SMART: physical activity and cerebral metabolism in older people: study protocol for a randomised controlled trial
Fleckenstein et al. Trials
SMART: physical activity and cerebral metabolism in older people: study protocol for a randomised controlled trial
Johannes Fleckenstein 0
Silke Matura 2
Tobias Engeroff 0
Eszter Fzki 0
Valentina A Tesky 2
Ulrich Pilatus 1
Elke Hattingen 1
Ralf Deichmann 3
Lutz Vogt 0
Winfried Banzer 0
Johannes Pantel 2
0 Department of Sports Medicine, Institute of Sports Sciences, Goethe University , Ginnheimer Landstrasse 39, Frankfurt am Main 60487 , Germany
1 Institute of Neuroradiology, Goethe University Hospital Frankfurt , Frankfurt , Germany
2 Institute of General Practice, Goethe University , Frankfurt/Main , Germany
3 Brain Imaging Centre , Frankfurt/Main , Germany
Background: Physical activity exerts a variety of long-term health benefits in older adults. In particular, it is assumed to be a protective factor against cognitive decline and dementia. Methods/design: Randomised controlled assessor blinded 2-armed trial (n = 60) to explore the exercise- induced neuroprotective and metabolic effects on the brain in cognitively healthy older adults. Participants (age 65), recruited within the setting of assisted living facilities and newspaper advertisements are allocated to a 12-week individualised aerobic exercise programme intervention or a 12-week waiting control group. Total follow-up is 24 weeks. The main outcome is the change in cerebral metabolism as assessed with Magnetic Resonance Spectroscopic Imaging reflecting changes of cerebral N-acetyl-aspartate and of markers of neuronal energy reserve. Imaging also measures changes in cortical grey matter volume. Secondary outcomes include a broad range of psychometric (cognition) and movement-related parameters such as nutrition, history of physical activity, history of pain and functional diagnostics. Participants are allocated to either the intervention or control group using a computer-generated randomisation sequence. The exercise physiologist in charge of training opens sealed and opaque envelopes and informs participants about group allocation. For organisational reasons, he schedules the participants for upcoming assessments and exercise in groups of five. All assessors and study personal other than exercise physiologists are blinded. Discussion: Magnetic Resonance Spectroscopic Imaging gives a deeper insight into mechanisms of exercise-induced changes in brain metabolism. As follow-up lasts for 6 months, this study is able to explore the mid-term cerebral metabolic effects of physical activity assuming that an individually tailored aerobic ergometer training has the potential to counteract brain ageing.
Magnetic resonance spectroscopic imaging; Aerobic exercise training; Cognitive impairment; Older adults; Psychometric tests; Cognition; Dementia; Prevention
Cognitive impairment and dementia is a pressing health
care issue in older people (as described previously ).
However, physical activity is thought to be beneficial in
altering the trajectory of cognitive decline in older adults
[2-4]. Although there is still considerable uncertainty
concerning the appropriate type, intensity and duration
of physical activity, there is evidence that regular low- to
medium-level exercise leads to a 35% risk reduction in
cognitive decline in people aged 65 and above compared
to inactive older people .
The potential mechanisms behind the protective effects
of physical activity on cognitive function are thought to be
multidimensional. It has been suggested that aerobic
exercise renders the brain more efficient, plastic, and adaptive,
which leads to improved memory and executive function
[2,6,7]. In brief, mechanisms comprise positive functional
changes in haemodynamic activity , neurogenesis and
neural cell proliferation  with newly formed neurons
being integrated functionally into neural networks  and
synaptic plasticity . On a molecular basis, exercise
differentially regulates synaptic proteins associated with the
function of the brain-derived neurotrophic factor (BDNF)
. Further, exercise is assumed to impact the production
of insulin-like growth factor 1 (IGF-1) .
As a correlate of neural plasticity, neuroimaging trials
show physical activity to induce structural changes in
the human brain [13-16]. A reduced loss of grey matter
volume in the brain has been associated with higher levels
of cardiorespiratory fitness (for review: ). These changes
in grey matter volume, especially in the hippocampus have
been linked to an improved memory function , which
could potentially delay the onset of dementia. The influence
of physical activity on neural plasticity is closely linked or
even dependent on various aspects of brain energy
metabolism. Exercise up-regulates multiple proteins within the
hippocampus that have a defined role in energy
metabolism, comprising enzymes involved in glucose catabolism,
ATP synthesis and glutamate turnover .
In addition to the structural changes in the ageing
brain, other cofactors have been attributed to cognitive
decline. Ito et al. showed not only older age, but also
lower mental health well-being, daytime sleepiness, pain
and lower instrumental activities of daily living to be
significant correlates of memory complaints . Chronic
pain seems to play an important role as related states of
mood such as depression, fatigue and pain catastrophising
have been associated with subjective cognitive complaints
. This has been shown to remarkably impair cognitive
We conduct a randomised controlled assessor blinded
2-armed trial to investigate the effects of a 12-week
individualised aerobic exercise programme on cerebral
metabolism, as well as grey matter volume and cognitive
functioning in cognitively healthy older adults, when
compared to a waiting control group. To address the
complexity of several other biopsychosocial cofactors of
brain metabolism, we take every-life confounders such
as nutrition, lifetime physical activity or pain experience
Design of the study
This is a randomised controlled partially blinded 2-armed
trial to evaluate the effects of a 12-week individualised
aerobic exercise programme on the cerebral metabolism in
cognitively healthy older adults, when compared to a
waiting control group. The study has been approved by the
Ethics Committee of the Goethe University of Frankfurt
am Main, Germany (reference 107/13) and is in agreement
with the Declaration of Helsinki (Version Fortaleza 2012).
Trial registration is NCT02343029 (clinicaltrials.gov).
Main outcome is the change in cerebral metabolism,
assessed by Magnetic Resonance Spectroscopic Imaging
(MRSI). Analysis of all records is performed by blinded
evaluators. The total follow-up period per participant is
6 months (see Figure 1).
Recruitment of participants and implementation of the
intervention takes place within the setting of three
assisted living facilities in Frankfurt am Main, Germany,
all together offering residency to more than 300 people.
In addition, the press agency of the university released
information to local print media on a single occasion.
Besides common supportive facilities, the living
residences provide a regular programme for different leisure
activities for their residents, including cultural activities,
lectures and sport/physical activities.
Participants likely for inclusion are screened by the
Institute of General Practice, Goethe University, Frankfurt
am Main, Germany. Written informed consent is
obtained. Baseline cognitive data is assessed by means of
questionnaires and psychological testing (Visit 1a, Figure 1).
Subsequently, participants are grouped into blocks of five
people and scheduled for a visit at the Department of
Sports Medicine (Visit 1b, Figure 1), where they pass a
thorough medical check-up, to screen for clinically
significant health conditions. At Visit 1b we also assess
movement-related parameters; that is strength and posture,
specific questionnaires (for example, nutrition, history of
every day physical activity, history of pain) and a
cardiopulmonary exercise test (CPET). Five days later, the same
group undergoes brain scans at the Brain Imaging Centre
Frankfurt, Germany, for the assessment of brain structure
(grey and white matter volume) and brain metabolites
(Nacetyl-aspartate (NAA), glutamine, glutamate, myo-inositol,
creatine, phosphocreatine, adenosine triphosphate (ATP),
adenosine diphosphate (ADP) (calculated based on the
equilibrium constant of the creatine-kinase reaction),
inorganic phosphate, phosphoethanolamine,
glycerophosphoethanolamine, phosphocholine, and
glycerophosphocholine; Visit 1c, Figure 1). Participants are
randomised to either receive intervention during the
subsequent 12 weeks (group INT) or after a waiting
period of 12 weeks (group CON). If allocated to INT,
participants start the individualised exercise intervention
in the integrated gym hall of one of the participating
residencies 6 days after the magnetic resonance imaging
(MRI) scans. After 4 weeks, the CPET is repeated and
exercise intensity adjusted accordingly. All participants are
told not to change their habitual physical activity during
the following 3 months, except for the intervention in
group INT. Twelve weeks after allocation all participants
Figure 1 Study design. The figure details the dates in which participants are assessed or receive intervention. After screening at baseline,
participants pass three visits (Visits 1a-c) at the respective departments; that is, the Institute of General Practice for psychometric testing, the
Department of Sports Medicine for movement-related testing and the Institute of Neuroradiology for the conduction of the magnetic resonance
(MR) protocol. Participants fulfilling all inclusion criteria are than randomly allocated to two groups: the intervention group (INT) or the waiting
control group (CON). In the INT group, participants start a 12-week individualised aerobic exercise programme on a bicycle ergometer whereas in
the CON group they continue their used daily activity for another 12 weeks. After 12 weeks, participants are reassessed at the above mentioned
departments (Visits 2a-c). Participants in the CON group can now decide to perform the exercise programme too. Follow-up ends at 24 weeks
are scheduled for Visits 2a-c adhering once again to fixed
inter-assessment intervals. Exercise intervention starts at
this point for participants in group CON. Participants in
group INT can continue their exercise voluntarily.
Twentyfour weeks after inclusion, both groups are assessed once
again (Visits 3a-c), complying with defined timeframes
Types of participants
Only cognitively healthy participants are included in the
study. Here, cognitively healthy is defined as presenting
no signs of dementia in cognitive performance during
neuropsychological assessment and no impairment in
activities of daily living. For inclusion participants must
meet the following criteria: 1) aged 65 years or above,
2) show voluntariness, 3) have capacity to consent, 4)
having passed a medical entry exam by the Department
of Sports Medicine, 5) having given written informed
consent. Participants presenting with any of the
following exclusion criteria may not be included in the trial:
1) untreated clotting disorders; 2) musculoskeletal
diseases significantly reducing mobility; 3) severe bacterial or
viral infections; 4) severe respiratory diseases (Gold IV); 5)
acute pulmonary embolism; 6) unstable angina pectoris or
severe heart failure (New York Heart Association (NYHA)
III or IV); 7) severe vascular disease of the extremities or
the brain; 8) severe cardiopulmonary dysfunction; 9) acute
myocardial infarction or early phase of rehabilitation:
10) critical aortic stenosis; 11) severe hypertrophic and
obstructive cardiomyopathy; 12) untreated malignant
arrhythmias; 13) untreated severe hypertension; 14)
severe pulmonary hypertension15) symptomatic cardiac
malformations (for example, septal defects, patent ductus
arteriosus or valvular stenosis); 16) atrioventricular
(AV)block grade II or III; 17) left bundle-branch block; 18)
complex ventricular arrhythmias; 19) cognitive impairment
reflected in a score < 27 in a dementia screening test (Mini
Mental State Examination) ; 20) specific exclusion
criteria regarding MRI scans.
The randomisation is performed on a 1:1 basis. If
participants comply with inclusion criteria, the exercise
physiologist opens a sealed and opaque envelope (compiled
by an independent third party), allocating participants
to either INT or CON. The randomisation sequence is
generated using a computer-based algorithm (Research
Randomiser, Version 4.0). For organisational reasons,
the exercise physiologist schedules participants into
groups of five. Participants within these blocks belong
to the same treatment modality (that is intervention or
control). Grouping is only allowed in the order of
recruitment to the study. All assessors and study personal
other than exercise physiologists are blinded. The same
physiologist schedules upcoming visits. Participants are
instructed not to communicate their random assignment to
other assessors within the study. Organisational reasons for
building groups of five include: a) facilitation of comparable
timeframes between assessments (for example, sports
medicine and brain imaging), visits (for example, Visit 1a and
exercise (for example, from last assessment (MRSI) to the
first exercise session or from the last exercise session to the
beginning of the next assessment), and b) to conduct the
exercise intervention in familiar groups of five participants.
Individualised aerobic exercise training
Participants in the INT group exercise 3 times a week
for 30 minutes on a bicycle ergometer (optibike med,
ergoline GmbH, Bitz, Germany) in the integrated gym
hall of one of the participating residencies. Training is
individualised as respective performance is adapted to
the power at the first ventilator threshold (assessed
during the CPET). The respective training intensity is stored
on a chip card, which, when inserted into the ergometer,
automatically sets the intensity and records training data
(flash card system). During the first 4 weeks of
intervention 2 of the 3 weekly training sessions are offered as
group training supervised by the respective qualified
exercise physiologist of the Department of Sports Medicine
(group size: 5 participants). After 4 weeks, participants
physical performance is reassessed at the Department of
Sports Medicine. If necessary, workload is readjusted to
achieve the initially defined exercise intensity. Starting
the fifth week, only one session every 4 weeks is
supervised, otherwise participants exercise unsupervised. After
the 12-week exercise period participants can continue
exercising voluntarily for the next 12 weeks.
For the whole duration of the study, all exercise
performed by the participants on the ergometer is individually
and automatically recorded on the respective chip card.
At all time points, outcome parameters will be assessed
within a timeframe of 1 week. At baseline it is the week
immediately prior to inclusion into the study; at 12 and
24 weeks it is the week immediately following thereafter.
Main outcome measure is the change in cerebral
metabolism assessed by MRSI. This method allows to display
several parameters reflecting metabolic changes in the
central nervous system. Therefore, we established three
hypotheses, each to be tested individually:
Primary hypothesis is that aerobic exercise leads to
an increase of cerebral NAA mediated by plasma
Secondary hypothesis stipulates an increase of
markers of neuronal energy reserve: that is the ratio
of phosphocreatine to creatine and of ATP to ADP
Third hypothesis is an increase in the volume of
cortical grey matter.
Measures for cerebral metabolism include MRI data
acquisition and venous blood sampling. The MRI scans
take place at the Brain Imaging Centre, Frankfurt am
Main, Germany. Data are acquired using a 3-Tesla whole
body scanner (Magnetom Trio, Siemens Medical AG,
Erlangen, Germany) optimised for examinations of the
The entire MR protocol consists of two parts. The MRSI
part is performed using a double tuned 1H/31P volume
head coil (Rapid Biomedical, Wrzburg, Germany) while
the quantitative magnet resonance imaging (qMRI) data
are acquired with an 8-channel array head coil (Siemens
Medical, Erlangen, Germany). A three-dimensional
T1-weighted image acquired during the MRSI part
(2.5 minutes for acquisition) is used to coregister the
MRSI to the qMRI data.
The MRSI protocol is planned on T2-weighted (T2-w)
images in 3 orientations. For 1H MRSI a transversal slice
(240 240 mm2 field-of-view (FOV), 16 16 matrix,
12 mm thickness, circular weighted acquisition scheme
with 2 acquisitions at centre of k-space, 1,500 ms
repetition time (TR), 30 ms echo-time (TE)) is recorded
within a measurement time of 5 minutes. The volume of
interest is selected by a combination of point-resolved
selective spectroscopy and outer volume suppression.
For 31P MRSI, a three-dimensional MRSI slab (240
240 200 mm3 FOV, 8 8 8 matrix, circular weighted
acquisition scheme with 10 acquisitions at the centre of
k-space, 2 s repetition time, 2,000 ms TR, 60 pulses,
2.3 ms delay between excitation and recording of
freeinduction decay (FID), 12-minute measurement time)
Finally, the hippocampus contralateral to the dominant
hemisphere is recorded with single voxel (SVS) 1H
magnetic resonance spectroscopy (MRS providing
concentration values for NAA, myo-inositol, glutamate, glutamine,
the aggregated concentration of creatine and
phosphocreatine, and the aggregated concentration of phosphocholine
and glycerophosphocholine. A 15 20 30 mm3 voxel is
recorded with Point Resolved Spectroscopy (PRESS) (TR
3 s, TE 30 ms, 96 acquisitions) in 5 minutes. The position
of the voxel is planned on the three-dimensional
Before spatial Fourier transformation the matrix size
of the MRSI data is doubled in all dimensions by zero
filling. Within this process, the 31P slab is adjusted by
grid-shifting to provide an ideal matching of 31P and 1H
voxels; that is the 1H slice is positioned in the centre of
a 31P slice and the in-plane 31P grid matches the 1H grid
just exhibiting twice the scale.
qMRI of the brain is performed via T1 mapping based
on the variable flip angle method . In summary, two
gradient echo data sets with different excitation angles are
acquired with a FLASH-EPI readout to improve the
signalto-noise ratio (SNR) . The acquisition parameters are:
excitation angles 4/24, TR/TE = 16.4 ms/6.7 ms, matrix
size 256 224 160, isotropic spatial resolution 1 mm,
duration 9:48 minutes. B1 is measured according to
, the duration of this measurement is 0:53 minutes.
The T1 maps are corrected for B1 inhomogeneities and
insufficient spoiling of transverse magnetisation .
Spatial non-uniformities of the receive RF coil are
determined via a method that exploits the linear
relationship between 1/PD and 1/T1 . PD maps are derived
by correcting the low angle data set for any T1, B1, and
receive profile bias . The total acquisition time of
the qMRI protocol is 11 minutes.
Quantification of the neurotrophin BDNF is performed
from venous blood samples in the Laboratory for Clinical
Pharmacology, Psychiatric University Hospital Charit in
Berlin using a modified fluorometric ELISA method as
described previously .
Secondary outcome measures include psychometric
testing and movement-related parameters.
Psychometric testing is performed at the Institute of
General Practice and assesses the following cognitive
functions: verbal declarative memory (Verbal Learning and
Memory Test ; adapted German version of the Rey
Auditory Verbal Learning Test ), frontal executive
control (Colour-Word-Interference Test  adapted German
version of the Stroop test  Trail-Making-Test Part B
) working memory (Digit Span Test forward and
backward ) as well as semantic and phonematic fluency,
nonverbal declarative memory and visual-constructive
abilities by means of the CERAD-Plus (Consortium to
Establish a Registry for Alzheimers Disease) Neuropsychological
Battery . In addition, the speed of cognitive processing
is assessed by means of the Trail-Making-Test Part A .
Participants are screened for depressive symptoms with the
Geriatric Depression Scale (GDS) . Age-associated
subjective memory impairment is assessed using a
memory complaint questionnaire (MAC-Q ).
Additionally, crystallised intelligence is assessed by
means of a verbal intelligence test (Multiple-Choice
Word Test: MWT-B, ).
Potential participants are screened for dementia and
mild cognitive impairment using the Mini Mental State
Examination  and the Instrumental Activities of
Daily Living Questionnaire .
Movement-related parameters are assessed at the
Department of Sports Medicine including different parameters:
a) Basic parameters:
assessment of vital parameters, body weight and height,
anthropometry (Body Impedance Analyzer Nutriguard
MS, Data Input, Pcking, Germany) and waist-hip ratio.
b) Cardiopulmonary exercise test:
aerobic exercise capacity is determined by a
physiciansupervised CPET, a safe and effective method to assess
functional capacity . Participants are asked to refrain
from alcohol or caffeine use and strenuous physical
activity for 24 hours, from light physical activity for
4 hours, and from eating 2 hours before CPET. Body
weight and height in light clothing are measured using
standard techniques and calibrated equipment. During a
graded exercise test on an electrically braked cycle
ergometer (custo control, customed GmbH, Munich,
Germany) the initial workload of 0 Watt is increased by
25 Watt every 3 minutes until exhaustion. Heart rate,
electrocardiogram (ECG) data and ventilator data
(breathby-breath, open-circuit indirect spirometry (Cortex
Metalizer 3B, Leipzig, Germany)) are registered
continuously. Stringent quality protocols are followed to
control for activities, mechanical and
environmentrelated influences like relative humidity, mask fitting,
sampling lines. Before each test the metabolic cart is
calibrated using standard ventilatory volumes (0.2 and 3 l
air/minute) and gases (outside air and 5% CO2, 16% O2)
after sufficient warm-up. Ratings of perceived exertion
(RPE; Borg-scale) and lactate concentrations (Lactate
Scout+, EKF Diagnostics, Magdeburg, Germany) are
measured at the end of each stage and after CPET
termination. Participants are strongly encouraged throughout the
test. Criteria for test cessation are volitional exhaustion
(cadence below 60 rev/minute) or symptom limitation.
For data analysis, peak oxygen uptake (VO2peak) is
defined as the highest of all 30-s averages elicited during
CPET . First ventilatory threshold (VT1) was
defined as: 1) non-linear increase in VCO2 versus VO2; 2)
first non-linear increase of ventilation versus workload
(VE/WL); 3) first increase of expiratory partial pressure
of oxygen versus workload (PETO2/WL); 4) first
nonlinear increase of ventilatory equivalent of oxygen (VE/
VO2) versus workload with no concomitant increase of
equivalent of carbon dioxide (VE/VCO2) [42,43].
of the knee muscles are performed on the random leg
determined at Visit 1. All measures are performed in a
respective standardised seated position, all
participants are held fixed with a belt to the seat to avoid
auxiliary muscle contraction. Three tests per muscle
are performed with contractions lasting 5 s, separated
by 2-minute rest intervals. Force time is displayed on
a screen providing an immediate feedback. In addition,
participants are verbally encouraged in a standardised
order to elicit maximal effort. Sufficient test-retest
reliability and construct validity has been shown for this
d) Pain assessment:
German Pain Questionnaire (baseline and follow-up
version; ), which includes the assessment of
quantitative and qualitative pain description, pain intensity,
disability and impairment, causalities and attributions,
mental well-being, anxiety and depression,
comorbidities, pretreatments and medications. The questionnaire
consists of additional sections for optional use, assessing
the quality of life impairment by pain inventory, quality
of life and social law issues. Special follow-up forms are
included that allow the assessment of the items at
upcoming visits .
c) Balance and strength : e) Dietary history: For postural sway (balance) and gait data acquisition, the capacitive force-measuring platform (30 Hz) WinFDM
v0.0.41 (Zebris GmbH, Isny, Germany) is used. Postural
sway is estimated by the area of the 95% confidence ellipse
calculated by using the maximum medial/lateral and
anterior/posterior excursion of the centre of pressure (COP). For
the measurement, we ask participants to stand upright (feet
shoulder-width apart) as still as possible for 3 intervals of
90 s with a 2-minute rest interval in-between with arms
folded across their chest and eyes covered. Gait speed
(distance per time between subsequent floor contacts) is
averaged on the basis of 10 individual strides monitored in the
middle of a 10-m walkway when participants are required
to walk across the sensor platform in a self-determined
(usual) free-walking speed. Acceptable test-retest reliability
has been described for this approach .
To obtain maximum isometric voluntary force (MIVF),
the m3 (multi-muscle machine) Diagnos + (Schnell
Trainingsgerte GmbH, Peutenhausen, Germany) is used.
The MIVF is obtained from the knee flexors/extensors of a
randomly selected leg (a computer-compiled randomisation
list defining right and left leg had been prepared prior to
the experiment; predefined m3 angle for knee extensors =
120/for knee flexors = ) and the lumbar muscles
(extensors = 120/for lumbar flexors = ). All subsequent measures
Food frequency questionnaire DEGS1 assessing the
nutrition of 53 different types of food over the last 4 weeks
. The questionnaire is only assessed at baseline.
f ) History and fear of falling:
German version of the Falls-Efficacy-Scale International
Version (FES-I) .
g) Physical activity:
As indicated by surveying the present and past history.
In addition, accelerometry objectively reflects physical
activity at baseline.
a. Physical activity at present, assessing the last 7 days
by means of the International Physical Activity
Questionnaire (IPAQ) .
b. Lifetime patterns of total physical activity including
occupational, household, commuting and exercise/
sports activities are assessed with a translated
combination of the Lifetime Total Physical Activity
Questionnaire , Historical Leisure Activity
Questionnaire  and Retrospective Physical
Activity Survey .
c. Accelerometry (GT3X v4.4.0, ActiGraph, Pensacola
FL, USA) assessing the average physical activity of 4
valid (at least 10 hours wear time) out of 7
consecutive days, at baseline .
Data analysis and power calculations
Power calculations have been estimated on data
published by Pajonk et al. , who showed a 3-month
exercise programme to change the ratio of hippocampal
NAA to total creatinetCr by 15% (n = 3 8). In our
group, longitudinal changes of this effect size have been
shown previously in groups larger than 15 subjects.
Given poor data quality and a drop-out ratio of included
subjects, both at 25%, into account, we estimated a
group size of 30 participants to be adequate. Thus, the
total sample size is 60.
Statistical analysis is performed according to current
standards in reporting clinical trials differentiating for
parametric and non-parametric data first and applying
the respective tests thereafter. Changes over time are
analysed applying repeated measures methods. If statistically
different at baseline, secondary outcomes are introduced
as possible confounders by means of covariate analysis.
MRSI data analysis
The 1H MRSI spectra are fitted with the commercially
available software tool LCModel (downloadable test
version at: http://s-provencher.com/pages/lcmodel.shtml;
), which simulates the spectra with a linear
combination of model spectra and is considered to be the most
suitable tool for the analysis of short-TE spectra .
Baseline correction is performed including
macromolecules. The 31P data is analysed with the tool jMRUI ,
which was found to be more appropriate for these types of
qMRI data analysis
From the quantitative maps of PD and T1, it is possible
to calculate synthetic anatomical data sets, showing the
same contrasts as data sets acquired with the respective
standard sequences. The advantage is that synthetic data
sets do not suffer from any RF coil bias. Furthermore,
purely T1-weighted data sets can be calculated by
omitting the inclusion of PD, thus enhancing the contrasts.
In the present case, MPRAGE  data sets are
calculated, using a mathematical formalism described in the
literature , assuming the parameters TR = 2,420 ms,
TI = 960 ms, excitation angle 9.
Changes in grey matter volume following the
intervention are analysed with voxel-based morphometry (VBM)
 in SPM8 (Wellcome Department of Cognitive
Neurology, London, UK) running under Matlab 8
(Mathworks, Sherborn, MA, USA). Data preprocessing includes
segmentation, spatial smoothing with a Gaussian Kernel of
10 mm full width at half maximum (FWHM) and spatial
normalisation using the DARTEL toolbox (SPM8). The
whole brain analysis is followed by a Region of Interest
(ROI) Analysis. To allow the detection of alterations in
hippocampal morphology, a VBM analysis using the
hippocampus as ROI is performed. The hippocampus ROI is
derived from the Wake Forest University (WFU) PickAtlas
toolbox. Small volume correction (SVC) is used to reduce
the number of comparisons being performed, increasing
the chance of significant results in the ROI.
Psychometric data analysis
Neuropsychological test scores are used to calculate
domain specific measures. Six cognitive domains are assessed
from 8 tests: Executive functioning (Colour-Word
Interference Test, Trail-Making Test Part B), Working memory
(Digit Span Test forwards and backwards), Memory
(Verbal Learning and Memory Test, CERAD figure
recall), Visuospatial performance (CERAD figure
drawing), Language (CERAD phonematic fluency, CERAD
semantic fluency) and speed of cognitive processing
(Trail-Making-Test Part A). Individual test scores are
converted to z-scores using the mean and standard
deviation of the entire sample. Similar to the approach by
Vemuri et al.  the individual z-scores are averaged
to create six domain scores. The six domain scores are
averaged to calculate a global cognitive summary score.
Balance and MIVF data analysis
The average of the 3 posture measurements (areas of the
95% confidence ellipse) is used for data analysis.
Collected data is analysed by Diagnos 2000
(Trainsoft GmbH, Moorenweis, Germany). The highest value
of the three trials (randomised leg selection) (N m kg1)
is considered to be representative of MIVF and is used
for statistical analysis.
This study explores the effects of a supervised aerobic
exercise intervention on cerebral metabolism as a
correlate of cognitive functioning in cognitively healthy older
adults. It is a randomised controlled intervention study
comparing aerobic exercise on an ergometer in older
people with a waiting control group. Beside severe
restraints in patients lives, cognitive impairment is
associated with higher mortality and lower functional recovery
. Several cofactors account for this condition [19,20].
In some cases, memory complaints have been described
uncoupled from dementia as expressions of low mood
and impairments in activities of daily living (for review:
). The strength of the present protocol is to control
for a large subset of possibly influencing factors, in
particular history of physical activity, diet and pain. This
comprehensive understanding allows us to identify or
control for confounders predicting improved or reduced
benefit from physical exercise in older people. Still,
multiple measures can be concerned a limitation when
interpreting the results of a study. In the present study, we
accentuate on the primary outcome (changes in cerebral
metabolism) and will strictly adhere to statistical
conventions with the analysis of secondary outcomes.
Participants exercise at intensities derived from an
individually measured and consecutively readjusted
submaximal physiologic threshold. This threshold concept
is regarded as a standard in cardiopulmonary exercise
testing in public health recommendations  and
allows valid and comparable intensity determination even
if maximal workload (VO2max) is not attainable.
This is the first study assessing the influence of
ergometer exercise at individually established and readjusted
intensities on brain metabolism in cognitively healthy
older adults. Yet, a dose-dependency between physical
exercise and cognitive performance in older adults in
neuroprotection has been suggested . Both higher
levels of fitness  and a higher estimated VO2max ,
have been shown to be favourable regarding cognitive
performance in older people. A meta-analyses including
16 prospective studies with 3,219 patients at follow-up
showed the relative risk for dementia to be reduced by
28% when comparing the highest to the lowest physical
activity category . Still, the optimal exercise dosage
and type of exercise remain unclear.
Beside aerobic training, the effects of resistance,
cognitive and novel dual-task exercise training interventions
for the preservation or improvement of cognitive health
have proven to be effective, well-tolerated and safe for
older adults (for review: ). However, their potential
in the improvement of cognitive impairment seems to
be maximised when coupling individualised or
progressive, moderate-to-high aerobic-based exercise with
dualtask training over a period of 1 to 12 months. Effects of
resistance training (RT) programmes are promising, but
current evidence is inconclusive supporting the
effectiveness of RT as a stand-alone treatment (for review: ).
Accordingly, we decided to investigate the effects of a
fully individualised, structured aerobic exercise
intervention, with a training intensity that is adjusted to
participants performance for a period of 12 weeks, within a
24-week follow-up for preserving or enhancing cognitive
performance in older adults . The regimen is
conducted in groups of five participants each. Trainings take
place in the familiar setting of the living facilities.
Compared to laboratory animals the neuronal
mechanisms underlying the positive influence of physical
activity on cognition in humans are far less understood.
Previously, neuroimaging has been used to investigate
the effect of regular aerobic exercise on brain structure
and function in older healthy adults in vivo. Structural
MRI (sMRI) studies demonstrate an exercise-induced
increase of grey matter volume in several brain regions,
particularly within the hippocampus and prefrontal
cortex [13,71,72], thereby counteracting an age-associated
atrophy in these regions. The observed brain changes
were positively correlated with improvement in cognitive
function and with an increase in serum BDNF [13,72].
Studies using functional MRI (fMRI) could show that
exercise increases functional connectivity in higher-level
cognitive networks, thereby improving executive
function [73,74]. Although these studies support a positive
effect of physical activity on structural and functional
cerebral plasticity in healthy ageing they do not
contribute to the clarification of metabolic pathways underlying
the observed cognitive improvement. In contrast to
sMRI and fMRI, information on brain metabolism can
be gathered by two complementary and fully quantitative
neuroimaging methods in vivo: MRS and positron
emission tomography (PET). 31P MRS is the gold standard
technique allowing absolute quantification of
metabolites closely related to cerebral energy metabolism (ATP,
ADP, phosphocreatine, creatine), while 1H MRS provides
information on neuronal viability/integrity (via the
neuronal marker NAA) in different brain regions. On the
other hand, PET with [18 F]fluoro-deoxy-glucose ([18 F]
FDG) is the gold standard technique for estimation of
glucose turnover providing quantitative assessments of
the (regional) metabolic rate of glucose metabolism.
Although the feasibility of using MRS and FDG-PET
for studying brain metabolism in ageing and
neurodegenerative disorders has been demonstrated in numerous
studies there is a paucity of studies using these methods to
investigate regional metabolic changes induced by physical
exercise. To our knowledge, only one recently published
study addressed the relationship between aerobic fitness,
cognition, and the regional concentrations of
MRSIderived metabolites in the brains of older people . This
study found a positive association between aerobic fitness
and NAA in the frontal lobe indicating an influence of
physical fitness on regional neuronal viability and/or
density. However, this was a cross-sectional study which
precludes a sound conclusion on the causal relationship
between exercise and brain metabolism.
The current study aims to shed light on the influence of
physical exercise on brain metabolism in healthy ageing.
Based on the findings mentioned above the main
hypothesis under investigation is that regular physical exercise
leads to an enhancement of cerebral energy metabolism in
the brains of older people that is closely related to an
increase in the concentration of metabolic markers for
neuronal viability and density. We assume that these
changes occur particularly in the hippocampus, are
mediated by a release of the neurotrophin BDNF, and
predict an improvement of cognitive function including
memory and executive control. Specifically, we are
interested in the short- and mid-term cerebral metabolic and
cognitive effects of a supervised individualised exercise
intervention assuming that regular physical activity has the
potential to counteract brain ageing.
ADP: adenosine diphosphate; ATP: adenosine triphosphate;
AV: atrioventricular; BDNF: brain-derived neurotrophic factor;
CERAD: Consortium to Establish a Registry of Alzheimers Disease;
COP: centre of pressure; CPET: cardiopulmonary exercise test;
ECG: electrocardiogram; ELISA: enzyme-linked immunosorbent assay;
FDG: 18fluoro-deoxy-glucose; FES-I: Falls-Efficacy-Scale International Version;
FID: free-induction decay; fMRI: functional MRI; FWHM: full width at half
maximum; GDS: Geriatric Depression Scale; IGF-1: insulin-like-growth factor 1;
IPAQ: Activity Questionnaire; MAC-Q: memory complaint questionnaire;
MIVF: maximum isometric voluntary force; MRI: magnet resonance imaging;
MRS: magnetic resonance spectroscopy; MRSI: Magnet Resonance
Spectroscopic Imaging; NAA: N-acetyl-aspartate; NYHA: New York Heart
Association; PET: positron emission tomography; PRESS: Point Resolved
Spectroscopy; qMRI: quantitative magnet resonance imaging; ROI: Region of
Interest; RPE: ratings of perceived exertion; sMRI: structural MRI; SNR:
signalto-noise ratio; SVC: small volume correction; SVS: single voxel spectroscopy;
TE: echo-time; TR: repetition time; VBM: voxel-based morphometry;
VO2peak: peak oxygen uptake; VT1: first ventilatory threshold; WFU: Wake
All authors substantially contributed to the conception and design of the
study. JF and SM coordinated the study and wrote the first draft of this
manuscript. TE, EF, VT, UP, EH, RD, LV, WB and JP participated in the
conduction of the study and critically revised the manuscript for important
intellectual content. JF, TE, EF, LV and WB provided all scientific and practical
information in the context of exercise physiology. SM, VT and JP provided all
scientific and practical information for neuropsychological testing. UP, EH
and RD provided all scientific and practical information for neuroimaging.
WB and JP conceived of the study. All authors read and approved the final
Parts of this study constitute the Bachelor Thesis (BA) of Jonas Newrly and
Christian Hantke, the Master Thesis (MA) of Sina Schwarz and Sabrina Weber
and the Thesis for a Medical Doctorate of Natkay Rahi, Alexandra Fischer,
Katharina Dietz and Tobias Engeroff. We especially recognize the assistance
of Mrs. Romy Schild, the medical technician at the Department of Sports
Medicine and of Mrs. Bianca Lienerth, the medical technician for radiology at
the Brain Imaging Centre. We want to thank Horst Michaelis, former Director
at the Cronstetten-Haus, for his patronage.
The trial has been granted by the Else-Krner-Fresenius-Stiftung and the
Cronstetten-Stiftung, both German non-profit foundations guaranteeing
independency of research.
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