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The Effect of Brain Atrophy on Cerebral Hypometabolism in the Visual Variant of Alzheimer Disease
Arun L. W. Bokde, PhD;
Pietro Pietrini, MD, PhD;
Vicente Ibáñez, MD, PhD;
Maura L. Furey, PhD;
Gene E. Alexander, PhD;
Neill R. Graff-Radford, MD;
Stanley I. Rapoport, MD;
Mark B. Schapiro, MD;
Barry Horwitz, PhD
Arch Neurol. 2001;58:480-486.
ABSTRACT
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Background Brain glucose metabolic rates measured by positron emission tomography
can be more affected by partial volume effects in Alzheimer disease (AD) than
in healthy aging because of disease-associated brain atrophy.
Objective To determine whether the distinct distribution of cerebral metabolic
lesions in patients with the visual variant of AD (AD + VS) represents a true
index of neuronal/synaptic dysfunction or is the consequence of brain atrophy.
Setting Government research hospital.
Design Resting cerebral metabolic rate for glucose was measured with positron
emission tomography in a cross-sectional study of AD and AD + VS groups and
in healthy control subjects. Segmented magnetic resonance images were used
to correct for brain atrophy.
Patients Patients with AD + VS had prominent visual and visuospatial symptoms.
There were 15 patients with AD, 10 with AD + VS, and 37 age-matched control
subjects.
Main Outcome Measure Measurement of the rate of cerebral glucose metabolism.
Results Before atrophy correction, the AD + VS group, compared with the control
subjects, showed hypometabolism in primary and extrastriate visual areas and
in parietal and superior temporal cortical areas. Compared with the AD group,
the AD + VS group showed hypometabolism in visual association areas. After
atrophy correction, hypometabolism remained significantly different between
patients and controls and between the 2 AD groups.
Conclusions The reductions in cerebral hypometabolism represent a true loss of functional
activity and are not simply an artifact caused by brain atrophy. The different
patterns of hypometabolism indicate the differential development of the lesions
between the AD and AD + VS groups.
INTRODUCTION
ALZHEIMER disease (AD) is a neurodegenerative disorder that most often
manifests itself initially through memory loss, followed by decreases in higher-order
cognitive skills such as attention, language, and planning.1, 2
Results from structural imaging studies, using both magnetic resonance (MR)
imaging and computed tomography, have shown increases in brain atrophy consistent
with the clinical and neuropathologic findings.3, 4, 5, 6
Results from functional imaging studies using positron emission tomography
(PET) have identified reductions in the regional cerebral metabolic rate for
glucose (rCMRglc)7 and oxygen8
in patients with AD compared with healthy control subjects in temporal, parietal,
and prefrontal cortex and in limbic structures.
In a less frequent clinical subtype of AD, the visual variant of AD
(AD + VS), the initial symptoms are characterized by functional impairment
in visuospatial skills in the absence of memory complaints, followed by alexia,
agraphia, and visual agnosia.9 Postmortem findings
in patients with confirmed AD + VS demonstrate a concentration of neuropathologic
lesions in occipital, parietal, and posterior cingulate cortex with a relative
sparing of the frontal and temporal lobes.9, 10, 11, 12
Structural MR imaging results have shown marked posterior cortical atrophy,11, 13 with relative sparing of frontal
and temporal cortices. Findings on PET imaging have identified reduced rCMRglc
in posterior cortical areas, with less hypometabolism in frontal and limbic
regions.14, 15, 16
Thus, patterns of brain atrophy and functional hypometabolism are different
between patients with AD + VS and those with typical AD.
Because of its limited spatial resolution, PET measures are subject
to partial volume effects (PVE), which may result in artificially decreased
values of rCMRglc. In PET studies of patients with AD, it is critical to know
if reduced rCMRglc reflects a reliable in vivo index of neuronal/synaptic
dysfunction or is merely a consequence of increased PVE caused by brain atrophy.
Recently we showed that rCMRglc remained lower in patients with typical AD
than in matched controls after PVE correction, indicating that brain atrophy
alone does not account for the observed hypometabolism.17
Given that posterior brain atrophy in patients with AD + VS is generally
greater than in patients with AD, and given its atypical distribution, the
question arises as to what proportion of the occipital hypometabolism observed
in AD + VS is caused by cortical atrophy. Our objective was to determine whether
rCMRglc abnormalities observed in patients with AD + VS are a true index of
neuronal/synaptic dysfunction, or simply a reflection of brain atrophy. We
compared rCMRglc in patients with AD + VS with that in age-matched healthy
control subjects, before and after rCMRglc was corrected for brain atrophy
by means of segmented structural MR images. To examine whether the distinct
distribution of rCMRglc abnormalities in patients with AD + VS compared with
patients with typical AD is caused by different brain atrophy patterns, we
compared these patients with AD + VS with a group of patients with typical
AD from a previously reported study.17
SUBJECTS AND METHODS
PATIENTS AND CONTROLS
We used 4 different groups: 2 patient groups and 2 healthy control groups
that have already been described.14, 17
Clinical and demographic data of the 4 groups are presented in Table 1.
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Table 1. Clinical and Demographic Characteristics of Patients With
AD + VS and Their Healthy Control Subjects and Patients With AD and Their
Healthy Control Subjects*
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The first 2 groups consisted of 10 patients with AD + VS and 18 age-matched
healthy control subjects, respectively. A detailed description of the clinical,
neuropsychological, and neuro-ophthalmologic examinations of the patients
with AD + VS is provided elsewhere.14, 18
Briefly, all patients met the National Institute of Neurological and Communicative
Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association
(NINCDS-ADRDA) criteria19 for probable AD and
had a history of early and prominent visual and visuospatial symptoms.14, 18 Nine of the 10 patients with AD +
VS were included in the original reports14, 18;
1 was recruited subsequently. The 18 healthy control subjects were part of
the original control group of 25.14, 18
One patient and 7 control subjects from the previous study were excluded because
adequate MR images were unavailable.
Data from the 15 patients with typical AD and their 19 age-matched healthy
control subjects have been published previously.17
Briefly, all patients fulfilled NINCDS-ADRDA criteria for probable AD. All
the subjects in the original report were included in this study.
Criteria for inclusion of patients in the AD + VS group are presented
in detail elsewhere.14, 18 Clinical
and psychological evidence18 demonstrate that
patients with AD + VS had more deficits in visuoconstructional abilities and
visuospatial attention than did the patients with typical AD. In addition,
the patients with AD + VS had better verbal memory than did those with typical
AD. Both patient groups differed from healthy controls in all measures of
cognitive function, including memory, visuospatial ability, and language.
Patients (or holders of durable power of attorney) and healthy control
subjects gave their written informed consent after a full explanation of the
procedures and risks of the study.
PET SCANNING
Details regarding imaging procedures have been published previously.14 Briefly, for the patients with AD + VS and their
control subjects, a Scanditronix PC-1024-7B tomograph (Scanditronix, Uppsala,
Sweden) with an in-plane resolution of 6.0 mm at full-width half-maximum (FWHM)
and axial resolution of 10 mm (FWHM) was used to measure rCMRglc following
an intravenous injection of 185 MBq of [18F] fluorodeoxyglucose.
Forty-five minutes after injection of the radiotracer, 2 interleaved sets
of 7 images offset by 6.9 mm were obtained parallel to and 10 to 100 mm above
the inferior orbitomeatal line. Subjects were studied at rest with eyes covered
and ears occluded. Arterial blood samples were collected for measurement of
plasma radioactivity and glucose concentration. Values of rCMRglc were calculated
in units of milligrams of glucose per 100 g of tissue per minute.20, 21 Images were reconstructed and then
interpolated to 48 slices for a voxel size of 2 x 2 x 2 mm.
The PET scanner used for the patients with typical AD and their control
subjects was a Scanditronix PC-2048 tomograph (Scanditronix) that acquires
15 slices with an in-plane resolution of 6.5 mm FWHM and 6.5 mm between slice
centers. Glucose metabolism was measured following an intravenous bolus injection
of 157.25 MBq of [18F] fluorodeoxyglucose, according to the same
procedure as above. The images were reconstructed and then interpolated to
43 slices with a 2 x 2 x 2-mm voxel size.
MR IMAGING
The MR images were acquired in patients with AD + VS and their control
subjects with a Picker 0.5-T scanner (Picker, Cleveland, Ohio) using both
axial and coronal T1-weighted images (repetition time, 2000 milliseconds;
echo time, 20 milliseconds). The field of view was 25 cm, with voxel sizes
of 0.976 x 0.976 x 6 mm for the coronal images and 0.976 x
0.976 x 7 mm for the axial images. In the AD + VS group, 3 subjects
had axial images and 7 had coronal images. In the healthy control group, 8
subjects had axial images and 10 had coronal images. The MR images were taken
within 2 months of the PET scans for each patient with AD + VS, except 1 whose
MR images were obtained 1 year later. For the healthy controls, 9 scans were
within 1 years of the PET scan, and the rest were within 6 years.
The MR images for the typical AD group and their control subjects were
acquired within 1 year of the PET scan. Two types of scans were used for the
atrophy correction. For 7 patients with AD and 11 controls, a Picker 0.5-T
scanner (Picker) was used, and for 8 patients with AD and 4 controls, a GE
Signa 1.5-T scanner (General Electric Co, Milwaukee, Wis) was used. The structural
images were T1 weighted (repetition time, 24 milliseconds; echo time, 5 milliseconds;
flip angle, 45°) with a field of view of 26 cm for the Picker scanner
and 24 cm for the GE scanner. Voxel sizes of the images were 1.02 x
1.02 x 2 mm for the Picker scanner and 0.938 x 0.938 x 2.0
mm for the GE scanner.
DATA ANALYSIS
Computations were performed on a Sun SPARC computer (Sun Microsystems,
Palo Alto, Calif) with ANALYZE version 7.5.4 software (BRU; Mayo Foundation,
Rochester, Minn), and also with algorithms implemented using MATLAB version
4.2 software (MathWorks Inc, Natick, Mass) and the C computer language.
The atrophy correction algorithm uses an individual's MR image to correct
for PVE in the PET scan.17, 22
Scans were edited manually for nonbrain and were segmented into brain and
cerebrospinal fluid compartments. For the AD + VS group and its healthy control
group, the 2 interleaved PET images were registered to one another.23 The MR images were then registered to the PET images
using a rigid model body transformation,24
and the same transformation was applied to the segmented MR volume. A mask
was made based on the brain tissue compartment from the segmentation. The
dispersion coefficient was calculated by the convolution of the brain mask
with the point spread function of the PET camera. The original PET volume
was then divided by the dispersion coefficients to obtain the atrophy-corrected
volume. Each PET volume was corrected separately. The algorithm limits the
corrected values to the maximum measured value before PVE correction.17
STATISTICAL ANALYSIS
The PET scans were transformed into the stereotactic space of the Talairach
and Tournoux atlas25, 26 and smoothed
with an isotropic gaussian filter (FWHM, 10 mm). The voxel dimensions after
transformation were 2 x 2 x 4 mm. Statistical parametric maps
were calculated by means of SPM95 software (Wellcome Department of Cognitive
Neurology, London, England; available at: http://www.fil.ion.ucl.ac.uk/spm/). The voxel values were normalized by proportional scaling to the global
activity. Linear contrasts were used to estimate the differences in ratio-normalized
rCMRglc, before and after PVE correction, between both patient groups and
their respective controls and between the 2 patient groups.
Regions of interest (ROIs) were used to calculate changes in absolute
CMRglc caused by PVE and group differences in regional brain volumes. The
ROIs were located at the maxima of significant differences in the statistical
parametric maps between the patients with AD + VS and their healthy controls.
The ROIs consisted of 5-mm-radius cylinders and a volume of 1.2 cm3.
Paired t tests were used to calculate whether differences
in CMRglc in each ROI before and after PVE correction were significant. Unpaired t tests were used to compute whether group differences
in regional brain volume were significant.
RESULTS
Before atrophy correction, compared with their healthy control subjects,
the patients with AD + VS showed areas of reduced rCMRglc bilaterally in primary
and association visual cortex, posterior cingulate and cuneus, and parietal
and posterior temporal areas. There were no group differences in frontal regions,
in medial and inferior temporal regions, or in subcortical structures. After
atrophy correction, the regions with significant hypometabolism remained the
same as before correction (P<.01) (Figure 1), despite larger PVE corrections in the posterior cortex
in patients with AD + VS than in control subjects. The mean PVE correction
in global CMRglc in the patients with AD + VS was significantly greater (P<.001) than in the healthy subjects. The increase for
the AD + VS group was 19.2% (range, 5.1%-31.9%) and 12.5% (range, 6.5%-19.7%)
for their healthy control group. These numbers are comparable to the increases
in mean global CMRglc PVE correction for the patients with typical AD and
their control subjects, 19.4% and 11.9%, respectively.17
Locations and z values for the peaks of the significant
differences between the AD + VS group and the healthy controls, before and
after PVE correction, are given in Table
2. Although these local maxima after atrophy correction are located
more dorsally than in the uncorrected data, their anatomic position remains
in the occipital and parietal lobes. Similar results, before and after atrophy
correction, were obtained when the AD + VS patient group was compared with
the healthy control group corresponding to the typical AD group (data not
shown).
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Figure 1. Statistical parametric maps showing
the voxels with regional cerebral metabolic rates for glucose (rCMRglc) in
the group with visual variant of Alzheimer disease (AD + VS) less than that
in the healthy control group. The projections are with a threshold of z = 2.3, uncorrected (A) and corrected (B) for partial volume effects
(PVE). The areas of significant hypometabolism in the AD + VS group did not
change after correction for PVE.
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Table 2. Local Maxima for Significant Differences in rCMRglc for AD
+ VS Group Less Than Healthy Control Group*
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The original report by Pietrini et al14
showed hypometabolism in the sensorimotor cortex of the patients with AD +
VS compared with healthy control subjects. Because we did not have MR images
for all subjects superior to 40 mm above the anterior commissure–posterior
commissure plane, we could not replicate this result here because the statistical
parametric map was limited to brain regions where MR imaging data were available.
Each patient group had a significantly smaller total brain volume (normalized
to cranial volume) than did the healthy control subjects (mean ± SD,
AD + VS, 0.730 ± 0.019; AD, 0.743 ± 0.033; healthy controls,
0.799 ± 0.031; P<.001). The 2 patient groups
were not significantly different from each other (P
= .27).
Regional CMRglc values were calculated by means of ROIs to evaluate
the percentage change in CMRglc caused by PVE correction. The ROIs were centered
at the local maxima of significant differences between the AD + VS group and
their healthy control group. In addition, 2 ROIs (in the frontal cortex) were
located at the maxima of significant hypometabolism of the typical AD group
compared with the AD + VS group. These changes are given in Table 3. In both the AD + VS patient group and the healthy control
group, there were significant increases in rCMRglc because of PVE correction
(P<.05).
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Table 3. Mean Absolute rCMRglc Before and After PVE Correction for
the AD + VS Group and Their Healthy Control Subjects*
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We calculated the proportion of brain tissue in the ROIs defined above
(Table 4). The proportion of tissue
in each ROI was significantly different (P<.05)
between the AD + VS group and the healthy control group, except in the left
medial frontal cortical ROI. The correlation coefficient between the increase
in rCMRglc caused by atrophy correction (Table 3) and the percentage of cerebrospinal fluid (defined as 100
minus percentage of brain tissue) in the ROI is 0.93 (P<.001).
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Table 4. Percentage of Brain Tissue in ROIs for AD + VS Group and Their
Healthy Control Subjects*
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The AD + VS group was significantly hypometabolic compared with the
typical AD group in primary and extrastriate visual areas (Figure 2), as previously reported in other studies14, 15
that did not correct for atrophy. After correction for atrophy, the AD + VS
areas remained hypometabolic relative to typical AD in the visual association
areas. The location of the hypometabolism maxima of the AD + VS group compared
with the AD group is given in Table 5.
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Figure 2. Statistical parametric maps showing
the voxels with rCMRglc in the AD + VS group less than that in the group with
typical Alzheimer disease (AD). The projections are with a threshold of z = 2.3, uncorrected (A) and corrected (B) for PVE. The areas of significant
difference in glucose metabolism did not change after correction for PVE.
For an explanation of the other abbreviations, see the legend to Figure 1.
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Table 5. Local Maxima for Significant Differences in rCMRglc for AD
+ VS Group Less Than AD Group*
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Regions in the frontal cortex were hypometabolic in the patients with
AD compared with the AD + VS group (Figure
3) before atrophy correction and remained hypometabolic after atrophy
correction. The location of the maxima for hypometabolism of the AD group
compared with the AD + VS group is given in Table 6.
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Figure 3. Statistical parametric maps showing
the voxels with rCMRglc in the AD group less than that in the AD + VS group.
The projections are with a threshold of z = 2.3, uncorrected
(A) and corrected (B) for PVE. The areas of significant difference in glucose
metabolism did not change after correction for PVE. For an explanation of
the abbreviations, see the legends to Figure 1 and Figure 2.
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Table 6. Local Maxima for Significant Differences in rCMRglc for AD
Group Less Than AD + VS Group*
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COMMENT
In this article we have examined differences in rCMRglc between patients
with AD + VS and age-matched healthy control subjects, with and without PVE
correction. Previous studies have applied this correction to typical AD patient
groups.17, 27, 28 Here,
we studied a distinct AD subgroup with atypical clinical manifestations to
examine the effects of brain atrophy on calculated rCMRglc. Values of rCMRglc
before PVE correction are per unit volume in a PET image, whereas after PVE
correction the values are per unit volume of tissue. The differences in rCMRglc
between patients and controls are focused in the posterior cortical regions
and are consistent with previous PET studies.14, 15
Thus, the increased brain atrophy in the hypometabolic areas does not account
for the measured decrease in rCMRglc in the AD + VS patient group compared
with the control group. These PET results are consistent with the hypothesis
that glucose hypometabolism measured in AD represents an in vivo biochemical
index of neuronal/synaptic dysfunction.29 This
supports the validity of the PET fluorodeoxyglucose method to assess synaptic
viability in the brain during different stages of dementia severity and in
relation to brain cognitive and sensory stimulation or pharmacologic modulation.30, 31, 32
As was true for patients with typical AD,17
the increase in rCMRglc caused by PVE correction is larger in the AD + VS
patient group than in the healthy control group because of the greater brain
atrophy in the AD + VS patient group. In addition, the increases in rCMRglc
are localized in regions of greatest brain atrophy.
We found that, before PVE correction, the AD + VS group was hypometabolic
in posterior cortex when compared with the AD group, whereas patients with
AD were hypometabolic in frontal cortex when compared with the AD + VS group.
Correcting for brain atrophy did not alter this pattern of differences. Our
results show that this subgroup of patients with AD with early and prominent
visual dysfunction have a different pattern of rCMRglc hypometabolism from
that observed in patients with typical AD after the effects of atrophy caused
by neuronal loss have been accounted for by application of PVE correction.
Therefore, this difference in the pattern of hypometabolism is not caused
merely by different brain atrophy patterns, but rather reflects different
patterns of neuronal/synaptic dysfunction caused by distinct developments
of the AD neuropathologic process.
Various technical factors can affect our results. Perhaps the primary
one is the relative simplicity of the algorithm used for atrophy correction.
Correcting for PVE is an active area of research,33
but at present there is no consensus on the most appropriate method. All atrophy
correction algorithms assume uniform loss within gray and white matter compartments,
thus ignoring differential neuronal loss in the different cortical laminas.
In AD, neuronal loss is greatest in layers 3 and 5.3
The effect of this type of nonuniform neuronal loss on PVE correction is unknown.
Note that the differences observed between the AD + VS and the typical
AD patient groups are unlikely to be due to use of different PET cameras.
A comparison was made between each patient group and both healthy control
groups to see whether differences in PET camera resolution would affect the
statistical results. The findings (not shown) obtained with either healthy
control group were similar, and thus we believe that the differences in rCMRglc
between the 2 patient groups are not confounded by the use of different PET
cameras. Likewise, the use of different MR imagers also is unlikely to change
the PVE correction factors. The degree of global atrophy in the AD + VS group
compared with the typical AD group was not significantly different. The increase
caused by PVE correction was the same for both patient groups, as would be
expected for similar degrees of brain atrophy, thus indicating that the different
resolution of the MR imager is not affecting the correction coefficients.
In summary, hypometabolism measured by PET in patients with AD + VS
represents a real decrease in metabolism per gram of tissue and is not an
artificial decrease caused solely by increased brain atrophy.
AUTHOR INFORMATION
Accepted for publication July 11, 2000.
This work was supported by the National Institute on Aging Intramural
Research Program, Bethesda, Md.
From the Laboratory of Neurosciences, National Institute on Aging,
National Institutes of Health, Bethesda, Md (Drs Bokde, Pietrini, Furey, Rapoport,
Schapiro, and Horwitz); Department of Human and Environmental Sciences, University
of Pisa, Pisa, Italy (Dr Pietrini); Division de Neuropsychiatrie, Belle Idée,
Geneve, Switzerland (Dr Ibáñez); Arizona Alzheimer's Disease
Research Center and Department of Psychology, Arizona State University, Tempe
(Dr Alexander); and Department of Neurology, Mayo Clinic–Jacksonville,
Jacksonville, Fla (Dr Graff-Radford). Dr Horwitz is now with the Language
Section, National Institute on Deafness and Other Communication Disorders,
National Institutes of Health.
Corresponding author and reprints: Barry Horwitz, PhD, Language Section,
National Institute on Deafness and Other Communication Disorders, NIH, Bldg
10, Room 6C420, Bethesda, MD 20892 (e-mail: horwitz{at}helix.nih.gov).
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