A PET study of discrimination of cerebral glucose

metabolism in Alzheimer's disease and mild cognitive

impairment
Haining Sun, Bin Hu, Zhijun Yao

Mike Jackson

School of Information Science & Engineering

Lanzhou University
Lanzhou, China

Birmingham City Business School

Birmingham City University
Birmingham, United Kingdom

AbstractImaging cerebral glucose metabolism with positron

emission tomography (PET) has been widely used in studying
Alzheimer's disease (AD) and mild cognitive impairment (MCI). In
this study, we used uoro-deoxyglucose (FDG) PET images to
investigate reduced glucose metabolism in 90 AD subjects90 MCI
subjects and 90 healthy elderly normal controls (NC). Compared to
NC, the AD showed a signicant hypometabolism in left and right
middle temporal, left cingulate gyrus, medial frontal gyrus and left
parahippocampal gyrus. Compared to NC, the MCI showed a
signicant hypometabolism in the right inferior temporal gyrus and
right fusiform gyrus. Compared to MCIs, the AD also showed a
signicant hypometabolism in left and right middle temporal, left
cingulate gyrus, left angular gyrus and right parahippocampal
gyrus. This study demonstrates the different cerebral metabolic
patterns of AD MCI and controls. It also shows that glucose
metabolism is a sensitive measure of change in cognition and
functional ability in AD and MCI, and that might be valuable in
predicting future cognitive decline.
KeywordsAlzheimer's disease; Mild cognitive impairment;
PET; metabolism

I.

INTRODUCTION

Alzheimer's disease (AD) is classically diagnosed with

clinical and cognitive assessments [11]. This diagnosis occurs
late in the disease process (at the dementia stage), and it can
only be conrmed post-mortem [10]. Patients suffering from
AD at a prodromal stage are known to present a mild cognitive
impairment (MCI) [3, 28, 30]. Amnestic decit in subjects with
MCI is associated with the highest conversion rate to AD [7,
20]. Identication of the AD process at earlier stages is critical
for the development of disease modifying treatments, which
would offer greater protection against further neuronal damage
[28]. New diagnostic tools using imaging and other biomarkers
aimed at identifying the disease at the pre-dementia (and
ultimately asymptomatic) stage are being developed to
complement and enhance the specicity of the clinical
diagnosis. Among these, positron emission tomography (PET)
plays a major role in the characterisation and diagnosis of AD
through its capacity to detect both the presence of early events
and the progression of the disease. Molecular imaging with
PET using amyloid-specic ligands can provide insight into the
underlying pathophysiology by dysfunction which can be
captured by 18F-labelled uoro-deoxyglucose (FDG) PET

imaging.
These studies have revealed reduced glucose
metabolism in the parieto-temporal gyrus and posterior
cingulate gyrus cortices in AD [8, 19, 25, 31, 36, 37]. These
regions are involved in memory processing and structural and
functional changing during resting condition and tasks with
low cognitive demand [14, 22]. Such data contain a large
amount of unique information that can be used for disease
characterisation and classication. Voxel-based approaches
have been used in order to extract differential patterns from
tracer metabolic data in healthy and diseased populations. Ttest has classically been used to analyse such data on a voxelby-voxel basis [17]. However, most of the previous studies use
small cohorts of AD patients, MCI patients and normal elderly
controls to explore and study Alzheimer's disease [2, 7, 22, 37].
In the current study, we investigated reduced glucose
metabolism by using more subjects (patients with AD, patients
with mild cognitive impairment (MCI) and normal elderly
controls) than in previous studies. We performed voxel-based
analysis using a two-sample t-test. The t-tests were used to
determine differences between each groups (AD vs. cognitively
normal, AD vs. MCI and MCI vs. cognitively normal). We
identied the discriminating regions of metabolic decits. We
then veried that these disease-specic regions contained
information could be helpful to characterise the pathology.
II.

MATERIALS AND METHODS

A. The Alzheimers Disease Neuroimaging Initiative (ADNI)

ADNI was launched in 2003 by the National Institute on
Aging (NIA), the National Institute of Biomedical Imaging and
Bioengineering (NIBIB), the Food and Drug Administration
(FDA), private pharmaceutical companies, and non-prot
organizations as a $60 million, 5-year publicprivate
partnership. The primary goal of ADNI is to test whether serial
magnetic resonance imaging (MRI), positron emission
tomography (PET), other biological markers, and clinical and
neuropsychological assessment can be combined to measure
the progression of MCI and AD. Determination of sensitive
and specic markers of very early AD progression is intended
to aid researchers and clinicians in the development of new
treatments and monitor their effectiveness [13] as well as
lessen the time and cost of clinical trials.

The principal investigator of this initiative is Michael W.

Weiner, M.D., VA Medical Center and University of California,
San Francisco. ADNI is the result of efforts of many coinvestigators from a broad range of academic institutions and
private corporations, and subjects have been recruited from
over 50 sites across the U.S. and Canada. ADNI participants
include approximately 200 cognitively normal older
individuals to be followed for 3 years, 400 people with MCI to
be followed for 3 years, and 200 people with early AD to be
followed for 2 years. Participants are evaluated at baseline, 6,
12, 18 (for MCI only), 24, and 36 months (although AD
participants do not have a 36 month evaluation).
B. Subjects
All subjects were between ages 55 and 90 and had
completed at least 6 years of education. They were uent in
Spanish or English. AD subjects were recruited with the intent
to identifying individuals with early stages of disease. They
had a Clinical Dementia Rating (CDR) of 0.5 or 1.0, a minimental state examination (MMSE) of 2026 (inclusive), and
met the criteria set by the National Institute of Neurological
and Communicative Disorders and Stroke Alzheimers Disease
and Related Disorders Association (NINCDS/ADRDA) [11]
for probable AD. MCI subjects were classied as single or
multi-domain amnestic MCI according to the criteria of
Petersen. These criterias included a CDR of 0.5, MMSE scores
between 24 and 30 (inclusive), a memory complaint veried by
an informant, objective evidence of memory loss as measured
by education-adjusted scores on the Wechsler Memory Scale
RevisedLogical Memory II, absence of signicant levels of
impairment in other cognitive domains, and preserved activities
of daily living. Cognitively normal subjects had MMSE scores
between 24 and 30, a CDR of 0, no evidence of depression, and
no memory complaints. All subjects were free of any other
signicant neurological disease besides suspected incipient or
clinically diagnosed mild to moderate AD. All subjects gave
written, informed consent prior to participation through the
local industrial revenue bonds at participating institutions.
A subset of the subjects having baseline FDG-PET scans
(n=270) was used for our analysis. Based on their diagnosis at
baseline, groups of cognitively normal elderly controls (NC;
n=90), patients with mild cognitive impairment that had
remained stable (MCI; n=90), as well as patients diagnosed
with AD (AD; n=90) were matched for age, sex, and MMSE
score distributions (TABLE I). The matched subsets were used
to remove factors of age, sex and MMSE distribution on the
extraction of discriminating patterns, such that these patterns
would not be obtained because of the inherent differences of
TABLE I.

these variables, but only because of the difference between

controls and Alzheimer patients.
C. FDG-PET Data Acquisition and Processing
Baseline resting state positron emission tomographic scans
of glucose metabolism (FDG-PET) from the ADNI database
were used for this study. All baseline PET scans were acquired
according to one of three different standardised protocols: 1)
dynamic 30-min, six frame (5min each) acquisitions starting 30
min post 18 F-labelled uoro-deoxyglucose (18F -FDG) injection;
2) quantitative 60-min dynamic protocol with continuous
scanning from injection time to calculate absolute glucose
metabolic rate using an arterial input function measured in the
carotid; and 3) a single-frame 30-min acquisition starting
30min post-injection for scanners without dynamic capability.
Subjects were asked to remain still and keep awake with eyes
open looking straight ahead for the entire acquisition.
The co-registered, averaged, normalised (standardised
image and voxel size) and smoothed to a uniform resolution (8
mm full-width at half-maximum) PET images (also known as
post-processed data) were downloaded from the LONI
repository [1]. Images were then spatially normalised to the
PET Montreal Neurological Institute brain space template,
scaled, and averaged using SPM8 (Wellcome Department of
Cognitive Neurology, Institute of Neurology, University
College London) ,implemented in a Matlab 7.0 environment.
Spatial normalisation of all images involved a 12-parameter
afne transformation, followed by nonlinear iterative spatial
transformation as provided in SPM8 software package .
III.

STATISTICAL ANALYSES

Whole brain analyses were performed by computing voxelbased statistics using SPM8, implemented in Matlab 7.0. Twosample t-tests were used to determine differences between each
of the groups (AD vs. NC, AD vs. MCI and MCI vs. NC). Only
voxels surviving false discovery rate (FDR) correction for the
entire volume at a p value below 0.001 (minimum extent 30
voxels) were accepted in the statistical analysis in order to
avoid false positive results. For visualization of the t-score
statistics (SPM{t} map), significant voxels were projected onto
the 3-dimensional rendered brain or a standard high-resolution
MR image template provided by SPM8, thus allowing
anatomic identication. The MNI coordinates of the local
maximum of each cluster were converted into Talairach
coordinates, along with T-values and cluster sizes.
IV.

RESULTS

GROUP DISTRIBUTION FOR VOXEL-BASED ANALYSIS. VALUES ARE MEANSD.

Subjects

]Diagnosis At Inclusion

NC

MCI

AD

Number of subjects

90

90

90

Age
(years)
Gender (male/female)

75.94.8
(62.2-86.0)
53/37

75.48.5
(61.5-87.3)
56/34

75.26.7
(59.0-87.0)
57/33

MMSE
Education (years)

29.41.3
16.12.9

26.91.5
15.03.2

23.41.8
14.92.7

Regions with p<0.001 (corrected) and cluster size>30

voxels were considered to be statistically significant in three
comparisons (AD vs. NC, AD vs. MCI and MCI vs. NC).
Compared to NC at baseline, AD showed a hypometabolism in
left and right middle temporal, left cingulate gyrus, medial
frontal gyrus and left parahippocampal gyrus (Table IIA). The
two-sample t-test maps of their analysis are shown in Fig. 1.
Compared to NC at baseline, the metabolism of MCI is
signicantly reduced in the right inferior temporal gyrus and
right fusiform gyrus (Table IIB, Fig.2). Compared to MCI at
baseline, AD showed a signicant hypometabolism in the left
and right middle temporal, left cingulate gyrus, left angular
gyrus and right parahippocampal gyrus (Table IIC, Fig. 3).
V.

DISCUSSION

In the present study, we used a large number of FDG-PET

subjects (n=270) at baseline to explore voxel-based group
hypometabolic comparisons. The cerebral glucose metabolism
patterens that have been found in this study which was similar
to the previous study [15] may provide effective evidences for
the early diagnosis of AD and MCI.
Fig. 1 demonstrates that the metabolism in left and right
medial temporal gyrus, left cingulate gyrus, medial frontal
gyrus and left parahippocampal gyrus is reduced in AD
compared with NC. These areas are in concordance with the
literature describing the clinical presentation of the disease, and
include regions involved in memory processing that are known
to be affected in AD. Ranganath et al. reported that medial
temporal gyrus cortices contain the fundamental circuits for
declarative memory [4]. Desgranges et al. found that the
regional metabolic decits in the left cingulate gyrus cortex and

the left hippocampal / parahippocampal gyrus are specically

related to impairments in verbal episodic memory in a resting
FDG-PET study in AD [2]. The lesions to the medial frontal
gyrus were observed to have a close relationship with apraxia
of speech, which is one of the clinical manifestations of AD
[23]. The prefrontal cortex has been shown to be involved in
working memory and was also thought to play a key role by
contributing with attentional input and information integration
[18, 24]. Fig. 2 demonstrates that the metabolism is
signicantly reduced in the right inferior temporal gyrus and
right fusiform gyrus in MCI compared with NC. As we known,
Mller et al. reported that inferior temporal gyrus are related to
object recognition [24]. Fusiform gyrus are involved in face
recognition and spatial navigation, and impaired visuospatial
information processing is thought to be a characteristic of AD
[5, 21, 32, 35].
Compared to MCI at baseline, AD shows a signicant
hypometabolism in left and right middle temporal, left
cingulate gyrus, left angular gyrus and right parahippocampal
gyrus (see Fig. 3). MJ Penniello et al. found the left angular
gyrus are related to writing [12].
Two-sample t-test patterns closely resembled the known
distribution of memory-related areas. The pattern of reduced
activity in AD has been described in posterior associative
cortices, extending to medial frontal gyrus, with a relative
preservation of metabolism in the primary cortices and
subcortical structures using PET [16, 34].
Hypometabolic patterns of Fig. 2 show that fusiform gyrus
are affected in individuals with stable MCI, followed by
progressive involvement of more posterior regions (left and

TABLE II.
INTER GROUP ANALYSIS: COMPARISON OF HYPOMETABOLISM BETWEEN EACH GROUPS {AD PATIENTS (N=90) VS. NORMAL ELDERLY
CONTROLS (N=90), AD PATIENTS (N=90) VS. MCI PATIENTS (N=90) AND MCI PATIENTS (N=90) VS. NORMAL ELDERLY CONTROLS (N=90)} AT P (FDR) <
0.001 AND CLUSTER SIZE >30 VOXELS.

Local maximum (mm)

X
Y
Z
(A)

T-value
Voxel-level

Label
(Most probable from AAL toolbox)

Cluster volume
(#Voxels)

AD_NC (corrected p<0.001)

-63

-36

-13

8.88

left middle temporal gyrus

244350

67

-32

-12

8.23

right middle temporal gyrus

399070

-2

-52

24

7.52

left cingulate gyrus

9328

-29

-34

-12

5.81

left parahippocampal gyrus

3079

51

-3

5.27

medial frontal gyrus

1949

(B)

MCI_NC (corrected p<0.001)

28

-3

-37

6.41

right fusiform gyrus

3914

-27

-2

-40

5.93

right inferior temporal gyrus

5608

(C)

AD_MCI (corrected p<0.001)

-62

-44

-10

5.57

left middle temporal gyrus

3712

68

-33

-9

5.33

right middle temporal gyrus

2537

-1

-34

31

5.27

left cingulate gyrus

3632

-46

-63

44

4.88

left angular gyrus

1016

29

-37

-7

4.75

right parahippocampal gyrus

124

Fig.1. T-statistic maps for the comparison of AD patients with cognitively normal elderly controls. Results are presented at a cluster signicance level of
p<0.001 (corrected) with minimum extent of 30 voxels

Fig. 2. T-statistic maps for the comparison of MCI patients with cognitively normal elderly controls. Results are presented at a cluster signicance level of
p<0.001 (corrected) with minimum extent of 30 voxels.

Fig. 3. T-statistic maps for the comparison of AD patients with MCI patients. Results are presented at a cluster signicance level of p<0.001 (corrected) with
minimum extent of 30 voxels.

right medial temporal gyrus, parahippocampal gyrus, cingulate

gyrus) in subjects with AD (Fig. 3). As the disease progresses,
temporal gyrus become more involved.
When mild cognitive impairment converts to AD, the
glucose hypometabolic pattern begins as fusiform gyrus, then
appeared to follow a posterior temporal circuit to nally
become predominantly temporoparietal, with participation of
frontal gyrus areas, in long-established AD (Fig. 1). From this
study, there is a highly correlated co-activation of
parahippocampal gyrus with parietal and temporal gyrus when
subjects with stable MCI were compared to the AD (Figs. 1
and Figs. 3). These finding are similar to the previous study
[15].
There are previous reports of strong interconnection of the
posterior cingulate gyrus with hippocampal formation in
individuals with AD, probably as a compensatory response for
memory encoding mechanisms [14, 22, 27]. It is also known
that the posterior cingulate gyrus have reciprocal anatomical
connections with the prefrontal gyrus (superior and middle
frontal gyrus) and the superior temporal sulcus [9].
Based on these observations, the areas with discriminative
potential would be: 1. frontal gyrus (medial and superior) and
temporal gyrus for distinguishing AD from healthy controls,
and 2. inferior temporal gyrus and fusiform gyrus for
discriminating between stable MCI subjects and healthy
controls.
ACKNOWLEDGMENT

This work was supported by the National Basic Research

Program of China (973 Program) (No.2014CB744600), the
National
Natural
Science
Foundation
of
China
(grant No.60973138, grant No.61003240), the International
Cooperation Project of Ministry of Science and Technology
(No.2013DFA11140), the National Basic Research Program of
China(973 Program) (No.2011CB711000).
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