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Regional N-Acetylaspartate Reduction in the Hippocampus Detected With Fast Proton Magnetic Resonance Spectroscopic Imaging in Patients With Alzheimer Disease
Wolfgang Block, PhD;
Frank Jessen, MD;
Frank Träber, PhD;
Sebastian Flacke, MD;
Christoph Manka, MD;
Rolf Lamerichs, PhD;
Ewald Keller, MD;
Reinhard Heun, MD;
Hans Schild, MD
Arch Neurol. 2002;59:828-834.
ABSTRACT
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Objective To detect regional metabolic changes that resemble the expected spatial
pattern of neuronal loss in patients with Alzheimer disease (AD).
Methods Thirty-four patients with AD and 22 healthy control subjects were included
in the study. Single-slice fast proton spectroscopic imaging was performed
in parallel angulation to the temporal lobes. Proton spectra were selected
from the hippocampus, the lateral temporal lobe, and the occipital lobe of
both hemispheres to determine metabolite concentration of N-acetylaspartate (NAA), total creatine (tCr), including phosphocreatine
and creatine, and choline-containing compounds (Cho). The metabolic ratios
of NAA/tCr and Cho/tCr were calculated and compared between patients with
AD and healthy volunteers.
Results The NAA/tCr ratios were significantly reduced in the left (F1,1 = 4.34, P = .04) and right hippocampus (F1,1 = 9.96, P = .003) in patients with AD.
The Cho/tCr ratios remained unchanged in both hippocampi. There was no significant
change of either NAA/tCr or Cho/tCr in the lateral temporal and occipital
lobes of patients with AD.
Conclusion This study provides evidence that fast proton spectroscopic imaging
may detect the regional pattern of disturbed neuronal integrity in patients
with AD with high spatial resolution in a short acquisition time.
INTRODUCTION
PROTON MAGNETIC resonance spectroscopy (1H-MRS) is a noninvasive
method to investigate changes of the tissue metabolite composition in different
brain diseases. At long echo times (TE >100 milliseconds), the resonance lines
of the N-acetyl groups, mainly N-acetylaspartate (NAA), total choline-containing compounds (Cho),
and total creatine (tCr), including phosphocreatine and creatine, can be detected. N-acetylaspartate is only located in neurons1
and represents a marker for neuronal integrity. A reduction of NAA has been
reported in various brain regions in Alzheimer disease (AD)2
and other neurodegenerative disorders.3-5
Choline-containing compounds represent a constituent of cell membrane metabolism
and have been found to be elevated in AD in some6-10
but not all studies.11-18
Total creatine, which is engaged in the cell's energy metabolism, has been
reported to remain stable in AD10, 19
and other neurodegenerative disorders.20-21
Changes of NAA and Cho are therefore commonly assessed in relation to tCr.
An inherent limitation of 1H-MRS is the lack of specificity
of the observed changes for any disease. In addition to neurodegenerative
disorders, a reduction of NAA has been reported in vascular,22-23
metabolic,24 and inflammatory25
diseases. To circumvent this limitation, recent studies4, 26-27
have investigated those brain regions that specifically characterize the distribution
of neuronal damage in an individual disease. According to Braak and Braak,28 the neuronal damage in AD occurs earliest in the
medial temporal lobe (ie, hippocampus and parahippocampal region). During
the disease, the neuronal loss spreads to lateral temporal, frontal, and parietal
regions. The occipital lobe and the precentral and postcentral regions are
only affected in very late disease stages. Three MRS studies have investigated
these medial temporal lobe structures in patients with AD. These studies,
however, were limited by long data acquisition time,6
which reduces its feasibility in patients with AD, low spatial resolution29 owing to the use of single-voxel 1H-MRS,
or examination of only parts of the hippocampus without including an unaffected
control region.19 The last approach can detect
localized neuronal damage in the hippocampus, but it does not reveal the spread
of neuronal loss from medial temporal structures to less affected brain regions.
In this study, we use 1H-MRS imaging to acquire data of an
entire brain section in temporal angulation. This allows metabolic mapping
of both hippocampi in their longitudinal axis, the lateral temporal lobes,
and the occipital lobes with high spatial resolution. Several concepts have
been proposed recently to reduce the long acquisition time of conventional
MRS imaging by performing k-space sampling in a more time-efficient way.30-32 In our fast spectroscopic
imaging study, the acquisition time for the entire slice was reduced to 11
minutes, which is advantageous especially in patients with dementia. Details
of the acquisition technique were described in a previously published article
by Träber et al.33
According to the characteristic distribution of neuropathologic features
in AD, we expected a reduction of NAA in the hippocampi and to a lesser extent
in the lateral temporal lobe of patients with AD. We did not expect a difference
between the patients and the control group in the occipital lobe. Finally,
we expected a correlation of the degree of NAA reduction with disease severity.
PATIENTS, MATERIALS, AND METHODS
PATIENTS
Thirty-four patients (mean age, 70 years; SD, 8 years; 10 men, 24 women)
who met the National Institute of Neurological and Communicative Disorders
and Stroke–Alzheimer's Disease and Related Disorders criteria for probable
AD and 22 healthy subjects (mean age, 69 years; SD, 9 years; 12 men, 10 women)
were included in the study. The Mini-Mental State Examination (MMSE)34 and the cognitive part of the AD Assessment Scale
(ADAScog)35 were applied for disease staging.
The MMSE scores range from 0 to 30 points, with 30 points being the best score,
whereas the ADAScog scores range from 0 to 70 points, with 70 points expressing
most severe cognitive deficits.
At the time of the MRS examination, mean ± SD scores for patients
with AD were 20.1 ± 4.5 (range 10-27) on the MMSE and 23.6 ±
12.8 (range, 8-56) on the ADAScog. The control subjects underwent the same
neuropsychological examination to ensure normal cognitive functioning (MMSE
score, 28.6 ± 2.1; ADAScog score, 7.2 ± 1.6). The study protocol
was approved by the ethics committee of the University of Bonn and is in accordance
with the Declaration of Helsinki. All patients and control subjects gave informed
consent before participation.
MAGNETIC RESONANCE EXAMINATIONS
Magnetic resonance investigations were performed on 1.5-T whole-body
magnetic resonance system Gyroscan (ACSNT PT6000; Philips Medical Systems,
Best, the Netherlands) using a mirror head coil suited for magnetic resonance
imaging and fast spectroscopic imaging. Coronal T2-weighted turbo spin-echo
sequences with repetition time (TR)/TE of 2700/120 milliseconds, axial proton
density and T2-weighted spin-echo sequences with TR/TE1, TE2 of 2400/20, 90
milliseconds, and axial, sagittal, and coronal T1-weighted spin-echo sequences
with TR/TE of 300/15 milliseconds were obtained for image-guided localization
of the single-slice turbo spectroscopic imaging (TSI).
An axial slice 2 cm thick on the hippocampal level was selected for
the TSI acquisition, and a field of view of 20 to 22 cm was covered by 32
x 32 phase encoding steps. Lipid signals from the skull base and from
the retro-orbital space were eliminated by polygonal outer volume presaturation36 using 10 MREST (multiple regional saturation technique)
slabs. This scheme was combined with slice-selective 90° excitation, resulting
in a volume of interest with contours matching the frontal, occipital, and
lateral borders of the temporal lobe (Figure
1A-B). A TE of 272 milliseconds was chosen for further reduction
of lipid artifacts and for in-phase detection of lactate signals. With a TR
of 2000 milliseconds and with 3 phase-encoded echos per excitation (turbo
factor, 3), the acquisition took 11 minutes, including a non–water-suppressed
data set for susceptibility shift correction.30
With symmetric echo registration within an acquisition interval of 250 milliseconds,
a frequency resolution of 4 Hz was obtained. Signal processing of the TSI
data set included Lorentz-Gauss spectral and cosine spatial filtering, susceptibility
correction, zero filling, and digital shift subtraction for improved water
suppression. Metabolic maps displaying the local concentrations of NAA (Figure 1C), Cho, tCr, and lactate were calculated
by gray-level encoding of the respective peak integrals in the B0-corrected
TSI spectra (B0 indicates the main magnetic field). Metabolite
ratios NAA/tCr and Cho/tCr were determined in TSI spectra from voxels selected
in the hippocampal, lateral temporal, and occipital region of both hemispheres
(Figure 1D). To increase quantification
accuracy, a representative spectrum with improved signal-to-noise ratio was
generated for each region by averaging the signals from 6 adjacent 1-mL voxels
by time-domain superposition (Figure 2). Metabolite ratios for these cerebral areas were compared with the values obtained
from healthy controls using the same acquisition and processing protocol.
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Figure 1. Acquisition of a turbo spectroscopic
imaging (TSI) data set from a 71-year-old man with Alzheimer disease. A, Image-guided
selection for single-slice TSI with polygonal outer volume suppression using
10 presaturation slabs (hatched areas with vertical lines, center of each
slab indicated by a circle) displayed on a sagittal T1-weighted spin-echo
magnetic resonance image. Selected slice is positioned parallel to the temporal
lobe and includes both hippocampi. B, Same slice selection displayed on an
axial T2-weighted turbo spin-echo magnetic resonance image. C, N-acetylaspartate
metabolite image, interpolated to 256 x 256 matrix, with overlay of
brain contour taken from T2-weighted turbo spin-echo magnetic resonance image
(B). D, Anatomic T2-weighted magnetic resonance image with the position of
selected TSI spectra indicated by squares. Numbers 1 through 6 indicate hippocampal
spectra; 7 through 12, lateral temporal spectra; and 13 through 18, occipital
spectra.
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Figure 2. Spectra selected from the processed
turbo spectroscopic imaging data set of the same patient as in Figure 1. Left
column shows proton spectra (corresponding to the outlined numbers in Figure
1D) selected from the hippocampal, the lateral temporal, and the occipital
regions. Right column shows the summation of these spectra for each region.
NAA indicates N-acetylaspartate; Cho, choline-containing compounds;
and tCr, total creatine, including phosphocreatine and creatine. Metabolic
ratios (NAA/tCr and Cho/tCr) calculated from the summation spectra are as
follows: hippocampal, 2.08 and 1.21; lateral temporal, 4.37 and 1.32; and
occipital, 4.27 and 0.95.
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STATISTICAL ANALYSIS
Group comparisons of metabolic ratios were performed using a 2-factorial
analysis of variance (diagnosis and sex). Even though age did not differ significantly
between groups (t = 7.48, P
= .46), it was included as a covariate because of recent reports of age effects
on the metabolic ratios in various brain regions.37
Correlations of MMSE and ADAScog scores with metabolite ratios were evaluated
using Spearman rank correlation. Calculations were performed with the SPSS
9.0 computer software package (SPSS Inc, Chicago, Ill).
RESULTS
Data sets of 31 patients and 19 volunteers were of sufficient quality
to be included in the statistical analysis. In some of these cases, however,
the TSI spectra of certain regions, which are particularly sensitive to susceptibility
artifacts (eg, the anterior parts of the temporal lobe slice), had to be discarded
because of extensive line broadening. In 3 patients with AD and 3 controls,
the entire data set had to be discarded because of extensive movement of the
subject during the TSI acquisition. However, there was no relationship between
the severity of dementia and the technical success rate of the applied technique.
The number of cases used for the group comparison is given in Table 1 for each region.
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Regional Distribution of Metabolite Ratios for Patients With AD and
Healthy Controls*
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Analysis of TSI spectra revealed a significant reduction of NAA/tCr
in the left (F1,1 = 4.34, P = .04) and
right hippocampus (F1,1 = 9.96, P = .003)
in the patients with AD compared with healthy control subjects. Mean NAA/tCr
of patients with AD was reduced by 11% in the left hippocampus and 16% in
the right hippocampus. No significant differences were found for Cho/tCr ratios
calculated from spectra selected in both hippocampi. Group comparison of metabolite
ratios determined for the occipital and lateral parts of the temporal lobes
yielded no significant differences between patients with AD and controls (Figure 3). There were no age or sex effects
on any metabolite ratio, and there were no significant correlations between
any metabolite ratio and the MMSE or ADAScog scores. Means and SDs of all
metabolite ratios are summarized in Table
1.
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Figure 3. Box plots displaying the distribution
(median, quartiles, and range, outliers as circles) of the metabolic ratios
NAA/tCr and Cho/tCr acquired from the hippocampal, lateral temporal, and occipital
regions (right hemisphere) of patients with Alzheimer disease (AD) compared
with healthy controls. NAA indicates N-acetylaspartate; Cho,
choline-containing compounds; and tCr, total creatine, including phosphocreatine
and creatine.
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COMMENT
The main finding of this study is a significant decrease of NAA/tCr
in the left and right hippocampi of patients with AD compared with healthy
control subjects. The expected reduction of NAA/tCr in the lateral temporal
lobe did not reach significance, and there was no significant change of NAA/tCr
in the occipital lobes. Since the metabolite ratio NAA/tCr reflects neuronal
integrity, this pattern mirrors the neuropathologic features of mild-to-moderate
AD. The results of this metabolic mapping study of a temporally angulated
entire brain section are in agreement with other MRS studies that reported
a reduction of NAA in the hippocampus of patients with AD. The present approach,
however, extends previous reports by several points. In addition to the study
by Schuff et al,19 which only reported NAA
alterations in the hippocampus, the present study also included unaffected
control regions, which allows the detection of the specific pattern of neuronal
damage in AD. The approach of including an unaffected control region was already
presented in recent studies by our group,29, 38
which investigated the medial temporal lobe and the precentral and postcentral
region. That study, however, used single-voxel MRS with limited spatial resolution,
thus including the hippocampus plus adjacent nontarget tissue in the voxel
of interest. In the present study, the spatial resolution was improved by
using MRS imaging, which allows the examination of the hippocampus and other
areas in much greater detail and reduces partial volume effects of nontarget
regions. Whether the inclusion of unaffected control regions will contribute
to the discrimination of AD from other dementing disorders will have to be
assessed in future studies.
Furthermore, we improved the acquisition technique compared with our
earlier study6 by using a nonrectangular slice
in temporal angulation, which covers larger regions of the tissue of interest,
and by reducing the acquisition time for the entire slice from 30 to 11 minutes,
which makes the examination much more feasible for patients with AD.
The present approach, however, also has limitations. Less than optimal
B0-field homogeneity and contamination from lipid-containing structures,
especially in the anterior parts of the temporal slice, affect the quality
of spectra. The enhanced sensitivity of fast spectroscopic imaging to susceptibility
artifacts associated with a decreased signal-to-noise ratio resulted in the
failure to obtain valid spectra in some patients and control subjects. These
limitations may also be the reason for the failure to detect a correlation
of the NAA/tCr reduction with the cognitive dysfunction in the group of patients
with AD. A further limitation of the present protocol is the inability of
gray-white matter differentiation within single spectra. Because the white
matter proportion is larger in the lateral temporal lobe than, for example,
in the hippocampus, this would confound a direct comparison of these 2 regions
within a single group of subjects. Therefore, each region was separately analyzed
only with respect to group differences.
In summary, we present a metabolic mapping technique that covers the
crucial brain regions in patients with AD in a short examination time. With
this technique, we were able to detect a reduction of the neuronal marker
NAA in both hippocampi but not in control areas in patients with AD. Future
developments will have to focus on increasing the accuracy and stability of
the method to recognize pathologic conditions not only by a group comparison
but also on an individual patient scale in the diagnostic workup of dementia.
AUTHOR INFORMATION
Accepted for publication December 19, 2001.
Author contributions: Study concept and design (Drs Block, Jessen, Träber, Flacke, Keller, Heun, and Schild); acquisition of data (Drs Block, Jessen, Träber,
Manka, Lamerichs, and Heun); analysis and interpretation of data (Drs Block, Jessen, Träber, Flacke, and Heun); drafting
of the manuscript (Drs Block and Jessen); critical
revision of the manuscript for important intellectual content (Drs Jessen, Träber, Flacke, Manka, Lamerichs, Keller, Heun, and Schild); statistical expertise (Drs Block, Jessen, Flacke,
and Heun); obtained funding (Drs Träber, Keller,
Heun, and Schild); administrative, technical, and material support (Drs Manka, Lamerichs, Keller, and Schild); and study supervision (Drs Block, Jessen, Träber, Heun, and Schild).
This study was sponsored by Bayer Vital GmbH, Pharmaceutical Division,
Leverkusen, Germany (Drs Heun and Keller); the Förderverein für
Radiologie der Universität Bonn e.V., Bonn, Germany (Drs Block, Flacke,
and Manka); and the Deutsche Forschungsgemeinschaft, Bonn, Germany (TR 428/1-1,
Dr Träber).
Corresponding author and reprints: Wolfgang Block, PhD, Department
of Radiology, University of Bonn, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany
(e-mail: block{at}uni-bonn.de).
From the Departments of Radiology (Drs Block, Träber, Flacke,
Manka, Keller, and Schild) and Psychiatry (Drs Jessen and Heun), University
of Bonn, Bonn, Germany; and Philips Medical Systems, Best, the Netherlands
(Dr Lamerichs).
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