Alzheimer Disease Clinical Trial
Official title:
GERO Cohort Protocol, Chile, 2017 - 2019: Community-based Cohort of Functional Decline in Subjective Cognitive Complaint Elderly
Background With the global population aging and life expectancy increasing, dementia has
turned a priority in the health care system. In Chile, dementia is one of the most important
causes of disability in elderly, corresponding nearly to 40% of cases, and the most rapidly
growing cause of death in the last twenty years. Cognitive complaints are considered a marker
able to predict cognitive and functional decline, incident mild cognitive impairment (MCI),
and incident dementia. The Gero cohort is the Chilean core clinical project of the Gerocenter
on Brain Health and Metabolism (GERO), whose aim is to establish the capacity in Chile to
foster cutting edge and multidisciplinary research on aging.
Objective This study has two main objectives. First, i) to analyze the rate of functional
decline and progression to clinical dementia and their risks factors (biomedical, imaging,
psychosocial, and clinical) in a community-dwelling elderly with subjective cognitive
complaint, through a population-based study. Second, ii) to build the capacity to undertake
clinical research on brain aging and dementia disorders and create Data-Bank and Bio-Banks
with an appropriate infrastructure to further studies and facilitate access to the data and
samples for research.
Methods The Gero cohort aims at recruiting 300 elderly subjects (>70 years) from the
community of Santiago (Chile), following them up for at least 3 years. Eligible people are
non-demented adults with subjective cognitive complaint, which are reported either by the
participant, the proxy or both. Participants are identified through a household census. The
protocol of evaluation is based on a multidimensional approach including socio-demographic,
biomedical, psychosocial, neuropsychological, neuropsychiatric and motor assessments.
Neuroimaging, blood and stool sample samples are also included. This multidimensional
evaluation is carried out in a baseline assessment and 3 follow-ups assessment, at 18 and 36
months. In addition, in months 6, 24, and 30, a telephone interview is done in order to keep
contact with the participants and to assess general well-being.
Objectives of the Study:
The general objective of this study is to analyze the rate of functional decline (FD) and
progression to clinical dementia and their risks factors (biomedical, imaging, psychosocial,
and clinical) in a community-dwelling elderly with subjective cognitive complaint (SCC),
through a population-based study. The specific objectives are to determinate (i) longitudinal
evolution of biomarkers measured from blood, stool and structural and functional neuroimaging
(MRI), (ii) evolution of the health-related quality of life; (iii) rate of cardiovascular
events (stroke and coronary events), and (iv) mortality rates. The investigators also aim to
build the capacity to undertake clinical research on brain aging and dementia disorders and
create Data-Bank and Bio-Banks with an appropriate infrastructure to further studies and
facilitate access to the data and samples for research.
The Gero cohort is the core clinical project of the GERO, supported by the Fund for Research
Centers in Priority Areas Program (FONDAP) of the Chilean National Commission for Scientific
and Technological Research (CONICYT). GERO is initially funded for 5 years, and its main aim
is to establish a center for studying Brain Aging in Chile including basic and clinical
research.
Methods/Design
Field work during the first contact
The recruitment process considers two steps. Firstly, a lay team contacts each home to
determine the presence of eligible individuals. In positive cases, the person receives a
second visit by a trained psychologist who proceeds to check the eligibility. In case of
acceptance, the inclusion and exclusion criteria protocol are applied. If the subject
fulfills the criteria, the psychologist schedule a medical interview. Following this
evaluation, a neurologist decides if the subject fulfill the inclusion criteria of the
cohort.
The fieldwork is preceded by an outreach campaign (flyers, local radio advertisements, and
presentations to community-organized groups) raising awareness about the visit of
interviewers and the relevance of participating in the study. Rates of contact and response
are monitored permanently, and the procedures around the contact and first interview are
checked in the field and also by telephone to a subsample of participants. Contact to homes
is attempted up to three times on different days and hours before considering it frustrated.
The fieldwork started in November 2017 and is expected to finish at the end of 2019.
The lay team and psychologists involved in the first contact and recruitment received
specific training on their labour in the field. The lay team completed a whole week training,
which included theoretical and practical elements. Psychologists received a twelve weeks
length training, which covers several sessions of neuropsychological assessment, including
performance psychology.
Sample size
The sample size had to satisfy two criteria, one concerned with the statistical power
required to explore multiple associations with outcomes, and other related to the feasibility
to perform a wide range of assessments to each participant assuming costs and logistics. Both
criteria meant a trade-off between the tolerance to uncertainty around the parameters to be
estimated and the number of assessments that would be investigated throughout the study. The
final sample chosen was 300 participants. This number allows maintaining the integrity of the
original protocol and permits to test associations equivalent to an odds ratio (OR) around
1.5 (Cohen's d equal to 0,22) in cases of exposition and probability of the outcome close to
50%, using a significance of 5%. It is expected to follow each participant between 2 and 3
years, accumulating roughly 750 person-years of follow up.
Follow-up and retention strategy
Socio-demographic, clinical, psychosocial, neuropsychological, neuropsychiatric, motor,
neuroimaging, blood biomarkers, stool, and genetic samples will be performed as baseline
evaluation and every 18 months, with the exception of genetic study that will be performed
only at baseline and neuroimaging at baseline and the 36 month. Patients' health status,
functionality, and involvement in the Gero cohort will be monitored every 6 months by a
telephonic questionnaire.
To avoid a significant attrition of the sample a set following strategies have been
considered: to recruit only people who have at least one person that can facilitate the
contact with him or her, it means a person who can be contacted for asking about the location
of the participant; telephone contact every six months; and domicile visit in case of absence
of contact or attending to assessment appointments. Additionally, all transport costs of
participants will be covered by the Gero cohort administration, as well as any food that is
required during the days of assessment. Initially, the end of the follow up of the cohort is
programmed for October 2022.
Assessments and measurements
The protocol considers an intensive and deep multidimensional study of factors related to the
prognosis of FD and dementia development. The range of assessments includes:
socio-demographic, psychosocial, neuropsychological, neuropsychiatric, motor, neuroimaging,
blood biomarkers, genetic and stool samples to perform gut microbiome studies. Neuroimaging
protocol will allow assessing brain atrophy, structural and functional connectivity and white
matter lesions. Gero biological samples of whole blood, buffy coat, plasma, serum, and
peripheral mononuclear cells are taken and processed according to the guidelines published in
2015. Samples are stored in our Gero biobank for long-term storage at -80 °C or in liquid
nitrogen. Stool samples will be collected using standardized kits and DNA extracted using the
protocol Q suggested by the international human microbiome standards (IHMS SOP 06 V1). Data
are recorded in an ad-hoc platform developed by bioinformatics and bioengineers personal of
Gero.
Data analysis plan
The Gero cohort offers a unique opportunity for multiple analyses to identify, correlate and
analyze multidimensional factors related to FD and progression to dementia in elderlies with
SCC.
In broad terms, a descriptive of baseline measurements (either outcomes or potential
predictive factors) will be performed. The procedure will be repeated at each measurement
time, every 18 months. Random effect models will be used for describing trajectories of
participant subgroups and the whole cohort according to main variables, using Markov-Chain
Montecarlo procedures.
The association between variables and outcomes will be explored broadly using different
machine learning methods, such as elastic net procedure, random forest procedure, based-tree
methods, and support vector machines. These procedures are suitable to lead with
multi-collinearity and also high dimensional data (e.g. the number of predictive variables is
larger than the number of participants in the cohort). Interpretation of causality will be
conducted using standard random effect models and eventually structural equation modeling.
Missing data and loss of follow up of participants are common in observational studies,
mainly in cohorts. Firstly, cases with missing data in any outcome will be explored and
compared with cases without missing data describing any pattern. Secondly, two strategies
will be followed to estimate results: (1) to analyze only cases with complete information
(i.e. assuming that missing data is completely at random); and (2) imputing data according to
multivariate imputation by chained equation techniques. The analysis will be performed using
the statistical software R.
Coordination with local health services
The Gero cohort has been carefully design to avoid undermining the usual care of participants
in their common health services facilities. Even more, a linkage between the health
assessments provided by the cohort and the usual health care has been promoted.
In cases when the cohort's assessment detects a new health condition (diabetes, depression,
hypertension, etc.), participants are derived to the primary healthcare centre of their
territory. In case of detection of a significant neurological disorder (dementia syndrome,
Parkinson, etc.) the participants are directly derived to specialized care according to their
health district, communicating the decision to the primary health care.
Primary care health centres, specialized care polyclinics and the direction of the Health
District involved have been informed about the study and jointly the protocol of derivation
and communication were established.
Regulation of access to data/biospecimens
The access to data and biospecimens is regulated by the GERO directorate in accordance with
the local Institutional Review Board authorization. A bilateral agreement must be signed
before sharing of data. Access to the server will not be granted.
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