Magnetization transfer and diffusion tensor MR imaging of basal ganglia from patients with multiple sclerosis

Magnetization transfer and diffusion tensor MR imaging of basal ganglia from patients with multiple sclerosis

Journal of the Neurological Sciences 183 (2001) 69–72 www.elsevier.com / locate / jns Magnetization transfer and diffusion tensor MR imaging of basal...

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Journal of the Neurological Sciences 183 (2001) 69–72 www.elsevier.com / locate / jns

Magnetization transfer and diffusion tensor MR imaging of basal ganglia from patients with multiple sclerosis a, a b Massimo Filippi *, Marco Bozzali , Giancarlo Comi a

Neuroimaging Research Unit, Department of Neuroscience, Scientific Institute Ospedale San Raffaele, Via Olgettina, 60, 20132 Milan, Italy b Clinical Trials Unit, Department of Neuroscience, Scientific Institute Ospedale San Raffaele, University of Milan, Milan, Italy Received 14 July 2000; received in revised form 31 October 2000; accepted 1 November 2000

Abstract Although post-mortem studies have shown that lesions of multiple sclerosis (MS) can be detected in the basal ganglia, conventional T2-weighted magnetic resonance (MR) imaging is poorly sensitive for detecting such abnormalities. This study was performed to investigate whether magnetization transfer (MT) and diffusion tensor MR imaging are able to detect in vivo basal ganglia changes in patients with MS. After image coregistration, MT ratio (MTR) and mean diffusivity (D¯ ) maps were obtained and MTR and D¯ values of the putamen, head of the caudatus and thalamus measured from 31 patients with clinically definite MS and 14 age- and sex-matched healthy volunteers using region of interest analysis. Although we found slightly decreased MTR and increased D¯ in the basal ganglia from patients compared to controls, suggesting increased extra-cellular water and reduced amount of ‘barriers’ restricting water molecular motion in the basal ganglia of patients with MS, none of the differences was statistically significant. These data suggest that the more sophisticated MR probes of tissue disruption and cellular integrity are no more sensitive than current conventional imaging for detecting basal ganglia abnormalities in patients with MS.  2001 Elsevier Science B.V. All rights reserved. Keywords: Multiple sclerosis; Basal ganglia; Lesions; Magnetization transfer imaging (MTI); Diffusion tensor imaging (DTI) MR imaging

1. Introduction Although post-mortem studies have shown that the basal ganglia are not spared by multiple sclerosis (MS) [1,2], conventional T2-weighted magnetic resonance (MR) imaging is poorly sensitive for detecting such MS-related abnormalities [3]. This might be due to three reasons, which are not mutually exclusive. First, basal ganglia are mainly constituted by gray matter and gray matter has longer relaxation times than normal white matter. This results in poor contrast resolution between gray matter and MS lesions compared with MS lesions and white matter.

*Corresponding author. Tel.: 139-02-2643-3033; fax: 139-02-26433031. E-mail address: [email protected] (M. Filippi).

Second, gray matter lesions are characterized by a higher cellular density than white matter lesions. This might not allow a sufficient expansion of the extracellular space of gray matter lesions, thus preventing a sufficient increase in relaxation times to allow these lesions to be detected at visual inspection of MR scans. Third, basal ganglia lesions are likely to be small and, as a consequence, can be masked by partial volume effects from the surrounding tissues. Other MR techniques, such as magnetization transfer imaging (MTI) and diffusion tensor imaging (DTI), which provide quantitative indices of tissue damage, might overcome the limitations of conventional MR to detect basal ganglia abnormalities in MS. MTI and DTI were shown to be able to detect subtle MS-related changes in the white matter which appears normal on conventional T2 MR scans [4]. This study was performed to investigate

0022-510X / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 00 )00471-8

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whether MTI and DTI are also able to detect in vivo basal ganglia changes in patients with MS.

2. Patients and methods We studied 31 patients with clinically definite MS [5]. Eighteen were women and 13 men. Their mean age was 40.2 years (S.D.511.9 years), median duration of the disease was 8.5 years (range 1–20 years) and median Expanded Disability Status Scale (EDSS) score [6] was 3.5 (range 1.0–7.0). Seventeen patients had relapsing– remitting and 14 secondary progressive MS [5]. When MRI scans were obtained, none of the patients was experiencing an acute relapse nor was being treated with corticosteroids. Fourteen sex- and age-matched subjects (ten women and four men; mean age540.2 years, S.D.5 10.0 years) with no history of neurological disorders and a normal neurological examination served as controls. Local Ethical Committee approval and written informed consent from all the subjects were obtained before study initiation. The following sequences were obtained from all the subjects during a single imaging session using a 1.5 T scanner: (a) dual-echo turbo spin echo (TSE) (TR53300, first echo TE516, second echo TE598, echo train length55); (b) 2D gradient-echo (GE) (TR5640, TE512, flip angle5208), with and without an off-resonance radiofrequency (RF) saturation pulse (offset frequency51.5 kHz, Gaussian envelope duration57.68 ms, flip angle5 5008); (c) pulsed-gradient spin-echo echo-planar pulse sequence (inter-echo spacing50.8, TE5123), with diffusion gradients applied in eight non-collinear directions, with a maximum b factor in each direction of 1044 mm 2 / s. In order to optimize the measurement of diffusion only two b factors were used [7] (b 1 ¯0, b 2 51044 mm 2 / s). Fat saturation was performed using a four RF binomial pulse train to avoid chemical shift artifacts. For the dualecho and the GE, 24 contiguous interleaved axial slices were acquired with 5 mm slice thickness, 2563256 matrix and 2503250 mm field of view. The slices were positioned on a plane running parallel to a line that joins the most infero-anterior and infero-posterior parts of the corpus callosum. For the DW scans, ten 5-mm thick slices were acquired, with the same orientation of the dual echo and GE scans, positioning the second-last caudal slice in order to match exactly the central slices of the dual-echo and GE sets. These central slices are less affected by the distortions due to B 0 field inhomogeneity, which can affect image co-registration. A 1283128 matrix and 2503250 mm field of view were used. After coregistration of the two GE scans using a surfacematching technique based on mutual information [8], MT ratio (MTR) images were derived pixel-by-pixel according to the following equation: MTR 5 (M0 2 MS ) /M0 3 100%, in which M0 is the signal intensity for a given pixel without the saturation pulse and MS is the signal intensity

for the same pixel when the saturation pulse is applied. Diffusion weighted images were first corrected for distortion induced by eddy currents using an algorithm which minimizes mutual information between the diffusion unweighted and weighted images [8]. Then, the diffusion tensor was calculated for each pixel using a non-linear fitting of the data, according to the Marquardt–Levenberg method. From the tensor, D¯ was derived for every pixel. The b50 step of diffusion images (T2-weighted, but diffusion-unweighted) were coregistered on the T2weighetd scans using the same technique as above [8]. The registration parameters were then used to transform D¯ maps. Similarly, MTR maps were coregistered with the T2-weighted images. MTR and D¯ values of different structures of the basal ganglia were measured using region of interest (ROI) analysis. First, a single experienced observer placed ROIs of 333 pixels bilaterally on the same areas selected on the T2-weighted scans from controls and patients. These ROIs were placed in the putamen, head of the caudate nucleus and thalamus with care to avoid partial volume effects from the surrounding tissues. Second, the outlined regions were superimposed automatically onto the co-registered MTR and D¯ maps and the average MTR and D¯ of all the ROIs calculated. A two-tailed Student’s t-test for non-paired data was used to compare MTR and D¯ values of the basal ganglia from the patients with the corresponding quantities from the controls.

3. Results No abnormalities were found on any of the scans from healthy controls. No lesions were detected in the basal ganglia from MS patients by visual inspection of the dual echo scans. T2 lesion load of the brain was measured for all patients using a segmentation technique based on local thresholding [9]. The mean T2 lesion load was 17.3 ml (range51.8–58.7 ml). In Table 1, mean MTR and D¯ values of the basal ganglia from MS patients and healthy Table 1 Mean (S.D.) MTR and D¯ values of basal ganglia from MS patients and healthy controls a Controls

MS patients

Caudatus MTR (%) D¯ (mm 2 / s 310 23 )

37.8 (1.6) 0.85 (0.08)

37.2 (1.6) 0.90 (0.14)

Thalamus MTR (%) D¯ (mm 2 / s 310 23 )

42.1 (1.7) 0.75 (0.04)

41.9 (2.7) 0.77 (0.05)

Putamen MTR (%) D¯ (mm 2 / s 310 23 )

38.6 (1.6) 0.79 (0.04)

38.1 (1.8) 0.80 (0.06)

¯ mean diffusivity. * For statistiMTR, magnetization transfer ratio; D, cal analysis, see text. a

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controls are presented. No statistically significant difference was found in any of the basal ganglia regions studied for both the MR quantities.

4. Discussion The lesions of MS typically arise within the central nervous system white matter and are readily detected in vivo by means of T2-weighted MR imaging [10]. However, post-mortem studies showed that MS lesions are also located within gray matter structures of the brain [1,2,11]. Brownell and Hughes [1] in a series of 32 cases found that 4% of all hemispheric lesions were located in the central gray matter. Lumdsen [2] in a series of ten patients reported that 7.3% of brain lesions are located in the basal ganglia. Interestingly, the estimated lesion number per gram of wet weight of basal ganglia was 0.65 and, due to the relatively small size of the basal ganglia, it was higher than that of other brain structures, such as the centrum semiovale and the corpus callosum, where more MS lesions are found in absolute terms [2]. The in vivo quantification of MS-related damage of the basal ganglia using MR imaging might be relevant to better understand the clinical manifestations of the disease and to strengthen the correlation between clinical and MR findings in MS. Basal ganglia receive and send projections to several nervous structures related to mobility, sensation and cognition [12]. Therefore, it is possible that lesions located in the basal ganglia may result in sensory–motor, cerebellar and cognitive deficits, which are all known to occur frequently in patients with MS. In the light of the known poor sensitivity of conventional MR imaging for detecting basal ganglia lesions [3], we investigated the ability of MTI and DTI to quantify MS-related tissue damage in this brain region. Both these techniques have proved to be sensitive in detecting microscopic MS abnormalities in the white matter from patients with MS, which were not seen on conventional T2-weighted MR scans [4]. Although we found slightly decreased MTR and increased D¯ in the basal ganglia of patients compared to controls, suggesting increased extra-cellular water and reduced amount of ‘barriers’ restricting water molecular motion in the basal ganglia of patients with MS, none of the differences was statistically significant. This indicates that tissue damage of the basal ganglia is modest in MS and partially disagrees with post-mortem data [1,2]. There are at least four reasons to explain this discrepancy. First, due to the relatively small sample sizes of our study and of previous post-mortem studies [1,2], this discrepancy might just be the reflection of the high inter-patient variability in MS lesion location. Second, the tissue architecture of the basal ganglia with densely packed fibers might determine, in case of MS-related tissue damage, shrinkage of tissue, which, on turn, prevents interstitial water accumulation and

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¯ Third, the size of thus detectable changes of MTR and D. basal ganglia lesions might be too small to determine MTI and DTI changes detectable with the presently available technology. Fourth, reactive gliosis might be a relevant feature of basal ganglia lesions. Gliosis secondary to previous tissue damage, on the one hand, would not result in a significant change of the relative proportions of intrato extra-cellular water, and, on the other, would restore structural barriers to water molecular motion. As a consequence, gliosis would lead to a ‘pseudo-normalization’ of MTR and D¯ values in the diseased tissues. Nevertheless, our results confirm those of other in vivo MR studies using quantitative analysis of T2 relaxation times [13,14] or MTR [15,16]. All these studies failed to detect MS-related structural changes in the basal ganglia. Admittedly, we can not exclude that conventional MRI, MTI and DTI might be able to show subtle basal ganglia abnormalities in more severely affected MS patients with clinical deficits potentially attributable to the damage of these structures. Nevertheless, significant metabolic changes have been detected in the basal ganglia of patients with MS using positron emission tomography [17,18], suggesting a functional component of the basal ganglia dysfunction in MS.

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