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In vivo detection of myelin phospholipids in multiple sclerosis with phosphorus magnetic resonance spectroscopic imaging.

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In Vivo Detection of
Myelin Phospholipids in
Multiple Sclerosis with
Phosphorus Magnetic
Resonance Spectroscopic
Materials and Methods
Thirteen subjects with clinically definite MS (1 1 women, 2
men; mean age t standard deviation [SD} = 40
1 1 years;
mean expanded disability status score [lo} = 5.5 2.0) and
9 control subjects ( 5 women, 4 men; mean age c SD = 33
? 14 years) were studied with 31PMRSI. Patients with MS
were stable without evidence of an acute exacerbation at the
time of the examination. All studies were approved by the
University of California at San Francisco Human Research
Committee and informed consent was obtained prior to the
C. A. Husted, PhD,? G . B. Matson, PhD,f
D. A. Adams, PhD,"" D. S. Goodin, MD,§ and
M. W. Weiner, MDTn
The goal of this study was to investigate myelin phospholipids in vivo in multiple sclerosis lesions and
normal-appearing white matter by evaluating the spectral broad component from phosphorus 3 1 magnetic resonance spectroscopic imaging data. The phospholipid
broad component was reduced nearly 35% ( p :< 0.001)
in both lesions and in normal-appearing white matter in
multiple sclerosis subjects compared to control subjects,
suggesting reduced myelin phospholipid concentration
or altered relaxation times.
Husted CA, Matson GB, Adams DA, Goodin DS,
Weiner MW. In vivo detection of myelin
phospholipids in multiple sclerosis with phosphorus
magnetic resonance spectroscopic imaging.
Ann Neurol 1994;36:239-241
Phosphorus (31 P) magnetic resonance spectroscopic
imaging (MRSI) provides spectra with seven narrow
peaks representing lipid and energy metabolites super~~
imposed on a spectral broad component. T o enable
accurate fitting of narrow peaks, the 31Pspectral broad
component is usually removed prior to peak fitting,
as demonstrated in a previous report on multiple sclerosis (MS) [l]. The 31P spectral broad component coresonates with phosphodiesters (PDE) and contains
nearly half of the "P spectral area 121. Recently it was
shown that the 31Pspectral broad component arises
from myelin membrane phospholipids and thus, provides a direct marker of myelin in vivo r2-91. This is
of particular value when assessing in vivo biochemical
changes in diseases of myelin, such as MS. The goal of
this study was to investigate myelin phospholipids in
vivo in MS lesions and normal-appearing white matter
by evaluating the spectral broad component from 31P
MRSI data. To the best of our knowledge, this represents the first report of changes in the 31P spectral
broad component with disease.
From the *Magnetic Resonance Unit, Department of Veterans Affairs Medical Center, San Francisco; the Departments of tRadiology,
$Pharmaceutical Chemistry, $Neurology, and TMedicine,University
of California, San Francisco, CA; and the ""Department of Clinical
Radiology, Columbia University, NY.
Received Dec 27, 1993, and in revised form Feb 18,1994. Accepted
for publication Mar 9, 1994.
Address correspondence to Dr Husted, Magnetic Resonance Unit
(1 lM), Department of Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121.
Experimental Protocol
The magnetic resonance imaging (MRI) and MRSI studies
were conducted with a 2.0-T Gyroscan S15 whole-body
MRUMRS system (Philips Medical Systems, Shelton, CT).
Sixteen transverse slices (7.7-mm thick, 0.8-mm gap; TR
2500/TE 30, 80) were obtained angulated 20 degrees supraorbitally beyond the orbital-auditory meatal plane. The MRI
gap was used to reduce MRI acquisition time, and caused 10
to 15% of the MRSI data not to be sampled with MRI.
Angulated transverse 31PMRSI studies were carried out using gradient phase encoding in three spatial dimensions and
a spin-echo technique (TE 3.5) in which the second half of
the 31Pecho was acquired with an effective partial tip excitation pulse and rapid repetition rate (350 msec) to improve
efficiency. Twelve phase-encoding gradient steps were applied in all three directions over a 27-cm' field of view. A
spherical k-space sampling scheme was used to roughly halve
the number of k-space points sampled. The effective voxel
size was 27 cm3, and the experimental protocol is further
described elsewhere [ 1, 111.
Data Analysis
MRSI data were processed as previously described E12). The
curve fittings were performed by an individual blinded to the
subject's condition and to the apparent lesion burden in the
voxels selected. Spectra were selected only from the region
of the centrum semiovale. Voxels that were selected contained either entirely normal-appearing white matter or pre-
Copyright 0 1994 by the American Neurological Association
dominantly MS lesion. The normal-appearing white matter
voxels were selected well away from lesions to minimize any
potential contamination (i.e., partial voluming) from lesions.
The 31Pspectral broad component was removed with a
300-Hz convolution difference filter in order to provide a
spectrum of only the narrow components. The spectrum of
narrow components was then subtracted from the spectrum
of broad plus narrow components in order to obtain a signal
of the broad component. The broad signal was separately
evaluated by curve fitting with multiple gaussian lines in
order to accommodate the asymmetrical line shape characteristic of phospholipids in a bilayer configuration [13]. Two
overlapping broad peaks fit most of the broad component
peak area, and five to six smaller peaks were typically used
to accommodate the asymmetrical nature of this peak. The
sum of all peaks was used to represent the broad component
peak area. The residual after curve fitting was used as the
criteria for goodness of fit. Due to limitations in the curve
fitting software available in this laboratory, we chose this
method. Given the large differences in areas between the
control and MS populations, and the small standard errors,
we believe this methodology provides a good first approximation of the spectral area of the broad component. MS and
control data were compared with Student’s t tests.
The Figure shows at the top a typical 31Psingle-voxel
spectrum processed without convolution difference,
and at the bottom the same spectrum processed with
a 300-Hz convolution difference filter to remove the
broad baseline. Superimposed on this spectrum is the
computer-generated curve fit of the spectral broad
component. Mean peak areas of control and MS spectral broad component signals are given in the Table.
The phospholipid broad component was reduced
nearly 35% ( p < 0.001) in both MS lesions and in MS
normal-appearing white matter.
The major finding of this study was that the phosphorus spectral broad component, which arises from myelin phospholipids, was significantly reduced in both
MS lesions and normal-appearing white matter. Reduced MRSI signal intensity could be due to reduced
phospholipid concentration or could reflect an alteration in the signal T 1 or T2 relaxation times, which in
turn reflect changes in phospholipid molecular motions. Relaxation measurements would determine the
extent to which changes in relaxation, as opposed to
changes in phospholipid concentrations, contribute to
the reduced broad component in MS.
Myelin consists of 70% lipids and 30% proteins. It
is well established that there is a general reduction of
myelin in MS plaques 1141; thus, in MS plaque there
is reduced lipid content, largely due to myelin loss.
Consistent findings from several laboratories include
decreased myelin yield and decreased total lipid content in MS normal-appearing white matter [l5]. These
postmortem chemical analyses were performed with240 Annals of Neurology Vol 36 No 2 August 1994
(Top) Phosphorus single-voxel magnetic raonance spectroscopic
imaging spectrum displayed with phospholipid spectral broad
component included. (Bottom) Identical spectrum displayed
with phospholipid spectral broad component removed by convolution difference. The computer-simulated fit of the filtered broad
signal is superimposed on the spectrum.
”P Magnetic Resonance SpectroscopicImaging Broad
Component in Multiple Sclerosis (MS)a
MS Normal-Appearing
White Matter
MS Lesions
3,264 ? 189
N = 20
2,187 ? 83b
N = 25
2,140 ? 97b
N = 25
‘Values are given in arbitary units t standard error. N equals rhe
number of voxels selected from 10 control subjects and 13 patients
with MS.
bP < 0.001.
out histology to rule out the presence of microscopic
lesions, and it remains unclear if reduced myelin content in MS normal-appearing white matter is secondary
to the presence of miscroscopic lesions or represents
a change of histologically normal white matter.
A limitation is that some or all of the MRSI findings
in normal-appearing white matter reflect inflammation
and lesions that are below the spatial resolution of spinecho MRI. It is also possible that acquiring MRI with
gaps may obscure detection of small MS lesions. Although removal of the broad component with convolution difference has limitations, it is an accepted method
for evaluation of in vivo phosphorus spectra [b].It is
possible that inclusion of some degree of lesion in the
voxels selected from normal-appearing white matter,
due to contamination from surrounding voxels (i.e.,
partial voluming), could result in reduced broad component in normal-appearing white matter in MS. This
explanation is unlikely, however, due to a careful spectral selection protocol. An outline of a single voxel
appeared on the MRI and MRSI images for spectral
selection. Voxels that were selected contained either
entirely normal-appearing white matter or predominantly MS lesions. The normal-appearing white matter
voxels were selected well away from lesions to minimize any partial voluming from lesions.
Our in vivo results of reduced ?‘P phospholipid
broad component support ex vivo results of reduced
myelin in both MS lesions and normal-appearing white
matter, and emphasize the importance of evaluating
the 31Pspectral broad component in diseases of myelin.
Whether the reduced broad component signal intensity
is due to decreased concentration, altered relaxation
times, or both in no way diminishes the importance of
the in vivo finding of altered phospholipids in MS
lesions and normal-appearing white matter. Although
it remains unclear whether these findings represent a
primary white matter defect or are secondary to microscopic lesions, these results suggest the presence of
biochemical abnormalities in MS normal-appearing
white matter not detected by standard spin-echo MRI.
This investigation was supported in part by a postdoctoral fellowship
from the National Multiple Sclerosis Society (to C. A. H.) and by
National Institutes of Health grant R01-DK33293 (to M. W. W.),
Philips Medical Systems, and the Department of Veterans Affairs
Medical Research Service (to M. W. W.).
The authors thank D. J. Meyerhoff, PhD, and M. Dickinson for
assistance with data analysis.
1. Husted CA, Goodin DS, Hugg JW,
et al. Biochemical alterations in multiple sclerosis lesions and normal-appearing white
matter detected by in vivo "P and 'H spectroscopic imaging.
Ann Neurol 1994;36:157-165
2. Kilby PM, Bolas NM, Radda GK. 31P-NMR study of brain
phospholipid structures in vivo. Biochim Biophys Acra 1991;
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Positron Emission
Tornouabhic Measurement
of Cerebral Blood Flow
and Temporal Lobectomy
William H. Theodore,* William D. Gaillard,'
Susumu Sato,* Conrad Kufta,? and Deborah Leiderman"
We used positron emission tomography (PET) and bolus
injection of H,I5O to measure interictal cerebral blood
flow (CBF) in 32 patients who had temporal lobectomy
for uncontrolled complex partial seizures. Seizure focus
localization was confirmed by ictal video-electroencephalographic (video-EEG)telemetry, and patients who had
imaging findings suggesting the presence of a tumor
were excluded. PET-CBF studies were interpreted using
a standard template by raters blinded to EEG and clinical data, and were not used in surgical planning. After
surgery, patients were followed for 32 k 18 months.
Twenty-six patients were seizure free and 6 had persistent seizures. Mean lateral temporal hypoperfusion was
8 f 14% in patients who became seizure free and 9 f
6% in patients with persistent seizures. Fourteen patients had at least 15%, and l l at least 20% hypoperfusion, but were not more likely to be seizure free. Three
additional patients had 15 to 20% hypoperfusion in the
temporal lobe contralateral to their EEG focus. PET
measurement of CBF using bolus H,"O should not be
used to help select patients for temporal Iobectomy.
Theodore WH, Gaillard WD, Sato S, Kufta C,
Leiderman D. Positron emission tomographic
measurement of cerebral blood flow and temporal
lobectomy. Ann Neurol 1994;36:241-244
Positron emission tomography (PET) using 2-[18F)
deoxyglucose ('*FDG) for estimation of local cerebral
metabolic rate for glucose (LCMRglc) predicts successful temporal lobectomy El, 2). FDG-PET temporal
lobe hypometabolism is associated with the presence of
an epileptogenic zone in patients with complex partial
From the "Epilepsy Research Branch and ?Surgical Neurology
Branch, National Institute of Neurological Disorders and Stroke,
National Institutes of Health, Bethesda, MD.
Received Dec 8, 1993, and in revised form Jan 26, 1994. Accepted
for publication Jan 27, 1994.
Address correspondence to Dr Theodore, N I H Building 10, Room
5C-205, Bethesda, M D 20892.
Copyright 0 1994 by the American Neurological Association
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spectroscopy, detection, magnetic, imagine, vivo, myelin, sclerosis, multiple, resonance, phospholipid, phosphorus
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