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GERO Cohort Protocol, Chile, 2017–2022: Community-based Cohort of Functional Decline in Subjective Cognitive Complaint elderly


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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 the elderly and the most rapidly growing cause of death in the last 20 years. Cognitive complaint is considered a predictor for cognitive and functional decline, incident mild cognitive impairment, and incident dementia. The GERO cohort is the Chilean core clinical project of the Geroscience Center for Brain Health and Metabolism (GERO). The objective of the GERO cohort is to analyze the rate of functional decline and progression to clinical dementia and their associated risk factors in a community-dwelling elderly with subjective cognitive complaint, through a population-based study. We also aim to undertake clinical research on brain ageing and dementia disorders, to create data and biobanks with the appropriate infrastructure to conduct other studies and facilitate to the national and international scientific community access to the data and samples for research. Methods The GERO cohort aims the recruitment of 300 elderly subjects (> 70 years) from Santiago (Chile), following them up for at least 3 years. Eligible people are adults not diagnosed with dementia with subjective cognitive complaint, which are reported either by the participant, a proxy or both. Participants are identified through a household census. The protocol for evaluation is based on a multidimensional approach including socio-demographic, biomedical, psychosocial, neuropsychological, neuropsychiatric and motor assessments. Neuroimaging, blood and stool samples are also obtained. This multidimensional evaluation is carried out in a baseline and 2 follow-ups assessments, at 18 and 36 months. In addition, in months 6, 12, 24, and 30, a telephone interview is performed in order to keep contact with the participants and to assess general well-being. Discussion Our work will allow us to determine multidimensional risks factors associated with functional decline and conversion to dementia in elderly with subjective cognitive complain. The aim of our GERO group is to establish the capacity to foster cutting edge and multidisciplinary research on aging in Chile including basic and clinical research. Trial registration NCT04265482 in Registration Date: February 11, 2020. Retrospectively Registered.
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S T U D Y P R O T O C O L Open Access
GERO Cohort Protocol, Chile, 20172022:
Community-based Cohort of Functional
Decline in Subjective Cognitive Complaint
Andrea Slachevsky
, Pedro Zitko
, David Martínez-Pernía
, Gonzalo Forno
, Felipe A. Court
Patricia Lillo
, Roque Villagra
, Claudia Duran-Aniotz
, Teresa Parrao
, Rodrigo Assar
, Paulina Orellana
Carolina Toledo
, Rodrigo Rivera
, Agustín Ibañez
, Mario A. Parra
, Christian González-Billault
Helena Amieva
and Daniela Thumala
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 the elderly and the
most rapidly growing cause of death in the last 20 years. Cognitive complaint is considered a predictor for
cognitive and functional decline, incident mild cognitive impairment, and incident dementia. The GERO cohort is
the Chilean core clinical project of the Geroscience Center for Brain Health and Metabolism (GERO). The objective
of the GERO cohort is to analyze the rate of functional decline and progression to clinical dementia and their
associated risk factors in a community-dwelling elderly with subjective cognitive complaint, through a population-
based study. We also aim to undertake clinical research on brain ageing and dementia disorders, to create data and
biobanks with the appropriate infrastructure to conduct other studies and facilitate to the national and international
scientific community access to the data and samples for research.
(Continued on next page)
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changes were made. The images or other third party material in this article are included in the article's Creative Commons
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permission directly from the copyright holder. To view a copy of this licence, visit
The Creative Commons Public Domain Dedication waiver ( applies to the
data made available in this article, unless otherwise stated in a credit line to the data.
* Correspondence:
Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile
Neuropsychology and Clinical Neuroscience Laboratory (LANNEC),
Physiopathology Department - Institute of Biomedical Sciences (ICBM),
Neuroscience and East Neuroscience Departments, Faculty of Medicine,
University of Chile, Santiago, Chile
Full list of author information is available at the end of the article
Slachevsky et al. BMC Geriatrics (2020) 20:505
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
(Continued from previous page)
Methods: The GERO cohort aims the recruitment of 300 elderly subjects (> 70 years) from Santiago (Chile), following
them up for at least 3 years. Eligible people are adults not diagnosed with dementia with subjective cognitive complaint,
which are reported either by the participant, a proxy or both. Participants are identified through a household census. The
protocol for evaluation is based on a multidimensional approach including socio-demographic, biomedical, psychosocial,
neuropsychological, neuropsychiatric and motor assessments. Neuroimaging, blood and stool samples are also obtained.
This multidimensional evaluation is carried out in a baseline and 2 follow-ups assessments, at 18 and 36 months. In
addition, in months 6, 12, 24, and 30, a telephone interview is performed in order to keep contact with the participants
and to assess general well-being.
Discussion: Our work will allow us to determine multidimensional risks factors associated with functional decline and
conversion to dementia in elderly with subjective cognitive complain. The aim of our GERO group is to establish the
capacity to foster cutting edge and multidisciplinary research on aging in Chile including basic and clinical research.
Trial registration: NCT04265482 in Registration Date: February 11, 2020. Retrospectively Registered.
Keywords: Cognitive aging, Subjective cognitive complaint, Dementia, Alzheimer, Functional decline, Geroscience
Population ageing, driven by rising life expectancies and
declining fertility rates, is one of the most important
transformations the world is undergoing today. World
population over 60 years old is now 12% and is expected
to reach 21.5% by the year 2050. Within the same
period, the increase in the population over 80 years old
will be even more pronounced, going from 1.7 to 4.5%
of the population [1]. This demographic change is ad-
vancing faster in Latin America (LA) than in European
and North American countries [2,3]: by 2025, the total
number of individuals over 60 years old will reach ap-
proximately 57 million [4]. Among the countries in this
region, Chile shows one of the fastest life expectancy
growth rates [2,3,5]. By 2050, Chileans older than 60
years will increase from the current 15.7% of the popula-
tion to 32.9%, while people older than 80 years will reach
10.3% [5].
This population ageing is associated with a strong in-
crease in the number of people living with dementia,
which is estimated to reach 140 million by 2050. De-
mentia is the most significant global challenge for health
and social care in the twenty-first century [6]. In Chile,
dementia is the leading cause of dependency (36%) in
older people [79]. The National Survey of Dependency
in the Elderly reported an estimated prevalence of de-
mentia of 7.0% (women 7.7%, men 5.9%) in people aged
60 years and older [7]. This prevalence is equivalent to
what is reported in a systematic review of epidemiologic
studies of dementia in Latin America [10]. In addition,
the number of deaths attributed to dementia in Chile
has increased by 526% from 1990 to 2010, which means
that dementia is the most rapidly growing cause of death
in the last 20 years [11].
Most of the dementia syndromes are preceded by a
prodromal phase characterized by the presence of a
broad range of very subtle manifestations of cognitive
decline. Common presentations are, amongst others,
concerns about cognitive decline, also known as subject-
ive cognitive complaint (SCC), of people who may or
may not have deficits in objective testing [12], reported
either by the person her/his-self, or by an informant,
mild cognitive impairment (MCI), and the recently pro-
posed mild behavioral impairment [13]. Although many
subjects with SCC and MCI are at high risk to progress
to a dementia syndrome (i.e. conversion rates to demen-
tia range from 2 to 15% per year in subjects with MCI),
some of them remain stable over time while others re-
vert to healthy cognition, particularly in epidemiological
settings [1416]. This uncertain prognosis makes cogni-
tive complaints and MCI important construct in terms
of targeting interventions for secondary prevention in
dementia [14,17].
On the other hand, studies focused on the risk factors
associated with functional decline (FD), i.e. the ability to
perform daily routines, are less known. The determination
of FD has been commonly used as a critical line dividing
between predementia and dementia stages. However, the
notion that FD starts only at the stage of dementia has
been challenged with several studies showing that minor
impairment in complex activities of daily life (ADL) pre-
cedes dementia in many years [18,19], and is already
present at the stage of MCI [20,21]. Moreover, standard-
izing the degree of functional impairment that is associ-
ated with dementia rather than MCI has been problematic
and the categorical classification of MCI and Alzheimers
Disease (AD) has been criticized [22]. Studying the
amount and trajectories of FD could allow overcoming
limitations associated with categorical outcomes, such as
the conversion to dementia. Moreover, impairment in the
ability to perform everyday activities and the eventual loss
of independence are major concerns for older adults [23].
Finally, predicting the risk of FD and the risk of de-
mentia is associated with a complex interplay of non-
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modifiable and modifiable risk factors such as overall
health and lifestyle factors [24]. The interplay of these
factors could be divided into five dimensions: i) biologic,
ii) neuroimaging, iii) clinical phenotype (cognition, be-
havioral, motor and functional domains), iii) metabolic,
systemic diseases and habits and v) psychosocial. A
multidimensional assessment including all dimensions
mentioned above would increase either the differenti-
ation of healthy and pathologic brain aging and the pre-
diction of the risk of FD and dementia [25].
To the best of our knowledge, no previous study has
reported multidimensional risk factors (biomedical, im-
aging, psychosocial, and clinical) associated with the
prognosis of elderly with SCC on the evolution of FD.
Also, there is a scarcity of cohort study on cognitive de-
cline in Latin-American and no studies have been car-
ried out in Chilean on risks associated with progression
to dementia. The present paper reports the aims and de-
sign of a cohort study, being conducted in Chile by the
Geroscience Center for Brain Health and Metabolism
Objectives of the study
The general objective of this study is to analyze the rate
of functional decline and progression to clinical demen-
tia and their associated risk factors (biomedical, imaging,
psychosocial, and clinical) in a community-dwelling eld-
erly with SCC, through a population-based study. The
specific objectives are to determine: i) longitudinal evo-
lution of biomarkers measured from blood, stool and
structural and functional magnetic resonance neuroim-
aging (MRI), ii) evolution of health-related outcomes, in-
cluding quality of life, comorbidity and risk factors, and
iii) mortality rates. We also aim to build the capacity to
undertake clinical research on brain ageing and demen-
tia disorders and to create data and biobanks with the
appropriate infrastructure to conduct other studies and
facilitate to the national and international scientific com-
munity access to the data and samples for research.
The GERO cohort is the core clinical project of the
GERO program grant, which is supported by the Fund
for Research Centers in Priority Areas Program (FON-
DAP) of the Chilean national research and development
agency (ANID, for its acronym in Spanish). GERO is ini-
tially funded for 5 years, and its main aim is to establish
a center for studying brain aging in Chile, including
basic and clinical research.
The cohort recruits the potential participants from the
general population, using a door-to-door strategy. The
sample framework corresponds to the territories
assigned to three primary healthcare centers selected by
convenience according to their socioeconomic hetero-
geneity, which belong to three different districts in
Santiago (Chile): Macul, Peñalolen and La Reina. The
sample considers a two-stage selection process. The first
stage includes a sample of quadrants within each terri-
tory, where the contact to all houses is attempted. The
second stage proceeded when in a home is found more
than one potential eligible participant, choosing one ran-
domly. Territories encompassed a population between
14,937 and 39,458 people [26], of which between 4.6 and
8.0% is expected to be older than 70 years old. Follow up
of the participants is performed in the Memory and
Neuropsychiatry Clinic (CMYN, for its acronym in
Spanish) at the Universidad de Chile, located next to the
Hospital Salvador, hospital of reference for territories in-
cluded in the sample.
Participant, eligibility, inclusion, and exclusion
Subjects are eligible for the study if they fulfil the follow-
ing criteria: i) 70 years old or older; ii) presence of a
knowledgeable informant and/or presence of a contact
that allows the follow up of the participant, and iii) being
affiliated to the public health insurance.
Eligible participants are invited to the study and re-
ceive a first evaluation to confirm the following criteria:
Inclusion criteria: Eligibility criteria plus:
Subjective cognitive complaint either self-reported
or reported by a knowledgeable informant.
Clinical Dementia Scalefrontotemporal lobar
degeneration (CDR-FTLD) equal or inferior to 0.5
Signed informed consent.
Exclusion criteria:
Report of medical diagnosis of dementia.
Mini-mental State Examination (MMSE) < 21 and
Pfeffer questionnaire > 2 [28,29].
Institutionalization (for example, living in an elderly
home or a skilled nursing facility).
Illiteracy, meaning that is not able to write or read.
Visual and auditory acuity not adequate for
neuropsychological testing.
Important limitation of mobility incompatible with
the availability to be independent in daily life
activities and/or attending a clinical center for
further evaluation.
Report of medical diagnosis of Parkinsons disease.
Report of medical diagnosis of one or more of the
following conditions causing severe impairment in
functionality: any psychiatric or neurological
disorders, brain tumor, subdural hematoma,
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progressive supranuclear palsy, or history of head
Report of medical diagnosis of stroke occurred in
the last 3 months.
Presence of a fatal disease (less than 1 year of
Field work during the first contact
The recruitment process considers two steps. First, 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 for eligibility. In case of acceptance, the inclusion
and exclusion criteria protocol are applied. If the subject
fulfils the criteria, the psychologist schedules a medical
interview. Following this evaluation, a neurologist de-
cides if the subject fulfil the inclusion criteria of the co-
hort (see Fig. 1).
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 participat-
ing in the study. Rates of contact and response are mon-
itored permanently, and the procedures around the
contact and first interview are checked in the field and
also by telephone to a subsample of the participants.
Contact to homes is attempted up to three times on dif-
ferent days and hours before considering it frustrated.
The fieldwork started in November 2017 and is expected
to finish at the middle of 2020. Up to date, the recruit-
ment has not been completed.
The lay team and psychologists involved in the first
contact and recruitment received specific training on
their labor in the field. The lay team completed a whole
training week, which included theoretical and practical
elements. Psychologists received a 12 weeks length train-
ing, which covers several sessions of neuropsychological
Sample size
The sample size needs to satisfy two criteria, one con-
cerned 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 un-
certainty 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 integ-
rity of the original protocol and permits to test associa-
tions equivalent to an Odds Ratio (OR) around 1.5
(Cohens equal to 0,22) in cases of exposition and prob-
ability of the outcome close to 50%, using a significance
of 5%. It is expected to follow each participant 3 years,
accumulating roughly 900 person-years of follow up.
Follow-up and retention strategy
Socio-demographic, health-related outcomes (quality of
life, arthrometric measures and risk factors), clinical
stages and symptoms, psychosocial, neuropsychological,
neuropsychiatric, motor, neuroimaging, blood bio-
markers, stool, and genetic samples will be performed as
baseline evaluation and every 18 months, with the excep-
tion of the genetic study that will be performed only at
baseline and neuroimaging at baseline and 36 months.
Patientshealth status, functionality, and involvement in
the GERO cohort will be monitored every 6 months by a
telephonic questionnaire in order to assess general well-
being and keep contact with the participants.
To avoid a significant attrition of the sample the fol-
lowing 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 partici-
pant; telephone contact every 6 months; and domicile
visit in case of absence of contact or attending to assess-
ment appointments. Additionally, all transport costs of
participants are being covered by the GERO cohort ad-
ministration, 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 multidi-
mensional study of factors related to the prognosis of
FD and dementia development. The range of assess-
ments includes: socio-demographic, health-related out-
comes (quality of life, arthrometric measures and risk
factors), clinical stages and symptoms, psychosocial,
neuropsychological, neuropsychiatric, motor, neuroimag-
ing, blood biomarkers, genetic and stool samples to per-
form gut microbiome studies (see Table 1, Fig. 1and
Additional file 1). Neuroimaging protocol will allow
assessing brain atrophy, structural and functional con-
nectivity and white matter lesions [83,84] (see Add-
itional file 1). 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 [85]. Samples are stored in our GERO
biobank for long-term storage at 80 °C or in liquid ni-
trogen (see details in annex). Stool samples are being
collected using standardized kits and DNA extracted
using the protocol Q suggested by the international hu-
man microbiome standards (IHMS SOP 06 V1). Data
are recorded in an ad-hoc platform developed by bio-
informatics and bioengineers personal of GERO (see
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Fig. 1 Flow Chart of Study Procedure
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Table 1 Schedule of enrolment, assessments and close-out
Enrolment Assessment Close-
Eligibility screen
Informed consent
Technological - Activities of Daily Living Questionnaire (T-ADLQ) [30]. X X X
Everyday Cognition Scale (ECog) [31]. X X X
Pfeffer Functional Activities Questionnaire (PQAF) [29]. X X X
[67] Marital status. X X X
Education. X
Occupational background. X
Ethnicity. X
Individual and household income. X X X
Assets inventory. X X X
Health insurance. X X X
Household conformation. X X X
Social network information. X X X
Health, risk factors,
anthropometric and laboratory
Health related quality of life (EQ-5D) [32]. X X X
Tabacum and alcohol consumption (Alcohol Use Disorders Identification
Test, AUDIT) [33].
Audition and vision section of the Chilean National Health Survey [34]. X X X
Physical activity, sedentarism and diet [34]. X X X
Oral health thought the Oral Health Impact Profile (OHIP). X X X
Frailty: Fried Frailty Phenotype and the Frail Questionnaires [35,36]. X X X
Anthropometric measurements: weight, body mass index (BMI), systolic and
diastolic blood pressure (seat and standing).
Framingham Cardiovascular Risk Scale. X X X
Laboratory evaluation: hemogram, glycaemia, lipid profile, level of vitamin
B12 and folic acid, thyroid hormone (TSH and free T4) and hepatic profile.
Health inventory on 18 health conditions (including cardiovascular events). X X X
Psychological assessment
Engagement in stimulating activities. X X X
Ageing related losses. X X X
Personality traits [37,38]. X X X
Psychological well-being [39]. X X X
Geriatric Depression Scale - Brink and Yesavage [40]. X X X
Depression, Anxiety and Stress Scale (DASS-21) [41]. X X X
Coping processes [42]. X X X
Social integration. X X X
Cognitive reserve scale [43]. X X X
Stage and clinical symptoms
Clinical Dementia Rating for Frontotemporal Lobar Degeneration (CDR-
FTLD)-eight domains [44].
Alzheimer Disease- 8 (AD8) [45,46]. X X X
Neuropsychological evaluation Global Cognitive Function:
- Minimental-State Examination (MMSE) [47]. X X X
- Montreal Cognitive Examination (MoCA) [48]. X X X
- Addenbrookes Cognitive Examination (ACE III) [49]. X X X
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Additional file 1). A schematic representation of instru-
ments and assessments is presented in Table 1.
Data analysis plan
The GERO cohort offers a unique opportunity for mul-
tiple analyses to identify, correlate and analyze multidi-
mensional 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 partici-
pant subgroups and the whole cohort according to main
variables, using Markov-Chain Montecarlo procedures
Table 1 Schedule of enrolment, assessments and close-out (Continued)
Enrolment Assessment Close-
- Short Term Memory Binding Test [50,51].
- Free and Cued Selective Reminding Test (FCRST) [5254]
- Supermarket task [55].
Executive functions:
- Ineco Frontal Screening [56].
- Verbal fluency test [57].
- Color Trail Test Part B [58,59].
Language: Sydney Language Battery (Sydbat) [60]. X X X
Visuo-constructive abilities: Rey Complex Fig [61,62].. X X X
Social Cognition: MiniSea [63]. X X X
Motor assessment
Soft neurological signs:
-Heidelberg Neurological Soft Signs [64].
-Edinburgh Motor Assessment (EMAS) [65].
Balance: simple-task, dual-task (including cognitive task), and sensorimotor
Walking assessment: carrying a cup with water, and counting backwards
from 100.
Other scales:
- Tinetti test [66].
- Activities-Specific Balance Confidence Scale (ABC) [67].
- Timed up and go [68].
Three whole-brain sequences:
- High-resolution T1-weighted magnetic resonance image (MRI).
- Resting-state functional magnetic resonance images (RS-fMRI)
- Diffusion tensor-based images (DTI).
- Axial T2 and Flair sequences to detect infarcts and white-matter alterations.
Gut microbiome 16S analysis from stool samples [69]. X X X
Biomarkers Six inflammatory biomarkers, IL-2, IL-6, IL-10, TNFα, SAP and CRP [7074]. X X
Genetic study Family pedigree through a questionnaire in accordance to Goldman criteria
Candidate genes associated with neurodegenerative diseases (ApoE, TREM2
and MAPT) using real time PCR analysis.
Genome-Wide Association Study (GWAS) [76]. X
This module used standard items taken from previous studies [34]
Chile has its own prices to valuate health states using EQ5D [32,77]. Items for tabacum consumption, physical activity, sedentarism, diet evaluation were taken
from the National Health Survey 20092010, many of them in accordance to PAHO monitoring instruments [34]. AUDIT instrument has been validated in Chile
[33]. Health inventory includes items for diagnosis, past and current treatment [78]. Operational measure of frailty includes a brief 5 items scale: unintentional
weight loss, weakness, exhaustion, slow gait, and low physical activity [79,80]. Framingham scale (validated in Chile) includes diabetes, hypertension,
dyslipidemia, tabacum consumption, male gender and age as risk factor of cardiovascular disease [81]
Instruments previously validated for the Chilean population. Instruments developed by GERO (engagement in stimulating activities, aging related losses and
social integration) and validated in a pilot study with a sample of 250 elderlies
AD8 has been validated in Chile [82]
Balance is evaluated using a Bertec FP406005-PT force platform (Bertec Corporation, Columbus, Ohio, USA). Electro-cardi o-physiological and electrodermal
activity is collected through a BIOPAC MP150 device (BIOPAC Systems Inc., Goleta, CA, USA). A custom-made MATLAB script is used to present the stimuli and
send triggers to the AcqKnowledge software (BIOPAC) in sync with the onset of the stimuli
For a more detailed information of the neuroimaging protocol see Additional file 1
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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 ma-
chines [88]. These procedures are suitable for leading 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 modelling [89].
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: i) to analyze only cases with
complete information (i.e. assuming that missing data is
completely at random); and ii) imputing data according
to multivariate imputation by chained equation tech-
niques [90,91]. The analysis will be performed using the
statistical software R.
Coordination with local health services
The GERO cohort has been carefully designed to avoid
undermining the usual care of participants in their com-
mon health services facilities. Even more, a linkage be-
tween the health assessments provided by the cohort
and the usual health care has been promoted.
In cases when the cohorts assessment detects a new health
condition (diabetes, depression, hypertension, etc.) the partic-
ipants are derived to the primary healthcare center of their
territory. In the case of detection of a significant neurological
disorder (Dementia syndrome, Parkinson, etc.) the partici-
pants are directly derived to specialized care according to
their Health District, communicating the decision to the pri-
mary health care.
Primary care health centers, specialized care polyclinics
and the direction of the Health District involved have been
informed about the study and jointly the protocol of deriv-
ation 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 Institu-
tional Review Board authorization. A bilateral agreement
must be signed before sharing of data. Access to the ser-
ver will not be granted.
The project was approved September 2016 by the Ethic
Committee of the Servicio de Salud Metropolitano
Oriente, Santiago (Chile). A written informed consent to
participate in the study is obtained for all participants of
the GERO cohort.
Outreach/dissemination and clinical impact of the GERO
Our group, in collaboration with the Ministry of Health,
the Hospital del Salvador and other faculties of the Uni-
versity of Chile, created in 2018 the CMYN, a clinical fa-
cility that houses one of the three Memory Units of the
Chileans Dementia Plan, and it is conformed by a multi-
disciplinary team (neurologist, psychiatrist, nurse, neuro-
psychologist, clinical psychologist, occupational therapist,
speech therapist and social worker). Nowadays, GERO
and CMYN train professionals in primary care centers
and neurology, psychiatric and geriatric residents in brain
ageing and dementia. Additionally, we perform outreach
activities on geroscience, brain ageing, and dementia to
the broad community, mainly in the three districts of the
GERO cohort and in Hospital Salvador, and to the scien-
tific and health community. We designed a brochure to
inform about the GERO cohort and performed broader
dissemination through media (print, television, radio). Fi-
nally, our group lead a policy paper on dementia to inform
public policy [92].
The current paper presents the study protocol of a Chil-
ean cohort in brain aging and dementia: the GERO co-
hort study. This project mainly focuses in identifying
risk factors associated with functional decline and pro-
gression to clinical dementia in the elderly with SCC by
determine factors related to biomedical, clinical and psy-
chosocial variables.
To date, important contributions have been realized in the
Latin-America region allowing to know the prevalence and
incidence of dementia [7,10,93], the subjective memory
complaints in people with and without dementia [94], the
neuropsychiatric symptoms as a risk of dementia [95], the
unawareness of memory impairment in dementia [96], and
biomarkers profiles in AD and MCI [97] in non-Caucasian
population. However, study on the risk to conversion to de-
mentia in elderly subjective cognitive complaint and MCI
[98107]. Epidemiologic studies of pathologic brain aging,
SCC and MCI from Latin America and in particular Chile
are still scarce in comparison with those from northern
countries [9] and none of them have addressed risk factors
related to FD, and its relationship with the progression to de-
mentia. The transference of data collected from longitudinal
and transversal European and North American studies to
Latin-America population is limited due to the important
differences in genetic, medical and social factors associated
with FD and the risk of Dementia. In this context, the study
of risk factors associated with dementia in non-Caucasian
population has emerged as priority area in research [108].
GERO cohort address an under represented population in
the literature [9].
Slachevsky et al. BMC Geriatrics (2020) 20:505 Page 8 of 13
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
From a public health perspective, identification of SCC
and MCI subjects with higher risk of pathologic trajector-
ies would be valuable as a diagnostic tool to focus preven-
tion in subjects at higher risk of FD and dementia.
Additionally, between SCC and MCI, SCC could be a bet-
ter valuable target for public policy interventions, since it
is built on the subjective self or informant-reported per-
ceptions, which are closer to the awareness that could tar-
get health care consultation. Moreover, the diagnosis of
MCI required the demonstration of an objective decline in
cognitive performance limiting the diagnosis of MCI in
primary care centers. Also, the concept of MCI has been
criticized due to overlap of MCI and AD dementia sug-
gesting ambiguity in the MCI concept and the criteria of
MCI are continuing evolving [22].
The collective approach will allow us to i) improve
diagnosis for neurodegenerative disease, ii) evaluate age-
related risk factors and genetic variations linked to neu-
rodegeneration, iii) understand how molecular mecha-
nisms involved in aging lead to neurodegeneration and
iv) explore novel biomarkers to evaluate the onset and
progression of neurodegeneration. GEROs aim is to es-
tablish a center for studying brain aging in Chile, includ-
ing basic, translational and clinical research.
The availability of a GERO biobank will allow fostering
translational studies by collecting peripheral samples for
research use to improve our understanding of health
and disease in the Chilean population. Additionally, bio-
logical analysis and associated clinical data are necessary
to contribute in early diagnosis, prognostic and treat-
ment for the aging population [14]. The development of
and ad-hoc platform constitute an important step to the
development of a brain aging registry in Chile who could
contribute to advance in research in brain aging by col-
lecting either epidemiologic data and data from other
sources, such us from clinical practice with patients with
brain disorders [109]. GERO translational approach
combines basic and clinical scientists who are targeted
to fills the void in aging research that exists in our coun-
try, specifically toward the interface between aging and
neurodegenerative diseases.
Furthermore, GERO platform will provide strategies,
methods and tools to conduct longitudinal studies on a
community base in populations with diverse epidemio-
logical settings.
Main strengths and weakness of the GERO cohort
The main strengths of the GERO cohort is recruitment
of participants at their home, allowing recruiting either
people attending clinical center and people not attend-
ing. People not attending clinical center probably repre-
sent a higher risk group under-represented in previous
studies [110]. Moreover, feasibility of memory clinical-
based study in Latin America is limited, due to the
important barriers to the diagnosis of dementia in
Latino-America and generally consultation for memory
problems occur in late stage of dementia disorder [9];
second, GERO cohort implemented a multidimensional-
based evaluation, categorized in five main levels: i) bio-
markers, ii) neuroimaging, iii) clinical phenotype (cogni-
tion, neuropsychiatric, motor and functionality), iv)
metabolic, systemic diseases, and habits and v) psycho-
social. This multidimensional approach is in line with
evidence explaining FD of older adults with cognitive
impairment by multiple factors [111]. Dementia also is
umbrella term that include several diseases with import-
ant variability of genetic, neural, and behavioral manifes-
tations [112], therefore a multilevel approach including
molecular biomarkers, neuroimaging, genetic and clin-
ical phenotypic allow a better characterization [25].
Third, we will explore predictive algorithms that will
eventually predict rates of FD and conversion to demen-
tia [113115]. The development of bioinformatics and
modelling algorithms during data analysis will allow the
integration of complex data from multiple sources to
build a comprehensive interaction model in our local
aging population, which expect to uncover complex de-
terminants of aging and brain diseases. Finally, establish-
ing comprehensive databases for studies on aging can
create the opportunity to formulate and validate tools
for early detection of people who are at increased risk of
late-life cognitive impairment, to identify important tar-
gets (risk factors) for preventive interventions, and to
test such interventions in randomized control trials.
Potential limitations
One of the main limitations of our study is a relatively
small sample size. Due to our research strategy to
prioritize a multidimensional and extensive evaluation,
time and budget constraint, we limited the cohort size.
Nevertheless, we selected a continuous outcome and will
study the rate of change rather than a categorical out-
come that allow to overcome possible limitations due to
the sample size [22,116]. Also due to budget constraint,
we do not include determination of specific biomarkers
for Alzheimers disease in spinal fluid and with PET (Pet
amyloid and tau) [117], nevertheless we store blood sam-
ple that will allow to study blood-based biomarkers
when available. Finally, as explained above, we have im-
plemented a strategy to avoid limitation associated with
attrition and missing data.
Final message
Our work will allow us to determine multidimensional
risks factors associated with the prognosis of elderly with
cognitive complaint on functional decline in Chilean
population. The GERO cohort will help to design public
health policies tailored to prevent aging disease, and
Slachevsky et al. BMC Geriatrics (2020) 20:505 Page 9 of 13
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
contribute to a better understanding of cognitive impair-
ment and dementia in Latin America and the world.
GEROs aim is to establish a center for studying Brain
Ageing in Chile including basic and clinical research.
Supplementary Information
The online version contains supplementary material available at https://doi.
Additional file 1.
AD: Alzheimers disease; ADL: Activities of daily life; ANID: National Research
and Development Agency (ANID, for its acronym in Spanish); CDR-
FTLD: Clinical dementia scale - frontotemporal lobar degeneration;
CMYN: Memory and Neuropsychiatry Clinic (CMYN, for its acronym in
Spanish); DSM-V: Diagnostic and statistical manual for mental disorders fifth
edition; FONDAP: Fund for research centers in priority areas program;
GERO: Geroscience Center for Brain Health and MetabolismFDFunctional
decline; LA: Latin America; MCI: Mild cognitive impairment; MMSE: Mini-
mental State Examination; MRI: Magnetic resonance neuroimaging; OR: Odds
ratio; SCC: Subjective cognitive complaint
Servicio de Salud Metropolitano Oriente, Hospital del Salvador and CESFAM
Santa Julia (Macul), CESFAM Ossandón (La Reina), CESFAM Juan Pablo II (La
Reina), and CESFAM Cardenal Silvia Henríquez (Peñalolén) for their
contribution to the realization of the cohort.
Designed the study: AS, PZ, FC, PL, RV, RA, AI, CG, HA, DT. Field work and
coordination of study: AS, DMP, GFM, PL, RV, CDA, TP, PO, CT, DT. Draft
Manuscript: AS, PZ, DMP, GFM, PO, DT. Wrote and revised the manuscript
critically: AS, PZ, DMP, GFM, FC, CDA, TP, AI, CG, DT. All authors read and
approved the final manuscript.
ANID/FONDAP/15150012; AS and AI are partially supported by the
Interamerican Development Bank (IDB) and the Multi-partner consortium to
expand dementia research in Latin America (ReDLat)which is supported by
grants from the National Institutes of Health (R01AG057234), Alzheimers
Association (SG-20-725707), Rainwater Charitable Foundation, and The Global
Brain Health Institute. AI is partially supported by grants from CONICET,
ANID/FONDECYT Regular 602 /1171200, FONCyT-PICT 20171818, FONCyT-
PICT 20171820, ANID/FONDAP 15150012, Alzheimers Association GBHI ALZ
UK-20-639295, and NIH NIA R01 AG057234.
The contents of this publication are solely the responsibility of the
authors and does not represent the official views of these institutions. The
funding body has not involvement in the design of the study and collection,
analysis, and interpretation of data and in manuscript writing.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The study protocol was approved by the Ethic Committee of the Servicio de
Salud Metropolitano Oriente, Santiago (Chile) on September 2016. A written
informed consent to participate in the study is obtained for all participants
of the GERO cohort.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests. The Geroscience
Center for Brain Health and Metabolismis funded by the National Agency
of Research and Technology (Agencia Nacional de Investigación y
Tecnología, ANIT), entity under the Chilean Ministry of Science and
Technology, through the Priority Areas Research Center Founding (Fondo
de Financiamiento de Centros de Investigación en Áreas Prioritarias,
FONDAP) N° 1510012. The project was founded in 2015 with US$5.284.791
(equivalent to national currency), for a period of 5 years (20152020).
Author details
Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile.
Neuropsychology and Clinical Neuroscience Laboratory (LANNEC),
Physiopathology Department - Institute of Biomedical Sciences (ICBM),
Neuroscience and East Neuroscience Departments, Faculty of Medicine,
University of Chile, Santiago, Chile.
Memory and Neuropsychiatric Clinic
(CMYN) Neurology Department, Hospital del Salvador and Faculty of
Medicine, University of Chile, Santiago, Chile.
Department of Neurology and
Psychiatry, Clínica Alemana-Universidad del Desarrollo, Santiago, Chile.
Department of Neurosciences, Faculty of Medicine, Universidad de Chile,
Santiago, Chile.
Health Service & Population Research Department, IoPPN,
Kings College London, London, UK.
Escuela de Salud Pública, Universidad
de Chile, Santiago, Chile.
Center for Social and Cognitive Neuroscience
(CSCN), School of Psychology, Universidad Adolfo Ibáñez, Santiago, Chile.
Center for Integrative Biology, Faculty of Sciences, Universidad Mayor,
Santiago, Chile.
The Buck Institute for Research on Aging, Novato, USA.
South Neurology Department, Faculty of Medicine, University of Chile,
Santiago, Chile.
Unidad de Neurología, Hospital San José, Santiago, Chile.
East Neurology Department, Faculty of Medicine, University of Chile,
Santiago, Chile.
Facultad de Psicología, Universidad Alberto Hurtado,
Santiago, Chile.
Institute of Biomedical Sciences (ICBM), Faculty of Medicine,
University of Chile, Santiago, Chile.
Neuroradiologic Department, Instituto
de Neurocirugia Asenjo, SSMO, Santiago, Chile.
Cognitive Neuroscience
Center (CNC), Universidad de San Andrés, Buenos Aires, Argentina.
Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina.
Universidad Autónoma del Caribe, Barranquilla, Colombia.
Global Brain
Health Institute (GBHI), University of California San Francisco (UCSF),
California, USA.
Psychology Department, School of Psychological Sciences
& Health, University of Strathclyde, Glasgow, UK.
Department of Biology,
Faculty of Sciences, Universidad de Chile, Santiago, Chile.
Bordeaux Population Health Research Center, UMR 1219, Univ. Bordeaux,
F-33000 Bordeaux, France.
Escuela de Psicologia, Facultad de Ciencias
Sociales, University of Chile, Santiago, Chile.
Received: 19 May 2020 Accepted: 3 November 2020
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Recently, Alzheimer’s Disease International (ADI) stressed that around 75% of people living with dementia globally are still not receiving a diagnosis. In this commentary, I reflect on how efforts towards better cognitive assessments, particularly of memory, can be aligned and harmonized to contribute to such needs. I highlight some barriers that ongoing collaborations and trials are facing and their potential drivers. I suggest some strategies that can help overcome them and in so doing, integrate research agendas. We need to ignite the debate towards strategies that can help level the playfield to tackle Alzheimer’s disease with true global solutions.
Full-text available
Background: Despite the increasing availability in brain health related data, clinically translatable methods to predict the conversion from Mild Cognitive Impairment (MCI) to Alzheimer's disease (AD) are still lacking. Although MCI typically precedes AD, only a fraction of 20–40% of MCI individuals will progress to dementia within 3 years following the initial diagnosis. As currently available and emerging therapies likely have the greatest impact when provided at the earliest disease stage, the prompt identification of subjects at high risk for conversion to AD is of great importance in the fight against this disease. In this work, we propose a highly predictive machine learning algorithm, based only on non-invasively and easily in-the-clinic collectable predictors, to identify MCI subjects at risk for conversion to AD. Methods: The algorithm was developed using the open dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI), employing a sample of 550 MCI subjects whose diagnostic follow-up is available for at least 3 years after the baseline assessment. A restricted set of information regarding sociodemographic and clinical characteristics, neuropsychological test scores was used as predictors and several different supervised machine learning algorithms were developed and ensembled in final algorithm. A site-independent stratified train/test split protocol was used to provide an estimate of the generalized performance of the algorithm. Results: The final algorithm demonstrated an AUROC of 0.88, sensitivity of 77.7%, and a specificity of 79.9% on excluded test data. The specificity of the algorithm was 40.2% for 100% sensitivity. Conclusions: The algorithm we developed achieved sound and high prognostic performance to predict AD conversion using easily clinically derived information that makes the algorithm easy to be translated into practice. This indicates beneficial application to improve recruitment in clinical trials and to more selectively prescribe new and newly emerging early interventions to high AD risk patients.
Full-text available
Background: Dementia is underdiagnosed in both the general population and among Veterans. This underdiagnosis decreases quality of life, reduces opportunities for interventions, and increases health-care costs. New approaches are therefore necessary to facilitate the timely detection of dementia. This study seeks to identify cases of undiagnosed dementia by developing and validating a weakly supervised machine-learning approach that incorporates the analysis of both structured and unstructured electronic health record (EHR) data. Methods: A topic modeling approach that included latent Dirichlet allocation, stable topic extraction, and random sampling was applied to VHA EHRs. Topic features from unstructured data and features from structured data were compared between Veterans with (n = 1861) and without (n = 9305) ICD-9 dementia codes. A logistic regression model was used to develop dementia prediction scores, and manual reviews were conducted to validate the machine-learning results. Results: A total of 853 features were identified (290 topics, 174 non-dementia ICD codes, 159 CPT codes, 59 medications, and 171 note types) for the development of logistic regression prediction scores. These scores were validated in a subset of Veterans without ICD-9 dementia codes (n = 120) by experts in dementia who performed manual record reviews and achieved a high level of inter-rater agreement. The manual reviews were used to develop a receiver of characteristic (ROC) curve with different thresholds for case detection, including a threshold of 0.061, which produced an optimal sensitivity (0.825) and specificity (0.832). Conclusions: Dementia is underdiagnosed, and thus, ICD codes alone cannot serve as a gold standard for diagnosis. However, this study suggests that imperfect data (e.g., ICD codes in combination with other EHR features) can serve as a silver standard to develop a risk model, apply that model to patients without dementia codes, and then select a case-detection threshold. The study is one of the first to utilize both structured and unstructured EHRs to develop risk scores for the diagnosis of dementia.
Full-text available
Alzheimer's disease and related dementias (ADRD) are highly prevalent conditions, and prior efforts to develop predictive models have relied on demographic and clinical risk factors using traditional logistical regression methods. We hypothesized that machine-learning algorithms using administrative claims data may represent a novel approach to predicting ADRD. Using a national de-identified dataset of more than 125 million patients including over 10,000 clinical, pharmaceutical, and demographic variables, we developed a cohort to train a machine learning model to predict ADRD 4-5 years in advance. The Lasso algorithm selected a 50-variable model with an area under the curve (AUC) of 0.693. Top diagnosis codes in the model were memory loss (780.93), Parkinson's disease (332.0), mild cognitive impairment (331.83) and bipolar disorder (296.80), and top pharmacy codes were psychoactive drugs. Machine learning algorithms can rapidly develop predictive models for ADRD with massive datasets, without requiring hypothesis-driven feature engineering.
Full-text available
Background The Addenbrooke's Cognitive Examination III (ACE-III), an adaptation of the ACE cognitive screening test, has been demonstrated to have high sensitivity and specificity in detecting cognitive impairment in patients with dementia and other neurological and psychiatric disorders. Although the Spanish-language version of the ACE-III has already been validated in Spain, it is yet to be validated in Latin America. The aim of this study was to validate the ACE-III test in an Argentinean and Chilean population. Methods ACE-III was administered to 70 patients with Alzheimer disease, 31 patients with behavioural variant frontotemporal dementia, and a control group of 139 healthy volunteers. Participants were recruited at centres in both countries. Results The Spanish-language version of ACE-III was found to have good internal consistency (Cronbach's alpha = 0.87). We found significant differences in total ACE-III scores between patients with Alzheimer disease and controls (P < .05) and between patients with Alzheimer disease and bvFTD (P < .05). With a cut-off point of 86, 98.6% of AD patients, 83.9% of behavioural variant frontotemporal dementia patients, and 84.2% of controls were correctly classified. Conclusions This study shows that the Spanish-language version of ACE-III continues to be an effective tool for detecting cognitive dysfunction in patients with dementia.
Full-text available
Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise "state-of-the-science" report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.
Full-text available
Personality and dementia are connected in different ways. A broad knowledge about personality and prodromal stages of dementia might be helpful to identify dementia as early as possible. Hence, personality differences between three cognitively impaired groups on the basis of patients’ self-assessments of personality traits and connections between personality and cognitive functioning were examined via a cross-sectional study. The sample consisted of cognitively impaired patients (N = 133), aged 50 and older, who came to a memory clinic due to cognitive complaints. The test procedure encompassed a cognitive screening, the Neuropsychological Test Battery Vienna (NTBV), and self-assessment questionnaires such as the Big Five Plus One Persönlichkeitsinventar (B5PO). While patients with subjective cognitive decline (SCD) did not differ from those with non-amnestic mild cognitive impairment (naMCI) concerning the different personality traits, patients with amnestic mild cognitive impairment (aMCI) showed significantly lower scores for extraversion (p < 0.05), openness (p < 0.001), and empathy (p < 0.001) than patients with SCD as well as patients with naMCI. Thus, cognitively impaired groups mainly differ concerning personality traits depending on whether they do show memory decline or not.
Full-text available
In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.
OBJECTIVE: To generate normative data on the Trail Making Test (TMT) across 11 countries in Latin America, with country-specific adjustments for gender, age, and education, where appropriate. METHOD: The sample consisted of 3,977 healthy adults who were recruited from Mexico, Argentina, Peru, Paraguay, Honduras, Chile, Cuba, Puerto Rico, Guatemala, El Salvador, and Bolivia. Each subject was administered the TMT as part of a larger neuropsychological battery. A standardized five-step statistical procedure was used to generate the norms. RESULTS: The final multiple linear regression models for the TMT-A explained 23-50% of the variance, and the final multiple linear models for the TMT-B explained 22-49% of the variance. Although there were gender differences on the TMT in Mexico, Peru, Paraguay, and Honduras, only Honduras had an effect size greater than 0.3. As a result, gender-adjusted norms were generated for the Trail Making Test-A, but not B, in this country.
Background: Neuropsychiatric symptoms and cognitive impairment are independent contributors of functional impairment in activities of daily living (ADL) in Alzheimer's disease (AD) patients. ADL could be divided according to its complexity in three subdomains: basic (BADL), instrumental (IADL), and advanced (a-ADL). Objective: Studying the cognitive and neuropsychiatric determinants of BADL, IADL, and a-ADL in normal cognitive elders and AD patients. Methods: 144 subjects were graduated using the clinical dementia rating (CDR) in CDR = 0, n = 52 (control group) and 92 AD patients CDR = 0.5, n = 34 and CDR = 1&2, n = 58. They were assessed with measures of cognitive performance and neuropsychiatric symptoms that were included in regression models to measure the best predictors for each ADL subdomain at every CDR status. Results: AD patients were significantly older, and had significantly more severe functional impairment, neuropsychiatric symptoms, and cognitive decline than controls. The best predictors of functional impairment in controls and CDR = 0.5 AD patients were neuropsychiatric symptoms; in the CDR 0.5 patients, apathy severity was the most important determinant of IADL and a-ADL impairment. While in the CDR 1&2 AD patients, cognitive impairment was the principal determinant of functional impairment, being memory the best determinant of IADL and a-ADL impairment, while global cognition was of BADL impairment. Conclusions: The contribution of cognitive impairment and neuropsychiatric symptoms varied according to the subdomain of ADL, and the CDR. In very mild AD and controls the neuropsychiatric symptoms are the best predictors of more complex ADL impairment, while cognitive impairment is more important at mild to moderate states of AD.