The efficacy of Cognitive training in patients with VAsCular Cognitive Impairment, No dEmentia (the Cog-VACCINE study): study protocol for a randomized controlled trial
Tang et al. Trials
The efficacy of Cognitive training in patients with VAsCular Cognitive Impairment, No dEmentia (the Cog-VACCINE study): study protocol for a randomized controlled trial
Yi Tang 0 1
Zude Zhu 0 3
Qing Liu 1
Fang Li 2
Jianwei Yang 1
Fangyu Li 1
Yi Xing 1
Jianping Jia 1 4
0 Equal contributors
1 Department of Neurology, Xuan Wu Hospital, Capital Medical University , 45 Changchun Street, Beijing 100053 , China
2 Department of Geriatric Medicine, Fu Xing Hospital, Capital Medical University , Beijing , China
3 Collaborative Innovation Center for Language Competence, Jiangsu Normal University , Xuzhou, Jiangsu , China
4 Department of Neurology, Beijing Friendship Hospital, Capital Medical University , Beijing , China
Background: Vascular cognitive impairment, no dementia (VCIND) refers to cognitive deficits associated with underlying vascular causes that fall short of a dementia diagnosis. There is currently no treatment for VCIND. Computerized cognitive training, which has significantly improved cognitive function in healthy older adults and patients with cognitive impairment has not yet been applied to VCIND. Methods/Design: The proposed study is a three-center, double-blinded, randomized controlled trial that will include 60 patients with VCIND. The patients will be randomized to either a training or a control group. The intervention is internet-based cognitive training performed for 30 min over 35 sessions. Neuropsychological assessment and functional and structural MRI will be performed before and after 7 weeks training. Primary outcomes are global cognitive function and executive function. Secondary outcome measures are neuroplasticity changes measured by functional and structural MRI. Discussion: Applying an internet-based, multi-domain, adaptive program, this study aims to assess whether cognitive training improves cognitive abilities and neural plasticity in patients with subcortical VCIND. In addition to the comprehensive assessment of the participants by neuropsychological tests, cerebrovascular risk factors and apolipoprotein E genotyping, neuroplasticity will be used as an evaluation outcome in this study for, to our knowledge, the first time. The combination of functional and structural MRI and neuropsychological tests will have strong sensitivity in evaluating the effects of cognitive training and will also reveal the underlying mechanisms at work. Trial registration: ClinicalTrials.gov NCT02640716. Retrospectively registered on 21 December 2015.
Cognitive training; Magnetic resonance imaging; Neuroplasticity; No dementia; Protocol; Randomized controlled clinical trial; Vascular cognitive impairment
Cerebrovascular disease remains the second leading
contributor to disability in older people in low- and
middleincome countries [
]. In addition to causing physical
disabilities, cerebrovascular disease has long been
recognized as an important cause of cognitive impairment.
The term ‘vascular cognitive impairment’ was introduced
to explain all forms of cognitive dysfunction caused by
cerebrovascular disease, ranging from mild cognitive
dysfunction (vascular cognitive impairment, no
dementia, VCIND) to overt dementia (vascular dementia) [
Vascular cognitive impairment, no dementia, which is
also termed mild vascular cognitive disorder [
to cognitive deficits associated with underlying vascular
causes that fall short of a diagnosis of dementia [
According to the China Cognition and Aging Study,
VCIND is the most common subtype of mild cognitive
impairment in China, accounting for 42.0 % of the total
cases . Fifty percent of patients with VCIND in the
Canadian Study of Health and Aging progressed to
dementia over 5 years of follow-up [
Although early intervention of VCIND holds the
potential to delay or even reverse cognitive impairment,
no treatment is available to prevent further decline in
patients with VCIND [
]. Because of the significant
heterogeneity of VCIND, clinical intervention trials need
to focus on a particular subtype to obtain an accurate
efficacy evaluation [
]. Owing to its relatively
homogeneous features, VCIND caused by subcortical ischemic
small vessel disease (subcortical VCIND) is a suitable
category for intervention trials.
Executive dysfunction is the characteristic impairment
in subcortical vascular cognitive impairment [
is mainly due to disruption of the frontal-subcortical
circuits, which are particularly vulnerable to ischemic lesions.
The occurrence of executive dysfunction also provides a
clue for cognitive training. Cognitive training refers to an
intervention that provides structured practice on tasks
relevant to different aspects of cognitive function, such as
memory and executive function. Training-related
cognitive improvements in healthy older people have been
found , with the effect being preserved 6 months after
Similar training-related cognitive improvements have
also been observed in patients with cognitive
] with a trend to apply multi-domain
programs . Those enhancements were preserved 6
] and 28 months [
] after training. Although
inconsistencies have been found in behavioral or clinical
symptom evaluation [
], recent studies using functional
or structural MRI have more consistently shown neural
plasticity in patients with amnestic mild cognitive
]. To date, no cognitive intervention
study on VCIND has been published. Whether and how
cognitive training improves cognitive function in
patients with VCIND remains largely unknown.
Brain structural and functional plasticity are the
underlying mechanism of cognitive training [
Structural plasticity included increased cortical thickness [
or improved white matter integrity [
plasticity included changes in brain function [
] or cerebral
blood flow [
]. This training-related neuroplasticity has
also been observed in patients with cognitive
]. Therefore, in addition to unveiling the
mechanism, neural plasticity change could also be used to
evaluate the efficacy of cognitive training.
This trial is the first study to test the efficacy of
cognitive training on VCIND using a double-blinded,
randomized controlled trial design. To evaluate the efficacy
of cognitive training, both traditional outcomes, such as
neuropsychological assessment, and neuroplasticity
outcomes, such as brain microstructure index, will be used.
Neuroplasticity outcomes might identify training-related
changes with more sensitivity. In addition, this study
seeks to investigate individual differences in training
outcome and its relationship with apolipoprotein E
genotyping and cerebrovascular risk factors.
This study will be implemented as a three-center
doubleblinded randomized trial. The study was registered under
clinicaltrials.gov (NCT02640716). This study will be
reported in accordance with both the CONSORT statement
and the CONSORT statement for non-pharmacological
The primary objective is to assess whether cognitive
training in patients with subcortical VCIND improves
their cognitive abilities. The second objective is to
evaluate the effect of cognitive training on neural
plasticity. Finally, possible genetic and plasma
biomarkers related to the effect of the training will be
Sixty patients with subcortical VCIND will be recruited
on fulfillment of the inclusion criteria. The patients will
be randomly allocated into the experimental group or
the control group. Patients will be recruited in neurology
clinics at Beijing Friendship Hospital, Xuan Wu
Hospital, and the geriatric clinic at Fu Xing Hospital, Capital
Literate Han Chinese, aged 50 years or older, with a
consistent caregiver who accompanies the subject at
least 4 days per week
Patient or informant report of cognitive impairment
involving memory or other cognitive domains
lasting for at least 3 months
Neither normal nor demented according to the
criteria of the Diagnostic and Statistical Manual
of Mental Disorders, Fourth Edition [
a Clinical Dementia Rating ≥0.5 on at least one
domain  and a global score ≤0.5; a Mini-Mental
State Examination score ≥20 (primary school),
or ≥24 (junior school or above) [
Normal or slightly impaired activities of daily
living as defined by a total score of ≤1.5 on the
three functional Clinical Dementia Rating domains
(home and hobbies, community affairs, and
personal care) 
MRI entry criteria:
o At least three supratentorial subcortical small
infarcts (3–20 mm in diameter), with or without
white matter lesions of any degree; or moderate
to severe white matter lesions (score ≥2
according to the Fazekas rating scale) [
or without small infarcts
o Absence of cortical and watershed infarcts,
hemorrhages, hydrocephalus, and white matter
lesions with specific causes (e.g., multiple
o No hippocampal or entorhinal cortex atrophy
(score 0 according to the medial temporal lobe
atrophy scale of Scheltens) [
Severe aphasia, physical disabilities, or any other
factor that might preclude completion of
Clinically significant gastrointestinal, renal, hepatic,
respiratory, infectious, endocrine, or cardiovascular
system disease; cancer; alcoholism; drug addiction
Disorders other than subcortical VCIND that
might affect cognition; a Hamilton Depression Scale
score >17 or schizophrenia; new strokes within 3
months before baseline; inherited or inflammatory
small vessel disease
Use of medications that may affect cognitive
functioning, including tranquilizers, anti-anxiolytics,
hypnotics, nootropics, and cholinomimetic agents;
and inability to undergo brain MRI
Participants will be randomly allocated to either the
intervention group or the control group in a ratio of 1:1.
After participants have given their informed consent,
randomization will be performed by an independent
statistician who is blinded to the patient interventions
using simple randomization of random number table
method in SAS software (SAS Institute, Inc., Cary, NC,
USA). Afterwards, the sealed randomization codes and
intervention number are sent out to each center.
Blinding will be broken only if a participant needs emergency
treatment. Once the blinding is broken, the participant
will be managed as off-trial.
Patients, caregivers, radiologists, statisticians, and
neuropsychologists who measure the outcomes will be blinded
to the randomization status. Blinding will also be
maintained for data management, outcome assessment, and
Previous studies showed that training approaches with
multi-domain, personalized, and adaptive training
features are more effective [
19, 37, 38
cognitive training will be a computerized multi-domain
adaptive training program in this trial. Training paradigms
that were successfully used in previous studies will be
], including processing speed, attention,
long-term memory, working memory, flexibility,
calculation, and problem solving. Specific training paradigms
include a time perception task, visual search task, rapid
serial presentation task, delayed match to sample task,
paired-associate recall task, attention span task, digit
span task, go–no go task, Stroop task, task switching,
and n-back working memory task. To enable adaptive
training, each task was designed with several difficulty
levels. Based on previous tests with a large size sample,
the tasks will be further grouped in each domain with
varied task difficulty. At the beginning, assignment tasks
from these domains will be similar across participants.
On each training day, five tasks (2 min per task, each
three times, in total 30 min per day) will be assigned.
Within each task, high accuracy (>80 %) is required to
upgrade. To manipulate the adaptive change, the
number of types of stimuli, the presentation probability of
each type of stimuli, and the size and duration of a
stimulus were systematically set. To keep a systematical
setting, only one parameter will be changed, while the
other parameters will be kept as constant in one level
upgraded. Once the task performance is higher than
80 % of the norm performance of a normal aging
population, the task will be replaced by a harder task
from the same domain. The training is thus also
adaptive at participant level, with a similar setup but
personalized progress across participants.
For the control group, processing speed and attention
tasks are included, with five tasks and 30 min training in
each day. Importantly, a fixed, primary difficulty level for
all participants in the control group is set. The training
will be completed at home and supervised by an
independent neurologist over the internet (www.66nao.com).
Primary outcome measures
The primary outcome measures are global cognitive
function measured by the Montreal Cognitive Assessment and
executive function measured by the Trail Making Test B-A.
Secondary outcome measures
The secondary outcome measure is neuroplasticity
changes, as measured by MRI. Specifically, the brain
functional response, including regional activation
magnitude and functional connectivity across regions
will be assessed. For fMRI, both before and after the
trial, a resting state scan, a scan with a cognitive
control task, and a scan with an episodic memory task
will be included. The brain response change during
the tasks and functional connectivity across regions in
the task and the resting state sessions will be
examined between groups. The structural change, including
gray matter volume, measured by voxel-based
morphometrics, and white matter microstructure,
measured by diffusion tensor imaging, will be assessed.
At screening, the following data will be collected:
demographic data (sex, age, education, and occupation);
medical history; concomitant medications; findings from a
complete physical examination and neurological
examination; neuropsychological assessment; blood analysis;
inclusion and exclusion criteria will be assessed;
functional and structural brain MRI will be carried out if the
patient meets the inclusion and exclusion criteria.
Blood samples will be collected and the following tests
will be carried out: complete blood count, liver enzymes,
kidney function, blood glucose, cholesterol,
homocysteine, and apolipoprotein E genotyping.
A follow-up assessment will be scheduled after 7
weeks of cognitive training. Data from the following
examinations will be collected: physical and neurological
examinations; neuropsychological assessment; functional
and structural brain MRI (Fig. 1).
The neuropsychological evaluation includes the
administration of several commonly used measures (tests,
interview, and questionnaires) of cognitive and daily
functions. Measures include the Mini-Mental State
Examination, the Montreal Cognitive Assessment, the
Clinical Dementia Rating scales, Digit Span, Trail
Making Test A and B, the WHO-UCLA Auditory Verbal
Learning Test, the Boston Naming Test, the Hachinski
Ischemic Scale, the Geriatric Depression Scale, the
Neuropsychiatric Inventory, and an activities of daily
living assessment. Furthermore, in the executive domain,
a task-switching paradigm that includes non-switch and
switch blocks will be administered inside the scanner. In
the memory domain, an episodic memory task that
includes a learning session and a test session will be
administered both outside and inside the scanner.
Patients will undergo brain MRI at baseline and 7 weeks
after training. The brain MRI will be performed using an
optimized protocol, with the same 3 T MRI scanner
(Magnetom Skyra, Siemens Healthcare, Erlangen,
Germany). Following a pilot scan, a three-dimensional
magnetization-prepared rapid gradient-echo scan will
be performed (repetition time = 1690 ms, echo time =
2.56 ms, flip angle = 12°, 1 mm isotropic voxels
covering the whole brain). T2*-weighted functional images
will be collected using a gradient-echo echo-planar
imaging sequence (33 interleaved slices, repetition
time = 2000 ms, echo time = 30 ms, flip angle = 83°,
field of view = 224 mm2, matrix = 64 × 64, 3.5 mm
isotropic voxels). Diffusion tensor imaging will use a
double spin-echo echo-planar imaging sequence
(repetition time = 8000 ms, echo time = 96 ms, flip
angle = 90°, field of view = 224 mm2, in-plane
resolution =1.75 × 1.75 mm voxels, 54 contiguous 2 mm
thick axial slices). Diffusion tensor images will be
acquired with 64 noncollinear encoding directions (b =
1000 s/mm2) and 11 images without diffusion
weighting (b = 0 s/mm2, b0). All scans will be reviewed
qualitatively by a radiologist to screen for possible brain
lesions or structural abnormalities. Diffusion tensor
imaging and functional MRI data collected during the
episodic memory task will be analyzed using the FSL
package (FMRIB Analysis Group, Oxford, UK). Brain
activation and connectivity changes before and after
training will be compared between experimental and
control groups. By using tract-based spatial statistics
implanted in FSL, fractional anisotropy and mean
diffusivity values in central white matter tracts will be
measured and compared before and after training.
Apolipoprotein E genotyping
High-molecular-weight DNA will be isolated from
peripheral blood leukocytes using a QIAamp DNA Blood
Kit (QIAGEN, Valencia, CA, USA). Genomic DNA will
be amplified by PCR using the primers ApoE-5′:
ApoE3′: 5′-CCCTCGCGGGCCCCGGCCTGGTACAC-3′ with
the following conditions: denaturation at 95 °C for 5
minutes, followed by 30 cycles at 95 °C for 30 s, annealing at
60 °C for 30 s, and extending at 72 °C for 30 s. The PCR
products will be digested with HhaI (R0139S, New
England BioLabs, Beverly, MA, USA). The fragments will be
separated by electrophoresis on a 20 % polyacrylamide gel
and visualized using GelGreen™ nucleic acid gel stain
(89139–144, Biotium, Hayward, CA, USA).
All participants from three centers will be evaluated by
the same trained neuropsychologists and undergo brain
MRI using the same MRI scanner. Imaging data are
checked for quality and protocol conformity after each
Sample size estimates
In preliminary tests, the observed mean difference in
change from baseline in the DST, WHO-UCLA Auditory
Verbal Learning Test, and Boston Naming Test scores
between training and control groups were 14.92, 3.35,
and 7.59, respectively, and the standard deviations were
18.41, 4.05, and 9.06, respectively. Based on these data,
sample sizes of 48, 46, and 46, respectively, were needed
to obtain a statistical power of 80 % with a significance
level of 5 %. We used the largest sample size of 48, and
the inclusion number has been set to 60 patients,
allowing for a maximum dropout rate of 20 %. Power
calculations are based on the primary outcome measures,
which are assessed by neuropsychological tests. The
statistical power measures will be calculated using the
POWER procedure in SAS® Version 9.3.
Performance changes in the assessment scores related to
global cognitive function (Montreal Cognitive Assessment)
and executive function (Trail Making Test B-A) are the
primary outcome measures of interest. An
independentsample t test will be used separately for the assessment
criterion and the rating scales of function, to ensure that
baseline levels are comparable between the training and
control groups. A paired-samples t test will be conducted
to compare the changes in scores in the trained tasks to
investigate the training efficacy. The performance change
of the trained tasks will be further correlated with the
neuropsychological change. To test whether the training
will improve neuropsychological performance in the
control group, correlation analysis will be conducted between
the performance of trained tasks and the
neuropsychological change. To determine the training transfer effect, a
series of 2 × 2 ANOVAs will be conducted with group and
time points as the two factors. For all analyses,
significance levels will be set to 0.05, and effect sizes refer to
partial η-square values. Statistical analysis will be
conducted using SPSS20.0 software. Imaging data will be
analyzed using FSL to detect any changes in brain function
and structure due to cognitive training.
To our knowledge, this trial is the first to evaluate the
cognitive training efficacy in VCIND patients. This study has
several strengths. First, the multi-domain cognitive training
applied in this study is highly adaptive and internet-based.
Such training is believed to be effective in enhancing
cognitive function. Conducting training on the internet is
convenient, allowing patients to train at home and doctors to easily
manage the training protocol and monitor training progress.
Second, functional and structural plasticity are used as
the evaluation outcome measures. Compared with the
traditional efficacy evaluations, which use
neuropsychological tests, the combination of neuroplasticity and
neuropsychological tests in this study will be more
sensitive in testing cognitive training efficacy, because smaller
training effects could be detected by MRI indices, such as
brain activity and connectivity [
]. In this trial, by
including the functional and structural MRI measurements, a
further purpose is to reveal the underlying mechanism at
work. For instance, fMRI measurement would provide
evidence to distinguish whether neural efficiency was
improved or the brain function was reorganized to achieve
cognitive enhancement. The structural MRI measurement
would provide evidence on the structural constraint on
functional change due to cognitive training.
Another strength of this trial is the comprehensive
assessment of the participants on multiple levels,
including neuropsychological tests, neuroplasticity analysis,
cerebrovascular risk factors, and apolipoprotein E
genotyping. This comprehensive assessment will be able to
identify possible biomarkers involved in the effects of
cognitive training in VCIND.
This trial is currently recruiting participants.
Cog-VACCINE, Cognitive training in patients with VAsCular Cognitive
Impairment, No dEmentia; CONSORT, Consolidated Standards of Reporting
Trials; MRI, magnetic resonance imaging; PCR, polymerase chain reaction;
VCIND, vascular cognitive impairment, no dementia
This trial is supported by Beijing Municipal Science & Technology Commission
(Z151100004015078), Beijing Talents Fund (2014000021223ZK31), and the
National Natural Science Foundation of China (31571156).
Availability of data and materials
YT and ZDZ conceived and designed the trial, collected and analyzed data,
wrote the manuscript, and approved the final version of the manuscript. QL,
FL, JWY, YX, and FYL collected and analyzed data and approved the final
version of the manuscript. JPJ conceived and designed the study, collected
and analyzed data, wrote and critically revised the manuscript, and approved
the final version of the manuscript:. All authors read and approved the final
ZZ is a consultant in Wispirits Inc. (66nao.com).
Consent for publication
Ethics approval and consent to participate
The study was approved by the Ethics Committee of Xuan Wu Hospital,
Capital Medical University, on March 13, 2015 (Ref: 2015010) and the
methods were carried out in accordance with the Declaration of Helsinki.
Informed written consent was obtained from each participant.
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