MRI measures of temporoparietal regions show differential rates of atrophy during prodromal AD.
ABSTRACT MRI studies have demonstrated differential rates of atrophy in the entorhinal cortex and hippocampus during the prodromal phase of Alzheimer disease (AD). The current study was designed to determine whether a broader set of temporoparietal regions show differential rates of atrophy during the evolution of AD.
Sixteen regions of interest (ROIs) were analyzed on MRI scans obtained at baseline and follow-up in 66 subjects comprising three groups: controls = individuals who were cognitively normal at both baseline and follow-up; nonconverters = subjects with mild cognitive impairment (MCI) at both baseline and follow-up; converters had MCI at baseline but had progressed to AD at follow-up.
Annualized percent change was analyzed with multivariate analysis of variance (MANOVA), covaried for age. The MANOVA demonstrated an effect of group (p = 0.004). Post hoc comparisons demonstrated greater rates of atrophy for converters vs nonconverters for six ROIs: hippocampus, entorhinal cortex, temporal pole, middle temporal gyrus, fusiform gyrus, and inferior temporal gyrus. Converters showed differentially greater rates of atrophy than controls in five of the same ROIs (and inferior parietal lobule). Rates of change in clinical status were correlated with the atrophy rates in these regions. Comparisons between controls and nonconverters demonstrated no differences.
These results demonstrate that temporoparietal regions show differential rates of atrophy on MRI during prodromal Alzheimer disease (AD). MRI data correlate with measures of clinical severity and cognitive decline, suggesting the potential of these regions of interest as antemortem markers of prodromal AD.
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ABSTRACT: Regulatory qualification of a biomarker for a defined context of use provides scientifically robust assurances to sponsors and regulators that accelerate appropriate adoption of biomarkers into drug development.Alzheimer's & dementia: the journal of the Alzheimer's Association 07/2014; 10(4):421-429.e3. · 14.48 Impact Factor
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ABSTRACT: This review focuses on the ex vivo magnetic resonance imaging (MRI) modeling of medial temporal cortices and associated structures, the entorhinal verrucae and the perforant pathway. Typical in vivo MRI has limited resolution due to constraints on scan times and does not show laminae in the medial temporal lobe. Recent studies using ex vivo MRI have demonstrated lamina in the entorhinal, perirhinal, and hippocampal cortices. These studies have enabled probabilistic brain mapping that is based on the ex vivo MRI contrast, validated to histology, and subsequently mapped onto an in vivo spherically warped surface model. Probabilistic maps are applicable to other in vivo studies. J. Comp. Neurol. 521:4177–4188, 2013. © 2013 Wiley Periodicals, Inc.The Journal of Comparative Neurology 12/2013; 521(18). · 3.51 Impact Factor
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ABSTRACT: Mild Cognitive Impairment (MCI) is a transitional stage between age-related cognitive decline and Alzheimer's disease (AD). For the effective treatment of AD, it would be important to identify MCI patients at high risk for conversion to AD. In this study, we present a novel Magnetic Resonance Imaging (MRI)-based method for predicting the MCI-to-AD conversion from one to three years before the clinical diagnosis. First, we developed a novel MRI biomarker of MCI-to-AD conversion using semi-supervised learning and then integrated it with age and cognitive measures about the subjects using a supervised learning algorithm resulting in what we call the aggregate biomarker. The novel characteristics of the methods for learning the biomarkers are as follows: 1) We used a semi-supervised learning method (low density separation) for the construction of MRI biomarker as opposed to more typical supervised methods; 2) We performed a feature selection on MRI data from AD subjects and normal controls without using data from MCI subjects via regularized logistic regression; 3) We removed the aging effects from the MRI data before the classifier training to prevent possible confounding between AD and age related atrophies; 4) We constructed the aggregate biomarker by first learning a separate MRI biomarker and then combining it with age and cognitive measures about the MCI subjects at the baseline by applying a random forest classifier. We experimentally demonstrated the added value of these novel characteristics in predicting the MCI-to-AD conversion on data obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. With the ADNI data, the MRI biomarker achieved a 10-fold cross-validated area under the receiver operating characteristic curve (AUC) of 0.7661 in discriminating progressive MCI patients (pMCI) from stable MCI patients (sMCI). Our aggregate biomarker based on MRI data together with baseline cognitive measurements and age achieved a 10-fold cross-validated AUC score of 0.9020 in discriminating pMCI from sMCI. The results presented in this study demonstrate the potential of the suggested approach for early AD diagnosis and an important role of MRI in the MCI-to-AD conversion prediction. However, it is evident based on our results that combining MRI data with cognitive test results improved the accuracy of the MCI-to-AD conversion prediction.NeuroImage 10/2014; · 6.13 Impact Factor
MRI measures of temporoparietal regions
show differential rates of atrophy during
R.S. Desikan, BA
B. Fischl, PhD
H.J. Cabral, PhD
T.L. Kemper, MD
C.R.G. Guttmann, MD
D. Blacker, MD
B.T. Hyman, MD
M.S. Albert, PhD
R.J. Killiany, PhD
Background: MRI studies have demonstrated differential rates of atrophy in the entorhinal cortex
and hippocampus during the prodromal phase of Alzheimer disease (AD). The current study was
designed to determine whether a broader set of temporoparietal regions show differential rates
of atrophy during the evolution of AD.
Methods: Sixteen regions of interest (ROIs) were analyzed on MRI scans obtained at baseline and
follow-up in 66 subjects comprising three groups: controls ? individuals who were cognitively
normal at both baseline and follow-up; nonconverters ? subjects with mild cognitive impairment
(MCI) at both baseline and follow-up; converters had MCI at baseline but had progressed to AD at
Results: Annualized percent change was analyzed with multivariate analysis of variance
(MANOVA), covaried for age. The MANOVA demonstrated an effect of group (p ? 0.004). Post
hoc comparisons demonstrated greater rates of atrophy for converters vs nonconverters for six
ROIs: hippocampus, entorhinal cortex, temporal pole, middle temporal gyrus, fusiform gyrus, and
of the same ROIs (and inferior parietal lobule). Rates of change in clinical status were correlated with
the atrophy rates in these regions. Comparisons between controls and nonconverters demonstrated
Conclusion: These results demonstrate that temporoparietal regions show differential rates of
atrophy on MRI during prodromal Alzheimer disease (AD). MRI data correlate with measures of
clinical severity and cognitive decline, suggesting the potential of these regions of interest as
antemortem markers of prodromal AD. Neurology®2008;71:819–825
AD ? Alzheimer disease; APC ? annualized percent change; CDR-SB ? Clinical Dementia Rating Sum of Boxes; CVLT ?
California Verbal Learning Test; MANOVA ? multivariate analysis of variance; MCI ? mild cognitive impairment; ROI ? region
of interest; SRT ? Selective Reminding Test.
Longitudinal MRI studies have focused on volumetric changes primarily in the hippocampus
and entorhinal cortex. Postmortem studies indicate that additional regions beyond hippocam-
pus and entorhinal cortex are involved in the early phases of Alzheimer disease (AD).1-5The few
longitudinal studies examining temporoparietal changes in subjects with mild cognitive im-
pairment (MCI) who progressed to AD found atrophy in inferior and middle temporal gyrus,
posterior cingulate, and precuneus,6and in medial temporal lobe and posterior cortical
Address correspondence and
reprint requests to Dr. Ronald J.
Killiany, Dept. of Anatomy and
Neurobiology, Center for
Biomedical Imaging, Boston
University School of Medicine,
Boston, MA 02118
e-Pub ahead of print on July 30, 2008, at www.neurology.org.
From the Department of Anatomy and Neurobiology (R.S.D., T.L.K., R.J.K.) and Center for Biomedical Imaging (R.J.K.), Boston University School
of Medicine; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology (B.F.), Department of Psychiatry (D.B., R.J.K.), and
Department of Neurology (B.T.H.), Massachusetts General Hospital; Computer Science and Artificial Intelligence Laboratory (B.F.), Massachusetts
Institute of Technology; Departments of Biostatistics (H.J.C.) and Environmental Health (R.J.K.), Boston University School of Public Health;
Department of Radiology (C.R.G.G., R.J.K.), Brigham and Women’s Hospital, Boston, MA; and Department of Neurology (M.S.A.), Johns
Hopkins University School of Medicine, Baltimore, MD.
Supported by grants from the National Institute on Aging (P01-AG04953), the National Center for Research Resources (P41-RR14075, R01-
RR16594, U24-RR021382), the National Institute for Biomedical Imaging and Bioengineering (R01-EB001550), the National Institute for
Neurological Diseases and Stroke (R01 NS052585), the BIRN Mophometric Project, and the Mental Illness and Neuroscience Discovery (MIND)
Disclosure: The authors report no disclosures.
Copyright © 2008 by AAN Enterprises, Inc.
regions.7Two studies have also demon-
strated differential rates of atrophy between
individuals without dementia with a domi-
nant genetic mutation in comparison to
controls in posterior cingulate, medial tem-
poral lobe, neocortical temporoparietal re-
In this study, we used analysis tools to con-
duct an assessment of temporoparietal gray
matter regions in order to determine which
regions demonstrate greater rates of atrophy
among individuals destined to develop AD.
Measures of clinical severity and neuropsy-
chological performance were available on the
subjects, allowing us to examine the relation-
ship between the atrophy rates and the rate of
change in the clinical status. The clinical rele-
vance of atrophy in the MRI measures was
also examined by performing power calcula-
tions to determine the sample size needed for
a clinical trial that used the three regions of
interest (ROIs) with the largest effect size.
METHODS Subjects. A total of 66 individuals were exam-
ined. The subjects were chosen from the larger population of
339 subject as being the only ones who met the clinical criteria
for this study and had two MRI scans that were acquired on a
1.5T GE scanner, obtained with an SPGR sequence. Subjects
were originally recruited through the print media. The details of
the screening procedures have been described elsewhere.10All
subjects provided informed consent prior to the initiation of
the study, in accordance with the requirements of the Human
Research Committee of Massachusetts General Hospital
The subjects were selected to fit into three groups based
upon their clinical status at baseline and follow-up: (A) control
(n ? 19), cognitively normal at both baseline and follow-up; (B)
nonconverter (n ? 22), MCI at both baseline and follow-up; (C)
converter (n ? 25), MCI at baseline (2 were cognitively normal
at baseline), but progressed to a diagnosis of probable AD on
follow-up (table 1). Nonconverters and converters showed no
difference (p ? 0.05) in their baseline CDR-SB scores. A com-
parison of baseline age showed a difference between the groups
(p ? 0.05). No other demographic or genetic variables differed
between the groups. Data from baseline scans for 18 of the sub-
jects have been included in prior publications related to manual
Assessment of clinical severity. The degree of clinical sever-
ity was evaluated by an annual semi-structured interview that
generated both an overall Clinical Dementia Rating (CDR) rat-
ing the CDR Sum of Boxes (CDR-SB).13The mental status eval-
uation included the Blessed Memory and Orientation Test,14a
set of similarities and differences, calculations, and a standard-
ized language evaluation. Mean inter-rater reliability of the CDR
rating was high (r ? 0.99, p ? 0.0001), as was the inter-rater
reliability of the 6 CDR subcategories (r ? 0.90).
Annually, a consensus diagnostic process determined 1) pres-
ence of sufficient impairment for a diagnosis of dementia, and if
so, 2) whether the dementia was consistent with criteria for AD15
or another entity, e.g., frontotemporal dementia, vascular de-
mentia.16,17Diagnoses were based on clinical history, medical
records, laboratory evaluation, and neuroimaging studies (pres-
ence of infarcts). Only subjects with a diagnosis of probable AD
on follow-up were included in the converter group.
Measures of clinical status. Subjects were administered a
neuropsychological battery.10Three test scores from this battery
were selected for analysis in the present study because they had
previously been shown to be sensitive predictors of progression
from MCI to AD.18The three scores were total recall score on
the California Verbal Learning Test (CVLT),19free recall score
on the Selective Reminding Test (SRT),20and time to complete
Trail Making Test B.21Mean interval between acquisition of the
MRI scan and the semi-structured interview was 4.7 months;
mean interval between acquisition of the MRI scan and adminis-
tration of the neuropsychological tests was 3.6 months.
MRI acquisition. MRI scans were obtained at baseline and
were repeated, based on a priori criteria concerning progression
in level of clinical severity (i.e., subjects who crossed specific
Table 1Descriptive statistical information for the subjects in the study, mean (SD)
Variable ControlsNonconverters Converters
Years of age
69.7 (3.7) 70.1 (4.4) 72.8 (4.7)
Time between scans, y
3.0 (0.4)3.1 (0.7) 4.5 (3.8)
Years of education
15.8 (2.7)16.1 (2.1)14.9 (3.2)
29.7 (0.6)29.4 (1.0)28.9 (1.3)
MMSE time 2
29.7 (0.6) 27.8 (2.3) 27.8 (2.3)
0.00 (0.0) 1.34 (0.6)1.48 (0.8)
CDR-SB time 2
0.0 (0.0)1.8 (1.0)4.7 (0.6)
Total follow-up time, y
6.4 (4.3)8.8 (4.8) 9.7 (4.2)
Descriptive statistics for the groups at baseline.
MMSE ? Mini-Mental State Examination; CDR-SB ? Clinical Dementia Rating Sum of Boxes.
Neurology 71September 9, 2008
thresholds were reevaluated; those who remained stable for spe-
cific amounts of time were also reevaluated) (figure). This ap-
proach oversamples subjects who are changing the most in
comparison to those who remain stable.
MRI scans were acquired on a 1.5-T scanner (General Elec-
tric, Milwaukee, WI). T1-weighted three-dimensional spoiled
gradient echo (SPGR) scans were acquired using the following
sequence: coronal acquisition, repetition time ? 35 msec, echo
time ? 5 msec, field of view ? 220 mm, flip angle ? 45°, slice
thickness ? 1.5 mm, matrix size ? 256 * 256 NEX ? 1.
Each individual’s registered scan pair was assessed for prob-
lems of movement artifact, adequacy of scan coverage of the
whole head, and change in acquisition parameters. Scan pairs
were given a grading of unusable (unlikely to give a reliable esti-
mate of volume change) or usable. Any scan pairs with a change
that appeared to be due to poor scan pair quality were not in-
cluded in the study.
The first MRI scan was acquired at baseline for all subjects.
For controls and nonconverters, we used the follow-up scan ob-
tained approximately 3 years after baseline. For converters, we
used the scan that was obtained closest in time to the consensus
diagnosis of AD.
Regions of interest. The MRI scans were processed using the
FreeSurfer software package (http://surfer.nmr.mgh.harvard.
edu).22,23The ROIs that were generated were examined for ana-
tomic accuracy and edited by an anatomically knowledgeable
operator (R.S.D.), in order to ensure that they adhered to previ-
ously published boundary definitions.24We focused on 14 ROIs
from the temporal and parietal cortices. These included 1) banks
of superior temporal sulcus, 2) entorhinal cortex, 3) fusiform
gyrus, 4) inferior parietal lobule, 5) inferior temporal gyrus, 6)
isthmus of cingulate cortex, 7) posterior cingulate cortex, 8)
middle temporal gyrus, 9) parahippocampal gyrus, 10) precu-
neus cortex, 11) superior parietal lobule, 12) superior temporal
gyrus, 13) supramarginal gyrus, and 14) temporal pole.
The non-neocortical regions of the brain were edited by an
anatomically knowledgeable operator (R.J.K.), as needed, in or-
der to ensure that they adhered to previously published bound-
ary definitions.12We selected two non-neocortical ROIs:
amygdala and hippocampus.
In total, 16 neocortical and non-neocortical temporoparietal
ROIs were used in this study. For all of the analyses performed
here, the volume of the right and the left hemispheres for each
individual ROI were added together. The ROIs from the base-
line scans were utilized to help identify regions on follow-up
Statistical analyses. To account for differences in the time
between MRI scans, the atrophy rate for each ROI was expressed
as annualized percent change (APC), using the formula (time-
point 1 volume ? timepoint 2 volume)/(timepoint 1 volume) *
(time between scans) * 100. This measure has been employed in
a number of previous MRI studies.26-28The APC values for each
ROI were analyzed using a multivariate analysis of variance
(MANOVA), with group as a between subject variable. Since age
differed between the groups at baseline, the MANOVA per-
formed included baseline age as a covariate. In order to deter-
mine the exact nature of the difference between the groups and
control for multiple comparisons, the overall MANOVA was by
followed by Tukey HSD tests.29
In order to compare the magnitude of the differences among
the groups in terms of rates of atrophy, effect sizes were com-
puted for those ROIs with greater rates of atrophy on the basis of
the post hoc comparisons. The effect size was measured using the
The clinical relevance of these effect size calculations was
evaluated by power calculations to determine the sample size
needed for a theoretical clinical trial that used the three with the
largest effect size. Sample size estimates needed to detect both a
25% and a 50% treatment effect were performed.31All calcula-
tions incorporated the assumption that a clinical trial should
have 90% power to detect a treatment effect, with a two-tailed
5% level of significance. Sample size estimates were recalculated
to reflect a 10% loss to follow-up, and an additional 10% loss of
MRI scans. Similar estimates were calculated for the CDR-Sum
of Boxes and the Selective Reminding Test.
Correlation coefficients were used to examine the relation-
ship between rates of atrophy in the ROIs and rates of change in
the measures of clinical status for the subjects who were MCI at
baseline. Spearman rank correlation coefficients32were utilized.
In order to account for multiple comparisons a p value of ?0.01
was used for interpreting statistical significance.
RESULTS Table 2 presents the mean APC for each
of the ROIs. The MANOVA revealed an effect of
group (Wilks’ lambda ? 2.04, df ? 32, p ? 0.004).
Post hoc comparisons demonstrated that six ROIs
were different between converters and nonconvert-
ers: hippocampus (p ? 0.001), temporal pole (p ?
0.001), entorhinal cortex (p ? 0.01), fusiform gyrus
(p ? 0.01), middle temporal gyrus (p ? 0.01), and
inferior temporal gyrus (p ? 0.01). Post hoc compari-
sons between converters and controls demonstrated
that six ROIs were different, including hippocampus
FigureSagittal reconstructions of one MRI
scan at the level of the medial
temporal lobe where the temporal
pole, entorhinal cortex, and
hippocampus are evident
Lower left panel shows more selectively the regions of in-
terest with the brain/tissue boundaries traced. Lower right
panel shows the tracing with the structures of interest la-
beled. Hipp ? hippocampus; Ent ? entorhinal cortex; Temp
Pole ? temporal pole.
Neurology 71September 9, 2008
(p ? 0.001), entorhinal cortex (p ? 0.001), temporal
pole (p ? 0.001), middle temporal gyrus (p ? 0.01),
fusiform gyrus (p ? 0.01), and inferior parietal lobule
in the comparisons between controls and nonconvert-
Table 3 shows the effect size calculations for each
ROI with a significant APC, based on the post hoc
comparisons (d values greater than 0.73 correspond
to an effect size of p ? 0.05). Between converters and
controls, large effects were observed for hippocampus
(d ? 1.69), entorhinal cortex (d ? 1.53), temporal
pole (d ? 1.51), fusiform gyrus (d ? 1.01), and mid-
dle temporal gyrus (d ? 1.0). Between converters
and nonconverters, large effects were observed for
hippocampus (d ? 1.39), temporal pole (d ? 1.17),
middle temporal gyrus (d ? 0.88), fusiform gyrus
(d ? 0.87), and entorhinal cortex (d ? 0.84).
We calculated sample size estimates needed to de-
tect 25% and 50% reduction for the ROIs that dem-
onstrated the largest effect size for comparison of
controls vs converters (i.e., entorhinal cortex, hip-
Table 2 Annualized percent change for 16 temporoparietal regions of interest in the three groups,
Temporoparietal regions of interestControls (mean APC)Nonconverters (mean APC)Converters (mean APC)
Banks superior temporal sulcus
Inferior parietal lobule
Inferior temporal gyrus
Isthmus of cingulate cortex
Middle temporal gyrus
Posterior cingulate cortex
Superior parietal lobule
Superior temporal gyrus
The symbols reflect the significant differences between the controls vs converters, and the converters vs nonconverters,
which used age-adjusted data.
*p ? 0.01.
†Only different in comparison of converters vs controls.
‡p ? 0.001.
§p ? 0.05.
¶Only different in comparison of converters vs nonconverters.
APC ? annualized percent change.
Table 3Effect size (Cohen d) calculation for the regions of interest that demonstrated different rates of
atrophy in the post hoc comparisons
Temporoparietal regions of interest Converters vs controlsConverters vs nonconvertersControls vs nonconverters
Inferior parietal lobule
Inferior temporal gyrus
Middle temporal gyrus
*p ? 0.001.
†p ? 0.01.
‡p ? 0.05.
Neurology 71September 9, 2008
pocampus, temporal pole). Estimates were calculated
for each ROI individually and for a ROI that com-
bined the three. All subjects categorized as MCI at
baseline were included in the analysis. The estimated
sample sizes were smaller for the three ROIs in com-
bination than for any of the ROIs individually (table
4). Moreover, the sample size estimates for each
MRI-based ROI were notably smaller than any clin-
ical or cognitive measures.
For the correlations between the ROIs that dif-
fered and the annualized change in clinical measures,
all of the ROIs, except the inferior parietal lobule,
demonstrated a strong relationship (hippocampus [r ?
?0.52, p ? 0.001], entorhinal cortex [r ? ?0.51,
p ? 0.001], temporal pole [r ? ?0.47, p ? 0.001],
and middle temporal gyrus [r ? ?0.46, p ? 0.002])
with CDR-SB. With CVLT, only hippocampus (r ?
0.44, p ? 0.003) showed a relationship. With SRT,
none of the ROIs showed a relationship. With Trails
B, only entorhinal cortex showed a relationship (r ?
?0.37, p ? 0.01).
DISCUSSION Results show that specific temporal
and parietal cortices have greater rates of atrophy in
MCI subjects who progress to AD within 4–5 years
than controls who remain cognitively normal and
MCI subjects who do not progress to AD within this
time frame. Three regions that were most discrim-
inate were hippocampus, entorhinal cortex, and
temporal pole. Of clinical interest, atrophy rates in
these regions correlated with changes in clinical
severity and declines in cognition. Utilizing the
atrophy rate from a combined measure of these
regions reduced the estimated sample size needed
for a clinical trial in MCI.
The hippocampal APC had the largest effect size
overall. The entorhinal cortex had a large effect size
in comparison of controls vs converters. These
findings corroborate reported progressive atrophy
in these medial temporal regions in the evolution
These results emphasize the importance of other
regions within the temporal and parietal lobes as an-
temortem markers of AD. In particular, atrophy
within the temporal pole has not been previously re-
ported. Additional regions as markers of AD include
fusiform gyrus and middle temporal gyrus. Examina-
tion of other reports reveal that these regions were
included within areas identified by comparing
groups of converters and controls, using voxel-based
morphometry6,34or fluid registration methods.7
The atrophy rates of controls and nonconverters
in this study were not different from one another.
Atrophy rates of nonconverters fell midway between
those of controls and converters for most ROIs (table
2). We found that the effect size of the entorhinal
cortex approached statistical significance in the com-
parison of controls and nonconverters indicating that
more work needs to be done to better understand the
differences between these groups.
A concern in this study pertains to the difference
in baseline age between the groups. Since converters
were older than the other groups at baseline, one pos-
sibility is that age could be a cause for the increased
rates of atrophy observed. In order to investigate this
possibility, a MANOVA, using intracranial-corrected
volumes for each ROI at the baseline timepoint, with
baseline age as a covariate and group as a between
subjects variable, was conducted. This analysis
showed that the hippocampus, entorhinal cortex,
and temporal pole did not differ between the groups
indicating that disease progression, not age, is the
The regions that did not differ between the
groups in the prodromal phase of AD are also of
interest. They include amygdala, banks of superior
temporal sulcus, superior parietal lobule, superior
Table 4 Sample size estimates needed per group to detect either 25% or 50% treatment effects using
mean rates of atrophy in subjects with mild cognitive impairment (calculated with 90% power
and an alpha level of 0.05 using unpaired two-tailed t tests)
Temporoparietal regions of interest
Based on atrophy
of scans are unusable
Combined ROI (entorhinal cortex ?
hippocampus ? temporal pole)
CDR-Sum of Boxes
467/117 514/129 565/142
Selective Reminding Test
Values are 25% treatment effect/50% treatment effect.
ROI ? region of interest; CDR ? Clinical Dementia Rating.
Neurology 71September 9, 2008