Eur Radiol (2017) 27:1568–1576
DOI 10.1007/s00330-016-4485-1
MAGNETIC RESONANCE
Evaluation of brain ageing: a quantitative longitudinal MRI study
over 7 years
René-Maxime Gracien 1,2 & Lucas Nürnberger 1,2 & Pavel Hok 1,2,3 &
Stephanie-Michelle Hof 1,2 & Sarah C. Reitz 1,2 & Udo Rüb 4 & Helmuth Steinmetz 1 &
Rüdiger Hilker-Roggendorf 1,2 & Johannes C. Klein 1,2,5 & Ralf Deichmann 2 &
Simon Baudrexel 1,2
Received: 24 March 2016 / Revised: 27 May 2016 / Accepted: 21 June 2016 / Published online: 5 July 2016
# European Society of Radiology 2016
Abstract
Objectives T1 relaxometry is a promising tool for the assess-
ment of microstructural changes during brain ageing. Previous
cross-sectional studies demonstrated increasing T1 values in
white and decreasing T1 values in grey matter over the life-
time. However, these findings have not yet been confirmed on
the basis of a longitudinal study. In this longitudinal study
over 7 years, T1 relaxometry was used to investigate the dy-
namics of age-related microstructural changes in older healthy
subjects.
Methods T1 mapping was performed in 17 healthy subjects
(range 51–77 years) at baseline and after 7 years. Advanced
cortical and white matter segmentation was used to determine
mean T1 values in the cortex and white matter.
René-Maxime Gracien and Lucas Nürnberger contributed equally to this
work.
Electronic supplementary material The online version of this article
(doi:10.1007/s00330-016-4485-1) contains supplementary material,
which is available to authorized users.
* René-Maxime Gracien
Rene-Maxime.Gracien@kgu.de
1
Department of Neurology, Goethe University, Frankfurt/
Main, Germany
2
Brain Imaging Center, Goethe University, Frankfurt/Main, Germany
3
Department of Neurology, Palacky University,
Olomouc, Czech Republic
4
Dr. Senckenberg Chronomedical Institute, Goethe University,
Frankfurt/Main, Germany
5
Nuffield Department of Clinical Neurosciences, University of
Oxford, Oxford, UK
Results The analysis revealed a decrease of mean cortical T1
values over 7 years, the rate of T1 reduction being more prom-
inent in subjects with higher age. T1 decreases were predom-
inantly localized in the lateral frontal, parietal and temporal
cortex. In contrast, mean white matter T1 values remained
stable.
Conclusions T1 mapping is shown to be sensitive to age-
related microstructural changes in healthy ageing subjects in
a longitudinal setting. Data of a cohort in late adulthood and
the senescence period demonstrate a decrease of cortical T1
values over 7 years, most likely reflecting decreasing water
content and increased iron concentrations.
Key Points
• T1 mapping is sensitive to age-related microstructural
changes in a longitudinal setting.
• T1 decreases were predominantly localized in the lateral
frontal, parietal and temporal cortex.
• The rate of T1 reduction was more prominent in subjects
with higher age.
• These changes most likely reflect decreasing cortical water
and increasing iron concentrations.
Keywords Quantitative magnetic resonance imaging . T1
relaxation . Ageing . Cerebral cortex . White matter
Abbreviations
CSF Cerebrospinal fluid
FSL FMRIB Software Library
GE Gradient echo
GM Grey matter
MNI Montreal Neurological Institute
MP-RAGE Magnetization-prepared rapid gradient-echo
MRI Magnetic resonance imaging
qMRI Quantitative magnetic resonance imaging
Eur Radiol (2017) 27:1568–1576
RF Radio frequency
ROI Region of interest
WM White matter
Introduction
Understanding the processes of human brain ageing has be-
come an important research field. Life expectancy is continu-
ously increasing in our societies and mental capabilities are
one of the most important factors for an individual’s quality of
life in the senescence period [1]. Understanding healthy brain
ageing might help to clarify when and under which conditions
normal brain ageing diverges into pre-pathological neurode-
generation and, possibly, how to prevent the latter [2].
Structural brain imaging of cortical grey (GM) and white
matter (WM) is a suitable tool to track age-associated changes
in vivo. Studies using conventional magnetic resonance imag-
ing (MRI) techniques revealed characteristic patterns of corti-
cal thinning [3], regional atrophy [4] and alterations in surface
morphometry [5]. However, images acquired via conventional
MRI techniques are based on mixed signal contrasts and, thus,
only allow very limited insights into the underlying micro-
structural tissue processes [6].
In contrast, quantitative MRI (qMRI) enables the calcula-
tion of well-defined physical parameters, such as the relaxa-
tion times T1 and T2*, or the proton density independent from
specific hardware parameters [7]. As qMRI parameters can be
more specifically related to biophysiological processes, they
can provide valuable information about tissue composition
and changes in both GM and WM during ageing [6, 8].
The longitudinal relaxation time (T1) of a given brain voxel
is generally thought to be dependent on the microstructural
properties of the underlying tissue such as water content, cell
and dendritic density, degree of myelination and iron content
[9–12]. From a histological point of view, ageing is associated
with regression of the neuropil, synaptic degeneration, axonal
demyelination, iron accumulation and a reduction in cerebral
water content [13–16]. Since all these processes affect the
longitudinal relaxation time T1, this parameter can be consid-
ered a promising marker for the investigation of brain ageing
processes. Longitudinal measurements of T1 in older healthy
subjects could thus provide useful baseline information which
might be important to disentangle normal from pathological
brain ageing.
Several previous cross-sectional studies have analysed T1
in GM and WM regions of subjects of different age. The
respective studies could demonstrate an age-related T1 de-
crease in cortical GM in late life periods [17–20]. With respect
to WM a T1 increase was consistently shown for older partic-
ipants [17, 18, 21, 22].
However, a longitudinal study design is required to assess
the evolution of age-related T1 changes, as it avoids some of
1569
the inherent shortcomings of a cross-sectional design, which
may yield biased results due to the relatively large interindi-
vidual variability of T1 values and also generation effects.
A previous longitudinal study over a 5-year period which
primarily focused on multiple sclerosis patients failed to detect
T1 changes in the GM and WM of the healthy control group
[23]. However, the mean age of study participants was 36.7
± 8.4 years, which does not represent the critical life period
(>60 years) when the effects of normal ageing on brain func-
tion, e.g. on cognition or motor function, start to become de-
tectable. It is therefore desirable to specifically investigate the
evolution of T1 in an older cohort.
Here, we use an established qMRI technique for quantita-
tive T1 mapping [24] in combination with advanced cortical
GM and WM segmentation procedures [25] to investigate T1
changes in a longitudinal study over 7 years to assess healthy
ageing with a focus on the 5th to 8th decades. According to the
results of previous cross-sectional studies, which demonstrat-
ed decreasing cortical [17–20] and increasing WM T1 values
[17, 18, 21, 22] during ageing in late life periods, we also
expected a homogenous T1 decline in cortical GM and a T1
increase in WM.
Materials and methods
Participants
Twenty healthy subjects (11 female) were initially recruited
for the study. Exclusion criteria were neurological/psychiatric
disease, structural brain lesion, alcohol/substance abuse, se-
vere arterial hypertension or diabetes mellitus, as assessed
by systematic history evaluation and clinical examination.
Written informed consent was given, and the study was ap-
proved by the institutional review board.
Three subjects had to be excluded because of MRI artefacts
or exclusion criteria that occurred during the duration of the
study. Data of 17 subjects (eight female) were further
analysed. Baseline data were used for group comparisons in
a previous study [26].
T1 mapping and calculation of the synthetic MP-RAGE
data set
Subjects participated in two MRI scans at an interval of
7 years.
For each time point, T1 mapping was performed identically
on a 3-T MR scanner system (Magnetom Trio, Siemens
Medical Solutions, Erlangen, Germany) using an eight-
channel phased-array head coil for signal reception and a
whole body coil for radio frequency (RF) transmission. T1
maps were calculated offline using custom-built scripts writ-
ten for MATLAB (The MathWorks Inc., Natick, MA, USA).
1570
The T1 mapping method applied in this study was de-
scribed earlier [24]. In summary, T1 mapping required the
acquisition of two RF-spoiled three-dimensional (3D) gradi-
ent echo (GE) data sets with different flip angles (4° and 18°).
Acquisition parameters were TR/TE = 7.6 ms/2.4 ms, matrix
size = 256 × 224 × 160, isotropic spatial resolution = 1 mm,
band width = 206 Hz/pixel, scan duration = 9:05 min. T1
values were calculated from contrast differences as described
elsewhere [27]. T1 maps were corrected on the basis of an
additionally obtained B1 field map (duration 4:51 min) to
account for spatial inhomogeneities in RF transmission [28].
Stability and accuracy were improved by optimizing the RF
phase increment and furthermore by correcting for the effects
of incomplete spoiling according to Preibisch and Deichmann
[24]. The analysis of a repeated in vivo measurement revealed
a low scan–rescan variability of 2–3 % (coefficient of varia-
tion), rendering the T1 mapping technique suitable for longi-
tudinal studies [24].
For the second time point, additional synthetic anatomical
MP-RAGE data sets with pure T1 weighting without RF bias
were calculated solely from the quantitative T1 maps as de-
scribed elsewhere [29] using the following parameters: isotro-
pic spatial resolution = 1 mm, field-of-view as above,
TR = 1900 ms, TI = 900 ms, α = 9°.
The MP-RAGE data served as basis for the following
postprocessing and segmentation procedures using FMRIB
Software Library (FSL) and SPM, as these programs are op-
timized for this kind of image contrast.
Data postprocessing and analysis
Custom-built scripts using the FSL [30], SPM (Wellcome
Department of Imaging Neuroscience, Institute of
Neurology, UCL, London, UK, available at http://www.fil.
ion.ucl.ac.uk/spm) and MATLAB were applied for further
data processing.
The longitudinal change of cortical T1 was assessed with
region of interest (ROI) and voxel-based statistics. For ROI-
based analyses, cortical volume was defined on the basis of
the synthetic MP-RAGE images (i.e. those derived from T1
maps of the second time point): After brain extraction, MP-
RAGE images were registered into Montreal Neurological
Institute (MNI) 152 standard space using the rigid body trans-
formation with six degrees of freedom implemented in
BFLIRT^ to normalize the head position. The respective data
sets (MP-RAGEnorm) were used for all further tissue segmen-
tation procedures.
GM segmentation was performed with the FSL tool
BFAST^ [31]. The GM maps were utilized to identify the
cortical volume by removing voxels with a PVE less than
0.95 and voxels belonging to non-cortical structures by apply-
ing standard space masks [25]. The T1 maps of both time
points were then coregistered to the synthetic MP-RAGEnorm
Eur Radiol (2017) 27:1568–1576
images, the cortical PVE maps were applied to the T1 maps
and mean cortical T1 values were subsequently extracted. It
has to be mentioned that the rigid body registration with six
degrees of freedom of MP-RAGE images to MNI space be-
fore performing the segmentation was a necessary step to en-
sure similar postprocessing conditions, i.e. that of a necessary
coregistration for both T1 maps. If the segmentation had been
performed in the native space of the second image without
normalizing the head position, coregistration of the T1 maps
to the synthetic anatomies would have been required for the
images of the first time point only. This might have systemat-
ically affected the results because of a possible registration
bias.
Because of the high heterogeneity of T1 values across the
cortical volume even in healthy persons [25], absolute cortical
T1 changes were obtained by calculating the difference of the
mean cortical T1 values of both time points for each partici-
pant. Spearman’s rank coefficients of correlation were used to
assess the relationship between T1 change over 7 years (sec-
ond value minus first value) and age.
Furthermore, to investigate T1 changes in deep GM, a
combined mask of the caudate nucleus, putamen, globus
pallidus and thalamus was obtained as described elsewhere
[32] from the synthetic MP-RAGEnorm, identifying the respec-
tive regions with FSL BFIRST^ and performing an erosion
with a 3 × 3 × 3 mm kernel to avoid partial voluming. Mean
T1 values were extracted by applying this deep GM mask and
also for a mask combining cortical and deep GM to the T1
maps which had been taken to the space of the MP-RAGEnorm
data sets.
To additionally investigate T1 changes of WM on an ROI
basis, 3D WM masks were derived from the WM PVE maps
calculated with BFAST^ based on the MP-RAGEnorm data
sets. To avoid partial voluming with GM and cerebrospinal
fluid (CSF) compartments, the outermost voxels of the respec-
tive WM ROIs were eroded using a 6 × 6 × 6 mm kernel. For
better comparison with a previous study, an additional ROI
was manually placed into the frontal WM as described else-
where [18]. The WM masks were then applied to the T1 maps
which had been coregistered to the MP-RAGEnorm data sets
and mean WM T1 values were obtained for both WM ROIs
and both time points.
Statistical analyses were carried out with SPSS for
Windows (20.0.0). Non-parametric testing was used (paired
sample Wilcoxon signed-rank test) for comparisons of the
respective mean parameter values in WM and GM of both
time points.
For the voxel-based analysis of cortical T1 change, T1
maps of both time points were segmented with SPMs BNew
Segment^. The resulting GM PVE maps were thresholded
using PVE greater than 0.95 and used to mask the T1 maps.
GM T1 maps were normalized to MNI space using the trans-
formations generated with BDartel^. The option Bno
Eur Radiol (2017) 27:1568–1576
modulation^ was used for normalization. GM T1 maps were
then smoothed with an 8-mm isotropic Gaussian kernel.
Voxels displaying T1 values less than 100 ms for at least
one subject were excluded from further analysis. Statistical
comparison of GM T1 maps between both time points was
performed with paired t tests using FSL Brandomise^ with
5000 permutations [33]. The thresholding with correction for
multiple comparisons was performed using threshold-free
cluster enhancement. Significant cortical clusters were plotted
on the surface of the MNI 152 standard brain with BMRIcron^,
using a search depth of 16 voxels [34].
To compare the pattern of cortical T1 changes with the
changes in cortical thickness, an additional segmentation with
Freesurfer was performed [35, 36] using the longitudinal pro-
cessing stream [37]. The GE image acquired with the higher
excitation angle of 18° served as input image since it produced
the most robust results. Cortical thickness values for each time
point were projected onto an average surface and smoothed
with a Gaussian kernel with a full width at half maximum of
5 mm. BMri_glmfit^ (Freesurfer) was used to calculate paired
t test statistics between both time points to identify significant
clusters indicating a decreased cortical thickness after correc-
tion for multiple comparisons.
P values below 0.05 were considered significant for all
statistical tests.
Results
Across the 17 healthy participants (eight female), the average
age at which the first MRI scan was performed was 65.2
± 6.33 years (mean ± standard deviation, range 51–77 years).
Figure 1 shows transversal sections of the synthetic MP-
RAGE data (top row) and the T1 map (bottom row) for a
representative subject (MNI space, z coordinates = −2, 10,
22). The GM and WM ROIs identified by the algorithm de-
scribed above are indicated in red and green, respectively, and
superimposed onto the synthetic MP-RAGE image. The man-
ually placed WM ROI is indicated in blue. Figure 2 shows box
plots (median, upper and lower quartile and 95 % confidence
interval (CI)) of the mean T1 values for the cortical GM (a)
and the large WM ROIs (b) for all subjects and both time
points. Mean cortical T1 decreased significantly over time
(p = 0.039, rate 5.1 ± 7.81 ms/year) while WM T1 remained
stable (p = 0.38). Average T1 values across the small frontal
WM ROI also failed to show significant changes over time
(p = 0.59, baseline 1032.8 ± 64.87 ms, follow-up 1036.8
± 79.15 ms).
Supplementary Fig. 1 demonstrates T1 maps and the re-
spective normalized histograms at baseline and follow-up for
one representative participant.
Figure 3 shows individual changes of mean cortical T1
(expressed as the average T1 value at follow-up minus the
1571
average T1 value at baseline measurement) plotted against
the subjects’ age at baseline. The T1 decrease was negatively
correlated with age (r = −0.59, p = 0.012, Spearman rank co-
efficient of correlation) indicating a higher T1 decrease with
higher age.
Clusters of significant cortical T1 decrease are displayed in
Fig. 4. The pattern of T1 decrease was widespread and most
prominent in lateral frontal, temporal and parietal areas.
Significant increases of cortical T1 could not be detected.
T1 decrease could also be observed in the combined (corti-
cal and deep) GM ROI (p = 0.044, baseline 1649.8 ± 68.55 ms,
follow-up 1616.6 ± 52.80 ms), but not in deep GM (p = 0.62,
baseline 1365.8 ± 52.35 ms, follow-up 1358.2 ± 59.40 ms).
Results of the Freesurfer analysis are presented in Fig. 5.
Clusters with significantly decreasing cortical thickness are
indicated by the coloured overlays. The atrophy pattern differs
somewhat from the observed T1 changes and also included
mesiofrontal, inferior temporal and more occipital areas. The
rate of average cortical thickness reduction amounted to
0.010 ± 0.0135 mm/year.
Discussion
The goal of this study was to investigate the natural course of
T1 relaxation time changes during physiological brain ageing
in healthy subjects who are in a critical age period (age 65.2
± 6.33 years) with increasing incidence of pathological neuro-
degeneration for which it is of particular interest to know the
course and extent of physiological microstructural changes.
To this end, an established method for T1 mapping was per-
formed in a longitudinal study with measurements at baseline
and after 7 years. Data analysis was conducted using different
GM and WM segmentation strategies. T1 was chosen as the
parameter of interest since its value is influenced by different
cyto- and myelo-architectonical changes which are known to
occur during normal brain ageing [7].
The main finding of the study was a significant decrease of
cortical T1 values over 7 years (Fig. 2), which was more
prominent at higher ages (Fig. 3), suggesting an age-driven
acceleration of the underlying microstructural processes.
Spatial visualization of significant T1 decreases revealed a
predominant frontotemporal pattern also affecting parts of
the parietal lobe (Fig. 4), corroborating the concept of regional
selectivity in healthy brain ageing. Cortical T1 decrease was
confirmed with two different approaches, applying the cortical
maps of the second time point to both T1 maps acquired at an
interval of 7 years and performing a separate segmentation for
both time points.
Our finding of a significant GM T1 decrease in the cortex is
in line with several previous cross-sectional studies [17–20, 38].
A continuous decrease of cortical GM T1 over the whole
lifespan has been suggested [17, 18]. However, since T1
1572 Eur Radiol (2017) 27:1568–1576

Fig. 1 Cortical ROI (red), white

matter volume ROI (green) and
manually placed white matter
ROI (blue) of a representative
subject projected onto the
calculated synthetic MP-RAGE
data (top). The corresponding T1
map is shown at the bottom of the
figure. All data are presented for
three transversal slices in MNI
152 standard space (z = −2, 10,
22)

values were extracted from a single cortical ROI, the gen-
eralization of the results to the whole cortex might not be
possible because of the regional heterogeneity of age-
related cortical changes (Fig. 4). Other investigations
assessed the age dependence of the whole GM and reported
a linear decrease of GM T1 over the lifetime [19, 20, 38].
However, these studies did not distinguish between cortical
and subcortical GM in their analysis. Since an increase of
T1 in basal ganglia nuclei has been found in older subjects
[17, 18], the rate of cortical T1 decrease may have been
underestimated.
It should be noted that in contrast to these previous inves-
tigations the results presented here are based on a longitudinal
study design, which allowed for a more powerful detection of
T1 changes based on paired t test statistics.
In contrast to our results, longitudinal data published by
Papadopoulos et al. [23] did not show any significant T1 de-
creases in the cortical GM. However, considerably younger
subjects were included in the respective study (mainly 4th
decade) and a rather coarse slice thickness of 5 mm was used,
which may have influenced the results because of partial
voluming.

Fig. 2 Box plots (median, upper

and lower quartile and 95 %
confidence interval) of mean T1
relaxation times of the cortex (a)
and the white matter volume (b)
for both time points (baseline and
7 year follow-up)
Eur Radiol (2017) 27:1568–1576
Fig. 3 Cortical T1 change over time plotted against the subjects’ age at
baseline
The question arises which biological mechanisms cause the
decline of cortical T1. According to theory, T1 of brain tissue
is mainly determined by the following components: (i) the
water content, (ii) the concentrations and types of macromol-
ecules which in turn influence the water content, and (iii) the
iron content [10–12]. A strong positive linear relationship ex-
ists between T1 and water content [10], whereas T1 and iron
content are negatively correlated [12].
On this basis, we propose that an overall decrease in water
content, most likely mediated via changes in the macromolec-
ular composition of tissue, and an increase in iron levels are
the two main contributors to the observed decrease in cortical
T1. The former part of our hypothesis is heavily supported by
a previous study in which a sophisticated water mapping tech-
nique was used to demonstrate a continuous decline in GM
water content during physiological ageing [15]. This finding is
at first sight counterintuitive as one would expect a decrease of
cellular GM components due to neurodegeneration and thus
an increase in the cortical water content. In fact, it has mean-
while been shown by various histological studies that the
amount of neurons remains more or less stable during physi-
ological ageing [13, 14]. This implies an increase in neuronal
density during cortical volume loss, which seems to be more
Fig. 4 Cortical projection of
clusters indicating significant T1
reductions
1573
related to regression of the dendrites rather than neuronal
death [14].
Another candidate mechanism for the observed T1 de-
crease is iron deposition [39]. Age-related T2* decreases were
found in extensive regions of the human cortex [40], most
likely reflecting iron accumulation [41]. Cortical iron increase
during ageing was also shown by histopathological analysis
[16] and age-related alterations of iron storage in glia cells
were described by Connor et al. [42].
However, it has to be kept in mind, that other changes of
tissue microarchitecture have opposing effects on the T1
relaxation time. T1 relaxation time is also a parameter close-
ly related to myelin [9], as it is influenced by differences in
lipids and myelin-bound water [7, 43, 44]. In particular, it
has been demonstrated that cortical myelination is gradually
reduced with advancing age [45]. Accordingly, the increas-
ing T1 values observed for a few participants might be ex-
plained by predominating demyelination [46, 47], but T1-
decreasing mechanisms may outweigh this mechanism at
group level.
While T1 decrease could be observed in the cortical and the
combined GM ROI, no T1 changes could be demonstrated for
the deep GM. Previous cross-sectional studies suggested that
deep GM T1 increases at higher ages [17, 18]. The results
presented here indicate that microstructural changes might
differ between the cortex and deep grey matter. As iron depo-
sition is more prominent in deep GM [16] mechanisms that
prolong T1, such as demyelination and increased concentra-
tions of vascular lesions or widened perivascular spaces,
might counterbalance the T1 shortening caused by iron depo-
sition in deep GM.
We did not find a significant T1 increase in whole WM
analysis (Fig. 2), and also not when applying a similar WM
ROI as ref. [18] (Fig. 1). At first sight, this result is conflicting
with previous studies showing a T1 increase [17, 18, 48].
However efforts were made in the present study to avoid par-
tial voluming of the WM ROI with surrounding structures and
subcortical atherosclerotic lesions. Inclusion of such lesions
with higher T1 values in the WM ROI in previous studies
might explain the different results.
1574
Fig. 5 Cortical projection of
clusters indicating significant
reductions in cortical thickness
The cortical thickness analysis as displayed in Fig. 5 re-
vealed a widespread and rather global pattern of cortical atro-
phy over time, which appears to be accentuated in frontal,
temporal and some parietal regions, which is in good agree-
ment with several previous volumetric studies [2–4, 49, 50].
This indicates a normal rate and pattern of cortical atrophy in
our study cohort. The cortical T1 decrease was focused in
mainly lateral frontal, temporal and parietal areas, whereas
atrophy affected also mesiofrontal, inferior temporal and more
occipital areas, indicating that there might not be a one to one
correspondence between the tissue changes underlying T1
reductions and those underlying manifest atrophy.
As demonstrated in this pilot study, longitudinal T1 map-
ping unveils a specific pattern of microstructural change in
cortical GM associated with ageing in older people. This find-
ing may encourage future population-based studies to more
specifically investigate the dynamics of this pattern by
performing measurements at multiple time points and, impor-
tantly, to investigate the cognitive correlates of T1 change on
an individual basis. A multiparameter approach combining T1
mapping with other qMRI techniques, such as T2, proton
density and myelin mapping, is required to further disentangle
the effects of ageing on different microstructural compart-
ments and, also, for the search for patterns that may express
the transition from healthy to pathological ageing.
In summary, T1 mapping affords insights into changes of
the tissue architecture during physiological ageing and dem-
onstrates a cortical GM T1 decrease accentuated in the lateral
frontal, temporal and parietal lobes. These changes most likely
reflect a decreasing cortical water content and increasing iron
concentrations which may outweigh T1-increasing effects
such as age-dependent reductions in cortical myelination.
Eur Radiol (2017) 27:1568–1576
Acknowledgments The scientific guarantor of this publication is
Simon Baudrexel. The authors of this manuscript declare no relationships
with any companies relevant to this study:
Dr R.M. Gracien has received travel funding from Roche.
Dr L. Nürnberger has received travel funding from TEVA, Allergan
and Dysport.
Dr P. Hok was supported by the German Academic Exchange Service
(DAAD).
Dr Rüb has received funding from Dr. Senckenbergische Stiftung,
Frankfurt/Main, Germany.
Dr H. Steinmetz has received speaker’s honoraria from Bayer, Sanofi
and Boehringer Ingelheim.
Dr R. Hilker-Roggendorf has received speaker honoraria from
Medtronic, Orion, GlaxoSmithKline, TEVA, Cephalon, Solvay, Desitin,
and Boehringer Ingelheim as well as travel funding from Medtronic and
Cephalon. He serves or has served on a scientific advisory board for
Cephalon and has received research funding from the Deutsche
Parkinson Vereinigung (dPV), Bundesministerium für Bildung und
Forschung and Goethe-University Frankfurt.
Dr J.C. Klein received speaker honoraria and travel reimbursement
from Medtronic, AstraZeneca, Abbott Laboratories and AbbVie.
Dr R. Deichmann received compensation as a Consultant for MR
scanner procurement by the Wellcome Trust Centre for Neuroimaging,
UCL, London, UK.
Dr S. Baudrexel has received research funding from the
Bundesministerium für Bildung und Forschung and travel funding from
UCB Pharma.
This study has received funding by the Bundesministerium für
Bildung und Forschung [DLR 01GO0203; Brain Imaging Center
Frankfurt] and the Deutsche Forschungsgemeinschaft [DFG CRC-TR
128; Dr Deichmann].
One of the authors has significant statistical expertise.
Institutional review board approval was obtained.
Written informed consent was obtained from all subjects in this study.
Data from some study subjects have been previously reported in
Baudrexel S, Nürnberger L et al. Quantitative mapping of T1 and T2*
discloses nigral and brainstem pathology in early Parkinson’s disease.
NeuroImage 2010; 51(2):512–20.
Methodology: prospective, observational study performed at one
institution.
Eur Radiol (2017) 27:1568–1576
References
1. Connell J, Brazier J, O’Cathain A, Lloyd-Jones M, Paisley S (2012)
Quality of life of people with mental health problems: a synthesis of
qualitative research. Health Qual Life Outcomes 10:138
2. Fjell AM, McEvoy L, Holland D, Dale AM, Walhovd KB (2014)
What is normal in normal aging? Effects of aging, amyloid and
Alzheimer’s disease on the cerebral cortex and the hippocampus.
Prog Neurobiol 117:20–40
3. Thambisetty M, Wan J, Carass A, An Y, Prince JL, Resnick SM
(2010) Longitudinal changes in cortical thickness associated with
normal aging. NeuroImage 52:1215–1223
4. Long X, Liao W, Jiang C, Liang D, Qiu B, Zhang L (2012) Healthy
aging: an automatic analysis of global and regional morphological
alterations of human brain. Acad Radiol 19:785–793
5. Lemaitre H, Goldman AL, Sambataro F, Verchinski BA, Meyer-
Lindenberg A, Weinberger DR et al (2012) Normal age-related
brain morphometric changes: nonuniformity across cortical thick-
ness, surface area and gray matter volume? Neurobiol Aging 33:
617.e1-9
6. Tofts P (ed) (2003) Quantitative MRI of the brain: measuring
changes caused by disease. Wiley, Chichester
7. Deoni SCL (2010) Quantitative relaxometry of the brain. Top Magn
Reson Imaging 21:101–113
8. Callaghan MF, Freund P, Draganski B, Anderson E, Cappelletti M,
Chowdhury R et al (2014) Widespread age-related differences in
the human brain microstructure revealed by quantitative magnetic
resonance imaging. Neurobiol Aging 35:1862–1872
9. Lutti A, Dick F, Sereno MI, Weiskopf N (2014) Using high-
resolution quantitative mapping of R1 as an index of cortical
myelination. NeuroImage 93:176–188
10. Fatouros PP, Marmarou A, Kraft KA, Inao S, Schwarz FP (1991)
In vivo brain water determination by T1 measurements: effect of
total water content, hydration fraction, and field strength. Magn
Reson Med 17:402–413
11. Rooney WD, Johnson G, Li X, Cohen ER, Kim S-G, Ugurbil K et
al (2007) Magnetic field and tissue dependencies of human brain
longitudinal 1H2O relaxation in vivo. Magn Reson Med 57:308–
318
12. Gelman N, Ewing JR, Gorell JM, Spickler EM, Solomon EG
(2001) Interregional variation of longitudinal relaxation rates in
human brain at 3.0 T: relation to estimated iron and water contents.
Magn Reson Med 45:71–79
13. Pakkenberg B, Pelvig D, Marner L, Bundgaard MJ, Gundersen
HJG, Nyengaard JR et al (2003) Aging and the human neocortex.
Exp Gerontol 38:95–99
14. Freeman SH, Kandel R, Cruz L, Rozkalne A, Newell K, Frosch MP
et al (2008) Preservation of neuronal number despite age-related
cortical brain atrophy in elderly subjects without Alzheimer disease.
J Neuropathol Exp Neurol 67:1205–1212
15. Neeb H, Zilles K, Shah NJ (2006) Fully-automated detection of
cerebral water content changes: study of age- and gender-related
H2O patterns with quantitative MRI. NeuroImage 29:910–922
16. Hallgren B, Sourander P (1958) The effect of age on the non-
haemin iron in the human brain. J Neurochem 3:41–51
17. Steen RG, Gronemeyer SA, Taylor JS (1995) Age-related changes
in proton T1 values of normal human brain. J Magn Reson Imaging
5:43–48
18. Cho S, Jones D, Reddick WE, Ogg RJ, Steen RG (1997)
Establishing norms for age-related changes in proton T1 of human
brain tissue in vivo. Magn Reson Imaging 15:1133–1143
19. Saito N, Sakai O, Ozonoff A, Jara H (2009) Relaxo-volumetric
multispectral quantitative magnetic resonance imaging of the brain
over the human lifespan: global and regional aging patterns. Magn
Reson Imaging 27:895–906
1575
20. Suzuki S, Sakai O, Jara H (2006) Combined volumetric T1, T2 and
secular-T2 quantitative MRI of the brain: age-related global chang-
es (preliminary results). Magn Reson Imaging 24:877–887
21. Wahlund LO, Agartz I, Almqvist O, Basun H, Forssell L, Sääf J et
al (1990) The brain in healthy aged individuals: MR imaging.
Radiology 174:675–679
22. Breger RK, Yetkin FZ, Fischer ME, Papke RA, Haughton VM,
Rimm AA (1991) T1 and T2 in the cerebrum: correlation with
age, gender, and demographic factors. Radiology 181:545–547
23. Papadopoulos K, Tozer DJ, Fisniku L, Altmann DR, Davies G,
Rashid W et al (2010) TI-relaxation time changes over five years
in relapsing-remitting multiple sclerosis. Mult Scler 16:427–433
24. Preibisch C, Deichmann R (2009) Influence of RF spoiling on the
stability and accuracy of T1 mapping based on spoiled FLASH with
varying flip angles. Magn Reson Med 61:125–135
25. Gracien R-M, Reitz SC, Hof SM, Fleischer V, Zimmermann H,
Droby A et al (2015) Changes and variability of proton density
and T1 relaxation times in early multiple sclerosis: MRI markers
of neuronal damage in the cerebral cortex. Eur Rad. doi:10.1007
/s00330-015-4072-x
26. Baudrexel S, Nürnberger L, Rüb U, Seifried C, Klein JC, Deller T et
al (2010) Quantitative mapping of T1 and T2* discloses nigral and
brainstem pathology in early Parkinson’s disease. NeuroImage 51:
512–520
27. Deoni SCL, Peters TM, Rutt BK (2005) High-resolution T1 and T2
mapping of the brain in a clinically acceptable time with DESPOT1
and DESPOT2. Magn Reson Med 53:237–241
28. Yarnykh VL (2007) Actual flip-angle imaging in the pulsed steady
state: a method for rapid three-dimensional mapping of the trans-
mitted radiofrequency field. Magn Reson Med 57:192–200
29. Nöth U, Hattingen E, Bähr O, Tichy J, Deichmann R (2015)
Improved visibility of brain tumors in synthetic MP-RAGE anato-
mies with pure T1 weighting. NMR Biomed 28:818–830
30. Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens
TEJ, Johansen-Berg H et al (2004) Advances in functional and
structural MR image analysis and implementation as FSL.
NeuroImage 23(Suppl 1):19
31. Zhang Y, Brady M, Smith S (2001) Segmentation of brain MR
images through a hidden Markov random field model and the
expectation-maximization algorithm. IEEE Trans Med Imaging
20:45–57
32. Gracien RM, Jurcoane A, Wagner M, Reitz SC, Mayer C, Volz S et
al (2016) Multimodal quantitative MRI assessment of cortical dam-
age in relapsing-remitting multiple sclerosis. J Magn Reson
Imaging. doi:10.1002/jmri.25297
33. Winkler AM, Ridgway GR, Webster MA, Smith SM, Nichols TE
(2014) Permutation inference for the general linear model.
NeuroImage 92:381–397
34. Rorden C, Brett M (2000) Stereotaxic display of brain lesions.
Behav Neurol 12:191–200
35. Dale AM, Fischl B, Sereno MI (1999) Cortical surface-based anal-
ysis. I. Segmentation and surface reconstruction. NeuroImage 9:
179–194
36. Fischl B, Sereno MI, Dale AM (1999) Cortical surface-based anal-
ysis. II: inflation, flattening, and a surface-based coordinate system.
NeuroImage 9:195–207
37. Reuter M, Schmansky NJ, Rosas HD, Fischl B (2012) Within-
subject template estimation for unbiased longitudinal image analy-
sis. NeuroImage 61:1402–1418
38. Oros-Peusquens AM, Laurila M, Shah NJ (2008) Magnetic field
dependence of the distribution of NMR relaxation times in the
living human brain. Magn Reson Mater Phys 21:131–147
39. Ogg RJ, Steen RG (1998) Age-related changes in brain T1
are correlated with iron concentration. Magn Reson Med 40:
749–753
1576
40. Sedlacik J, Boelmans K, Löbel U, Holst B, Siemonsen S, Fiehler J
(2014) Reversible, irreversible and effective transverse relaxation
rates in normal aging brain at 3T. NeuroImage 84:1032–1041
41. Ordidge RJ, Gorell JM, Deniau JC, Knight RA, Helpern JA (1994)
Assessment of relative brain iron concentrations using T2-weighted
and T2*-weighted MRI at 3 Tesla. Magn Reson Med 32:335–341
42. Connor JR, Menzies SL, St Martin SM, Mufson EJ (1990) Cellular
distribution of transferrin, ferritin, and iron in normal and aged
human brains. J Neurosci Res 27:595–611
43. Koenig SH, Brown RD, Spiller M, Lundbom N (1990)
Relaxometry of brain: why white matter appears bright in MRI.
Magn Reson Med 14:482–495
44. Koenig SH (1991) Cholesterol of myelin is the determinant of gray-
white contrast in MRI of brain. Magn Reson Med 20:285–291
45. Lintl P, Braak H (1983) Loss of intracortical myelinated fibers: a
distinctive age-related alteration in the human striate area. Acta
Neuropathol 61:178–182
Eur Radiol (2017) 27:1568–1576
46. Dinse J, Härtwich N, Waehnert MD, Tardif CL, Schäfer A, Geyer S
et al (2015) A cytoarchitecture-driven myelin model reveals area-
specific signatures in human primary and secondary areas using
ultra-high resolution in-vivo brain MRI. NeuroImage 114:71–87
47. Bock NA, Kocharyan A, Liu JV, Silva AC (2009) Visualizing the
entire cortical myelination pattern in marmosets with magnetic res-
onance imaging. J Neurosci Methods 185:15–22
48. Andersen C (1997) In vivo estimation of water content in cerebral
white matter of brain tumour patients and normal individuals: to-
wards a quantitative brain oedema definition. Acta Neurochir
(Wein) 139:249–255, discussion 255–6
49. Fjell AM, McEvoy L, Holland D, Dale AM, Walhovd KB (2013)
Brain changes in older adults at very low risk for Alzheimer’s dis-
ease. J Neurosci 33:8237–8242
50. Fjell AM, Walhovd KB (2010) Structural brain changes in aging:
courses, causes and cognitive consequences. Rev Neurosci 21:187–
221