Quantitative proton MRS of Pelizaeus–
Evidence of dys- and hypomyelination
F.A. Hanefeld, MD; K. Brockmann, MD; P.J.W. Pouwels, PhD; B. Wilken, MD; J. Frahm, PhD;
and P. Dechent, PhD
Abstract—Background: Pelizaeus–Merzbacher disease (PMD) is a rare X-linked recessive neurologic disorder caused by a
mutation in the proteolipid protein (PLP) gene on chromosome Xq22. The associated depletion of PLP and severe
reduction of other major myelin proteins results in dysmyelination. MRI reveals loss of T1 contrast between gray and
affected white matter and T2 hyperintensities of white matter due to elevated water content. Methods: In vivo proton
magnetic resonance spectroscopy (MRS) was used to determine cerebral metabolite patterns in five patients with geneti-
cally proven PMD. Absolute metabolite concentrations were obtained in cortical gray matter, affected white matter, and
basal ganglia and compared to age-matched control values. Results: In comparison to age-matched controls, MRS of
affected white matter resembled the metabolite pattern of cortical gray matter, as indicated by increased concentrations of
N-acetylaspartate and N-acetylaspartylglutamate (tNAA), glutamine (Gln), myo-inositol (Ins), and creatine and phospho-
creatine. Most remarkably, the concentration of choline-containing compounds was reduced. Parietal gray matter and
basal ganglia appeared normal but showed a tendency for elevated tNAA, Gln, and Ins. Conclusions: Magnetic resonance
spectroscopy (MRS)–detected alterations are consistent with enhanced neuroaxonal density, astrogliosis, and reduction of
oligodendroglia. These disturbances in cellular composition are in close agreement with the histopathologic features
characteristic of dys- and hypomyelination. The proton MRS profile of Pelizaeus–Merzbacher disease (PMD) differs from
the pattern commonly observed in demyelinating disorders and allows PMD to be distinguished from other
Pelizaeus–Merzbacher disease (PMD, MIM #312080)
is an X-linked recessively inherited leukodystrophy
caused by mutation of the proteolipid protein (PLP)
gene on chromosome Xq 22. PLP encodes the two
major myelin proteins of the CNS, PLP and its iso-
form DM 20. Gene duplication is the most common
mutation in PMD, but missense mutations, inser-
tions, and deletions have been identified as well.
PLP mutations result in dysmyelination, a lack of
properly formed myelin, and in this respect PMD is
different from other leukodystrophies.1,2
Neuropathologic characteristics of PMD comprise
i) a reduction or even absence of myelin sheaths in
large areas of the white matter, predominantly in
periventricular regions; ii) well-preserved neurons
and axons; and iii) relatively preserved islets of mye-
lin giving white matter a patchy “tigroid” appearance
without active demyelination.3,4A close correlation
between the degree of dysmyelination and the clini-
cal severity was found.3The classification suggested
by Seitelberger3,4according to clinical and patho-
logic features is now largely reduced to two sub-
types, the classic and connatal forms. Onset of the
classic form is in the first year of life with muscu-
lar hypotonia, nystagmus, and delay in motor devel-
opment. Nystagmus may disappear and spasticity
and atactic-dystonic movements appear later. Slow
developmental progress is often observed in the first
decade of life, until relentless deterioration occurs
with death in mid-adulthood. Tigroid dysmyelination
is found in neuropathologic investigation. In con-
trast, patients with the rare and more malignant
connatal form show little developmental progress.
Severe neurologic symptoms include feeding prob-
lems, stridor, and marked spasticity resulting in
multiple contractures. Epileptic seizures may occur.
Patients usually die within the first decade of life.
Pathologic examination shows complete lack of my-
elination in the entire brain.1-3
MRI studies of PMD show early on a diffuse hy-
perintensity or patchy changes of white matter on
T2-weighted images and poor if any contrast be-
tween white and gray matter on T1-weighted im-
ages. It was proposed to divide the MRI changes into
From the Abteilung Kinderheilkunde, Schwerpunkt Neuropa ¨diatrie (Drs. Hanefeld, Brockmann, and Wilken) and MR-Forschung in der Neurologie und
Psychiatrie, Bereich Humanmedizin (Dr. Dechent), Georg-August-Universita ¨t; and Biomedizinische NMR Forschungs GmbH am Max-Planck-Institut fu ¨r
biophysikalische Chemie (Drs. Pouwels and Frahm), Go ¨ttingen, Germany.
Dr. Pouwels was supported by a fellowship of the European Community (ERBCHBGCT 940722) and Dr. Dechent by a grant from the VolkswagenStiftung.
Disclosure: The authors report no conflicts of interest.
Received March 11, 2005. Accepted in final form May 23, 2005.
Address correspondence and reprints requests to Dr. Peter Dechent, MR-Forschung in der Neurologie und Psychiatrie, Bereich Humanmedizin, Georg-
August-Universita ¨t, Robert-Koch-Strasse 40, 37075 Go ¨ttingen, Germany; e-mail: firstname.lastname@example.org
Copyright © 2005 by AAN Enterprises, Inc.
three subtypes according to extent and severity of
white matter alterations, with the most severe type I
indicating diffuse alteration in the hemispheres and
Proton magnetic resonance spectroscopy (MRS)
has been used to characterize the neurochemical dis-
turbances in a large variety of brain disorders in
childhood and, in particular, identify a consistent
pattern of active demyelination in a variety of leu-
kodystrophies of known and unknown origin.6,7Unfor-
tunately, applications of proton MRS to PMD have led
to conflicting results such as increased, decreased, or
unchanged metabolite levels,8-16which at least in part
may be explained by technical limitations.
The purpose of this work was to determine abso-
lute metabolite concentrations in cerebral gray and
white matter of genetically proven PMD patients us-
ing fully relaxed, short-echo time single-voxel proton
MRS. We hypothesized that quantitative proton
MRS will allow us to distinguish metabolite abnor-
malities in PMD from the metabolite patterns of
both controls and patients with other leukodystro-
phies. Part of this work was presented previously in
consistent with PMD were included in this study. Their ages at
MRS ranged from 7 months to 6.8 years (mean ? SD 3.5 ? 2.6).
Table 1 summarizes their clinical features. The diagnosis of PMD
was confirmed by mutation analysis of the PLP gene in all five
patients. Patients 2 and 3 were investigated three times, with
follow-up MRS performed 1 to 3 years after the initial examina-
tion. In all patients, MRI revealed diffuse white matter signal
alterations in the hemispheres and corticospinal tracts, according
to subtype I as defined by the classification proposed recently.5
MRS and MRI.
Written informed consent was obtained from
the parents. MR examinations were performed at 2.0 T (Siemens
Magnetom SP4000 and Siemens Magnetom Vision, Erlangen,
Germany) using the standard imaging head coil or, for children
with a body weight less than 10 kg, the extremity coil (Patients 1
and 3, first examination). Volumes-of-interest (VOI) for single-
Five boys with clinical and MRI features
voxel proton MRS were selected from T1-weighted images (three-
dimensional fast low angle shot) and T2-weighted images (fast
spin echo). Locations were placed in parietal gray matter (8 to
12.5 mL in a paramedian position), affected white matter (4 to 6
mL in parieto-occipital and frontal lobes), and basal ganglia (4 to 6
mL) as indicated in figures 1 and 2. Fully relaxed, short-echo time
proton MR spectra were recorded using a STEAM (STimulated
Echo Acquisition Mode) localization sequence (TR/TE/TM ? 6,000/
20/30 msec for Magnetom SP4000, TR/TE/TM ? 6,000/20/10 msec
for Magnetom Vision, 64 accumulations) as described previously.18
Absolute metabolite concentrations (expressed
in mmol/L VOI) were obtained with LCModel, a user-independent
fitting routine, which is based on a library of model spectra of
individual metabolites.19Metabolites routinely identified by this
procedure are the neuroaxonal markers N-acetylaspartate and
N-acetylaspartylglutamate (tNAA),20,21creatine and phosphocre-
atine (tCr) involved in energy metabolism,22choline-containing
compounds (Cho) connected to membrane turnover,23the glial (as-
trocytic) marker myo-inositol (Ins),24,25the excitatory neurotrans-
mitter glutamate (Glu) and its amidated form glutamine (Gln),
and lactate as an indicator of nonoxidative metabolism. Absolute
metabolite concentrations from patients with PMD were compared
to those of a group of age-matched controls specifically assembled
from our subject pool reported previously.26Statistical evaluation
was performed using a two-tailed Student t test assuming unequal
variances with a significance level of p ? 0.05.
Patient 4. At the age of 2.9 years, the abnormal stage of
myelination is readily observable. In T1-weighted MRI
(figure 1, A and C), the contrast between gray and white
matter is missing, and the thin corpus callosum is hardly
myelinated. Hyperintensities in T2-weighted images (fig-
ure 1, B and D) are consistent with lack of normal myelin
in white matter, which reverses the normal T2 contrast
between gray and white matter at this age. Despite
marked alterations in myelination as indicated by MRI,
the metabolite patterns detected by MRS appear compara-
tively normal. However, whereas cortical gray matter and
basal ganglia (figure 1, A and D) reveal the familiar me-
tabolite pattern of healthy controls, MRS of affected
parieto-occipital and frontal white matter (figure 1, B and
C) unravels clear disturbances that are most easily recog-
nized by the abnormally low Cho signal relative to that of
MRI typical for PMD is shown in figure 1 for
Table 1 Clinical, genetic, and neuroradiologic, features of five patients with Pelizaeus–Merzbacher disease
Feature Patient 1 Patient 2Patient 3Patient 4 Patient 5
PLP mutation Duplication DuplicationDuplicationDuplicationDuplication
Onset NeonatalNeonatalNeonatal InfantileNeonatal
Current age, y5 1486 14
Age at MRI/MRS, y 0.6 1.3, 4.6, 5.6*1.6*, 3.6, 4.7 2.9 6.8
Best motor skill achieved (at age, y)NoneNone Walking Sitting (5) Walking with support (4)
* Magnetic resonance spectroscopy (MRS) examination selected for the group analysis.
† Brainstem evoked response audiometry (BERA) with normal wave I and absent waves II to V.
‡ According to Nezu et al.5
? ? present; ? ? absent; N ? normal.
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tCr. Parallel to T1-weighted MRI, the resulting metabolite
pattern in white matter resembles the MRS characteristics
of cortical gray matter.
These observations are confirmed by a quantitative
analysis of absolute metabolite concentrations as summa-
rized in table 2. When averaged across all patients and
compared to age-matched controls, affected parieto-
occipital white matter shows a significantly altered metab-
olite pattern comprising increased concentrations of tNAA
(?29%), Gln (?50%), Ins (?89%), and tCr (?30%) as well
as decreased Cho (?17%). Even though statistically not
significant, a tendency for elevated Glu was observed
(?23%). In addition, the proton MR spectra of affected white
matter reveal much smaller resonance line widths than those
of age-matched children with normal myelination.
Although relatively normal concentrations are found in
cortical gray matter and basal ganglia, the data show a
similar tendency as in white matter for elevated tNAA
(?14% in cortical gray matter and ?12% in basal ganglia),
Gln (?26% and ?9%), and Ins (?20% and ?39%).
Figure 1. MRI and localized proton
magnetic resonance spectroscopy (MRS)
(boxes) of Patient 4 at the age of 2.9
years. (A) T1-weighted MRI and proton
MRS of paramedial parietal gray mat-
ter. (B) T2-weighted MRI and proton
MRS of right parieto-occipital white
matter. (C) T1-weighted MRI and pro-
ton MRS of right frontal white matter.
(D) T2-weighted MRI and proton MRS
of right basal ganglia. While MRS of
cortical and deep gray matter appears
normal, MRS of affected white matter
reveals a spectral pattern similar to
that of cortical gray matter. The spec-
tra of white matter and basal ganglia
are scaled by a factor of 2 relative
to cortical gray matter. tNAA ?
N-acetylaspartate and N-acetylaspar-
tylglutamate; tCr ? creatine and phos-
phocreatine; Cho ? choline-containing
compounds; Ins ? myo-inositol.
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Figure 2. T1-weighted MRI and local-
ized proton magnetic resonance spec-
troscopy (boxes) of Patient 3 at ages 1.6
(A), 3.6 (B), and 4.7 (C) years. Over the
course of 3 years, the spectral pattern
remains largely unchanged. tNAA ?
N-acetylaspartate and N-acetylaspar-
tylglutamate; tCr ? creatine and phos-
phocreatine; Cho ? choline-containing
compounds; Ins ? myo-inositol.
Table 2 Absolute concentrations (mmol/L) of brain metabolites in five patients with PMD and age-matched controls (mean ? SEM)
Gray matter White matter (parieto-occipital) Basal ganglia
PMD, n ? 5 Control, n ? 36PMD, n ? 5 Control, n ? 22 PMD, n ? 5Control, n ? 26
tNAA 8.8 ? 0.57.7 ? 0.28.8 ? 0.3*6.8 ? 0.18.5 ? 0.67.6 ? 0.2
tCr6.6 ? 0.4 6.3 ? 0.1 6.5 ? 0.1* 5.0 ? 0.1 8.5 ? 0.47.7 ? 0.1
Cho1.3 ? 0.051.2 ? 0.03 1.5 ? 0.1†1.8 ? 0.05 1.8 ? 0.1 1.9 ? 0.03
Ins 5.5 ? 0.44.6 ? 0.16.8 ? 1.0†3.6 ? 0.15.3 ? 0.63.8 ? 0.1
Glu 10.1 ? 0.69.0 ? 0.2 8.0 ? 0.7 6.5 ? 0.2 8.3 ? 0.98.2 ? 0.2
Gln 5.4 ? 0.3†4.3 ? 0.2 5.1 ? 0.6† 3.4 ? 0.26.0 ? 1.3 5.5 ? 0.3
FWHM‡ 2.8 ? 0.1 2.8 ? 0.1 2.5 ? 0.1†2.8 ? 0.13.5 ? 0.23.2 ? 0.1
PMD ? Pelizaeus–Merzbacher disease; tNAA ? N-acetylaspartate and N-acetylaspartylglutamate; tCr ? creatine and phosphocreatine;
Cho ? choline-containing compounds; Ins ? myo-inositol; Glu ? glutamate; Gln ? glutamine.
* Significant differences compared to controls (two-tailed Student t test, p ? 0.005).
† Significant differences compared to controls (two-tailed Student t test, p ? 0.05).
‡ Full width at half maximum (FWHM) of the creatine and phosphocreatine signal at 3.02 ppm in hertz.
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Elevated Lactate was observed only once in white mat-
ter of Patient 1, yielding 3.3 mmol/L as compared to con-
trol values less than 1 mmol/L.
Follow-up examinations of Patient 3 are shown in figure
2. Over a period of 3 years, the spectral pattern and abso-
lute concentrations of metabolites in parieto-occipital
white matter remained largely unchanged.
firmed PMD, a neurochemical assessment by proton
MRS revealed largely unchanged metabolite concen-
trations in cortical and subcortical gray matter. In
contrast, affected white matter as identified by MRI
was characterized by a reduction of Cho as well as
elevated concentrations of tNAA, Gln, Ins, and tCr.
Cho mainly represents contributions from phos-
phorylcholine and phosphorylethanolamine as pre-
cursors for membrane synthesis as well as from the
corresponding membrane degradation products glyc-
erophosphorylcholine and glycerophosphorylethano-
lamine.23The elevation of Cho in demyelinating
leukodystrophies is attributed to increased mem-
brane turnover. In our patients, the reduction of Cho
(?17%) in white matter may be assigned to the se-
vere reduction of choline-containing myelin proteins
and lipids caused by the lack of normally functioning
MRS measurements of tNAA have been validated
as an axon-specific monitor of white matter.21A close
correlation between neuronal loss and a decrease in
tNAA has been demonstrated in various cerebral dis-
orders.27Marked elevation of tNAA as detected by
MRS is highly characteristic of Canavan disease due
to deficiency of aspartoacylase activity. The moder-
ate increase of tNAA (?29%) observed in our pa-
tients with PMD probably reflects the elevated
density of axons in white matter lacking the oligo-
dendrocytic tissue and normal myelin sheaths be-
significant, the tendency for elevated tNAA, Gln, and
Ins in cortical and subcortical gray matter hints at a
similar effect in cortex and basal ganglia. In fact, the
occurrence of an enhanced neuroaxonal density is
further supported by the simultaneous observation
of slightly increased levels of the excitatory neuro-
transmitter Glu (?23% in white and ?12% in corti-
cal gray matter), which is synthesized in neurons.
Ins is a key precursor of membrane phospho-
inositides and phospholipids and involved in cell
membrane structure.28The Ins signal detected by
MRS reflects free Ins,24which has been recognized as
the most important nonnitrogenous organic osmolyte
in mammalian brain tissue.29For proton MRS of the
brain, Ins has been validated as a glia-specific
marker with particularly high concentrations in as-
trocytes.25Therefore, the increase of Ins (?89%) in
affected white matter is consistent with an astrocytic
proliferation. This notion is further supported by the
observed increase of Gln (?50% in white and ?26%
in cortical gray matter), which is mainly present in
In five patients with genetically con-
tCr is involved in energy metabolism and a con-
stituent of both neuronal and glial cells. In rats,
higher tCr concentrations have been found in astro-
cytes than in neurons.22Accordingly, the combina-
tion of a high neuroaxonal density with an increased
number of astrocytes should result in a higher con-
centration of tCr, which is indeed observed (?30%).
Taken together, the pronounced metabolite alter-
ations in PMD white matter are in line with en-
reduced oligodendroglia. These changes in cellular
composition are in close agreement with the his-
topathologic alterations typically seen in PMD. The
histologic hallmark that is the marked reduction or
even complete lack of myelin results in a higher con-
centration of axons, while areas devoid of myelin
show paucity or absence of oligodendroglia and a
diffuse moderate proliferation of astroglia.30Whether
the cerebral cortex is spared by the disease as previ-
ously suggested30remains an open question. It de-
serves further investigation in view of the enhanced
neuroaxonal and astrocytic density (elevated tNAA
and Ins) found in both cortical and deep gray matter.
The metabolite abnormalities in PMD are comple-
mented by the unexpected finding of markedly re-
duced resonance line widths in proton MRS of white
matter. Because the spectral resolution is directly
proportional to the magnetic field homogeneity,
smaller line widths indicate a better homogeneity. In
terms of structure, this may be related to the ab-
sence of myelin sheaths that allow for a more homo-
geneous tissue composition with markedly reduced
structural boundaries than in normal white matter.
In addition, the lack of oligodendrocytes may contrib-
ute to the field homogeneity as oligodendrocytes con-
tain a considerable amount of paramagnetic iron.31
Recent MRS studies of patients with PMD yielded
conflicting results despite the fact that PMD was
genetically proven. Apart from the possible influence
of differences in patients’ age or disease stage, the
reported increases and decreases in ratios of Cho/
tCr,11-13decreases in tNAA/tCr8,9,11-13and tNAA/
Cho,8,12increases in Ins/tCr13as well as decreases
and increases in the tNAA concentration9,15may re-
flect the use of different techniques ranging from
chemical shift imaging to single-voxel MRS. Further-
more, the discrepancies imbed the uncertainties in-
troduced by the use of ratios of T1- and T2-weighted
resonance intensities, which are sensitive to putative
alterations of T1 and T2 relaxation times even in the
absence of a true metabolic change. Here, the obser-
vation of a reduction of the Cho concentration
emerges as a novel spectroscopic hallmark of affected
white matter in PMD. So far, this finding has only
been reported based on metabolite ratios in a single
patient with genetically confirmed PMD32and in two
patients with connatal PMD but an absence of a
mutation of the PLP gene.14
The metabolite abnormalities detected by in vivo
proton MRS in white matter of patients with geneti-
cally proven PMD comprise enhanced neuroaxonal
September (1 of 2) 2005
density, astrogliosis, and reduced oligodendroglia. Download full-text
This profile clearly differs from the spectral alter-
ations seen in leukodystrophies with predominant
demyelination. MRS of white matter in demyelinat-
ing disorders like adrenoleukodystrophy is charac-
terized by a marked reduction of tNAA, indicating
loss of vital neuroaxonal tissue, in conjunction with
elevation of Cho and Ins, indicating demyelination
and glial proliferation.33Nevertheless, the cellular
alterations demonstrated here are unlikely to be spe-
cific for PMD. Instead we presume that other condi-
tions with hypo- and dysmyelination will present
with a similar metabolite profile. In fact, hypomyeli-
nation with atrophy of the basal ganglia and cerebel-
lum (H-ABC) revealed a corresponding metabolite
pattern except for a normal Cho level, which is ten-
tatively ascribed to compensation by strong glial pro-
liferation.34Further studies of hypomyelinating
disorders are needed to validate the common fea-
tures of hypomyelinating disorders. These investiga-
tions should include patients with the recently
identified PMD-like disease caused by mutations in
the gene encoding gap junction protein alpha 12
The authors thank Prof. Dr. O. Boespflug, Faculte ´ de Me ´dicine,
Clermont Ferrand, for molecular analyses of the PLP gene and
Drs. S. Dreha-Kulaczewski and G. Helms, Bereich Humanmedi-
zin, Georg-August-Universita ¨t Go ¨ttingen, for help regarding data
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