Whole brain atrophy based on Iterative Principal Component
Analysis and MRI techniques in the study of Alzheimer’s disease
Li Kong, Zhongdan Huan, Cole Reschke, Josh Shapiro, Xiaofen Liu, Napatkamon Ayutyanont, Justin
Venditti, Wendy Lee, Eric Reiman, Kewei Chen, and the Alzheimer’s Disease Neuroimaging Initiative*
Abstract— Magnetic resonance imaging (MRI) based
whole brain atrophy has been proposed as an imaging marker
in clinical trials to evaluate the effects of potential treatments
for Alzheimer’s disease (AD) due to its objectiveness and
sensitivity confirmed by a number of studies. Our study uses an
iterative principal component analysis (IPCA) technique to
measure whole brain atrophy from sequential MRI scans from
Manuscript received December, 2008. This work was supported in parts by
grants from the National Institute on Aging (R01 AG03158, R01
MH057899, P30 AG19610, the National Institute of Mental Health (R01
MH057899, the state of Arizona, and contributions from the Banner
Alzheimer’s Foundation, the Alzheimer's Disease Neuroimaging Initiative
(ADNI) NIH grant U01 AG024904. ADNI is funded by the National
Institute on Aging, the National Institute of Biomedical Imaging and
Bioengineering (NIBIB), and through generous contributions from the
following: Pfizer Inc., Wyeth Research, Bristol-Myers Squibb, Eli Lilly and
Company, GlaxoSmithKline, Merck & Co. Inc., AstraZeneca AB, Novartis
Pharmaceuticals Corporation, Alzheimer's Association, Eisai Global
Clinical Development, Elan Corporation plc, Forest Laboratories, and the
Institute for the Study of Aging, with participation from the U.S. Food and
Drug Administration. Industry partnerships are coordinated through the
Foundation for the National Institutes of Health. The grantee organization is
the Northern California Institute for Research and Education, and the study
is coordinated by the Alzheimer's Disease Cooperative Study at the
University of California, San Diego. ADNI data are disseminated by the
Laboratory of Neuro Imaging at the University of California, Los Angeles.
Li Kong is with Mathematics Science Department, Beijing Normal
University, Beijing, 100875 China. (e-mail: kongli2005@yahoo.com.cn)
Zhongdan Huan is with Mathematics Science Department, Beijing
Normal University, Beijing, 100875 China. (e-mail: zdhuan@bnu.edu.cn)
Cole Reschke (presenting author) is with Banner Alzheimer’s Institute
and Arizona Alzheimer’s Consortium (email:
Cole.Reschke@bannerhealth.)
Josh Shapiro is with Pomona College, California (email
jis02006@mymail.pomona.edu)
Xiaofen Liu is with Banner Alzheimer’s Institute and Arizona
Alzheimer’s Consortium (email: xiaofen.lui@bannerhealth.)
Napatkamon Ayutyanont is with Banner Alzheimer’s Institute, Arizona
Alzheimer’s Consortium (email: Napatkamon.Ayutyanont@bannerhealth.)
Justin Venditti is with Banner Alzheimer’s Institute and Arizona
Alzheimer’s Consortium (email: justin.venditti@bannerhealth.)
Wendy Lee is with Banner Alzheimer’s Institute and Arizona
Alzheimer’s Consortium (email: wendy.lee@bannerhealth.)
Eric Reiman is with Banner Alzheimer’s Institute, Departments of
Psychiatry, University of Arizona, Neurogenomics Division, Translational
Genomics Research Institute and Arizona Alzheimer’s Consortium, (email:
Eric.Reiman@bannerhealth.com.)
*Data used in the preparation of this article were obtained from the
Alzheimer’s Disease Neuroimaging Initiative (ADNI) database
(www.loni.ucla.edu/ADNI). As such, the investigators within the ADNI
contributed to the design and implementation of ADNI and/or provided data
but did not participate in the analyses or writing of this report. ADNI
investigators include (complete listing available at
www.loni.ucla.edu\ADNI\Collaboration\ADNI_Manuscript_Citations.pdf)
Kewei Chen (corresponding author) is with Banner Alzheimer’s
Institute, Departments of Radiology, University of Arizona, Department of
Mathematics, Arizona State University, Arizona Alzheimer’s Consortium,
and Department of Mathematics and Statistics, Beijing Normal University
(E-mail: kchen@math.la.asu.edu and kewei.chen@bannerhealth.com).
baseline and 12month followup. IPCA-detected whole brain
atrophy was significantly different among AD, MCI and
normal controls (ANOVA p=2.3e-7, linear trend 5.9e-8 using
disease severity of 0, 1, 2 for NC, MCI and AD). The
IPCA-detected atrophy was highly correlated with the
well-established brain boundary shift integration (BBSI)
estimated whole brain atrophy (R=0.69, p=5.8e-6 for AD,
R=0.53, p=1.2e-6 for MCI and R=0.3 and p=0.06 for NC). We
conclude that IPCA based whole brain atrophy measure can be
used together with MRI technique to distinguish patients with
AD from normal controls and from MCI, and to potentially
accelerate the treatment efficacy evaluation for AD.
I. INTRODUCTION
N EUROIMAGING techniques such as magnetic
resonance imaging (MRI) are increasingly considered
important tools not only for diagnosis, but for indexing
disease progression and severity in Alzheimer’s disease
(AD) and Mild cognitive impairment (MCI) which is the
prodromal stage of AD [1][2]. Using volumetric MRI, A
number of recent studies have investigated global brain
atrophy [10, 11], regional brain atrophy (such as in medial
temporal lobe, prefrontal cortices, posterior and precuneus)
using either voxel-based morphometry [3][4][5] or manual
delineation [6][7][8][9].
Using a previously introduced technique, Iterative
Principal Component Analysis (IPCA), this study attempts
to analyze volumetric MRI data acquired over one-year
period of time (baseline and 12month follow-up) from the
AD neuroimaging initiative (ADNI) project. IPCA is an
automated procedure for the computation of the annualized
change in the whole brain volume [12]. Previous studies
have demonstrated similar results using this technique
compared to the well-established brain boundary shift
integration (BBSI) technique for data acquired from single
site comparing patients with AD to normal controls, and
comparing cognitively normal people with differential risk
of getting AD. The current study is to evaluate the potential
use of IPCA for analyzing data acquired from multiple sites
in comparison to BBSI. In addition, the IPCA computing
procedure was further improved and made compatible to the
widely-used SPM5 package
(http://www.fil.ion.ucl.ac.uk/spm). We expected that the
whole brain atrophy rates detected by IPCA were
significantly different among the 3 groups and the whole
atrophy rate with AD detected via IPCA was highly
correlated with BBSI.
 II. MATERIALS AND METHODS
A. Subjects
A total of 34 patients with AD (mean±std=76.12±7.9
years old, male/female ratio=m/f=18/16), 75 patients with
mild cognitive impaired (MCI) (75.10±7.28 years old,
m/f=46/29), and 38 normal controls (NC) (78.16±4.38 years
old, m/f= 23/15) were downloaded from MRI database
(http://www.loni.ucla.edu/ADNI/Data/) and included in our
analysis. The interval between baseline and follow-up visit
is about one year. All ADNI participants were grouped into
AD, MCI and NL groups following the international
consensus diagnosis criteria (http://www.loni.ucla.edu/
ANDI/) as below.
The criteria for normal controls were as follows:
(1) No memory complaints aside from those common to
other normal subjects of that age range;
(2) Normal memory function documented by scoring at
specific cutoffs on the Logical Memory II subscale (delayed
Paragraph Recall) from the Wechsler Memory Scaled -
Revised (the maximum score is 25):
a) greater than or equal to 9 for 16 or more years of education
b) greater than or equal to 5 for 8-15 years of education
c) greater than or equal to 3 for 0-7 years of education;
(3) Mini-Mental State Exam (MMSE) score between 24
and 30 (Exceptions may be made for subjects with less than
8 years of education at the discretion of the project director);
(4) Clinical Dementia Rating = 0;
(5) Cognitively normal, based on an absence of significant
impairment in cognitive functions or activities of daily
l i v i n g . ensure consistency among scans acquired at different sites.
The criteria for MCI were as follows:
(1) Memory complaint by subject or study partner that is
verified by a study partner;
(2) Abnormal memory function documented by scoring
below the education adjusted cutoff on the Logical Memory
II subscale (Delayed Paragraph Recall) from the Wechsler
Memory Scale –Revised (the maximum score is 25):
a) less than or equal to 8 for 16 or more years of education
b) less than or equal to 4 for 8-15 years of education
c) less than or equal to 2 for 0-7 years of education.
(3) MMSE score between 24 and 30 (Exceptions may be
made for subjects with less than 8 years of education at the
discretion of the project director);
(4)Clinical Dementia Rating = 0.5;
(5) General cognition and functional performance
sufficiently preserved such that a diagnosis of Alzheimer’s
disease cannot be made by the site physician at the time of
the screening visit.
The criteria for AD were as follows:
(1) Memory complaint by subject or study partner that is
verified by a study partner;
(2) Abnormal memory function documented by scoring
below the education adjusted cutoff on the Logical Memory
II subscale (Delayed Paragraph Recall) from the Wechsler
Memory Scale – Revised (the maximum score is 25):
a) less than or equal to 8 for 16 or more years of education
b) less than or equal to 4 for 8-15 years of education
c) less than or equal to 2 for 0-7 years of education.
(3) MMSE score is between 20 and 26 (Exceptions may be
made for subjects with less than 8 years of education at the
discretion of the protocol PI);
(4) Clinical Dementia Rating = 0.5, 1.0;
(5) NINCDS/ADRDA criteria for probable AD.
All subjects gave written informed consent for their
participations in the ADNIproject.
B. MRI method
MRI is the main component of the ADNI project.
T1-weighted images were collected using a three
dimensional magnetization prepared rapid acquisition
gradient echo (MPRAGE) sequence. All study subjects of
ADNI have 1.5 Telsa MRI scans completed at regular
intervals throughout the study. The initial scan occurred
between screening and baseline and subsequent scans occur
at every in-clinic visit. To be more specific, high-resolution
T1-weighted MRI scans were acquired on 1.5 Tesla MRI
scanners with the standard ADNI MRI protocol. A smaller
subset of data collected at 3 Tesla was not included in our
analysis. Each subject was scanned with a sagittal 3D
MP-RAGE sequence, with acquisition parameters: inversion
time (TI)/repetition time (TR): 1000/2400 ms; flip angle: 8°;
24 cm field of view; 192x192x166 acquisition matrix, and a
voxel size of 1.25x1.25x1.2 mm3. In plane, zero-filled
reconstruction yielded a 256x256 matrix for a reconstructed
voxel size of 0.9375x0.9375x1.2 mm3. Images were
calibrated with phantom-based geometric corrections to
Additional image corrections were also applied, to adjust for
scanner- and session specific calibration errors. In addition
to the original uncorrected image files, images with all of
these corrections already applied (GradWarp, B1, phantom
scaling, and N3) are available to the general scientific
community (at www.loni.ucla.edu/ADNI ). The images with
all of these corrections applied were downloaded for our
analyses both at the Beijing Normal University, Beijing
China and the Banner Alzheimer’s Institute, Phoenix,
Arizona, USA.
C. Pre-processing and the measure of the whole brain
atrophy via IPCA:
Efforts were made to implement our IPCA computing
package, originally based on SPM99, into the SPM5
computing environment (http://www.fil.ion.ucl.ac.uk/spm)
for improved pre-processing accuracy and quality. As a
pre-processing step of IPCA, SPM5 automatically registered
within-subject images (baseline and month 12 scans) for
elimination of the effect of head position/reposition
difference. Subsequently, images were segmented into the
gray/white/cerebrospinal fluid (CSF) for the construction of
the intracranial volume (TIV). The TIV values provided
baseline measurements of whole brain volumes with some
minor modifications as reported previously [12].
TABLE I
 Probable AD, Amnestic MCI and Normal Control Group Characteristics ratio (Chi-square p=0.998). As expected, there were
significant differences between AD, MCI and NC in terms of
AD MCI NC t/F score p-
value their baseline MMSE (p=0.0001), MMSE declines from
Age 76.12±7. 75.08±7. 78.16±4. 2.57 0.08 baseline to 12 month followup (p=0.001) and the difference
9 28 38 of adasm-1yr (p=0.001), Adas11-1yr difference (p=0.001).
Sex ratio 18/16 46/29 23/15 0.001 0.998 Our primary research objective was to find out whether
(m/f)
Baseline 23.44±1. 26.91±1. 29.16±1. 107.484 0.0001
whole brain atrophy rate significantly differs among AD,
MMSE 89 80 03 MCI and NC using automated IPCA. The IPCA whole brain
Baseline 1.82±3.2 0.69±1.9 -0.13±1. 7.202 0.001 atrophy detected was significantly different among AD,
MMS – 7 6 19 MCI and normal controls (ANOVA p=2.3e-7, linear trend
m12 5.9e-8 using disease severity of 0, 1, 2 for NC, MCI and
MMSE
ADAS- -4.57±5. -1.77±4. 0.92±3.8 12.698 0.001 AD), see figure 1. The IPCA results were then compared to
COGm 14 59 3 the BBSI measured atrophy. The IPCA detected whole brain
one-year atrophy was highly correlated with BBSI estimated whole
differenc brain atrophy (R=0.69, p=5.8e-6 for AD, R=0.53, p=1.2e-6
e
ADAS- -3.45±4. -1.31±3. 1.29±2.8 13.884 0.001 for MCI and R=0.3 and p=0.06 for NC).
COG 11 70 82 9
one year
differenc
e
Demographic differences between NC, MCI, and AD participants,
baseline and baseline to 12 month followup changes, were analyzed using
one-way analysis of variance (ANOVA), Fisher’s exact and Chi-square (χ2)
tests.

IPCA was then applied to estimate the volume changes

for each subject (from baseline to the 12 month follow-up).
This method considers the voxel intensity pairs from
registered MRI and identifies those pairs that are a
sufficiently large distance away from the iteratively
determined PCA major axis. The IPCA automatically
characterizes the major axis, identifies significant outliers,
and computes between-scan changes in brain volume. The
change of brain volume was expressed as I%=((Na
−Ng)/N)×100 where Na and Ng are the number voxels
reflecting significant atrophy and gain, and N is the total
number of brain voxels at baseline. The rates of brain
atrophy were expressed as percentage of volume change
divided by the interval between the scans in years, yielding
an annualized measure of brain atrophy. See [12] for
detailed technical description of the IPCA procedure.
D. Statistical methods
The data were analyzed using Student’s t test, analysis of
variance (ANOVA), and Chi-square test. The level of
significance in all statistical tests was set at p < 0.05.
ANOVA was used to examine the age, sex difference and
whole brain atrophy rate difference among AD, MCI and
normal control subjects. Assigning the disease severity as 0,
1, 2, linear trend was also examined using simple linear
regression for whole brain atrophy. Whole brain atrophy
measurement similarity between BBSI and IPCA was
examined using correlation analysis between IPCA and
BBSI.
III. RESULTS
As shown in Table 1, there was no difference between
AD, MCI and NC in terms of age (ANOVA p=0.08) or sex
Fig. 1. The whole brain atrophy detected via IPCA among AD, MCI and
normal controls.
IV. DISCUSSION
In this preliminary study, we demonstrated that the whole
brain atrophy detected by IPCA is significantly different
among the three diagnostic groups, AD/MCI/NC, and we
demonstrated that IPCA detected atrophy is highly
correlated with the atrophy measured by the well-established
BBSI method.
As a method, further studies are needed to improve IPCA
and to evaluate various setting associated with its
pre-processing steps. We have totally relied on packages
developed by other researchers to pre-process MRI for IPCA
analysis; pre-processing is exclusively SPM based.
Consistent with that practice, we made extra efforts in this
current study to pre-process the MRI data using SPM5
package instead of the older version, SPM99. Efforts were
undertaken to evaluate the use of other neuroimaging
computer packages such as FreeSurfer
(http://surfer.nmr.mgh.harvard.edu/fswiki) for MRI data
pre-processing. The ADNI MRI dataset from multiple sites
is a valuable source in our efforts to improve the IPCA
procedure.
The evaluation of the methodology and associated
settings will be performed using cross-validation scheme. In
doing so, the data will be divided into training and testing
sub-sets. Various aspects, such as different computer
packages and pre-processing settings, will be evaluated in
the training dataset, using the statistical power to distinguish
AD, MCI and NC groups and longitudinal changes among
each group. Using the optimal settings determined from the
training dataset, the testing set would be used to report the
group differences and the changes over time within each
group. As part of this evaluation, relationship between the
measured atrophy and cognitive changes will be investigated
as well.
The current study used only MRI data to which the BBSI
measures are available to compare. As part of our ADNI
data analysis efforts, we continue to download newly
available data from the ADNI/LONI website. Results based
on more inclusive dataset will be reported separately.
Though volumetric MRI is the principal component of the
ADNI project, other modal neuroimaging data such as
fluorodeoxyglucose (FDG) positron emission tomography
(PET) and Pittsburgh Compound B (PIB) PET from sub-set
of the ADNI participants are continuously being made
available to the research community worldwide. Different
neuroimaging modalities provide complementary pieces of
information regarding the disease and the disease
progression. Researchers are interested in integrated
information obtained from different modalities to increase
the statistical power and sensitivity to detect difference
among diagnostic groups and changes over time within each
group. In addition to the IPCA procedure to analyze
volumetric MRI data alone, our group has been working on
way to combine information from multi-modal datasets,
findings of such efforts to be reported separately.
One important use of the whole brain atrophy is, as an
objective and sensitive imaging marker, for evaluating
potential treatment efforts in a designed multi-center clinical
trial. The statistical power analysis results will be reported in
a separate study.
We conclude that the IPCA based whole brain atrophy
measure can be used together with MRI technique to
distinguish patients with AD from normal controls and from
MCI, and to potentially accelerate the treatment efficacy
evaluation for AD. Our results also support the use of
imaging as a surrogate marker, and recommend the use of a
completely automated algorithm, such as IPCA, as the
method of choice calculating the atrophy in clinical trials.
ACKNOWLEDGMENT
We thank Dr. Nick Fox of Dementia Research Centre,
Institute of Neurology and Centre for Medical Image
Computing, University College London, London, for his
insightful comments and discussion about a number of
methodology issues, and the use of his BBSI results. The
authors also thank Prof. Huang Haiyang of Beijing Normal
University for her encouragements.
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