Devenney et al.

BMC Geriatrics (2017) 17:75

DOI 10.1186/s12877-017-0457-9

STUDY PROTOCOL Open Access

The effects of an extensive exercise

programme on the progression of Mild
Cognitive Impairment (MCI): study protocol
for a randomised controlled trial
Kate E. Devenney1*, Brian Lawlor2, Marcel G. M. Olde Rikkert3, and Stefan Schneider4,5, on behalf of the
NeuroExercise Study Group

Abstract
Background: Exercise interventions to prevent dementia and delay cognitive decline have gained considerable
attention in recent years. Human and animal studies have demonstrated that regular physical activity targets brain
function by increasing cognitive reserve. There is also evidence of structural changes caused by exercise in preventing
or delaying the genesis of neurodegeneration. Although initial studies indicate enhanced cognitive performance in
patients with mild cognitive impairment (MCI) following an exercise intervention, little is known about the effect of an
extensive, controlled and regular exercise regimen on the neuropathology of patients with MCI. This study aims to
determine the effects of an extensive exercise programme on the progression of MCI.
Methods/design: This randomised controlled clinical intervention study will take place across three European sites.
Seventy-five previously sedentary patients with a clinical diagnosis of MCI will be recruited at each site. Participants
will be randomised to one of three groups. One group will receive a standardised 1-year extensive aerobic exercise
intervention (3 units of 45 min/week). The second group will complete stretching and toning (non-aerobic) exercise
(3 units of 45 min/week) and the third group will act as the control group. Change in all outcomes will be measured
at baseline (T0), after six months (T1) and after 12 months (T2). The primary outcome, cognitive performance, will be
determined by a neuropsychological test battery (CogState battery, Trail Making Test and Verbal fluency). Secondary
outcomes include Montreal Cognitive Assessment (MoCA), cardiovascular fitness, physical activity, structural changes
of the brain, quality of life measures and measures of frailty. Furthermore, outcome variables will be related to genetic
variations on genes related to neurogenesis and epigenetic changes in these genes caused by the exercise
intervention programme.
Discussion: The results will add new insights into the prevailing notion that exercise may slow the rate of
cognitive decline in MCI.
Trial registration: ClinicalTrials.gov NCT02913053
Keywords: Mild cognitive impairment, Exercise intervention, Physical activity, Cognitive function, Brain
structure, Frailty, Epigenetics

* Correspondence: [email protected]
1
Discipline of Physiotherapy, Trinity College Dublin, Dublin, Ireland
Full list of author information is available at the end of the article

The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Devenney et al. BMC Geriatrics (2017) 17:75 Page 2 of 10

Background There is converging evidence from animal and human

With an advancing aging population and associated rise studies that regular aerobic exercise acts as a promoter
in dementia prevalence in developed countries, the asso- of brain health mediating neural homeostasis and, via
ciated costs and disease burden have exerted significant neuroprotective and neurorestorative mechanisms,
pressure on economic and social systems [1]. To help thereby counteracting brain ageing. At the behavioural
ensure an aging society live enjoyable and productive level, exercise has been found to upregulate affective
lives, research into treating or preventing conditions states [15, 16] and to improve cognition throughout dif-
such as Alzheimers disease (AD) and other forms of ferent age phases [1719] and different dimensions, in-
age-related neurodegenerative diseases is an urgent pub- cluding spatial/associative learning [20, 21], attentional
lic health priority. Today, longevity-related prevalence of processing [22], and executive control [23]. While ani-
neurodegenerative diseases and especially dementia, mal research has allowed the unravelling of the under-
along with the current absence of a cure are among the lying neurobiological mechanisms of exercise at the
top prominent societal health-related challenges ac- behavioural (e.g. water maze-type tests), cellular (e.g.
knowledged by the first G8 Summit on dementia held in neurogenesis, synaptogenesis, neuroangiogenesis), and
London on December 11th, 2013 [2]. humoral (e.g. neurotrophic factors, inflammatory cyto-
Published diagnostic criteria for AD in Lancet Neur- kines) levels [24, 25], so far the neurobiological and epi-
ology diagnose Mild Cognitive Impairment (MCI) as the genetic effects of exercise remains poorly understood in
preclinical or prodromal stage of AD [3]. In MCI, several humans. While preliminary results indicate that aerobic
of the clinical and neuropsychologic pathologic features exercise inhibits the progression of AD-like neuropathol-
are present prior to the onset of overt AD [4]. Patients ogy in an animal model [26, 27], currently there is little
with MCI in the earliest stage of neurodegeneration information about the effects of regular physical exercise
can be clinically diagnosed, and represent a patient on the progression of both functional and structural
cohort consistently able to participate in a structured markers at the pre-dementia and early dementia stages
exercise programme. Consequently, there has been an in humans.
increased research focus on both pharmacological and The aim of this study is to compare a 12-month struc-
non-pharmacological strategies to optimise cognitive tured exercise programme (aerobic and stretching and
function and enhance brain health in older age [5], par- toning group) to a control group for progression of cog-
ticularly for individuals at risk of developing AD [6]. nitive decline in MCI. The stretching and toning group
Previous cross-sectional studies have established that will act as a non-aerobic exercise group, controlling for
moderate activity during midlife is associated with a the social effect of a structured group exercise programme.
lower risk of having MCI in later life, with late-life par- This type of low-intensity exercise intervention has previ-
ticipation in moderate exercise also associated with ously shown some positive effects on cognitive outcomes,
lower risk for MCI [7]. A meta-analysis of randomised as it provides participants with equivalent opportunity for
controlled trials (RCTs) by Heyn et al. [8] reported bene- social interaction [28]. Previous exercise intervention stud-
ficial effects of physical activity on physical fitness and ies in MCI that have utilised non-aerobic exercise (e.g.
cognitive function in adults with cognitive impairment. stretching and toning) as a control intervention have noted
In recent years, a broad range of exercise intervention some improvement in cognitive performance [8, 29] while
studies have demonstrated cognitive benefits can be others have not demonstrated significant change in cogni-
achieved with varying exercise modalities in populations tive performance [9, 10]. The comparison between aerobic
with MCI [911]. Aerobic exercise has demonstrated exercise, non-aerobic exercise and a control group coupled
significant improvements in global cognitive scores with with the 12-month intervention period, concomitant brain
a weak but significant effect on memory [12]. A meta- scanning, genetic and epigenetic analyses is innovative and
analysis by Gates et al. [13] examining the effects of will be a strong addition to the growing body of literature
chronic exercise training on cognitive function in around exercise in MCI.
older adults with MCI found research quality was
modest, with many studies under-powered and only Methods/design
8% of cognitive outcomes demonstrating statistically Study aims
significant change. A limitation across a number of The primary aim of this study is to investigate the effects
these studies is the small sample size and variation in a 12-month structured exercise programme (aerobic,
MCI diagnostic criteria applied. The differing exercise and stretching and toning group) compared to a control
approaches used across exercise intervention studies, group for the progression of cognitive decline in MCI.
coupled with the wide variation in cognitive tasks uti- The primary hypothesis of this study is that participation
lised make it difficult to summarise and synthesise in an extensive exercise programme will demonstrate a
research findings [14]. slower rate of cognitive decline compared to the control
Devenney et al. BMC Geriatrics (2017) 17:75 Page 3 of 10

group. A secondary hypothesis is that participants in the will include changes in MoCA scores, cardiovascular fit-
aerobic exercise group will demonstrate a stronger posi- ness, physical activity, quality of life measures, measures of
tive effect of cognitive functioning than the stretching frailty, epigenetic and structural changes. Change in all
and toning (non-aerobic) group. outcomes will be measured at baseline (T0), after six
The secondary aims of this study are: months (T1) and after 12 months (T2) (see Fig. 1).

1. To examine the effects of a structured exercise Recruitment and screening

programme on MoCA scores, a screening tool of In total, 225 previously sedentary adults aged 50 years or
global cognition in MCI older who are diagnosed with MCI will be recruited via
2. To determine the effects of a structured exercise hospital memory clinics affiliated with the three sites
programme on cardiovascular fitness and from the community. Advertising will take place
3. To measure the effects of a structured exercise through community centres and newspaper articles. Ini-
programme on physical activity levels tial screening will be completed over the telephone to
4. To investigate a mechanism of action through determine eligibility. Participants who meet the following
epigenetic analysis and exploration of structural and diagnostic, inclusion and exclusion criteria and success-
functional changes on Magnetic Resonance Imaging fully complete baseline measures including a screening
(MRI) brain pre and post 12-month intervention exercise test will be enrolled.
5. To investigate the effects of a structured exercise
programme on quality of life measures and measures Diagnostic criteria
of frailty Participants will have a diagnosis of MCI due to AD
according to the Albert et al. [3] criteria. All enrolled
Study design participants with MCI will be classified as having mem-
This proof of concept will take the form of a randomised ory decline but not dementia (Clinical Dementia Rating
controlled trial to be completed across three centres in global score = 0.5), consistent with established MCI
Europe; the German Sport University Cologne, Germany, classification [3, 30].
University of Nijmegen, The Netherlands and Trinity
College Dublin, Ireland. A total of 225 participants will be Inclusion criteria
randomised (n = 75 at each site) to either a yearlong super- Participants who meet the following criteria will be eligible
vised and home based aerobic exercise programme (n = 75), to participate: (1) MoCA [31] 1826; (2) stable medical
an equivalent non-aerobic stretching/toning programme condition for more than 6 months; (3) stable medication
(n = 75) or to the control group (n = 75). The primary out- for more than 3 months; (4) adequate visual and auditory
come will be change in cognitive performance as measured acuity to complete neuropsychological testing; (5) electro-
by a neuropsychological test battery. Secondary outcomes cardiogram without significant abnormalities that might

Fig. 1 Participant flow through study

Devenney et al. BMC Geriatrics (2017) 17:75 Page 4 of 10

interfere with the study; (6) physical ability sufficient to Withdrawal of participants
allow performance of endurance exercise training; (7) cap- The investigator can decide to withdraw a subject from
acity to provide written and dated informed consent form; the study for urgent medical reasons. Subjects can leave
(8) medical clearance to undergo a symptom-limited car- the study at any time for any reason if they wish to do
diopulmonary exercise test and extensive aerobic exercise so without any consequences. All primary analyses will
training. be performed on an intention-to-treat basis with all ran-
Participants recruited from the community via news- domised participants included in the primary analyses.
paper articles and community advertisement will Participants who withdraw from the study will be invited
complete additional testing to determine MCI status. To to attend T1 and T2 assessments.
distinguish between amnestic and non-amnestic MCI,
agreed education adjusted cut-offs of -2 Standard Devi- Randomisation, allocation, concealment and blinding
ation (SD) for low education (<10 years of education), Following baseline assessment, participants will be ran-
-1.5 SD for the middle group (1013 years of education) domised to one of three arms using a centrally con-
and -1 SD for the highly educated (>13 years of educa- trolled computer generated randomisation list (for each
tion) will be taken from the delayed recall portion of an country) generated by an independent statistician. Par-
age adjusted episodic memory test. In Nijmegen and ticipants will be randomised to one of three arms as per
Dublin this will be evaluated using the Logical Memory Fig. 1. At each centre, the investigators will be blinded
(story recall) subtest of the Wechsler Memory Scale to allocation order and the treatment will be assigned
(WMS-IV) [32, 33]. In Cologne, education scores will be using sealed envelopes based on order of recruitment.
examined using the Repeatable Battery for the Assess- Outcome assessors and exercise trainers will not be
ment of Neuropsychological Status (RBANS) [34] Delayed blinded to the allocated treatment arm.
Memory Index (Score of < 85).
Interventions
Exclusion criteria Exercise intervention
Participants will be deemed ineligible if they meet any of The aim of both the aerobic intervention and stretching
the following criteria: (1) diagnosis of AD or other type and toning exercise intervention groups will be to accrue
of dementia; (2) history of familial early-onset dementia; 3 x 45 min exercise sessions per week over 12 months.
(3) enrollment in any investigational drug study; (4) his- Participants will complete a combination of supervised
tory in the past 2 years of epileptic seizures (participants instructor led classes and unsupervised home exercise
with epilepsy who have been stable off medication or sessions. Class attendance and adherence to unsuper-
seizure free for 2 years may be included); (5) any major vised home exercise sessions will be recorded for each
psychiatric disorder (a clinical diagnosis of major depres- participant by the class instructor each week over the
sive disorder, bipolar or schizophrenia); (6) past history 12 month intervention period.
or MRI evidence of brain damage, including significant The goal of the aerobic exercise class will be to accu-
trauma, stroke, hydrocephalus, mental retardation, or mulate at least 45 min of extensive aerobic exercise, pre-
serious neurological disorder; (7) carotid stent or severe scribed by heart rate (HR) calculated as 180 bpm age.
stenosis; (8) history of myocardial infarction within pre- Exercise intensity will be monitored during the super-
vious year; (9) congestive heart failure (New York Heart vised classes using a HR monitor and subjective report-
Association Class II, III or IV) (10) uncontrolled hyperten- ing of the exercise intensity using the Borgs Rating of
sion or hypotension (systolic blood pressure >200 mm Hg Perceived Exertion (RPE) [36]. Participants in the aer-
and/or diastolic blood pressure >110 mm Hg at rest) [35]; obic exercise group will aim to achieve a target RPE of
(11) unstable cardiac, renal, lung, liver, or other severe 13 while exercising. Each supervised class will be com-
chronic disease; (12) type 2 diabetes mellitus with prised of a 510 min warm up, 45 min of targeted aer-
hypoglycemia in the last 3 months; (13) significant history obic exercise and a 510 min cool down. A range of
of alcoholism or drug abuse within last 10 years; (14) en- aerobic exercise modalities will be offered including cyc-
gagement in moderate-intensity aerobic exercise training ling, treadmill walking, elliptical training, endurance re-
for more than 30 min, 3 times per week, during past 2 years; lated indoor activities, outdoor walking, jogging and
(15) history of vitamin B12 deficiency or hypothyroidism aqua jogging.
(stable treatment for at least 3 months is allowed); (16) The aim of the stretching and toning group will be to
serious or non-healing wound, ulcer, or bone fracture complete non-aerobic activities. Each supervised class
In Cologne and Nijmegen, participants will be invited to will be comprised of a 510 min warm up, 45 min of
complete brain MRI scans. Participants with pacemakers stretching, balance, coordination, relaxation, group
or other medical metal devices will not be eligible for MRI games and light resistance exercises and a 510 min
scanning as per standard procedures. cool down. During the stretching and toning class,
Devenney et al. BMC Geriatrics (2017) 17:75 Page 5 of 10

exercise intensity will not exceed an RPE of 10. Partici- Task measures visual attention. Participants must decide
pants in the stretching and toning group will not be ad- whether a playing card presented on screen is red, by
vised about aerobic activity and will not be instructed to pressing the Yes or No button. Reaction time is mea-
avoid completing routine aerobic activity. The stretch- sured and lower scores indicate better performance. The
ing and toning group will act as a social control group One Back Task assesses working memory. Participants
and it is not anticipated to see significant improve- are presented with a sequence of playing cards in the
ment in study outcomes. centre of a screen and must decide if the card presented
The control group will receive usual care and will not is the same as the one shown immediately before. The
be advised about exercise or attend supervised sessions. One Card Learning Task measures visual learning and
Participants in the control group will complete outcome memory. Participants are presented with a succession of
assessments. playing card on screen, and must decide if the card cur-
rently displayed has been displayed previously. Accuracy
Outcome assessment of performance is measured, with higher scores indicat-
All outcomes will be measured at T0 (Baseline), T1 ing better performance. A number of studies have found
(6 months) and T2 (12 months) time points. Brain MRI, that the CogState battery of tests are sensitive to detect-
blood sampling for epigenetic analysis and the NEO-Five ing cognitive impairment in mild to moderate AD and
Factor Inventory (NEO-FFI) will only be measured at T0 amnestic MCI populations relative to healthy matched
and T2. All participants will undergo described tests, controls [44]. CogState and has been validated across a
except for MRI (only in Cologne and Nijmegen). broad range of cognitively impaired populations [38].
Verbal fluency will be assessed with Letter Fluency
Primary outcome [39] and Category Fluency [40]. For the Letter Fluency
Cognitive function test participants are allowed one minute to generate as
The primary outcome is cognitive performance. Cogni- many words as possible that begin with a specific letter.
tive performance will be assessed by a neuropsycho- This task will be repeated three times with three differ-
logical test battery measuring six cognitive domains. The ent letters (e.g. F, A, S). For the category fluency test,
test battery will consist of a computer based CogState participants must give as many examples of animals as
Battery including the International Shopping List Task possible within one minute.
(ISLT) immediate and delayed recall, Detection Task, TMT will be completed as a paper and pen based task.
Identification Task, One Back Task and One Card Learn- The TMT consists of two sub trials. TMT-A require individ-
ing Task (https://cogstate.com/) [37, 38], Verbal fluency uals to sequentially connect 25 encircled numbers on a sheet
[39, 40] and Trail Making Test (TMT) [41]. of paper, while TMT-B require participants to draw a line, al-
The allocation of to the tests to the six cognitive domains ternating between numbers and letters in ascending order.
is based on the CogState Guidelines and conventional clas-
sification of neuropsychological tests [42]. Verbal memory Secondary outcomes
will be assessed by ISLT. Psychomotor function will be mea- Secondary outcomes will include global cognitive func-
sured with the Detection Task. Executive function will in- tion, cardiovascular fitness, physical activity, quality of life,
clude TMT-B, Letter Fluency and Category Fluency. depression, measures of frailty and epigenetic changes.
Attention will be assessed by the Identification Task and MoCA screening tool will be used as a broad measure
TMT-A. Working memory will be measured by One Back of global cognitive function. The MoCA is a one-page
Task, and Visual memory by the One Card Learning Task. 30-point test administered in 10 min which consists of
A description of the tasks is described below. 13 tasks covering the following eight cognitive domains:
The CogState battery will take approximately 30 min visuospatial/executive functions, naming, verbal memory
to complete. The ISLT is a 12 word, four trial (three registration and learning, attention, abstraction, delayed
learning trials and one delayed recall trial). Total num- verbal memory, and orientation. It has demonstrated
ber of correct responses made in remembering the list high sensitivity and specificity as a cognitive screening
on three consecutive trials at a single session and after a instrument and has been validated to detect MCI [31].
delay will be recorded. The ISLT has been shown to have Cardiovascular fitness will be assessed using an incre-
good sensitivity to verbal memory impairment [43]. The mental exercise test on a standard cycle ergometer. Par-
Detection Task measures psychomotor functioning and ticipants at the German Sports University and Trinity
speed of processing. Participants must respond as College Dublin will complete a maximal test in accord-
quickly as possible when the card shown face down in ance with the World Health Organisation Protocol [45].
the centre of the screen flips over by pressing a button The test will commence with 3 min cycling unloaded,
on the keyboard. Reaction time is measured with lower followed by the incremental phase of exercise during
scores indicating better performance. The Identification which the load will increase by 25 W every two minutes
Devenney et al. BMC Geriatrics (2017) 17:75 Page 6 of 10

until the test is terminated. Blood lactate levels and par- Venous blood samples will be collected for genetic and
ticipants reported BORG RPE scores will be measured at epigenetics analysis performed on a Sequenom Massarray
each stage of the test (2 min intervals). At the University Analyzer 4 at the Department of Psychology University of
of Nijmegen, aerobic fitness will be estimated from a Bonn, Germany. Genotyping of the Apolipoprotein E
submaximal exercise test completed according to the (APOE) and the Brain Derived Neurotrophic Factor
Astrand-Rhyming submaximal protocol [46]. During the (BDNF) genes and their epigenetic methylation patterns
first two minutes, resistance of the ergometer will be will be the primary focus. The genetic analyses will serve
increased until a steady state HR of 70% of the esti- as predisposed risk and resilience factors for cognitive
mated maximal HR is reached. Participants continue functioning and decline in MCI participants. The epi-
pedalling for 6 min. HR and RPE will be recorded genetic findings will shed new light on the link between
every minute. VO2max will be estimated using the aver- exercise and gene activation of relevant genes in the
age HR of minute 5 and 6 and the work load in the biochemical pathways underlying cognitive decline.
Astrand Nomogram. Given the moderating effect of the common genetic
Physical activity will be assessed objectively using an variation of APOE via personality on AD onset [58], the
activity accelerometer to be worn for seven consecutive NEO-Five Factor Inventory (NEO-FFI) will be included
days by study participants as each assessment time point to assess personality traits such as neuroticism or extra-
and subjectively with the LASA Physical Activity Ques- version, predicting an earlier onset of Alzheimer and
tionnaire (LAPAQ). The LAPAQ questionnaire is a valid cognitive decline in elderly humans [59]. NEO-FFI is a
and reliable self-reported questionnaire that captures psychological personality inventory consisting of 60
physical activity over the preceding 14 days [47]. items to measure five personality traits. The question-
Health related quality of life will be evaluated using naire will be completed following each blood draw to
the Health Related Quality of Life for People with form part of the epigenetics analysis. The NEO-FFI is
Dementia (DemQOL). DemQOL is a 28 item interview also discussed as a measure of emotional intelligence
administered questionnaire relating to different aspect of [60].
QOL. The DemQOL has been validated in a large sam- Structure and function of related brain regions will
ple of people with dementia and demonstrates good ac- be measured using functional MRI (fMRI) brain which
ceptability and internal consistency [48]. It has also been is a non-invasive method for examining brain activity
used in older adults and in patients with MCI [49]. In and structure. Structural imaging will include isotropic
addition, the Center for Epidemiologic Studies Depression T1-weighted-, T2-weighted- and FLAIR- sequences
(CES-D) questionnaire will be administered to determine with an isotropic spatial resolution of 1x1x1mm. The
depressive symptoms. The CES-D Scale is a short self- combination of the different image weightings allows
report questionnaire that measures symptomatic depression for an automatic detection/volumetry of white matter
[50] that has been validated as a depression screening tool lesions. Additionally, the combination of these se-
in older adults [51]. Depressive symptoms are associated quences improves image segmentation. The structural
with increased risk of MCI [52]. The association of de- protocol will be rounded up by a 3D-DTI sequence (60
pression with prevalent MCI and with progression from diffusion directions, 1.7x1.7x1.7 mm) and a resting
MCI to dementia, but not with incident MCI, suggests state fMRI Table 1.
that while depression is prevalent in MCI, it does not
precede it [53]. Safety
Measures of frailty will include The Timed Up and Go All serious adverse events (SAE)/adverse events (AE) will
(TUG) test, hand grip strength and 30 s chair stand. The be recorded on study specific adverse event forms. All
TUG will assess the participants mobility and balance. AEs will be registered with the local principle investiga-
The TUG is a reliable and valid test for quantifying func- tor (PI). These will be discussed at regular team meet-
tional mobility and is useful in following clinical change ings and collected and registered at the end of the study.
in frailty over time [54]. Hand grip strength will be mea- All SAEs will be registered centrally. In the case of an
sured using a Jamer Digital Dynamometer as a measure SAE, all site PIs will be informed both at time of occur-
of upper limb strength. A standardised approach will be rence (with 24 h) and for a final conclusion on causality.
taken to obtaining the measurement [55]. HandGrip
strength has been shown to predict future outcomes in Sample size
aging adults including mortality and future levels of dis- The sample size estimation was performed in G*Power, a
ability [56]. The 30 s chair stand will determine lower statistical software program. The effect size was estimated,
limb strength and endurance. Lower body strength is based on the effect size found in several studies examining
considered critical in evaluating the functional perform- the effect of exercise on cognition in elderly with MCI or
ance of older adults [57]. increased risk for AD [810, 61, 62]. Sample size was
Devenney et al. BMC Geriatrics (2017) 17:75 Page 7 of 10

Table 1 SPIRIT diagram outlining schedule of enrolment, interventions, and assessments for study participants
Timepoints Pre-screening Baseline assessment T0 Study assessment T1 Study assessment T2
telephone call
<13 days following 6 months after study 12 months after study
screening visit 1 visit 1
Enrolment Explain study X
Screen eligibility criteria X
Study Outcomes Neuropsychological testing X X X
MoCA X X X
DemQOL X X X
CES-D X X X
Incremental Exercise Test X X X
Physical Activity Tracker X X X
LAPAQ X X X
Blood sampling X X
NEO-FFI X X
MRI Braina X X
TUG X X X
Hand Grip Strength X X X
30 second chair stand X X X
Randomisation (after completion X
of all baseline assessments)
Exercise interventionb X X X
a
MRI brain will be performed in Cologne and Nijmegen sites
b
After completion of T0 assessment, participants will be randomised to one of the three groups (aerobic exercise, stretching and toning exercise, control group).
Exercise intervention will be continuous for a 12-month duration following completion of T0 assessments

calculated based on a two-tail statistical t-test set 1- = control group of n = 75 as input of an ANCOVA with
0.80, = 0.05, an effect size of 0.4, an allocation ratio N2/ dependent variable the change in cognitive composite
N1 of 2. A total sample size of 224 was calculated. Consid- score between T2 and T0, and as covariates baseline
ering a correlation of 0.5 between the outcome measures cognitive functioning, sex, age. In a secondary analysis
at T0 and T2, the design design-factor D = 1-0.52 = 0.75. the comparison between the two exercise forms will be
The expected dropout rate is 25%. 224*0.75*1.25 = 210. carried out in a similar ANCOVA analysis.
Considering the fact that the primary analysis will be a Analyses for all secondary outcome parameters will be
combination of the results of three different centres, the carried out with similar ANCOVA analyses. Secondary
final sample size n = 210 is rounded up to n = 225. analyses will also elucidate the contrasts between T0 and
T1 and T2 for the primary and secondary outcomes, and
Statistical analysis thus elucidate the course over time, without correction for
The primary analysis of this study will be comparison of multiple comparisons, as these analyses are exploratory.
cognitive functioning (primary outcome measure) be- Furthermore, to assess change in physical fitness, qual-
tween all three intervention arms before (T0) and after ity of life, cerebral structure and epigenetics a similar
(T2) the 1 year intervention. A composite score will be statistical approach will be used as for the primary study
calculated by averaging all six domain scores into one parameter. A p-value of < 0.05 will be used to assess stat-
overall cognition score. The obtained scores per test will istical significance.
be converted into z-scores based on the standard devi-
ation and mean of the total sample at baseline. In case Data management
of multiple tests within one domain, the average z-score All data will be managed using unique study codes to
for the domain will be calculated. Secondary outcome protect participant confidentiality, which will be used to
measures are the six separate cognitive domain scores code and file all electronic information. The key linking
and the other parameters. this code to participant identity will be stored in a secured
For the primary analysis we will have an intervention file, access to this key is available only to designated
group of n = 150 (both exercise forms together) and a members of the research team at each site. Raw data
Devenney et al. BMC Geriatrics (2017) 17:75 Page 8 of 10

will be stored in a file cabinet with a lock where only desig- University Medical Center, Donders Institute for Brain, Cognition and
nated research team members will have access to the key. Behaviour, Nijmegen, The Netherlands; Prof. Romain Meeusen, Human
Physiology Research Group, Vrije Universiteit Brussels, Belgium; Prof. Christian
Montag, Institute of Psychology and Education, Ulm University, Germany and
Discussion Key Laboratory for NeuroInformation/Center for Information in Medicine, and
School of Life Science and Technology, University of Electronic Science and
To the best of our knowledge, there have been no inter- Technology of China, Chengdu, China; Dr Ross T. Murphy, St. Jamess
vention trials evaluating the effect of an extensive, con- Hospital, Dublin, Ireland; Prof. M. Cristina Polidori, Ageing Clinical Research,
trolled and structured 12-month exercise programme on University Hospital of Cologne, Germany; Prof. Martin Reuter, University of
Bonn, Department of Psychology and Center for Economics & Neuroscience,
the progression of cognitive decline in an MCI popula- Laboratory of Neurogenetics, Bonn, Germany; Marit L. Sanders, Department
tion. Since the neuropathological change process can of Geriatric Medicine, Radboud University Medical Center, Donders Institute
take years after onset of MCI, the addition of longer for Brain, Cognition and Behaviour, Nijmegen, The Netherlands; Prof. Heiko K.
Strder, Institute of Movement and Neurosciences, German Sport University
intervention period may result in larger intervention effects. Cologne, Germany; Tim Stuckenschneider, Institute of Movement and
An important consideration of this study is the isolated aer- Neurosciences, German Sport University Cologne, Germany; Prof H.J. Thijssen,
obic exercise intervention. A number of exercise interven- Department of Physiology, Radboud University Medical Center, Nijmegen,
The Netherlands; Prof. Tobias Vogt, Institute for Professional Sport Education
tion studies have implemented multimodal exercise and Sport Qualifications, German Sport University Cologne, Germany; Prof.
interventions [11, 63], making it difficult to interpret the ef- Cathal Walsh, University of Limerick, Ireland; Prof. Bernd Weber, Department
fect of isolated exercise modalities. The large sample size, of Epileptology, University Hospital Bonn, Germany.
We would like to acknowledge the following network of hospital sites and
longer duration of exercise intervention, comprehensive investigators who have assisted in recruiting participants to this study at the
neuropsychological test battery will enhance the existing re- Dublin site; Dr Jennifer Hoblyn, Bloomfield Healthcare; Dr Andrew Eustace,
search around exercise and cognitive function in MCI. Highfield Healthcare; Dr Cora McGreevy, Mater Misericordiae University
Hospital; Dr Aisling Denihan, Old Age Psychiatry Navan; Dr Justin Kinsella, St.
The secondary outcomes will examine several potential Vincents University Hospital; Dr Declan Lyons, St. Patricks University Hospital
underlying mechanisms that may influence the exercise- and Dr Sean Kennelly, Tallaght Hospital.
cognitive relationship in MCI. The effect of exercise on
Funding
brain structure and function measured by MRI brain will The project has been supported by The EU Joint Programme
be examined. Methylation analyses of the APOE gene and Neurodegenerative Disease Research (JPND). JPND did not contribute to
neurotrophic genes will explore the effects of exercise on the study design or in writing the manuscript. German grant number BMBF
01ED1510A. Health Research Board Ireland grant number JPND-2014-1. Dutch
this known AD risk factor. Static gene polymorphisms will grant number: ZonMw 733051044.
be used to predict intervention outcomes. Finally, cardio-
vascular fitness will be measured and examined as a Availability of data and materials
moderator of the exercise-cognitive relationship in MCI. Data sharing not applicable to this article as no datasets were generated or
analysed during the current study.
While cognitive performance is the primary outcome, we
will also assess whether participation in a structured exer- Authors contributions
cise programme or changes in cognition can influence SS, BL and MOR developed the idea for the study. KD, EG and MS drafted
the protocol with input from all authors on study design and revisions to
quality of life and measures of frailty, known risk factors the protocol paper. All authors have approved the final version of this paper
for cognitive further decline [64]. prior to submission.

Abbreviations Competing interests

AD: Alzheimers disease; AE: Adverse event; ANCOVA: Analysis of covariance; The authors declare that they have no competing interests.
APOE: Apolipoprotein E; BDNF: Brain derived neurotrophic factor; CES-
D: Center for epidemiologic studies depression; DemQOL: Health related Consent for publication
quality of life for people with dementia; fMRI: functional magnetic resonance Not applicable.
imaging; HR: Heart rate; ISLT: International shopping list task; LAPAQ: LASA
physical activity questionnaire; MCI: Mild cognitive impairment; MRI: Magnetic Ethics approval and consent to participate
resonance imaging; NEO-FFI: NEO-five factor inventory; RBANS: Repeatable The study protocol is approved by the Tallaght Hospital/St. James's Hospital
battery for the assessment of neuropsychological status; RCT: Randomised Joint Research Ethics Committee Dublin Ireland (reference 2015/09/04; 14/
controlled trial; RPE: Rate of perceived exertion; SAE: Serious adverse event; 12/2015), the German Sport University, Cologne Germany (reference 9/2015;
SD: Standard deviation; TMT: Trail making test; TUG: Timed up and go; 21/01/15) by Commissie Mensgebonden Onderzoek Arnhem-Nijmegen,
WMS: Wechsler memory scale Netherlands (reference 2015-1872).

Acknowledgments Publishers Note

Members of the NeuroExercise Study Group (in alphabetical order by name). Springer Nature remains neutral with regard to jurisdictional claims in
Dr. Justine A. Aaronson, Department of Medical Psychology, Radboud published maps and institutional affiliations.
University Medical Center, Nijmegen, The Netherlands; Dr. Vera Abeln,
Institute of Movement and Neurosciences, German Sport University Cologne, Author details
1
Germany; Dr. Jurgen A.H.R Claassen, Department of Geriatric Medicine, Discipline of Physiotherapy, Trinity College Dublin, Dublin, Ireland. 2Trinity
Radboud University Medical Center, Donders Institute for Brain, Cognition College Institute of Neuroscience, Dublin, Ireland. 3Department of Geriatric
and Behaviour, Nijmegen, The Netherlands; Dr. Robert F. Coen, Mercers Medicine, Radboud Alzheimer Centre, Radboud University Medical Center,
Institute for Research on Ageing, St. Jamess Hospital, Dublin, Ireland; Dr. Nijmegen, The Netherlands. 4Institute of Movement and Neurosciences,
Emer M. Guinan, School of Medicine, Trinity College Dublin, Ireland; Dr. German Sport University Cologne, Cologne, Germany. 5Faculty for Science,
Damien Ferguson, Department of Neurology, St. Jamess Hospital, Dublin, Health, Education and Engineering, University of the Sunshine Coast,
Ireland; Prof. Roy P.C. Kessels, Department of Medical Psychology, Radboud Maroochydore, Australia.
Devenney et al. BMC Geriatrics (2017) 17:75 Page 9 of 10

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