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Department of Radiology and Cancer Biology, Nagasaki University School of Dentistry, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan.
Received April 8, 2004;
accepted after revision July 14, 2004.
Address correspondence to T. Nakamura
(taku{at}net.nagasakiu.ac.jp).
Abstract
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MATERIALS AND METHODS. Diffusion-weighted MRI was performed on 31 healthy volunteers and 11 Sjögren's syndrome patients with impaired lacrimal function. The volunteers and patients underwent MRI with a single-shot spin-echo echo-planar technique using a 47-mm microscopy coil. The apparent diffusion coefficient (ADC) of the lacrimal and parotid glands was obtained with b factors of 500 and 1,000 sec/mm2. T1-weighted and fat-suppressed T2-weighted MR microscopic images were also obtained to evaluate the gland morphology and signals.
RESULTS. MR microscopy provided high-resolution images of the lacrimal glands that enabled ADC measurements. The ADCs of the normal lacrimal glands showed no significant sex- or age-related changes. The ADCs for the lacrimal glands were significantly higher than those of the parotid glands in the same subjects (mean ± SD, 891 ± 103 vs 703 ± 84 x 10-6 mm2/sec, respectively; p < 0.0001, Mann-Whitney U test). We found that ADCs of the lacrimal glands in Sjögren's syndrome patients were significantly lower than those from the normal glands of age-matched healthy volunteers (736 ± 34 vs 923 ± 84 x 10-6 mm2/sec; p < 0.0001, Mann-Whitney U test).
CONCLUSION. These findings suggest that the measurement of ADCs may be a useful tool to assess abnormalities of the lacrimal glands in patients with Sjögren's syndrome.
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Recently, MRI techniques have been introduced for salivary gland evaluation in patients with Sjögren's syndrome [2, 3]. These studies convincingly showed that MRI can delineate pathognomonic changes in the affected glands. A similar technique was used to evaluate damaged lacrimal glands in Sjögren's syndrome to depict the morphologic changes of the glands [4].
More recently, Sumi et al. [5] applied diffusion-weighted MRI to the assessment of impaired salivary gland function in patients with Sjögren's syndrome to show that the apparent diffusion coefficients (ADCs) of the parotid glands were significantly lower than those of the healthy control subjects and inflammatory glands. Therefore, in the present study, we sought to determine whether diffusion-weighted MRI is also applicable to the dysfunctional lacrimal glands in patients with Sjögren's syndrome. ADC measurements of lacrimal glands require high-resolution images of the small glands to place the region-of-interest (ROI) precisely within the gland parenchyma, so we used a microscopy coil. Here, we show that the diffusion-weighted MR microscopic imaging well delineated the lacrimal glands in patients with Sjögren's syndrome.
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MRI
Axial and coronal spin-echo T1-weighted images (TR/TE, 400/10; number of
signal acquisitions, 3), T2-weighted images (2,000/80; number of signal
acquisitions, 3), and fat-suppressed (spectral presaturation with inversion
recovery [SPIR]) turbo spin-echo T2-weighted images (2,166/80; number of
signal acquisitions, 3) of the lacrimal glands were obtained by a 1.5-T MR
imager (Gyroscan Intera 1.5T Master, Philips Medical System) using a 47-mm
microscopy coil. The lacrimal glands were imaged with a field of view of 100
mm, a matrix of 160 x 144, a slice thickness of 2 mm, and slice gap of
0.2 mm.
Coronal diffusion-weighted images of the lacrimal and parotid glands were obtained by a single-shot, spin-echo type of echo-planar imaging sequence (2,292/121; number of signal acquisitions, 6) using the same 47-mm microscopy coil. The sequence was repeated for two values of the motionprobing gradients (b = 500 and 1,000 sec/mm2). The section thickness was 2 mm. Diffusion-weighted MRI was performed with a matrix of 80 x 56, a field of view of 10 cm, and an interslice gap of 0.2 mm. Coronal diffusion-weighted images of the parotid glands from the same subjects were also obtained using the same sequence parameters.
The measured voxel sizes and scanning times were, respectively, 0.62 x 0.69 x 2 mm and 150 sec for T1-weighted imaging, 0.62 x 0.74 x 2 mm and 90 sec for T2-weighted imaging, 0.62 x 0.70 x 2 mm and 80 sec for fat-suppressed T2-weighted imaging, and 1.25 x 1.82 x 2 mm and 100 sec for diffusion-weighted imaging.
Measurements of ADCs
The ADC was given by the following formula:
 | (1) |
where b1 and b2 are gradient factors of sequences S1 and S2, and SI1 and SI2 are signal intensities by sequence S1 and S2, respectively. In general, when one uses b factors greater than 300 sec/mm2, the resultant ADC contains negligible amounts, if any, of perfusion factor [5]. In the present study, we used two b factors of 500 and 1,000 sec/mm2 to neglect the effects of perfusion. Analysis was performed in ROIs placed in the glands on ADC maps. Each ROI was placed manually in the gland parenchyma on all slices that contained the gland. Three ROIs on average were obtained from each gland, and measurements were averaged for a single gland. Measurements obtained from bilateral glands were averaged in healthy subjects and patients with Sjögren's syndrome.
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Diffusion-Weighted MRI of Normal Lacrimal Glands
Diffusion-weighted single-shot spin-echo echo-planar imaging using a
microscopy coil successfully visualized the lacrimal glands of healthy
subjects (Figs. 2A,
2B,
2C). With increases in b
factors, the signals from the glands were gradually decreased
(Fig. 2D), while the gland
contour was readily detectable even with a b factor of 1,000
sec/mm2 (Fig. 2C).
Given satisfactory diffusion images of the glands, we calculated the ADCs of
the lacrimal glands on these images using b factors of 500 and 1,000
sec/mm2, and we compared those values with the ADCs of the parotid
glands.
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We found that the ADCs of normal lacrimal glands (mean ± SD, 891 ± 103 x 10-6 mm2/sec) were significantly greater than those of the parotid glands (703 ± 84 x 10-6 mm2/sec) (p < 0.0001, Mann-Whitney U test) (Fig. 3). There was no significant difference in ADCs between men (911 ± 115 x 10-6 mm2/sec) and women (881 ± 99 x 10-6 mm2/sec) (Fig. 4). Although slightly elevated with age, the ADCs did not show significant age-related change (ADC = 810.58 + 2.3114 x age; r = 0.30, p = 0.1529) (Fig. 5).
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MRI of the Lacrimal Glands in Patients with Sjögren's Syndrome
Consistent with the previously reported findings
[4], compared with the normal
lacrimal glands of healthy subjects (Figs.
1A,
1B,
1C,
1D,
1E, and
1F), the lacrimal glands in
patients with Sjögren's syndrome showed heterogeneous signal
distributions on T1-weighted MR images
(Fig. 6A). High-intensity
signals in the lacrimal glands of patients with Sjögren's syndrome were
suppressed on SPIR images, suggesting that high-intensity areas on T1-weighted
MR images are due to fat deposition in the glands
(Fig. 6B).
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Diffusion-Weighted MRI of Lacrimal Glands in Patients with Sjögren's Syndrome
No sex-related changes (Fig.
4) or laterality changes (Table
1) were observed, but our findings suggest that aging may affect
ADC levels of the lacrimal glands (Fig.
5). Therefore, we compared the ADCs between the selected healthy
volunteers whose age range was matched to that of the patients with
Sjögren's syndrome. We found that the lacrimal ADCs were significantly
lower in patients with Sjögren's syndrome (736 ± 34 x
10-6 mm2/sec) relative to the age-matched healthy
control subjects (923 ± 84 x 10-6 mm2/sec)
(p < 0.0001, Mann-Whitney U test)
(Fig. 7). The ADCs of
age-matched healthy women were also significantly higher (919 ± 82
x 10-6 mm2/sec) than those of the patients with
Sjögren's syndrome (p = 0.000196, Mann-Whitney U
test).
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Apoptosis of Lacrimal Gland Acinar Cells in Sjögren's Syndrome
In patients with Sjögren's syndrome, lymphocytic infiltration in the
lacrimal gland is thought to cause acinar cell destruction, resulting in
severe dysfunction of the involved gland
[6]. The lacrimal glands in
Sjögren's syndrome patients are well known to be associated with several
apoptotic figures [7,
8]. Indeed, the TUNEL assay and
histochemical staining of Fas and Fas ligand showed that there was a
correlation between function as assessed by the Schirmer's test and the number
of apoptotic figures in the lacrimal glands
[9]. In particular, detection
of Fas and Fas ligand protein may indicate an early phase of acinar cell
apoptosis.
MRI of Apoptosis
Apoptosis is a strictly coordinated process associated with enzymatic and
morphologic changes and is deeply involved in many types of diseases, such as
neurodegenerative diseases, pulmonary inflammation, myelodysplastic disorders,
and oncology [10]. Therefore,
we reasoned that apoptotic processes in the lacrimal glands of patients with
Sjögren's syndrome may be substantiated by ADC measurement on
diffusion-weighted MR images.
Diffusion-weighted MRI allows evaluation of differences in the extracellular space through variations in molecular water mobility at the microscopic level. Diffusion of water molecules depends on structures within tissues (intracellular organelles, macromolecules, membranes, and so on), viscosity, temperature, fiber packing, and the cell types present [11]. We found that the lacrimal glands of patients with Sjögren's syndrome exhibited significantly decreased ADCs compared with those of the healthy control subjects (Figs. 6A, and 6B). ADCs were shown to increase after induction of apoptosis by chemotherapy [12]. This may be caused by increases in extracellular water spaces. In contrast, decreased ADC values have been observed in isolated apoptotic cells [13], indicating restriction in the mobility of intracellular water molecules [14]. Therefore, the net changes in tissue ADCs may result from the balance between extracellular and intracellular spaces for freely diffusing water.
In the parotid glands of patients with Sjögren's syndrome, ADCs were found to decrease and were correlated with the severity of the disease [5]. As with the lacrimal glands, the parotid glands affected by Sjögren's syndrome were characterized histopathologically by the infiltration of mononuclear leukocytes, destruction of gland acini, and progressive fat deposition [2, 3, 5]. Although we did not examine apoptotic markers in the lacrimal gland specimens of the Sjögren's syndrome patients, these findings, together with the present observations, may indicate that acinar cell destruction due to apoptosis leads to decreased water mobility in the lacrimal glands of these patients.
MRI of the Lacrimal Gland
T1- and fat-suppressed T2-weighted MRI may be useful for the assessment of
affected lacrimal glands. The lacrimal glands were found to decrease in size
with patient age [15]. In
addition, fat deposition in the lacrimal glands may be depicted during the
late stages of Sjögren's syndrome
[4]. Furthermore, a preceding
study in which lacrimal glands were characterized as hypertrophic,
normalsized, and atrophic showed that the size of the lacrimal glands in
patients with Sjögren's syndrome varied from that of the healthy control
subjects [4]. Other
investigators also showed that in some Sjögren's syndrome patients, the
affected glands were enlarged where no apoptotic figures were observed
[7,
8]. Collectively, these studies
suggest that ADC levels of the lacrimal glands in Sjögren's syndrome
patients may fluctuate with the stages or severity of the disease.
Do abnormalities detected on diffusion-weighted imaging correlate with other functional studies of the lacrimal glands? A previous study showed that the lacrimal glands in patients with Sjögren's syndrome exhibited varying T1- and T2-weighted MRI features irrespective of lacrimal flow rates [4]. Therefore, it is plausible that the ADC levels of the lacrimal glands may not be linear with lacrimal gland function. The present study cohort did not include patients with enlarged lacrimal glands; all lacrimal glands were atrophic or normal-sized. This question remains to be clarified in a future study using a large cohort that includes patients with varying degrees of disease severity.
A major deficit of this study is the lack of the gold standard, which could be obtained by lacrimal gland biopsy. However, this is very risky, and we did not perform lacrimal gland biopsy in patients with findings suggestive of Sjögren's syndrome. On the other hand, pathologic features of the lacrimal gland were sometimes found to be inconsistent with gland function [9]. Therefore, it may be important to find an imaging indicator or indicators that provide reliable information about diseased states of the lacrimal glands involved by Sjögren's syndrome.
Use of a Microscopy Coil for Lacrimal Gland Imaging
In the present study, we used a 47-mm microscopy coil to obtain
high-resolution images of the lacrimal glands. However, this technique has
pros and cons: It is prone to motion artifacts, and the image quality is very
poor in the deep part of the orbit. The use of homogeneity correction
technology, such as CLEAR (Constant Level Appearance) software, could improve
the image quality in the deep parts, but motion artifacts are still a
problem.
ADC Measurements of the Lacrimal Gland
A broader evaluation of the major salivary glands in patients with
Sjögren's syndrome would be helpful. However, as we have mentioned, MRI
abnormalities may not be linear with lacrimal gland function, whereas the MRI
features of the parotid gland have been found to be linear with salivary flow
rate [2,
4]. The presence of impaired
lacrimal gland function is a chief criterion for the diagnosis of
Sjögren's syndrome. Furthermore, several drugs and other systemic
conditions distinctive from Sjögren's syndrome, such as aging,
sarcoidosis, and Mikulicz's disease, may hamper lacrimal gland function. In
addition, all the current tests for lacrimal gland abnormalities are invasive
or irritable. Therefore, the development of a noninvasive imaging technique is
required to assess abnormalities in the lacrimal glands in patients with
Sjögren's syndrome and would be helpful in diagnosis and treatment.
In conclusion, in this preliminary study, we have presented a noninvasive technique for the assessment of lacrimal glands in patients with Sjögren's syndrome. This technique can monitor intraglandular changes characterized by acinar cell apoptosis or other changes characteristic of the disease.
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Eß7+ T cells
around acinar epithelial cells with apoptosis in patients with Sjögren's
syndrome. J Immunol1999; 163:2226
-2235
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