Journal of Alzheimer’s Disease 22 (2010) 507–522 507

DOI 10.3233/JAD-2010-100234
IOS Press

Longitudinal Changes in Fiber Tract Integrity

in Healthy Aging and Mild Cognitive
Impairment: A DTI Follow-Up Study
Stefan J. Teipela,b,∗, Thomas Meindlc , Maximilian Wagnerd , Bram Stieltjese , Sigrid Reutera,b ,
Karl-Heinz Hauensteinf , Massimo Filippig , Ulrike Ernemannh, Maximilian F. Reiserc and
Harald Hampeld,i,j
a
Department of Psychiatry, University Rostock, Rostock, Germany
b
DZNE, German Center for Neurodegenerative Diseases, Rostock, Germany
c
Institute for Clinical Radiology, Ludwig-Maximilian University, Munich, Germany
d
Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany
e
Division of Radiology, German Cancer Research Center, Heidelberg, Germany
f
Department of Radiology, University Rostock, Rostock, Germany
g
Institute of Experimental Neurology, Scientific Institute and University Hospital San Raffaele, Milan, Italy
h
Department of Diagnostic and Interventional Neuroradiology, University Hospital Tübingen, Germany
i
Discipline of Psychiatry and Trinity College Institute of Neuroscience (TCIN), Trinity College Dublin, The
Adelaide and Meath Hospital incorporating the National Children’s Hospital (AMiNCH), Dublin, Ireland
j
Department of Psychiatry, University of Frankfurt, Frankfurt/Main, Germany

Handling Associate Editor: Uwe Friese

Accepted 2 July 2010

Abstract. Cross-sectional studies using diffusion tensor imaging (DTI) suggest decline of the integrity of intracortically projecting
fiber tracts with aging and in neurodegenerative diseases, such as Alzheimer’s disease (AD). Longitudinal studies on the change
of fiber tract integrity in normal and pathological aging are still rare. Here, we prospectively studied 11 healthy elderly subjects
and 14 subjects with amnestic mild cognitive impairment (MCI), a clinical risk group for AD, using high-resolution DTI and
MRI at baseline and after 13 to 16 months follow-up. Fractional anisotropy (FA), a DTI measure of fiber tract integrity, was
compared across time points and groups using a repeated measures linear model and tract based spatial statistics. Additionally,
we determined rates of grey matter and white matter atrophy using automated deformation based morphometry. Healthy elderly
subjects showed decline of FA in intracortical projecting fiber tracts, such as corpus callosum, superior longitudinal fasciculus,
uncinate fasciculus, inferior fronto-occipital fasciculus, and cingulate bundle (p < 0.05, corrected for multiple comparisons).
MCI subjects showed significant FA decline predominantly in the anterior corpus callosum (p < 0.05, corrected for multiple
comparisons). Grey and white matter atrophy involved prefrontal, parietal, and temporal lobe areas in controls and prefrontal,
cingulate, and parietal lobe areas in MCI subjects and agreed with the pattern of fiber tract changes. Our findings indicate that
DTI allows detection of microstructural changes in subcortical fiber tracts over time that are related to aging as well as to early
stages of AD type neurodegeneration. The underlying mechanisms for these changes are unknown.

Keywords: Cortical connectivity, fractional anisotropy, longitudinal study

Supplementary data available online: http://dx.doi.org/10.3233/JAD-2010-100234

∗ Correspondence to: Stefan J. Teipel, M.D., Department of Psy- 18147 Rostock, Germany. Tel.: +49 01149 381 494 9610; Fax: +49
chiatry and Psychotherapy, University Rostock, Gehlsheimer Str. 20, 01149 381 494 9682; E-mail: stefan.teipel@med.uni-rostock.de.

ISSN 1387-2877/10/$27.50  2010 – IOS Press and the authors. All rights reserved
508 S.J. Teipel et al. / Longitudinal DTI in Aging and MCI
INTRODUCTION
Neuroimaging and postmortem studies indicate a
wide range of morphological brain changes with ag-
ing. Magnetic resonance imaging (MRI) studies have
demonstrated cortical grey matter loss predominant-
ly located in prefrontal regions [1], but also resem-
bling pattern of grey matter loss in Alzheimer’s disease
(AD) [2,3]. Additionally, reduction of cerebral white
matter has been described in healthy aging with pre-
dominance in prefrontal lobe regions but extending to
temporal and parietal lobe areas [4,5]. The extent of
white matter changes in association tracts was correlat-
ed with decline of regional cortical glucose consump-
tion [6]. Postmortem studies suggest a relatively mod-
erate decline of neuron numbers across age groups. For
example, neuron numbers were reported to decline by
less than 10% over an age range from 20 to 90 years [7].
In contrast, length of subcortical fibers was reported to
decline by 40% between the age of 20 and 80 years [7,
8]. Therefore, white matter changes seem to play an im-
portant role in the development of age-related changes
in brain structure and function.
Diffusion tensor imaging (DTI) has evolved as a
powerful technique to determine fiber tract integrity
in the living human brain [9]. Fractional anisotropy
(FA) derived from DTI data is among the best estab-
lished scalar markers of fiber directionality and integri-
ty [10,11]. Knowledge on the underlying neurobiolog-
ical basis of FA reductions in aging and neurodegen-
eration as determined by DTI is limited. Subcortical
ischemic lesions have frequently been associated with
aging and can reduce FA values [12]. Studies on brain
maturation suggest that FA is sensitive to increases in
axonal growth and myelination [13,14]. FA changes
have also been suggested to reflect changes in axon-
al membranes [11]. Degradation of myelin and even
axon deletion accompany normal aging [15,16]. Con-
sistently, a broad range of cross-sectional studies has
shown significant age-related changes in fiber tract in-
tegrity [17–19]. Additionally, studies in early stages
of AD suggest a specific decline of subcortical fiber
tract integrity [20–22]. Subjects with amnestic mild
cognitive impairment (MCI) are believed to represent
a predementia stage with an increased risk to develop
AD during clinical follow-up [23]. Consistently, sub-
jects with MCI show reduced fiber tract integrity in
association fiber tracts [24–26].
Longitudinal studies on fiber tract changes using DTI
in aging and neurodegenerative disease are still rare.
Over three months follow-up fractional anisotropy in
fornix, cingulum, splenium, and cerebellar peduncle
remained stable in MCI, AD, and healthy elderly sub-
jects [27]. Over a longer follow-up period of 15-
months, a single case study of a subject with pos-
terior cortical atrophy detected decline of fractional
anisotropy in the white matter in the absence of sub-
stantial decline of grey matter volume [28]. Healthy
elderly subjects showed significant decline of FA after
2 years of follow-up [29].
In the present study, we investigated longitudinal
changes of fractional anisotropy in healthy elderly sub-
jects and subjects with MCI over an average follow-up
time of 13 months in MCI subjects and 16 months in
controls. We compared changes in white matter tract
integrity with regional decline of grey and white mat-
ter volumes. We used a cross-sectional analysis of FA
values derived from the multi-center study of a novel
physical DTI phantom [30] to establish an upper-limit
for the estimate of unsystematic within-scanner vari-
ability in FA values over time. We expect that our data
will help to determine the role of regional changes of
white matter tract integrity both in healthy aging and in
predementia stages of AD.
SUBJECTS AND METHODS
Subjects
We examined 14 right-handed subjects with the clin-
ical diagnosis of amnestic MCI [mean age: 73.1 (SD
7.4) years, ranging from 60 to 88 years, 6 women, mean
years of education: 11.2 (SD 2.3)] and 11 healthy el-
derly right-handed subjects [mean age: 67.4 (SD 7.7)
years, ranging from 59 to 83 years, 4 women, mean
years of education: 12.7 (SD 3.6)].
MCI subjects were recruited from the Memory Clin-
ic at the University Munich and fulfilled the Mayo clin-
ic criteria [31] for amnestic MCI. The healthy subjects
were recruited among spouses of patients with demen-
tia attending the Memory Clinic at the University Mu-
nich, who had no subjective memory complaints and
scored within one standard deviation of the age- and
education adjusted means of the Mini-Mental-Status
Examination (MMSE) [32], CERAD cognitive bat-
tery [33], Clock-drawing-test [34] and the trail-making
test [35].
MCI subjects and controls were not significantly dif-
ferent in mean age (T = −1.9, 23 df, p = 0.07), gender
distribution (Chi2 = 0.11, Fisher’s exact test p = 0.53),
years of education (T = 1.30, 23 df, p = 0.21), or num-
 S.J. Teipel et al. / Longitudinal DTI in Aging and MCI
ber of apolipoprotein E4 (ApoE4) alleles (Chi2 = 0.12,
Fisher’s exact test p = 0.55). As expected, both groups
differed significantly in MMSE scores, with a mean
MMSE score of 26.5 (SD 1.2) in the MCI subjects and
29.3 (SD 0.6) in the controls.
All subjects underwent clinical assessment, neu-
ropsychological testing, and MRI scanning both at
baseline and follow-up. Duration of follow-up was on
average 404 (SD 44, 311 to 456) days in MCI subjects
and 472 (SD 188, 347 to 966) days in controls and was
not significantly different between groups (T = 1.31,
23 df, p = 0.20).
The clinical assessment included detailed medical
history, clinical, psychiatric, neurological and neu-
ropsychological examinations, and laboratory tests
(complete blood count, electrolytes, glucose, blood
urea nitrogen, creatinine, liver-associated enzymes,
cholesterol, HDL, triglycerides, serum B12, folate, thy-
roid function tests, coagulation, serum iron). Addition-
ally, ApoE4 genotyping was performed (see below).
Selection of subjects included a semiquantitative rat-
ing of T2-weighted MRI scans [36]. To exclude sub-
jects with significant subcortical cerebrovascular le-
sions, only subjects were included which had no sub-
cortical white matter hyperintensities exceeding 10 mm
in diameter or 3 in number.
Subjects’ consent was obtained according to the Dec-
laration of Helsinki. The study was approved by the
ethics committee and the local authorities.
Apolipoprotein E genotyping
ApoE genotyping was performed using a polymerase
chain reaction (PCR) kit for the Light Cycler system for
real-time PCR (Roche Diagnostics, Mannheim, Ger-
many). In the MCI group, there were 3 of 14 subjects
carrying at least one ApoE4 allele, in the control group
there were 3 of 11 subjects carrying at least one ApoE4
allele.
MRI acquisition
MRI acquisitions of the brain were conducted with
a 3.0 Tesla scanner with parallel imaging capabili-
ties (Magnetom TRIO, Siemens, Erlangen, Germany),
maximum gradient strength: 45 mT/m, maximum slew
rate: 200 T/m/s, 12 element head coil.
For anatomical reference, a sagittal high-resolution
3-dimensional gradient-echo sequence was performed
(magnetization prepared rapid gradient echo MPRAGE,
field-of-view 250 mm, spatial resolution 0.8 × 0.8 ×
509
0.8 mm3 , repetition time 14 ms, echo time 7.61 ms,
flip angle 20◦ , number of slices 160). To identify
white matter lesions a 2-dimensional T2-weighted se-
quence was performed (fluid attenuation inversion re-
covery FLAIR, field-of-view 230 mm, repetition time
9000 ms, echo time 117 ms, voxel size 0.9 × 0.9 ×
5.0 mm, TA 3:20 min, flip angle 180◦ , number of slices
28, acceleration factor 2).
Diffusion-weighted imaging was performed with an
echo-planar-imaging sequence (field-of-view 256 mm,
repetition time 9300 ms, echo time 102 ms, voxel size
2 × 2 × 2 mm3 , 4 repeated acquisitions, b-value =
1000, 12 directions, noise level 10, slice thickness
2.0 mm, 64 slices, no overlap). Parallel imaging was
performed with a generalized auto-calibrating partial-
ly parallel acquisition (GRAPPA, [37]) reconstruction
algorithm and an acceleration factor of 2.
Phantom study
We used a physical phantom object manufactured
by the Division of Radiology of the German Cancer
Research Center, Heidelberg, Germany. The proper-
ties of this phantom have previously been described
in detail [30]. The phantom consists of polyamide
fibers of 15 µm diameter winded around a circular
acrylic glass spindle. The phantom was measured at
five different Siemens Avanto 1.5 Tesla MRI scan-
ners (Siemens Medical Solutions, Erlangen), using
echo-planar-imaging sequences (repetition time be-
tween 5100 ms and 5300 ms, echo time 85 ms, voxel
size 2 × 2 × 2 mm3 , 3 repeated acquisitions, b-value =
1000) At three sites 30 gradient directions were used,
at the other two sites only 12 gradient directions were
available due to software restrictions. Parallel imaging
was performed with a generalized auto-calibrating par-
tially parallel acquisition (GRAPPA, [37]) reconstruc-
tion algorithm and an acceleration factor of 2.
Diffusion tensor imaging analysis
DTI data were analyzed using tract-based spatial
statistics (TBSS) v1.2 implemented in FSL 4.1 (FMRIB
Analysis Group, Oxford, UK, http://www.fmrib.ox.ac.
uk/analysis/research/tbss) [38]. TBSS has been used
in one previous longitudinal study on Huntington’s dis-
ease [39]. TBSS allows spatial reorientation of frac-
tional anisotropy (FA) maps into standard space with-
out systematic effects of spatial transformation on fiber
tract directionality and without the need to select a spa-
tial smoothing kernel that may impact the effects of
510 S.J. Teipel et al. / Longitudinal DTI in Aging and MCI
interest. The approach is based on the use of an a
priori template of fiber tracts to which the individu-
ally extracted fiber tracts of each subject are coregis-
tered. First, FA images were created by fitting a ten-
sor model to the raw diffusion data using FDT (FM-
RIB’s Diffusion Toolbox integrated in the FSL soft-
ware), and then brain-extracted using BET (Brain Ex-
traction Tool) [40]. All subjects’ FA data were then
aligned into a common space using the nonlinear regis-
tration tool FNIRT [41,42], which uses a b-spline rep-
resentation of the registration warp field [43]. Next,
the mean FA image was created and thinned to obtain
a mean FA skeleton which represents the centers of all
tracts common to the group. Each subject’s aligned FA
data was then projected onto this skeleton and the re-
sulting data fed into voxelwise within-subject statistics.
In addition to voxel-wise analysis of fiber tract maps,
we extracted mean FA values in predefined fiber tracts
using a region of interest approach. We used white
matter regions in MNI standard space as represented in
the John Hopkins University (JHU) Fiber Tract–based
Atlas of Human White Matter Anatomy [44]. This
atlas template is implemented in the FSL software. We
used an in-house written Matlab script to overlay the
white matter atlas regions with the individual fiber tract
skeletons. We extracted mean FA values for the corpus
callosum genu, body and splenium, and fornix as well
as right and left superior longitudinal fasciculus and
cingulum, as indicated in Fig. 1.
Phantom data analysis
From the DTI data obtained from the physical phan-
tom object, we reconstructed the FA maps using DTI
studio version 2.4.01 (Laboratory of Brain Anatom-
ical MRI and Center for Imaging Science at Johns
Hopkins University, Baltimore, USA, available through
http://www.mristudio.org). FA values then were mea-
sured at the most superior, inferior, left and right po-
sition of the circular FA map using circular regions of
interest (ROI) with 3 mm diameter (Fig. 2).
Structural MRI data analysis
Structural MRI data were analyzed using deforma-
tion based morphometry based on diffeomorphic image
registration as implemented in the DARTEL toolbox in
spm8 [45], available through http://www.fil.ion.ucl.ac.
uk/spm. We followed the steps proposed by a pre-
vious publication [46] and modified them accord-
ing to the DARTEL framework. The modification
was inspired by a discussion on the spm archives
website (available at https://www.jiscmail.ac.uk/cgi-
bin/wa.exe?A2=ind0804&L=SPM&P=R48484). The
following procedure was applied to the MRI scans:
1. Scans were manually aligned to place the anterior
commissure at the origin of the three-dimensional
Montreal Neurological Institute (MNI) coordi-
nate system. The first scan of each subject then
was rigidly registered to the second scan using
maximizing the mutual information of the joint
intensity histogram of the images [47].
2. The first and second scans were segmented into
grey matter and white matter maps [48]. The
resulting grey (white) matter maps were rigidly
aligned to each other.
3. The grey (white) matter maps from the first scans
were warped to the grey (white) matter maps from
the second scans using high-dimensional diffeo-
morphic image registration [45]. This step results
in a deformation field that contains a mapping
from each point in the first image to the corre-
sponding point in the second image for each sub-
ject. The amount of regional expansion or con-
traction was extracted from this field, by taking
the determinant of the gradient of the deforma-
tion at each point (Jacobian determinant) [49].
Additionally, this step yields a subject specific
template across both time points. Due to the
intra-individual matching of scans, data were not
smoothed prior to warping.
4. The grey (white) matter maps of the first and sec-
ond scan were warped with the resulting defor-
mation field and modulated with the respective
Jacobian determinant map to obtain modulated
warped grey (white) matter maps that are in align-
ment across time points for each subject in the
space of the subject specific template.
5. The subject specific templates derived from step
3 were warped to match each other across sub-
jects using high-dimensional diffeomorphic im-
age registration [45]. The resulting deformation
fields and Jacobian determinant maps were ap-
plied to the grey (white) matter maps that were in
the space of the subject specific templates from
step 4. This resulted in the baseline and follow-
up scans of each subject within a group specific
common space where the effect of different time
points was preserved in the modulated warped
grey (white) matter maps.
 S.J. Teipel et al. / Longitudinal DTI in Aging and MCI 511

A B
Fig. 1. Regions of interest superimposed on the mean fiber tract skeleton. The regions of interest from the JHU Fiber Tract–based Atlas of
Human White Matter Anatomy [44] superimposed on the averaged fiber tract skeleton (green), representing th e mean skeleton across the healthy
controls and MCI subjects, in MNI space. A) Midsagittal section with genu (red), body (blue) and splenium (yellow) of the corpus callosum, and
fornix (pink). B) Axial sections with cingulum (red) and fasciculus longitudinalis superior (blue).

Fig. 2. DTI phantom measurement. From the DTI scans of the physical phantom object (left hand side), we constructed color maps (middle)
showing the fiber directions (red represents the direction ‘left–right’) and FA maps (right hand side). The FA values were measured from the FA
maps at the most superior, inferior, left and right position using circular regions of interest with 3 mm diameter (red filled circles).

6. The group specific template defining the common
space across subjects and time points was trans-
formed to MNI standard space [50,51] using 12-
parameter affine transformation. The resulting
parameters were applied to each scan in common
space to transform scans into MNI space.
Statistical analysis
Neuropsychological data. We used a repeated mea-
sures linear model with time point as within subjects
factor and diagnosis as between subjects factor to de-
termine changes in cognitive performance over time.
The interaction of time by diagnosis was used to deter-
mine differences between groups in rates of cognitive
change.
DTI data
We determined effects of time on values of the
TBSS FA maps using a voxel-based repeated mea-
sures ANOVA model with time as repeated mea-
sures factor and diagnosis as between subjects fac-
tor. We determined the effect of time on FA values
within each diagnostic group considering both possi-
512 S.J. Teipel et al. / Longitudinal DTI in Aging and MCI
ble directions, i.e., decline and increase of FA over
time. Statistical significance was determined at p <
0.05, corrected for multiple comparisons using per-
mutation test as implemented in the FSL 4.1 sub-
module Randomize (FMRIB Analysis Group, Oxford,
UK, http://www.fmrib.ox.ac.uk/analysis/research/tbss)
using 500 permutations and threshold-free cluster en-
hancement (TFCE) [52]. TFCE is a technique that does
not need pre-statistical smoothing of images and does
not depend on an initial clusterforming threshold such
as t-statistic thresholding. However, TFCE needs sev-
eral parameters to be set. Specifically these relate to
the cluster extent (E) and peak height (H) of the statistic
at a given voxel. As suggested by [52], these were set
to E = 0.5 and H = 2.0 to provide a statistic that is
sensitive to all levels of the signal. After TFCE voxel
clusters were deemed significant at p < 0.05.
The ROI data, representing mean FA in predefined
fiber tracts, were compared across time points and
groups using a repeated measures linear model with
time as within subject factor, diagnosis and the inter-
action between time and diagnosis as between subjects
factors.
To evaluate whether differences in extent of atrophy
between groups may be related to differences in the
variability of fiber tracts across subjects, we determined
the coefficient of variation at each single voxel within
the fiber tracts as determined by TBSS. The coefficient
of variation (CV) is defined as
std(xi )
CV = , battery except the Boston naming and the Drawing
mean(xi )
with xi equal to the FA value at voxel i. We deter-
mined the minimum and maximum value as well as the
mean and median value of the CV across all voxel for
each single group (MCI and controls) and each time
point (baseline and follow-up). We also plotted the
histograms and the spatial distribution of CVs for each
group and time point to assess local differences in FA
variability.
Phantom data
FA values were averaged across the four circular ROI
positions within each scanner. We determined the CV
across the five scanners as defined above.
MRI data
The modulated warped grey (white) matter maps rep-
resenting absolute values of grey (white) matter density
were smoothed using an isotropic Gaussian kernel at
8 mm FWHM. For statistical analysis we employed the
general linear model on a voxel basis implemented in
SPM8 using repeated measures ANOVA with time as
repeated measures factor and diagnosis as between sub-
jects factor. We considered significant effects in both
directions, i.e., decrease or increase of volumes over
time. Results were thresholded at an uncorrected p-
level < 0.001, and an extent threshold of 50 contiguous
voxels was applied.
RESULTS
Neuropsychological changes
One of the 14 MCI subjects converted to dementia
and AD during follow-up, further four subjects showed
overall cognitive decline in MMSE scores but did still
not meet criteria for dementia. The other nine MCI
subjects remained cognitively stable over the follow-up
period. None of the control subjects converted to MCI
or dementia. After 13 to 16 months follow-up, there
1
was no significant change in MMSE score (F23 = 1.0,
p = 0.3) across both groups and no significant group
1
by time interaction (F23 = 0.3, p = 0.6). There was
significant decline in Boston naming test in the MCI
subjects only, and a significant decline in word flu-
ency across both groups. MCI subjects showed sig-
nificantly lower performance at baseline compared to
controls in the Clock drawing test (rated according to
Shulman et al. [34]) and all subtests of the CERAD
test, consistent with the characterization of this group
as amnestic MCI of several domains. For further de-
tails refer to Supplementary Table 1 (available online:
http://www.j-alz.com/issues/22/vol22-2.html# supple-
mentarydata05).
Decrease in FA
In the cross-sectional analysis of the baseline scans,
there were no significant differences in FA values be-
tween MCI subjects and controls at p < 0.05 correct-
ed for multiple comparisons. Healthy control subjects
showed significant decline of FA in the corpus cal-
losum, intrahemispherically projecting tracts such as
the superior longitudinal fasciculus, the inferior fronto-
occipital fasciculus and the uncinate fasciculus as well
as cortico-petal and cortico-fugal tracts of the cortico-
spinal tract and the anterior thamalic radiation (Fig. 3)
at p < 0.05, corrected for multiple comparisons. Pa-
tients with MCI showed FA reductions exclusively in
 S.J. Teipel et al. / Longitudinal DTI in Aging and MCI 513

Table 1
FA changes in different white matter tracts
Side % change % change 1 main
F23 F231 time

controls MCI effect time by diagnosis

Corpus callosum genu −1.53 −1.25 8.93∗ 0.17
Corpus callosum body −3 −2.5 20.80∗∗∗ 0.42
Corpus callosum splenium −0.89 −0.73 6.51∗ 0.05
Fornix −2.11 −10.64 4.99∗ 3.35
Cingulum R −2.23 −2.77 7.93∗ 0.02
Cingulum L −1.08 −2.33 2.80 0.11
Superior long. fasciculus R −0.44 −0.33 0.99 0.01
Superior long. fasciculus L −1.14 −0.19 2.76 1.59
Changes are given as percent change per year (relative to the mean value across both time
points).
F-values with 1 denominator and 23 nominator degrees of freedom for the main effect of time
and the interaction effect of time by diagnosis.
∗ p < 0.05; ∗∗∗ p < 0.001; R – right; L – left.

Fig. 3. Reductions of fiber tract integrity in healthy controls. Reductions of FA in healthy controls determined using TBSS, p < 0.05, corrected
for multiple comparisons using permutation test. Effects (red) are projected on a fiber tract template in MNI standard space (green). Axial slices
go from MNI (Talairach-Tournoux) coordinate z = −12 to z = 43 (40) and are 5 mm apart in MNI space. A – anterior/P – posterior. L –
left/R – right. S- superior/I – inferior. Abbreviations for tracts: ATR – anterior thalamic radiation; CCr – corpus callosum rostrum; CCs –
corpus callosum splenium; CCt – corpus callosum truncus; Cg – cingulate; CST – corticospinal tract; FMi – forceps minor; FMa – forceps major;
IFOF – inferior fronto-occipital fasciculus; SLF – superior longitudinal fasciculus; UF – uncinate fasciculus.
514 S.J. Teipel et al. / Longitudinal DTI in Aging and MCI

Fig. 4. Reductions of fiber tract integrity in MCI subjects. Reductions of FA in MCI subjects determined using TBSS, p < 0.05, corrected for
multiple comparisons using permutation test. Effects (red) are projected on a fiber tract template in MNI standard space (green). Effects are
located in corpus callosum rostrum and truncus. A – anterior/P – posterior. L – left/R – right. S – superior/I – inferior.

Table 2
the corpus callosum (Fig. 4). The opposite contrast, Coefficient of variation of FA values, averaged across all
i.e., FA increase over time, showed no effects in either tracts
of both groups. Baseline Follow-up
When we considered the interaction of time by diag- Controls MCI Controls MCI
nosis, there was no significant difference between the Minimum 0.010 0.015 0.014 0.018
MCI and the control groups in rates of FA decline in Maximum 1.021 0.982 1.082 1.074
Median 0.176 0.184 0.187 0.209
either direction at a corrected p value of 0.05. Presence Mean 0.204 0.216 0.216 0.239
of an ApoE4 allele and gender had no effect on rates of
FA decline at a corrected p value of 0.05. were not significantly different between the controls
Similar to the voxelwise analysis, using ROIs to ex- and the MCI subjects. For details refer to Table 1.
tract mean FA values from predefined fiber tracts we We determined the coefficient of variation (CV) at
found significant reductions of FA in the corpus callo- each single voxel for each group and time point. The
sum genu, body and splenium, the fornix and the right mean and median values of the CV were numerically
cingulum. FA changes were not significant in the left higher at follow-up compared to baseline and higher
cingulum and the bilateral fasciculus longitudinalis su- in MCI compared to controls. However, the difference
perior. Percent reduction of FA per year ranged be- was relatively small, as can also be seen from the his-
tween 0.20 and 10%. There was no significant time by tograms (Table 2, Fig. 5). Local maps of the CV across
diagnosis interaction, suggesting that rates of change the fiber tracts revealed no obvious differences between
 S.J. Teipel et al. / Longitudinal DTI in Aging and MCI 515

Fig. 5. Histograms of the coefficients of variation of the FA values for both groups at follow-up. The frequency counts of the coefficients of
variation (CV) are plotted for the follow-up data of the MCI group (green) and the control group (red). Although the distribution of the MCI
group is slightly shifted to the right both distribution are not significantly different from each other.

MCI and control groups at both time points. CV values
were lowest for the corpus callosum in both groups at
both time points (data not shown).
Phantom data
The coefficient of variation across the five scanners
was 6.1%.
Decrease in cortical grey matter and in white matter
density
In the cross sectional analysis of the baseline scans,
MCI subjects showed significantly reduced grey mat-
ter of bilateral lateral and medial temporal lobes as
well as bilateral superior parietal lobes compared to
controls at p < 0.001. Reductions in white matter in
MCI subjects compared to controls were restricted to
a cluster in the lateral temporal lobe white matter (da-
ta not shown). Cortical grey matter decreased over
time in control subjects in parietal, temporal and pre-
frontal association areas and in medial temporal lobes,
particularly amygdala. Decrease was also detected in
cerebellum, midbrain and precentral gyrus (Table 3).
MCI subjects exhibited decline of grey matter densi-
ty over time in more restricted cortical areas involving
prefrontal lobe regions and precuneus (Table 4). White
matter reduction in controls involved frontal, parietal
and temporal lobe white matter and parahippocampal
gyrus white matter (Table 5). Reductions in MCI sub-
jects were spatially more restricted with predominance
in frontal lobe white matter, cingulate and corpus callo-
sum (Table 6). Additionally, cerebellum white matter
was reduced. Figure 6 shows grey and white matter
reductions in healthy controls and MCI subjects. The
516 S.J. Teipel et al. / Longitudinal DTI in Aging and MCI

Table 3 Table 5
Decline of grey matter in controls Decline of white matter in controls
Coordinates (mm) Coordinates (mm)
Region Side BA x y z T24 Region Side x y z T24
Superior parietal lobule L 7 −26 −77 46 6.86 Parahippocampal gyrus L −42 −18 −21 4.75
Inferior parietal lobule L 40 −46 −61 49 6.78 Superior frontal gyrus L −17 56 −17 4.52
Precuneus R 19 16 −85 39 6.42 Superior frontal gyrus L −12 64 −8 4.45
Cerebellum declive L −35 −63 −9 4.47 Medial frontal gyrus L −10 63 5 4.08
Medial frontal gyrus L 10 0 46 12 4.42 Precentral gyrus L −39 −1 40 4.40
Midbrain L −2 −7 −4 4.4 Paracentral lobulus L −11 −24 45 4.32
Superior parietal lobule R 7 34 −67 50 5.95 Paracentral lobulus L −14 −13 45 3.86
Precuneus R 7 24 −70 53 5.26 Medial frontal gyrus L −10 −18 53 3.83
Inferior parietal lobule R 39 48 −69 42 4.42 Middle frontal gyrus L −31 32 28 4.18
Cerebellum declive R 14 −67 −15 5.72 Lingual gyrus L −19 −92 −4 4.10
Lingual gyrus R 18 20 −76 −10 4.47 Cuneus L −15 −96 2 4.08
Cerebellum culmen R 28 −61 −23 4.36 Superior temporal gyrus L −39 6 −23 3.85
Middle frontal gyrus R 10 39 61 0 4.94 Cuneus R 24 −87 −2 5.00
Superior frontal gyrus R 10 30 58 5 3.71 Middle occipital gyrus R 24 −93 3 4.98
Precentral gyrus R 6 62 3 35 4.44 Lingual gyrus R 15 −93 −4 4.55
Inferior parietal lobule R 40 59 −39 48 4.38 Middle temporal gyrus R 34 −65 20 4.19
Amygdala R 33 −5 −11 4.02 Middle temporal gyrus R 45 −69 18 3.92
Middle temporal gyrus R 31 −75 25 3.89
The height threshold was set at p < 0.001, uncorrected for multi-
Superior frontal gyrus R 17 9 57 4.09
ple comparisons. The cluster extension, representing the number of
contiguous voxels passing the height threshold was set at > 50. For legend see Table 3.
Coordinates in bold delineate a cluster and the peak T-value (24 de-
grees of freedom) within the cluster. Subsequent non-bold coordi-
by the iteratively generated group template (step 5 of
nates identify further peaks within the same cluster that meet the
significance level. the structural MRI data processing), the results were
Brain regions are indicated by Talairach and Tournoux coordinates, identical. Additionally, results remained essentially
x, y and z [50]: x = the medial to lateral distance relative to midline unchanged, when grey and white matter maps were pro-
(positive = right hemisphere); y = the anterior to posterior distance
relative to the anterior commissure (positive = anterior); z = supe-
portionally scaled to the global mean before statistical
rior to inferior distance relative to the anterior commissure -posterior analysis.
commissure line (positive = superior).
R/L = right/left.
BA = Brodmann area.
DISCUSSION
Table 4
Decline of grey matter in MCI subjects We found statistically significant decline of the in-
Coordinates (mm) tegrity of subcortical fiber tracts over 13 to 16 months
Region Side BA x y z T24 follow-up in healthy elderly subjects and subjects with
Medial frontal gyrus R 9 4 52 19 8.71 MCI. Reductions involved predominantly the corpus
Medial frontal gyrus R 10 4 65 15 5.94 callosum. Healthy elderly subjects showed additional
Medial frontal gyrus R 10 2 44 14 5.49 reductions in the cingulate bundle, the inferior fronto-
Precuneus R 19 16 −83 41 5.44
Precuneus R 7 13 −77 46 4.10 occipital fasciculus, the superior longitudinal fascicu-
Superior frontal gyrus R 9 31 43 31 5.30 lus and the uncinate fasciculus. Minor effects were
Middle frontal gyrus R 10 35 53 10 4.80 found in the anterior thalamic radiation and the corti-
For legend see Table 3. cospinal tract. Parallel to the decline of the integrity
of inter- and intra-hemsipheric projections grey matter
opposite contrasts showed a small cluster of increasing and white matter volume decreased in parietal, tem-
grey matter in the left cerebellum and an increase of a poral and prefrontal lobe areas. Our findings provide
small cluster of white matter in the right occipital lobe evidence that DTI data can be employed to determine
in controls, and no effects in MCI subjects (data not changes of white matter microstructure over time both
shown). in cognitively healthy aging and in an at risk stage of
These results had been obtained with the grey and AD.
white mater maps in MNI standard space. When we re- The spatial pattern of FA reduction in our healthy el-
peated the analysis with the grey and white matter maps derly subjects reflects those areas that have been found
remaining in the group specific native space as defined involved in normal aging in cross-sectional analysis us-
 S.J. Teipel et al. / Longitudinal DTI in Aging and MCI 517

Table 6
Decline of white matter in MCI subjects
Coordinates (mm)
Region Side x y z T24
Cingulate gyrus L −10.0 −30.0 31.0 6.74
Cingulate gyrus L −14.0 −40.0 41.0 6.31
Corpus callosum splenium L −8.0 −41.0 18.0 4.27
Medial frontal gyrus L −16.0 −10.0 49.0 5.00
Precentral gyrus L −25.0 −24.0 57.0 4.79
Paracentral lobulus L −11.0 −24.0 47.0 4.34
Corpus callosum genu L −11.0 25.0 17.0 4.88
Anterior cingulate L −11.0 19.0 24.0 4.68
Cerebellum nodule L −7.0 −56.0 −29.0 4.64
Cerebellum inferior semi-lunar lobule L −16.0 −64.0 −36.0 4.44
Cingulate gyrus R 14.0 −9.0 46.0 7.13
Postcentral gyrus R 33.0 −25.0 35.0 4.88
Medial frontal gyrus R 19.0 −10.0 56.0 4.69
Cingulate gyrus R 24.0 30.0 27.0 5.24
Cingulate gyrus R 11.0 21.0 31.0 4.04
Corpus callosum truncus R 1.0 −22.0 20.0 5.22
Caudate R 6.0 7.0 0.0 4.37
Internal capsule R 6.0 1.0 5.0 4.13
Superior frontal gyrus R 14.0 53.0 29.0 3.92
For legend see Table 3.

Fig. 6. Grey matter and white matter atrophy in MCI subjects and controls. Cluster of significant decline of grey matter (left) and white matter
(right) projected on a surface rendering of the group specific grey and white matter template, respectively, in MNI space. Effects for controls are
in red, for MCI in green. Cluster extension set at > 50 contiguous voxels passing the significance threshold of p < 0.001, uncorrected.
518 S.J. Teipel et al. / Longitudinal DTI in Aging and MCI
ing DTI, including corpus callosum,the anterior and the
posterior limb of internal capsule, the posterior periven-
tricular regions, and the deep frontal regions [17–19].
It further matches the regional pattern of FA decline
in corpus callosum and posterior cingulate in a recent
study on healthy subjects aged between 50 and 90 years
after 2 years of follow-up [29]. Our data together with
the data from this previous study [29] suggest that age
associated fiber tract changes have a high temporal dy-
namic at 60 years of age and above that may account
for the strong effects of aging found in previous cross-
sectional studies.
At baseline, FA values were not different between
MCI subjects and controls using TBSS. This is in line
with a previous study, reporting significant differences
in FA between AD patients and elderly controls, but not
between MCI patients and controls using TBSS [53]. In
contrast, we found significant reductions in grey matter
of bilateral lateral and medial temporal lobes as well as
bilateral superior parietal lobes in MCI subjects com-
pared to controls, consistent with spatial pattern of grey
matter atrophy in previous studies [54] and the charac-
terization of these subjects as an at risk group of AD.
In the longitudinal data, we found significant decline
of fiber tract integrity in corpus callosum rostrum, genu
and anterior body in MCI subjects. This is consistent
with the longitudinal decline of corpus callosum area
over time in early AD [55]. One might have expected
to find more pronounced FA decline in MCI subjects
than in controls. However, there was no statistically
significant difference between groups when consider-
ing the interaction between time and diagnosis. We
can not finally explain this finding. One possible factor
may be the relatively small number of subjects limit-
ing the sensitivity of our analysis. Another possible
reason could be a higher variability of FA values in
the MCI group compared to controls that would mask
some of the longitudinal effects. The median coeffi-
cient of variation of FA values averaged across all tracts
ranged from 17.6% to 20.9% across diagnostic groups
and time points. This compares to a CV below 10% for
measures of hippocampus or amygdala volumes across
healthy elderly controls or MCI subjects [56], suggest-
ing higher variability in FA than in volumetric mea-
sures. When we checked the overall variability of FA
values, coefficients of variation were higher in the MCI
group compared to the controls particularly at follow-
up. This suggests that trajectories of change were more
variable in MCI than in healthy aging which may have
masked some of the overall effects. However, the dif-
ferences in variation was rather moderate amounting
to a 5% to 11% higher median coefficient of variation
in MCI compared to controls (Table 1) and therefore
may not be sufficient to entirely explain the limited FA
changes in MCI compared to controls.
We complemented the voxel-based findings with
rates of change of FA in selected fiber tracts. Rates of
decline of FA ranged between 0.20% per year in supe-
rior longitudinal fasciculus and 10% per year in fornix.
For comparison, changes in hippocampus volume over
time, one of the best established imaging markers to
date, range between 0.33 and 6.8% per year in aging
and AD [57]. Therefore, the reductions of FA values
over time are comparable in size to the reductions in
well established volumetric markers. Similar to the
voxel-wise analysis, there were no significant differ-
ences in rates of FA decline in the selected regions
between groups.
Follow-up studies using DTI in neurodegenerative
diseases are rare. After 3 months follow-up FA values
were not different to baseline in any of three groups
comprising 25 AD patients, 25 MCI subjects, and 25
elderly controls [27]. Probably, the follow-up interval
in this study was too short to detect age or neurodegen-
eration related changes in FA values.
We found no significant effect of ApoE4 genotype on
rates of FA decline across both diagnostic groups. In a
cross-sectional study on 53 cognitively healthy elderly
subjects, the presence of at least one ApoE4 allele had
a significant but spatially limited effect on FA values in
the left parahippocampal gyrus [58]. As only 6 of our
25 subjects carried at least one ApoE4 allele, the power
was likely not sufficient to detect such a limited effect
in our study. Likewise, gender had no significant effect
on rates of FA decline. Several cross-sectional studies
on brain aging using MRI found significant differences
between women and men in the pattern of brain atrophy,
with more pronounced age-related atrophy in frontal
and temporal lobes in men and a relative preservation
of these structures in women [59–61]. Longitudinal
studies on gender effects on brain atrophy are rare. The
lack of an effect in our sample, however, has to be
interpreted with caution, since the number of subjects
was relatively low so that a modest effect of gender on
rates of FA decline can not be precluded based on our
data.
Drift in scanner performance over time has to be
considered as potential confound in the analysis of lon-
gitudinal DTI data. A wide range of fiber tracts was
spared from significant changes over time, including
highly organized fiber tracts such as pyramidal tract
and cerebellar peduncules, but also less organized fiber
 S.J. Teipel et al. / Longitudinal DTI in Aging and MCI
tracts such as crossing fibers in the midbrain and cere-
bellum. Therefore it is unlikely that the selective in-
volvement of highly organized fiber tracts such as the
corpus callosum and less organized fiber tracts such as
longitudinal fascicles is related to scanner drift effects.
When we conducted the study, we had no access to a
physical DTI phantom to measure effects of scanner
drift over time. However, we recently scanned a novel
physical DTI phantom [30] at five different 1.5 Tesla
MRI scanners with similar hardware specifications and
acquisition protocols. Overall, the FA values measured
across the five sites showed a coefficient of variation
of 6.1%. This value represents an upper limit for the
variation of FA values due to scanner drift. As the mul-
ticenter data compromise differences in scanner hard-
ware, software and acquisition parameters, the varia-
tion due to scanner drift within one single scanner us-
ing constant scan parameters and software is expected
to lie below the multicenter variation. This notion is
supported by a study on 10 healthy subjects who were
scanned under two conditions: (i) scanned twice on the
same scanner three days apart and (ii) scanned at two
different scanners. The intracscanner CV of 2% for
FA measurements was below the inter-scanner CV of
4.5% [62]. The interval in this previous study, however,
was short (only few days), compared to the follow-up
of on average more than one year in our study. The
acquisition protocol of the phantom data differed from
the in vivo data. Specifically, three of the five sites
used 30 rather than 12 gradient directions. Although
a higher number of gradients may yield more reliable
estimates of FA values, findings from an experimental
study suggest that within the limits that are met by a
clinical protocol with 12 gradient directions, the dif-
ferences in DTI contrasts due to different numbers of
diffusion gradients are relatively small [63]. The issue
of scanner drift effects on FA measurements deserves
prospective studies using phantom measurements in a
longitudinal design.
Parallel to FA changes over time, we investigated the
pattern of grey and white matter atrophy in MCI sub-
jects and controls using deformation based morphom-
etry. The healthy elderly control subjects showed de-
cline of grey matter in superior and inferior parietal
lobes as well as prefrontal cortex and medial tempo-
ral lobes. Additionally, cerebellum grey matter was
involved. This pattern of grey matter atrophy is con-
sistent with previous reports on grey matter atrophy in
aging [1–3]. It further agrees with our DTI findings
with involvement of the superior longitudinal fascicu-
lus connecting parietal and prefrontal lobe areas [64],
519
the uncinate fasciculus projecting from hippocampus
and amygdala to the orbitfrontal cortex [65], and the
anterior and posterior corpus callosum, connecting ho-
mologous areas in bilateral prefrontal and parietal lobe
cortex [66,67]. The MCI subjects showed prefrontal
lobe atrophy, which is consistent with the involvement
of anterior corpus callosum fiber tracts in the DTI da-
ta (see supplemental figures 1 and 2 for a projection
of FA reductions and grey matter atrophy in the com-
mon MNI standard space in controls and MCI subjects,
respectively). Previous studies have described a sim-
ilar pattern of grey matter atrophy in MCI, however,
extending into parietal and temporal lobe areas [68].
Similar to the spatial distribution of grey matter at-
rophy, white matter atrophy involved frontal, parietal,
and temporal lobes, including mediotemporal areas, in
elderly subjects. This pattern is consistent with the pat-
tern of FA reduction in the subjects as determined from
the DTI data. White matter atrophy in MCI subjects
involved prefrontal lobe white matter, cingulate white
matter and corpus callosum. Additionally, cerebellum
and internal capsule were involved. Longitudinal stud-
ies on white matter atrophy in aging or MCI are rare.
The significant decline of corpus callosum white mat-
ter agrees with ROI-based findings on corpus callosum
atrophy in AD [55]. Furthermore, the involvement of
prefrontal lobe, cingulate gyrus and corpus callosum
in our MCI subjects agrees with the spatial pattern of
white matter atrophy in a study on MCI converters and
non-converters followed over 2 years [69].
All of our MCI subjects fulfilled clinical criteria for
amnestic MCI which is regarded a clinical at risk group
of AD [23,70]. However, only 5 of the MCI subjects
showed cognitive decline over the follow-up period and
only one out of these five converted to dementia and
AD. This rate of conversion of 7% per year is slight-
ly lower than the average 10% per year that has been
shown in a systematic review on 19 longitudinal studies
on rates of conversion in MCI [71]. The healthy control
subjects remained cognitively stable over the follow-up
period, with MMSE scores not dropping below 27 at
follow-up and no subject developing MCI or dementia.
Based on the concept of brain reserve capacity struc-
tural changes have to reach a critical threshold before
they become clinically manifest [72]. Therefore, de-
cline of fractional anisotropy and grey and white matter
volume in healthy controls may suggest that structural
changes precede the onset of cognitive decline.
In summary, we provide evidence for long-term lon-
gitudinal changes in fiber tract integrity in intracortical
projecting fiber systems over an average period of 13
520 S.J. Teipel et al. / Longitudinal DTI in Aging and MCI
to 16 months in healthy elderly subjects and MCI sub-
jects. The pattern of fiber tract changes was paralleled
by reductions in cortical grey matter and white matter
volumes whose distribution was consistent with the im-
pairment of connecting fiber systems. These findings
indicate that DTI may provide a useful biomarker of
structural disconnection in healthy aging and in prodro-
mal at risk stages of AD. Future studies need to employ
larger samples of subjects and will have to extend to
clinically manifest stages of AD.
ACKNOWLEDGMENTS
Part of this work was supported by grants of the
from the Interdisciplinary Faculty, Department “Age-
ing Science and Humanities”, University of Rostock,
to S.J.T., of the Hirnliga e. V. (Nürmbrecht, Germany)
to S.J.T., an investigator initiated unrestricted research
grant from Janssen-CILAG (Neuss, Germany) to H.H.
and S.J.T., and a grant from the Bundesministerium für
Bildung und Forschung (BMBF 01 GI 0102) award-
ed to the dementia network “Kompetenznetz Demen-
zen”. The study was further supported by the Science
Foundation Ireland (SFI) investigator program award
08/IN.1/B1846 to H.H. There are no conflicts of interest
associated with the work presented in this article. The
corresponding author had full access to all of the data
in the study and takes responsibility for the integrity of
the data and the accuracy of the data analysis.
Authors’ disclosures available online (http://www.j-
alz.com/disclosures/view.php?id=523).
REFERENCES
[1] Driscoll I, Davatzikos C, An Y, Wu X, Shen D, Kraut M,
Resnick SM (2009) Longitudinal pattern of regional brain vol-
ume change differentiates normal aging from MCI. Neurology
72, 1906-1913.
[2] Raji CA, Lopez OL, Kuller LH, Carmichael OT, Becker JT
(2009) Age, Alzheimer disease, and brain structure. Neurology
73, 1899-1905
[3] Davatzikos C, Xu F, An Y, Fan Y, Resnick SM (2009) Lon-
gitudinal progression of Alzheimer’s-like patterns of atrophy
in normal older adults: the SPARE-AD index. Brain 132,
2026-2035.
[4] Salat DH, Greve DN, Pacheco JL, Quinn BT, Helmer KG,
Buckner RL, Fischl B (2009) Regional white matter volume
differences in nondemented aging and Alzheimer’s disease.
Neuroimage 44, 1247-1258.
[5] Resnick SM, Pham DL, Kraut MA, Zonderman AB, Da-
vatzikos C (2003) Longitudinal magnetic resonance imaging
studies of older adults: a shrinking brain. J Neurosci 23, 3295-
3301.
[6] Kochunov P, Ramage AE, Lancaster JL, Robin DA, Narayana
S, Coyle T, Royall DR, Fox P (2009) Loss of cerebral white
matter structural integrity tracks the gray matter metabolic
decline in normal aging. Neuroimage 45, 17-28.
[7] Pakkenberg B, Pelvig D, Marner L, Bundgaard MJ, Gundersen
HJ, Nyengaard JR, Regeur L (2003) Aging and the human
neocortex. Exp Gerontol 38, 95-99.
[8] Marner L, Nyengaard JR, Tang Y, Pakkenberg B (2003)
Marked loss of myelinated nerve fibers in the human brain
with age. J Comp Neurol 462, 144-152.
[9] Teipel SJ, Meindl T, Grinberg L, Heinsen H, Hampel H (2008)
Novel MRI techniques in the assessment of dementia. Eur J
Nucl Med Mol Imaging 35(Suppl 1), S58-S69.
[10] Le Bihan D (2003) Looking into the functional architecture of
the brain with diffusion MRI. Nat Rev Neurosci 4, 469-480.
[11] Beaulieu C (2002) The basis of anisotropic water diffusion
in the nervous system – a technical review. NMR Biomed 15,
435-455.
[12] Gouw AA, Seewann A, Vrenken H, van der Flier WM,
Rozemuller JM, Barkhof F, Scheltens P, Geurts JJ (2008) Het-
erogeneity of white matter hyperintensities in Alzheimer’s
disease: post-mortem quantitative MRI and neuropathology.
Brain 131, 3286-3298.
[13] Lebel C, Walker L, Leemans A, Phillips L, Beaulieu C (2008)
Microstructural maturation of the human brain from childhood
to adulthood. Neuroimage 40, 1044-1055.
[14] Huppi PS, Dubois J (2006) Diffusion tensor imaging of brain
development. Semin Fetal Neonatal Med 11, 489-497.
[15] Aboitiz F, Rodriguez E, Olivares R, Zaidel E (1996) Age-
related changes in fibre composition of the human corpus
callosum: sex differences. Neuroreport 7, 1761-1764.
[16] Meier-Ruge W, Ulrich J, Bruhlmann M, Meier E (1992) Age-
related white matter atrophy in the human brain. Ann N Y Acad
Sci 673, 260-269.
[17] Westlye LT, Walhovd KB, Dale AM, Bjornerud A, Due-
Tonnessen P, Engvig A, Grydeland H, Tamnes CK, Ostby Y,
Fjell AM (2010) Life-span changes of the human brain white
matter: diffusion tensor imaging (DTI) and volumetry. Cereb
Cortex 20, 2055-2068.
[18] Bennett IJ, Madden DJ, Vaidya CJ, Howard DV, Howard JH, Jr.
(2009) Age-related differences in multiple measures of white
matter integrity: A diffusion tensor imaging study of healthy
aging. Hum Brain Mapp 31, 378-390
[19] Head D, Buckner RL, Shimony JS, Williams LE, Akbudak E,
Conturo TE, McAvoy M, Morris JC, Snyder AZ (2004) Differ-
ential vulnerability of anterior white matter in nondemented
aging with minimal acceleration in dementia of the Alzheimer
type: evidence from diffusion tensor imaging. Cereb Cortex
14, 410-423.
[20] Stricker NH, Schweinsburg BC, Delano-Wood L, Wieren-
ga CE, Bangen KJ, Haaland KY, Frank LR, Salmon DP,
Bondi MW (2009) Decreased white matter integrity in late-
myelinating fiber pathways in Alzheimer’s disease supports
retrogenesis. Neuroimage 45, 10-16.
[21] Nakata Y, Sato N, Abe O, Shikakura S, Arima K, Furuta
N, Uno M, Hirai S, Masutani Y, Ohtomo K, Aoki S (2008)
Diffusion abnormality in posterior cingulate fiber tracts in
Alzheimer’s disease: tract-specific analysis. Radiat Med 26,
466-473.
[22] Teipel SJ, Stahl R, Dietrich O, Schoenberg SO, Perneczky R,
Bokde AL, Reiser MF, Moller HJ, Hampel H (2007) Multi-
variate network analysis of fiber tract integrity in Alzheimer’s
disease. Neuroimage 34, 985-995.
 S.J. Teipel et al. / Longitudinal DTI in Aging and MCI
[23] Ravaglia G, Forti P, Maioli F, Martelli M, Servadei L, Brunetti
N, Pantieri G, Mariani E (2006) Conversion of mild cognitive
impairment to dementia: predictive role of mild cognitive
impairment subtypes and vascular risk factors. Dement Geriatr
Cogn Disord 21, 51-58.
[24] Stahl R, Dietrich O, Teipel SJ, Hampel H, Reiser MF, Schoen-
berg SO (2007) White matter damage in Alzheimer’s disease
and in mild cognitive impairment: assessment with diffusion
tensor MRI using parallel imaging techniques. Radiology 243,
483-492.
[25] Ukmar M, Makuc E, Onor ML, Garbin G, Trevisiol M, Cova
MA (2008) Evaluation of white matter damage in patients
with Alzheimer’s disease and in patients with mild cognitive
impairment by using diffusion tensor imaging. Radiol Med
113, 915-922.
[26] Fellgiebel A, Muller MJ, Wille P, Dellani PR, Scheurich A,
Schmidt LG, Stoeter P (2005) Color-coded diffusion-tensor-
imaging of posterior cingulate fiber tracts in mild cognitive
impairment. Neurobiol Aging 26, 1193-1198.
[27] Mielke MM, Kozauer NA, Chan KC, George M, Toroney J,
Zerrate M, Bandeen-Roche K, Wang MC, Vanzijl P, Pekar JJ,
Mori S, Lyketsos CG, Albert M (2009) Regionally-specific
diffusion tensor imaging in mild cognitive impairment and
Alzheimer’s disease. Neuroimage 46, 47-55.
[28] Duning T, Warnecke T, Mohammadi S, Lohmann H, Schiff-
bauer H, Kugel H, Knecht S, Ringelstein EB, Deppe M (2009)
Pattern and progression of white-matter changes in a case of
posterior cortical atrophy using diffusion tensor imaging. J
Neurol Neurosurg Psychiatry 80, 432-436.
[29] Barrick TR, Charlton RA, Clark CA, Markus HS White matter
structural decline in normal ageing: a prospective longitudinal
study using tract-based spatial statistics. Neuroimage 51, 565-
577.
[30] Laun FB, Huff S, Stieltjes B (2009) On the effects of dephasing
due to local gradients in diffusion tensor imaging experiments:
relevance for diffusion tensor imaging fiber phantoms. Magn
Reson Imaging 27, 541-548.
[31] Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins
PV, Ritchie K, Rossor M, Thal L, Winblad B (2001) Current
concepts in mild cognitive impairment. Arch Neurol 58, 1985-
1992.
[32] Folstein MF, Folstein SE, McHugh PR (1975) Mini-mental-
state: a practical method for grading the cognitive state of
patients for the clinician. J Psychiatr Res 12, 189-198.
[33] Berres M, Monsch AU, Bernasconi F, Thalmann B, Stahelin
HB (2000) Normal ranges of neuropsychological tests for the
diagnosis of Alzheimer’s disease. Stud Health Technol Inform
77, 195-199.
[34] Shulman KI, Shedletsky R, Silver IL (1986) The challenge of
time: Clock drawing and cognitive function in the elderly. Int
J Geriatr Psychiatry 1, 135-140.
[35] Chen P, Ratcliff G, Belle SH, Cauley JA, DeKosky ST, Gan-
guli M (2000) Cognitive tests that best discriminate between
presymptomatic AD and those who remain nondemented.
Neurology 55, 1847-1853.
[36] Scheltens P, Barkhof F, Leys D, Pruvo JP, Nauta JJP, Verm-
ersch P, Steinling M, Valk J (1993) A semiquantitative rating
scale for the assessment of signal hyperintensities on magnetic
resonance imaging. J Neurol Sci 114, 7-12.
[37] Griswold MA, Jakob PM, Heidemann RM, Nittka M, Jellus V,
Wang J, Kiefer B, Haase A (2002) Generalized autocalibrating
partially parallel acquisitions (GRAPPA). Magn Reson Med
47, 1202-1210.
521
[38] Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D,
Nichols TE, Mackay CE, Watkins KE, Ciccarelli O, Cader
MZ, Matthews PM, Behrens TEJ (2006) Tract-based spatial
statistics: Voxelwise analysis of multi-subject diffusion data.
Neuroimage 31, 1487-1505.
[39] Weaver KE, Richards TL, Liang O, Laurino MY, Samii A,
Aylward EH (2009) Longitudinal diffusion tensor imaging in
Huntington’s Disease. Exp Neurol 216, 525-529.
[40] Smith S (2002) Fast robust automated brain extraction. Hum
Brain Map 17, 143-155.
[41] Andersson JLR, Jenkinson M, Smith S (2007) in FMRIB tech-
nical report TR07JA1 .
[42] Andersson JLR, Jenkinson M, Smith S (2007) in FMRIB tech-
nical report TR07JA2.
[43] Rueckert D, Sonoda LI, Hayes C, Hill DLG, Leach MO,
Hawkes DJ (1999) Non-rigid registration using free-form de-
formations: Application to breast MR images. IEEE Trans
Med Imaging 18, 712-721.
[44] Wakana S, Jiang H, Nagae-Poetscher LM, van Zijl PC, Mori S
(2004) Fiber tract-based atlas of human white matter anatomy.
Radiology 230, 77-87.
[45] Ashburner J (2007) A fast diffeomorphic image registration
algorithm. Neuroimage 38, 95-113.
[46] Kipps CM, Duggins AJ, Mahant N, Gomes L, Ashburner J,
McCusker EA (2005) Progression of structural neuropathol-
ogy in preclinical Huntington’s disease: a tensor based mor-
phometry study. J Neurol Neurosurg Psychiatry 76, 650-655.
[47] Friston K, Ashburner J, Frith CD, Poline J-B, Heather JD,
Frackowiak RSJ (1995) Spatial registration and normalization
of images. Hum Brain Mapp 2, 165-189.
[48] Ashburner J, Friston KJ (2000) Voxel-based morphometry-the
methods. Neuroimage 11, 805-821.
[49] Freeborough PA, Fox NC (1998) Modeling brain deformations
in Alzheimer disease by fluid registration of serial 3D MR
images. J Comput Assist Tomogr 22, 838-843.
[50] Talairach J, Tournoux P (1988) Co-Planar Stereotaxic Atlas
of the Human Brain, Thieme, New York.
[51] Evans A, Collins D, Millst S, Brown E, Kelly R, Peters T
(1993) 3D statistical neuroanatomical models from 305 MRI
volumes. Proc IEEE-Nuclear Science Symposium and Medical
Imaging Conference, 1813-1817.
[52] Smith SM, Nichols TE (2009) Threshold-free cluster enhance-
ment: addressing problems of smoothing, threshold depen-
dence and localisation in cluster inference. Neuroimage 44,
83-98.
[53] Damoiseaux JS, Smith SM, Witter MP, Sanz-Arigita EJ,
Barkhof F, Scheltens P, Stam CJ, Zarei M, Rombouts SA
(2009) White matter tract integrity in aging and Alzheimer’s
disease. Hum Brain Mapp 30, 1051-1059.
[54] Hamalainen A, Tervo S, Grau-Olivares M, Niskanen E, Pen-
nanen C, Huuskonen J, Kivipelto M, Hanninen T, Tapiola M,
Vanhanen M, Hallikainen M, Helkala EL, Nissinen A, Vanni-
nen R, Soininen H (2007) Voxel-based morphometry to detect
brain atrophy in progressive mild cognitive impairment.
Neuroimage 37, 1122-1131.
[55] Teipel SJ, Bayer W, Alexander GE, Zebuhr Y, Teichberg D,
Kulic L, Schapiro MB, Moller HJ, Rapoport SI, Hampel H
(2002) Progression of corpus callosum atrophy in Alzheimer
disease. Arch Neurol 59, 243-248.
[56] Teipel SJ, Ewers M, Wolf S, Jessen F, Kölsch H, Arlt S,
Luckhaus C, Schönknecht P, Schmidtke K, Heuser I, Frölich
L, Ende G, Pantel J, Wiltfang J, Rakebrandt F, Peters O, Born
C, Kornhuber J, Hampel H (2010) Multicentre variability of
522 S.J. Teipel et al. / Longitudinal DTI in Aging and MCI
MRI-based medial temporal lobe volumetry in Alzheimer’s
disease. Psychiatry Res Neuroimaging 182, 244-250.
[57] Barnes J, Bartlett JW, van de Pol LA, Loy CT, Scahill RI,
Frost C, Thompson P, Fox NC (2009) A meta-analysis of
hippocampal atrophy rates in Alzheimer’s disease. Neurobiol
Aging 30, 1711-1723.
[58] Honea RA, Vidoni E, Harsha A, Burns JM (2009) Impact of
APOE on the healthy aging brain: a voxel-based MRI and
DTI study. J Alzheimers Dis 18, 553-564
[59] Curiati PK, Tamashiro JH, Squarzoni P, Duran FL, Santos LC,
Wajngarten M, Leite CC, Vallada H, Menezes PR, Scazufca
M, Busatto GF, Alves TC (2009) Brain structural variability
due to aging and gender in cognitively healthy Elders: results
from the Sao Paulo Ageing and Health study. AJNR Am J
Neuroradiol 30, 1850-1856.
[60] Alexander GE, Chen K, Merkley TL, Reiman EM, Caselli RJ,
Aschenbrenner M, Santerre-Lemmon L, Lewis DJ, Pietrini P,
Teipel SJ, Hampel H, Rapoport SI, Moeller JR (2006) Regional
network of magnetic resonance imaging gray matter volume
in healthy aging. Neuroreport 17, 951-956.
[61] Xu J, Kobayashi S, Yamaguchi S, Iijima K, Okada K, Ya-
mashita K (2000) Gender effects on age-related changes in
brain structure. Am J Neuroradiol 21, 112-118.
[62] Pfefferbaum A, Adalsteinsson E, Sullivan EV (2003) Replica-
bility of diffusion tensor imaging measurements of fraction-
al anisotropy and trace in brain. J Magn Reson Imaging 18,
427-433.
[63] Landman BA, Farrell JA, Jones CK, Smith SA, Prince JL, Mori
S (2007) Effects of diffusion weighting schemes on the repro-
ducibility of DTI-derived fractional anisotropy, mean diffu-
sivity, and principal eigenvector measurements at 1.5T. Neu-
roimage 36, 1123-1138.
[64] Makris N, Kennedy DN, McInerney S, Sorensen AG, Wang
R, Caviness VS, Jr., Pandya DN (2005) Segmentation of sub-
components within the superior longitudinal fascicle in hu-
mans: a quantitative, in vivo, DT-MRI study. Cereb Cortex 15,
854-869.
[65] Kier EL, Staib LH, Davis LM, Bronen RA (2004) MR imaging
of the temporal stem: anatomic dissection tractography of
the uncinate fasciculus, inferior occipitofrontal fasciculus, and
Meyer’s loop of the optic radiation. AJNR Am J Neuroradiol
25, 677-691.
[66] Sydykova D, Stahl R, Dietrich O, Ewers M, Reiser MF,
Schoenberg SO, Moller HJ, Hampel H, Teipel SJ (2006) Fiber
Connections between the Cerebral Cortex and the Corpus Cal-
losum in Alzheimer’s Disease: A Diffusion Tensor Imaging
and Voxel-Based Morphometry Study. Cereb Cortex 17, 2276-
2282
[67] De Lacoste MC, Kirkpatrick JB, Ross ED (1985) Topography
of the human corpus callosum. J Neuropathol Exp Neurol 44,
578-591.
[68] Leow AD, Yanovsky I, Parikshak N, Hua X, Lee S, Toga AW,
Jack CR, Jr., Bernstein MA, Britson PJ, Gunter JL, Ward CP,
Borowski B, Shaw LM, Trojanowski JQ, Fleisher AS, Harvey
D, Kornak J, Schuff N, Alexander GE, Weiner MW, Thomp-
son PM (2009) Alzheimer’s disease neuroimaging initiative:
a one-year follow up study using tensor-based morphome-
try correlating degenerative rates, biomarkers and cognition.
Neuroimage 45, 645-655.
[69] Misra C, Fan Y, Davatzikos C (2009) Baseline and longitudinal
patterns of brain atrophy in MCI patients, and their use in
prediction of short-term conversion to AD: results from ADNI.
Neuroimage 44, 1415-1422.
[70] Tabert MH, Manly JJ, Liu X, Pelton GH, Rosenblum S, Ja-
cobs M, Zamora D, Goodkind M, Bell K, Stern Y, Devanand
DP (2006) Neuropsychological prediction of conversion to
Alzheimer disease in patients with mild cognitive impairment.
Arch Gen Psychiatry 63, 916-924.
[71] Bruscoli M, Lovestone S (2004) Is MCI really just early de-
mentia? A systematic review of conversion studies. Int Psy-
chogeriatr 16, 129-140.
[72] Teipel SJ, Meindl T, Wagner M, Kohl T, Burger K, Reiser MF,
Herpertz S, Moller HJ, Hampel H (2009) White matter mi-
crostructure in relation to education in aging and Alzheimer’s
disease. J Alzheimers Dis 17, 571-583.