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Vol. 50, No. 9, September 2004, pp 2877–2881

DOI 10.1002/art.20654
© 2004, American College of Rheumatology

Selective Gray Matter Damage in Neuropsychiatric Lupus

A Magnetization Transfer Imaging Study

S. C. A. Steens, F. Admiraal-Behloul, G. P. Th. Bosma, G. M. Steup-Beekman, H. Olofsen,

S. le Cessie, T. W. J. Huizinga, and M. A. van Buchem

Objective. Damage of brain parenchyma in pa- Conclusion. This is the first study to demonstrate,
tients with primary diffuse neuropsychiatric systemic using MTI, that in SLE patients with a history of NP
lupus erythematosus (NPSLE) has been indicated by symptoms and without explanatory focal abnormalities
magnetization transfer imaging (MTI). However, the on MRI, the GM is particularly affected. These findings
location of MTI abnormalities is unknown. This study support the hypothesis that neuronal injury may under-
was undertaken to assess the distribution of MTI ab- lie central nervous system manifestations in NPSLE.
normalities over gray matter (GM) and white matter
(WM) in SLE patients with a history of NP symptoms Up to 75% of patients with systemic lupus ery-
without explanatory magnetic resonance imaging (MRI) thematosus (SLE) experience neuropsychiatric symp-
evidence of focal disease. toms indicative of central nervous system (CNS) involve-
Methods. MTI was performed in 24 female SLE ment. In primary neuropsychiatric SLE (NPSLE), these
patients with a history of diffuse NP symptoms and 24 NP manifestations are attributed to the SLE disease
healthy female controls. Magnetization transfer ratio process itself, rather than to secondary factors such as
(MTR) maps were calculated for GM and WM sepa- infections or metabolic disorders (1). Focal neurologic
rately, and GM and WM MTR histograms were gener- NP syndromes are often associated with antiphospho-
ated. Univariate and multivariate analyses with age as lipid antibodies; however, the cause of diffuse neuro-
an additional covariate were performed on the histo- logic and psychiatric symptoms is largely unknown (2).
gram parameters peak location (PL), peak height (PH), Findings of conventional magnetic resonance imaging
and mean MTR. (MRI) of the brain are frequently unremarkable, and
Results. Compared with controls, significantly abnormalities are nonspecific (3,4). However, quantita-
reduced PH (mean ⴞ SD 136 ⴞ 22 arbitrary units tive MRI techniques, such as magnetization transfer
versus 151 ⴞ 13 arbitrary units) and mean MTR imaging (MTI), diffusion-weighted imaging, and MR
(33.3 ⴞ 1.0 percent units versus 33.6 ⴞ 0.5 percent spectroscopy (MRS), are now being assessed for their
units) were found in the GM of NPSLE patients (P ⴝ diagnostic value (4).
0.002 and P ⴝ 0.033, respectively, in multivariate ana- Using MTI, a quantitative MRI technique that is
lyses). No significant differences were observed for WM sensitive to both macroscopic and microscopic CNS
MTR parameters. damage (4), abnormalities that had been invisible by
conventional MRI were demonstrated in the brain pa-
renchyma of NPSLE patients (5). Significant associa-
S. C. A. Steens, MD, F. Admiraal-Behloul, PhD, G. P. Th.
Bosma, MD, MA, PhD, G. M. Steup-Beekman, MD, H. Olofsen, MSc, tions with parameters of neurologic, psychiatric, and
S. le Cessie, PhD, T. W. J. Huizinga, MD, PhD, M. A. van Buchem, neuropsychological function demonstrated the clinical
MD, PhD: Leiden University Medical Center, Leiden, The Nether- relevance of these findings (6). Although the underlying
Address correspondence and reprint requests to S. C. A. pathogenesis of diffuse brain damage in NPSLE is
Steens, MD, Department of Radiology, C2-S, Leiden University largely unknown, recent findings of neuronal and astro-
Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands. cytic degradation products in the cerebrospinal fluid
E-mail: s.c.a.steens@lumc.nl.
Submitted for publication November 7, 2003; accepted in (CSF) of SLE patients have focused attention on the
revised form May 12, 2004. role of neuronal damage (7). Apart from small-vessel

disease as a suggested pathogenetic factor in diffuse

brain damage (2), an anti-DNA antibody that cross-
reacts with a neuronal receptor, and potentially induces
neuronal damage, has recently been identified in serum
and CSF of patients with SLE (8).
Neuronal damage may be the key to diffuse brain
damage in NPSLE. According to this hypothesis, the
gray matter (GM) would be preferentially affected in
NPSLE because of its high concentration of neurons. To
date, MTI analyses in NPSLE patients have focused on
the brain as a whole and have not been applied to
selectively study the GM compartment. To test the
hypothesis of preferential GM involvement in diffuse
NPSLE, we assessed the GM and white matter (WM)
compartments separately by MTI, in SLE patients with a
history of NP symptoms without MRI evidence of
explanatory focal disease.

PATIENTS AND METHODS Figure 1. Segmented magnetization transfer ratio (MTR) maps of
Twenty-four female patients diagnosed as having SLE gray matter (GM) and white matter (WM) at 4 different levels.
according to the 1982 American College of Rheumatology Locations of the axial MTR maps are displayed on sagittal T1-
revised criteria (9) and 24 healthy female controls were weighted magnetic resonance images shown to the left.
included in the study (age range 19–65 years in both groups;
mean age 35 years in the patient group and 39 years in the
control group). All subjects provided written informed con- voxel was calculated by the equation (M0 ⫺ Ms)/M0, with M0
sent. Patients were recruited from the Leiden University representing the intensity of voxels in a nonsaturated state and
Medical Center Department of Rheumatology. NPSLE was Ms the intensity in a saturated state (6) (in-house software;
diagnosed based on clinical findings, after exclusion of other Division of Image Processing, Department of Radiology, Lei-
possible causes of NP symptoms (10). The mean duration of den University Medical Center). Using Statistical Parametric
SLE was 8 years (range 1–29); time since the onset of NPSLE Mapping ’99 (Wellcome Department of Cognitive Neurology,
varied from 1 month to 18 years (mean 5 years). At the time of Institute of Neurology, London, UK [11]), Ms images were
scanning, no active NP symptoms or concurrent neurologic or segmented automatically based on a cluster analysis using prior
psychiatric diseases were present, and there was no indication spatial probabilities, signal intensity information, and maxi-
of previous neurologic or psychiatric disease in any of the mum image inhomogeneity correction. Probability maps for
subjects. Patients were included only if MRI revealed no GM, WM, and CSF were inspected visually to confirm ade-
abnormalities that could possibly explain a history of NP
symptoms. Patient characteristics, specific NP manifestations,
and abnormalities on conventional MRI are described in a
previous report on the same patient group (6).
MRI was carried out with a 1.5T MR scanner (Philips,
Best, The Netherlands). Scans were aligned parallel to the
axial plane through the anterior and posterior commissure and
covered the whole brain in all sequences. Conventional T1-
weighted spin-echo, fluid-attenuated inversion recovery and
dual (proton density and T2-weighted) images (6) were ac-
quired in all patients and interpreted by an experienced
neuroradiologist (MAvB). For MTI, a 3-dimensional gradient-
echo pulse sequence with an echo time/repetition time of 6/106
msec and a flip angle of 12° was chosen, resulting in proton
density contrast in the absence of MT saturation pulses (6). A
256 ⫻ 256 matrix with 50% acquisition and 220-mm field of
view was used for 28 contiguous 5-mm slices. Two consecutive Figure 2. Histograms of the magnetization transfer ratio (MTR) (in
sets of axial images were acquired, with and without a sinc- percent units [pu], after correction for volumes) for gray matter (solid
shaped radiofrequency saturation pulse 1,100 Hz upfield of lines) and white matter (broken lines) in healthy controls (gray lines)
H2O resonance (6). Scanning time for MTI was ⫾11 minutes. and patients with neuropsychiatric systemic lupus erythematosus
The magnetization transfer ratio (MTR) for every (black lines).

Table 1. MTR histogram parameters and results of univariate analysis and multivariate analysis with age as an additional covariate*
Univariate analysis Multivariate analysis
Healthy NPSLE
controls, patients, Mean ⫾ SEM Mean ⫾ SEM
Parameter mean ⫾ SD mean ⫾ SD difference† P difference† P
GM PL, pu 34.4 ⫾ 0.5 34.3 ⫾ 0.9 0.13 ⫾ 0.21 0.553 0.25 ⫾ 0.19 0.210
WM PL, pu 37.5 ⫾ 0.6 37.9 ⫾ 1.1 0.46 ⫾ 0.26 0.078 ⫺0.35 ⫾ 0.25 0.165
GM PH, AU 151 ⫾ 13 136 ⫾ 22 14.6 ⫾ 5.2 0.007 16.8 ⫾ 5.1 0.002
WM PH, AU 189 ⫾ 16 181 ⫾ 23 8.3 ⫾ 5.6 0.146 9.0 ⫾ 5.7 0.122
GM, mean MTR, pu 33.6 ⫾ 0.5 33.3 ⫾ 1.0 0.31 ⫾ 0.23 0.195 0.46 ⫾ 0.21 0.033
WM, mean MTR, pu 37.4 ⫾ 0.5 37.8 ⫾ 1.0 ⫺0.36 ⫾ 0.23 0.126 ⫺0.25 ⫾ 0.22 0.258

* MTR ⫽ magnetization transfer ratio; NPSLE ⫽ neuropsychiatric systemic lupus erythematosus; GM ⫽ gray matter; PL ⫽ peak location; pu ⫽
percent units; WM ⫽ white matter; PH ⫽ peak height; AU ⫽ arbitrary units (corrected for volumes).
† Estimated by the least squares method.

quate extraction of intracranial contents. To avoid partial patients (P ⫽ 0.002), and also revealed a significantly
volume effect on the segmentation of GM, WM, and CSF, reduced GM mean MTR as compared with healthy
voxels with a ⬎10% probability of belonging to the CSF were
excluded. Of the remaining voxels, only those for which the controls (P ⫽ 0.033). The degree of variation among the
probability of belonging to GM or WM reached ⬎80% were NPSLE patients was significantly greater than that
considered for the histogram analysis. Based on these conser- among controls for GM PH (P ⫽ 0.012) and GM mean
vative thresholds, binary masks were produced for the GM and MTR (P ⫽ 0.005) only. For GM PL and for all WM
WM and were applied to the original MTR maps, producing
parameters, no significant differences were observed
pure GM and WM MTR maps. From these MTR maps,
histograms were generated and the corresponding peak loca- (P ⬎ 0.05).
tion (PL), peak height (PH), and mean MTR were derived for
GM and WM separately. Since the PH is dependent on both
lesion load and the physiologic variation in volumes of the DISCUSSION
different compartments, a volume correction was performed Recently, MTI has been applied to detect and
by dividing the number of voxels for each MTR value by the
total number of voxels for that tissue type (6). quantify global, functionally relevant brain damage in
Univariate analyses and multivariate linear regression patients with NPSLE (5,6). However, no information on
analyses with age as an additional covariate were performed to the anatomic distribution of MTI abnormalities has
test for significant differences in GM and WM MTR para- previously been obtained. This is the first study to
meters between healthy controls and NPSLE patients. Vari- demonstrate MTI abnormalities indicative of parenchy-
ances in MTR parameters between NPSLE patients and
controls were assessed using Levene’s test. P values less than mal brain damage specifically in the GM in SLE patients
0.05 were considered significant. with a history of NP symptoms but without explanatory
focal abnormalities on MRI. When NPSLE patients
were compared with healthy controls, differences in
volumetric MTR measures indicating loss of structural
All images showed an accurate segmentation of integrity of tissue were observed in the GM, but not the
GM and WM, as seen in the example presented in WM. Moreover, the increased variance of PH and mean
Figure 1. The stringent probability thresholds resulted in MTR values in the NPSLE patients, reflecting variation
an exclusion of voxels with partial volume effects at the of cerebral lesion load in this group of patients who were
interfaces of GM, WM, and CSF (Figure 1), providing heterogeneous in terms of symptoms and disease dura-
pure GM and WM MTR maps. WM mean MTR values tion, was found only in the GM. These findings of GM
were higher than those in the GM, although there was involvement correspond with results of histologic, immu-
considerable overlap of MTR values between GM and nologic, and other quantitative neuroimaging studies.
WM in both the patient group and the control group The exact histologic changes in NPSLE remain
(Figure 2). unclear. However, several histopathologic studies have
Univariate analysis revealed a significantly lower demonstrated vasculopathy and microinfarcts in patients
GM PH in NPSLE patients as compared with healthy with NPSLE (2). Strikingly, the classic histopathologic
controls (P ⫽ 0.007) (Table 1). A subsequent multivar- study by Johnson and Richardson showed vascular
iate analysis with age as an additional covariate con- changes predominantly in the cerebral cortex and brain
firmed the significantly reduced GM PH in NPSLE stem of SLE patients (12). Moreover, a recent immuno-

chemical study demonstrated increased levels of the MTR values. The effect of neuronal loss might therefore
light subunit of the neurofilament triplet protein and the be easier to detect with MTI in that compartment.
glial fibrillary acidic protein in the CSF of NPSLE It could be argued that decreases in GM MTR
patients, indicating neuronal and astrocytic degenera- could be due to retrograde neuronal degeneration re-
tion (7). Due to the high concentration of neurons in sulting from transection of axons traversing WM lesions.
GM, neuronal and astrocytic damage will probably lead However, no significant differences in WM MTR histo-
to a decrease of mainly GM structural integrity, which is gram parameters were observed between NPSLE pa-
in accordance with the findings of the present study. tients and healthy controls, and therefore it is unlikely
Pathogenetically, thrombotic vasculopathy and that our GM MTR findings are secondary to a WM
cerebral infarcts may account for some focal NP syn- abnormality. Another potential confounder is the pres-
dromes; however, it is unlikely that all diffuse neurologic ence of cerebral atrophy, which is known to occur in
and psychiatric manifestations in NPSLE are attribut- NPSLE (3,4). Cerebral atrophy increases the number of
able solely to these factors. In fact, there has been a voxels at the parenchymal cortex containing a mixture of
gradual realization that SLE and NPSLE may represent GM and CSF, and classification of those voxels as GM
a more diffuse disease process, including nonthrombotic could also have resulted in decreased GM MTR values.
vascular injury at the endothelial level and involvement However, with the stringent classification thresholds
of complement cascades, cytokines, autoantibodies, and used, partial voluming effects were reduced as much as
hormones (2). Since GM is more susceptible than WM possible.
to many disease processes, such as hypoperfusion (13), it Patients and healthy controls were matched for
will be particularly affected by any kind of CNS injury. age (P ⫽ 0.193 by independent-samples t-test). How-
Small-vessel disease itself may also increase blood–brain ever, since MTR parameters may be differently associ-
barrier permeability, which facilitates the entrance of ated with age in healthy subjects and SLE patients, a
antineuronal antibodies such as the recently identified multivariate analysis was performed in which age was
anti–N-methyl-D-aspartate antibody into the brain pa- included as an additional covariate, thereby reducing the
renchyma (2,8). In either case, because of the higher residual variance. The significantly reduced GM PH in
concentration of neurons in GM, the GM will be partic- NPSLE patients was confirmed in this analysis, and
ularly affected. additionally, a significantly reduced GM mean MTR was
Abnormal GM has also been observed using noted. Both the higher least square mean, estimating the
spin-spin (T2) relaxation time measurements and MRS mean difference between the groups, and a lower stan-
(3,4). An increase in T2 relaxation time indicated cere- dard error contributed to this significant difference. A
bral edema and significant metabolic disturbance (14), potential difference in association between age and
while MRS revealed a decreased N-acetylaspartate:crea- MTR parameters in controls and NPSLE patients will be
tine (NAA:Cre) ratio, indicative of neuronal injury (15). the subject of further study.
With both techniques, however, WM abnormalities in In conclusion, this is the first study to demon-
NPSLE patients were also observed. Two explanations strate that in SLE patients with a history of NP symp-
with respect to the lack of abnormal MTR findings in the toms and without explanatory focal abnormalities seen
WM in the present study can be suggested. First, our on MRI, damage occurs in the GM. This observation
patients may comprise a subgroup of NPSLE patients supports the model of neuronal damage in diffuse
without WM involvement, since only patients who did NPSLE, and can be explained by the greater suscepti-
not have focal lesions that could explain the history of bility of GM to the sequelae of small-vessel disease or to
NPSLE were included. Second, MTI and MRS reflect the presence of antineuronal antibodies, for which new
different histologic conditions. MTI mainly reflects my- evidence (8) has recently been found.
elin and axonal concentrations, whereas the NAA:Cre
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