants will be repeated again after approximately 2 years. To assess reliability of magneto/electroencephalographic changes, a subset of 30 participants with mild cognitive impairment or early-stage Alzheimer's disease will also undergo repeat magneto/electroencephalography 2 weeks after baseline. Baseline and longitudinal changes in neurophysiology are the primary analyses of interest. Additional outputs will include atrophy and cognitive change and estimated numbers needed to treat each arm of simulated clinical trials of a future disease-modifying therapy.Ethics and data statementThe study has received a favourable opinion from the East of England Cambridge Central Research Ethics Committee (REC reference 18/EE/0042). Results will be disseminated through internal reports, peer-reviewed scientific journals, conference presentations, website publication, submission to regulatory authorities and other publications. Data will be made available via the Dementias Platform UK Data Portal on completion of initial analyses by the NTAD study group.

Project description:Alzheimer's disease is characterised by a loss of cognitive function and behavioural problems as set out in the term "Behavioural and Psychological Symptoms of Dementia". These behavioural symptoms have heavy consequences for the patients and their families. A greater understanding of behavioural symptoms risk factors would allow better detection of those patients, a better understanding of crisis situations and better management of these patients. Some retrospective studies or simple observations suggested that personality could play a role in the occurrence of behavioural symptoms. Finally, performance in social cognition like facial recognition and perspective taking could be linked to certain personality traits and the subsequent risks of behavioural symptoms. We propose to clarify this through a prospective, multicentre, multidisciplinary study. Main Objective: -To assess the effect of personality and life events on the risk of developing behavioural symptoms. Secondary Objectives: -To evaluate, at the time of inclusion, the connection between personality and performance in social cognition tests; -To evaluate the correlation between performance in social cognition at inclusion and the risks of occurrence of behavioural symptoms; -To evaluate the correlation between regional cerebral atrophy, using brain Magnetic Resonance Imaging at baseline, and the risk of behavioural symptoms.Study type and Population: Prospective multicentre cohort study with 252 patients with Alzheimer's disease at prodromal or mild dementia stage. The inclusion period will be of 18 months and the patients will be followed during 18 months. The initial evaluation will include: a clinical and neuropsychological examination, collection of behavioural symptoms data (Neuropsychiatric-Inventory scale) and their risk factors, a personality study using both a dimensional (personality traits) and categorical approach, an inventory of life events, social cognition tests and an Magnetic Resonance Imaging. Patients will be followed every 6 months (clinical examination and collection of behavioural symptoms data and risk factors) during 18 months.This study aims at better identifying the patients with Alzheimer's disease at high risk of developing behavioural symptoms, to anticipate, detect and quickly treat these disorders and so, prevent serious consequences for the patient and his caregivers.ClincalTrials.gov: NCT01297140.

Project description:BackgroundIn Alzheimer's disease (AD), pathological changes may arise up to 20 years before the onset of dementia. This pre-dementia window provides a unique opportunity for secondary prevention. However, exposing non-demented subjects to putative therapies requires reliable biomarkers for subject selection, stratification, and monitoring of treatment. Neuroimaging allows the detection of early pathological changes, and longitudinal imaging can assess the effect of interventions on markers of molecular pathology and rates of neurodegeneration. This is of particular importance in pre-dementia AD trials, where clinical outcomes have a limited ability to detect treatment effects within the typical time frame of a clinical trial. We review available evidence for the use of neuroimaging in clinical trials in pre-dementia AD. We appraise currently available imaging markers for subject selection, stratification, outcome measures, and safety in the context of such populations.Main bodyAmyloid positron emission tomography (PET) is a validated in-vivo marker of fibrillar amyloid plaques. It is appropriate for inclusion in trials targeting the amyloid pathway, as well as to monitor treatment target engagement. Amyloid PET, however, has limited ability to stage the disease and does not perform well as a prognostic marker within the time frame of a pre-dementia AD trial. Structural magnetic resonance imaging (MRI), providing markers of neurodegeneration, can improve the identification of subjects at risk of imminent decline and hence play a role in subject inclusion. Atrophy rates (either hippocampal or whole brain), which can be reliably derived from structural MRI, are useful in tracking disease progression and have the potential to serve as outcome measures. MRI can also be used to assess comorbid vascular pathology and define homogeneous groups for inclusion or for subject stratification. Finally, MRI also plays an important role in trial safety monitoring, particularly the identification of amyloid-related imaging abnormalities (ARIA). Tau PET to measure neurofibrillary tangle burden is currently under development. Evidence to support the use of advanced MRI markers such as resting-state functional MRI, arterial spin labelling, and diffusion tensor imaging in pre-dementia AD is preliminary and requires further validation.ConclusionWe propose a strategy for longitudinal imaging to track early signs of AD including quantitative amyloid PET and yearly multiparametric MRI.

Project description:BackgroundBecause of the enormous social and economic burden of disease, the prevention of mild cognitive impairment and Alzheimer's-type dementia has become a major global public health priority. Studies show that cognitively stimulating activities during middle adulthood might have a protective effect on the brain by boosting the cognitive reserve. The aim of this review is to identify evidence investigating the effects of continuing education for the prevention of mild cognitive impairment and Alzheimer's-type dementia in late life.MethodsOur approach employs a two-stage design: First, we will conduct a systematic review to assess the preventive effects of continuing education on mild cognitive impairment and Alzheimer's-type dementia. Second, because we expect to find few studies, we will perform a review of systematic reviews on leisure activities that mimic formal continuing education to determine their effects on the prevention of mild cognitive impairment and Alzheimer's-type dementia. We will search electronic databases (e.g., MEDLINE, PsycINFO, EMBASE, CENTRAL, CINAHL, and Scopus) for published studies and gray literature databases (e.g., trial registries) for unpublished studies. Two authors will independently screen abstracts and full-texts using pre-defined eligibility criteria, select studies, extract data, and assess the quality of included studies or reviews. Outcomes of interest include the incidence of mild cognitive impairment or Alzheimer's-type dementia, quality of life, functional capacity, and psychological wellbeing. Intermediate outcomes are cognitive (test) performance, cognitive functioning, and social inclusion. The review team is a multidisciplinary group consisting of methodological experts and dementia, geriatrics, and continuing education researchers.DiscussionWe anticipate that our review will highlight serious gaps in the current evidence. Results will build the basis for further research regarding the relation of continuing education and cognitive decline and dementia.Systematic review registrationPROSPERO CRD42017063944.

Dataset Information

European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (EPAD LCS): study protocol.

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European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (EPAD LCS): study protocol.

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