Single-dose gadolinium with magnetization transfer versus triple-dose gadolinium in the MR detection of multiple sclerosis lesions.

PURPOSETo compare the efficacy of single-dose gadolinium with magnetization transfer contrast (MTC) with that of triple-dose gadolinium in detecting enhancing multiple sclerosis lesions.METHODSTwenty-one patients with multiple sclerosis were examined with MR imaging first with 0.1 mmol/kg gadolinium (single dose) and then, after 24 to 72 hours, with 0.3 mmol/kg gadolinium (triple dose). T2-weighted fast spin-echo and T1-weighted spin-echo MR images with and without MTC were obtained before contrast administration followed by either T1-weighted spin-echo images with MTC (single dose) or conventional T1-weighted spin-echo images (triple dose), starting 5, 17, and 29 minutes after contrast administration. All images were evaluated in a blinded fashion and scored in random order by two readers. Outcome parameters included number of enhancing lesions, number of active MR examinations (those containing at least one enhancing lesion), contrast ratio (signal intensity of enhancing lesion divided by signal intensity of normal-appearing white matter), and size of enhancing lesions.RESULTSEighty-one percent more enhancing lesions and 49% more active MR examinations were detected when a triple dose of gadolinium was used as compared with a single dose. The level of agreement between readers as to the number of enhancing lesions was significantly higher for triple-dose than for single-dose gadolinium. With triple-dose gadolinium, contrast ratios and areas of enhancement increased by 10% and 33%, respectively. Delayed imaging increased the size of the lesion by 11% on single-dose MTC images and by 18% on triple-dose images.CONCLUSIONTriple-dose gadolinium is more effective (higher sensitivity and interobserver agreement) than single-dose gadolinium in combination with MTC in detecting enhancing multiple sclerosis lesions.     

Quantitative magnetic resonance of postmortem multiple sclerosis brain before and after fixation.

Unfixed and fixed postmortem multiple sclerosis (MS) brain is being used to probe pathology underlying quantitative MR (qMR) changes. Effects of fixation on qMR indices in MS brain are unknown. In 15 postmortem MS brain slices T(1), T(2), MT ratio (MTR), macromolecular proton fraction (f(B)), fractional anisotropy (FA), and mean, axial, and radial diffusivity (MD, D(ax), and D(rad)) were assessed in white matter (WM) lesions (WML) and normal appearing WM (NAWM) before and after fixation in formalin. Myelin content, axonal count, and gliosis were quantified histologically. Student's t-test and regression were used for analysis. T(1), T(2), MTR, and f(B) obtained in unfixed MS brain were similar to published values obtained in patients with MS in vivo. Following fixation T(1), T(2) (NAWM, WML) and MTR (NAWM) dropped, whereas f(B) (NAWM, WML) increased. Compared to published in vivo data all diffusivity measures were lower in unfixed MS brain, and dropped further following fixation (except for FA). MTR was the best predictor of T(myelin) (inversely related to myelin) in unfixed MS brain (r = -0.83; P < 0.01) whereas postfixation T(2) (r = 0.92; P < 0.01), T(1) (r = 0.89; P < 0.01), and f(B) (r = -0.86; P < 0.01) were superior. All diffusivity measures (except for D(ax) in unfixed tissue) were predictors of myelin content.     

Guidelines for using quantitative magnetization transfer magnetic resonance imaging for monitoring treatment of multiple sclerosis

Quantitative evaluation of brain magnetic resonance imaging (MRI) scans is now an accepted part of the trial of new putative treatments for multiple sclerosis (MS). However, conventional MRI is not pathologically specific, and it does not reveal the details of the pathological processes that underlie the progression of the disease. Magnetization transfer (MT) imaging is a relatively new quantitative technique that appears to offer some pathological specificity, and can be used to monitor the changes over time in both individual lesions and the central nervous system as a whole. This paper considers the case for incorporating MT imaging into new clinical trials, so that the utility of MT for monitoring the modification of MS progression by treatment can be assessed. Specific guidelines for implementing MT imaging as part of a large multicenter clinical trial are given, and practical considerations when planning such a trial are detailed. It is anticipated that MT imaging will be incorporated into many new trials in the near future.     

Quantitative magnetization transfer imaging in postmortem multiple sclerosis brain

PURPOSE: To investigate the relationship of myelin content, axonal density, and gliosis with the fraction of macromolecular protons (fB) and T2 relaxation of the macromolecular pool (T2B) acquired using quantitative magnetization transfer (qMT) MRI in postmortem brains of subjects with multiple sclerosis (MS). MATERIALS AND METHODS: fB and T2B were acquired in unfixed postmortem brain slices of 20 subjects with MS. The myelin content, axonal count, and severity of gliosis were all quantified histologically. t-Tests and multiple regression were used for analysis. RESULTS: MR indices obtained in unfixed postmortem MS brains were consistent with in vivo values reported in the literature. A significant correlation was detected between Tr(myelin) (inversely proportional to myelin content) and 1) fB (r = -0.80, P < 0.001) and 2) axonal count (r = -0.79, P < 0.001). fB differed between 1) normal-appearing white matter (NAWM) and remyelinated WM lesions (rWMLs) (mean: fB 6.9 [SD 2] vs. 4.0 [1.8], P = 0.01), and 2) rWMLs and demyelinated WMLs (mean: 4.2 [2.2] vs. 2.5 [1.3], P = 0.016). No association was detected between T2B and any of the histological measures. CONCLUSION: fB in MS WM is dependent on myelin content and may be a tool to monitor patients with this condition.     

Experimental allergic encephalomyelitis and multiple sclerosis: lesion characterization with magnetization transfer imaging.

Magnetization transfer imaging (MTI) was initially performed in normal guinea pigs and human volunteers. A magnetization transfer ratio (MTR) was calculated in the normal white matter and was found to be 42%-44%, with less than 2.5% variation, which indicates the high reproducibility of the measurement. MTI was then applied to an animal model of white matter disease, acute experimental allergic encephalomyelitis (EAE). In this model of EAE, pathologically proved lesions were edematous with essentially no demyelination. MTRs decreased slightly but significantly (5%-8%) compared with the MTRs of the same tissue region measured before the onset of the lesion [corrected]. Fifteen patients with multiple sclerosis (MS) also underwent MTI. In the 15 patients with MS, all lesions (209 plaques) had a significantly decreased MTR (average, 26%). The authors believe that demyelination produced the lower MTR, and, thus, lesions varied in transfer ratio on the basis of the extent of myelin loss. In patients with MS, particularly those with chronic and/or progressive MS, the MTR of the normal-appearing white matter was significantly decreased. The data suggest that calculated MTR obtained with in vivo MTI may enable differentiation of edema from demyelination, and that MTI can demonstrate white matter abnormalities that cannot be seen with standard spin-echo or gradient-echo magnetic resonance imaging.     

Improved detection of enhancing and nonenhancing lesions of multiple sclerosis with magnetization transfer.

PURPOSETo determine whether magnetization transfer imaging can improve visibility of contrast enhancement of multiple sclerosis plaques.METHODSFifty-nine enhancing and 63 nonenhancing lesions in 10 patients with multiple sclerosis were evaluated to calculate contrast-to-noise ratios on conventional T1-weighted and T1-weighted magnetization transfer images. The signal intensity of the lesion and the background (white matter) were measured on precontrast T1-weighted and T1-weighted magnetization transfer images (800/20/1 [repetition time/echo time/excitations]) and on postcontrast T1-weighted and T1-weighted magnetization transfer images. Mean contrast-to-noise ratios was calculated for all lesions.RESULTSThe contrast-to-noise ratio was significantly higher for enhancing and nonenhancing lesions on T1-weighted magnetization transfer images than on conventional T1-weighted images. For enhancing lesions, the contrast-to-noise ratio was significantly higher on postcontrast T1-weighted magnetization transfer images, 32 +/- 2 compared with 21 +/- 2 on conventional T1-weighted images. Fifty of the 59 enhancing lesions were seen on both the T1-weighted and the T1-weighted magnetization transfer images. Nine enhancing lesions were seen only on the postcontrast T1-weighted magnetization transfer images. In addition, of 63 nonenhancing lesions seen on proton-density, T2-weighted, and T1-weighted magnetization transfer images, 16 were not seen on the conventional T1-weighted images. Seven of the 63 nonenhancing lesions and 7 of the 59 enhancing lesions had high signal intensity on the precontrast T1-weighted magnetization transfer images suggestive of lipid signal, a finding not seen on the conventional precontrast T1-weighted images.CONCLUSIONMagnetization transfer improves the visibility of enhancing multiple sclerosis lesions, because they have a higher contrast-to-noise ratio than conventional postcontrast T1-weighted images. High signal intensity on both nonenhancing and enhancing lesions noted only on precontrast T1-weighted magnetization transfer suggests a lipid signal was unmasked. If magnetization transfer is used in multiple sclerosis patients, a precontrast magnetization transfer image is necessary.     

Quantitative magnetization transfer mapping of bound protons in multiple sclerosis

Quantitative analysis of magnetization transfer images has the potential to allow a more thorough characterization of the protons, both bound and free, in a tissue by extracting a number of parameters relating to the NMR properties of the protons and their local environment. This work develops previously presented techniques to produce estimates of parameters such as the bound proton fraction, f, and the transverse relaxation time of the bound pool, T(2B), for the whole brain in a clinically acceptable imaging time. This is achieved by limiting the number of data collected (typically to 10); to collect 28 5-mm slices with a reconstructed resolution of 0.94 x 0.94 mm. The protocol takes 82 sec per data point. The fitting technique is assessed against previous work and for fitting failures. Maps and analysis are presented from a group of seven controls and 20 multiple sclerosis patients. The maps show that the parameters are sensitive to tissue-specific differences and can detect pathological change within lesions. Statistically significant differences in parameters such as T(2B) and f are seen between normal-appearing white matter, multiple sclerosis lesions, and control white matter. Whole-brain histograms of these parameters are also presented, showing differences between patients and controls.     

Characterization of multiple sclerosis plaques with T1-weighted MR and quantitative magnetization transfer.

PURPOSETo investigate the relationship between the appearance of multiple sclerosis lesions identified on unenhanced T1-weighted images and their corresponding magnetization transfer ratios.METHODSA total of 119 white matter lesions seen on T2-weighted images in 17 patients with multiple sclerosis were evaluated. Axial T1-weighted images were used to classify the lesions as isointense to white matter (10 lesions), hypointense to white matter but hyperintense to gray matter (44 lesions), hypointense to gray matter (59 lesions), and relatively isointense to cerebrospinal fluid (6 lesions). The magnetization transfer ratio of each lesion was calculated, and an average magnetization transfer ratio for each subcategory was determined.RESULTSThe magnetization transfer ratio values became progressively lower with increasing hypointensity of lesions on T1-weighted images. The average magnetization transfer ratio for lesions isointense to white matter, hypointense to white matter but hyperintense to gray matter, hypointense to gray matter, and relatively isointense to cerebrospinal fluid was 34.90 +/- 2.67 mean +/- SD), 30.93 +/- 3.57, 27.27 +/- 3.56, and 23.62 +/- 2.83, respectively. All groups were significantly different from each other.CONCLUSIONLesions isointense to white matter exhibited higher magnetization transfer ratio values than lesions that were hypointense. These findings are consistent with relative preservation of the myelin structure in the former, perhaps indicating that these lesions are predominantly inflammatory (edematous) in nature. The proportionately lower magnetization transfer ratio values of lesions that appear progressively more hypointense on T1-weighted images may reflect varying degrees of demyelination, with increasing lesion hypointensity corresponding to more breakdown in the macromolecular structure. These results suggest that T1-weighted images may be useful in characterizing the underlying pathologic substrate in multiple sclerosis plaques.     

Volume measurement of multiple sclerosis lesions with magnetic resonance images

Summary The ability to visualise multiple selerosis lesions in vivo with magnetic resonance imaging suggests and important role in monitoring the course of the disease. In order to help the long-term assessment of prospective treatments, a semi-automated technique for measuring lesion volume has been developed to provide a quantitative index of disease progression. Results are presented from a preliminary study with a single patient and compared to measurements taken from lesion outlines traced by a neuroradiologist, two neurologists and a technician. The semi-automated technique achieved a precision of 6% compared to a range of 12–33% for the manual tracing method. It also reduced the human interaction time from at least 60 min to 15 min.     

Database for serial magnetic resonance imaging in multiple sclerosis

The unique sensitivity of magnetic resonance imaging (MRI) in detecting disease activity in multiple sclerosis (MS) and the objective nature of the information obtained suggest that MRI will be a useful and reliable way of monitoring treatment trials. There is a need to develop an appropriate database which would provide a standardised means of assessment, not only of MRI, but also of essential clinical information. As part of the program of Concerted Action in Multiple Sclerosis, funded by the Commission of the European Community (CEC), we have developed a database for recording serial brain MRI results. The database consists of core, entry and follow-up sections. Both entry and follow-up parts are subdivided into clinical, MR system and MRI data. We expect that the use of this database will maximise efficiency of MRI monitoring in MS treatment trials, particularly in multicentre studies.     

Increasing benefit of magnetic resonance imaging in multiple sclerosis

Magnetic resonance imaging (MRI) has emerged as an essential tool of multiple sclerosis (MS) diagnosis and has opened up completely new prospects in MS research and treatment trials. It is a sensitive method that gives direct evidence of tissue pathology and has greatly increased our knowledge of MS. In clinical work, MRI is used to confirm and exclude the diagnosis of MS. The international recommendation is that every suspected MS patient should undergo at least one brain MRI. T2-weighted images are the standard tool in clinical work, and functional imaging methods are mainly used in MS research. The subtypes and the course of the disease cause variation in MRI findings. Here, we present a general overview of MR findings in MS.     

Spinal cord magnetic resonance imaging in suspected multiple sclerosis

We examined the value of spinal cord magnetic resonance imaging (MRI) in the diagnostic work-up of multiple sclerosis (MS). Forty patients suspected of having MS were examined within 24 months after the start of symptoms. Disability was assessed, and symptoms were categorized as either brain or spinal cord. Work-up further included cerebrospinal fluid analysis and standard proton-density, T2-, and T1-weighted gadolinium-enhanced brain and spinal cord MRI. Patients were categorized as either clinically definite MS (n = 13), laboratory-supported definite MS (n = 14), or clinically probable MS (n = 4); four patients had clinically probable MS, and in nine MS was suspected. Spinal cord abnormalities were found in 35 of 40 patients (87.5 %), consisting of focal lesions in 31, only diffuse abnormalities in two, and both in two. Asymptomatic spinal cord lesions occurred in six patients. All patients with diffuse spinal cord abnormality had clear spinal cord symptoms and a primary progressive disease course. In clinically definite MS, the inclusion of spinal imaging increased the sensitivity of MRI to 100 %. Seven patients without a definite diagnosis had clinically isolated syndromes involving the spinal cord. Brain MRI was inconclusive, while all had focal spinal cord lesions which explained symptoms and ruled out other causes. Two other patients had atypical brain abnormalities suggesting ischemic/vascular disease. No spinal cord abnormalities were found, and during follow-up MS was ruled out. Spinal cord abnormalities are common in suspected MS, and may occur asymptomatic. Although diagnostic classification is seldom changed, spinal cord imaging increases diagnostic sensitivity of MRI in patients with suspected MS. In addition, patients with primary progressive MS may possibly be earlier diagnosed. Finally, differentiation with atypical lesions may be improved. Received: 21 April 1999; Revised: 3 August 1999; Accepted: 7 August 1999     

Global volumetric estimation of disease burden in multiple sclerosis based on magnetization transfer imaging.

We report a semiautomated postprocessing method based on magnetization transfer MR imaging that can quantify the extent of global disease in patients with multiple sclerosis. The technique combines segmentation and quantitative analysis of imaging data reflecting the structural integrity of white matter. Applications of this technique may include assessment of disease progress and of the efficacy of experimental therapeutic intervention. The height of the histogram peak corresponding to white matter was found to be lowered in patients with multiple sclerosis and the overall distribution of magnetization transfer ratios was shifted to lower values.     

Brain MR post-gadolinium contrast in multiple sclerosis: the role of magnetization transfer and image subtraction in detecting more enhancing lesions

Our purpose was to evaluate the role of magnetization transfer and image subtraction in detecting more enhancing lesions in brain MR imaging of patients with multiple sclerosis (MS). Thirty-one MS patients underwent MR imaging of the brain with T1-weighted spin echo sequences without and with magnetization transfer (MT) using a 1.5 T imager. Both sequences were acquired before and after intravenous injection of a paramagnetic contrast agent. Subtraction images in T1-weighted sequences were obtained by subtracting the pre-contrast images from the post-contrast ones. A significant difference was found between the numbers of enhanced areas in post-gadolinium T1-weighted images without and with MT (p=0.020). The post-gadolinium T1-weighted images with MT allowed the detection of an increased (13) number of enhancing lesions compared with post-gadolinium T1-weighted images without MT. A significant difference was also found between the numbers of enhanced areas in post-gadolinium T1-weighted images without MT and subtraction images without MT (p=0.020). The subtraction images without MT allowed the detection of an increased (10) number of enhancing lesions compared with post-gadolinium T1-weighted images without MT. Magnetization transfer contrast and subtraction techniques appear to be the simplest and least time-consuming applications to improve the conspicuity and detection of contrast-enhancing lesions in patients with MS.     

T2 relaxation time analysis in patients with multiple sclerosis: correlation with magnetization transfer ratio

The aim of the current study was to perform T2 relaxation time measurements in multiple sclerosis (MS) patients and correlate them with magnetization transfer ratio (MTR) measurements, in order to investigate in more detail the various histopathological changes that occur in lesions and normal-appearing white matter (NAWM). A total number of 291 measurements of MTR and T2 relaxation times were performed in 13 MS patients and 10 age-matched healthy volunteers. Measurements concerned MS plaques (105), NAWM (80), and dirty white matter (DWM; 30), evenly divided between the MS patients, and normal white matter (NWM; 76) in the healthy volunteers. Biexponential T2 relaxation-time analysis was performed, and also possible linearity between MTR and mean T2 relaxation times was evaluated using linear regression analysis in all subgroups. Biexponential relaxation was more pronounced in black-hole lesions (16.6%) and homogeneous enhancing plaques (10%), whereas DWM, NAWM, and mildly hypointense lesions presented biexponential behavior with a lower frequency(6.6, 5, and 3.1%, respectively). Non-enhancing isointense lesions and normal white matter did not reveal any biexponentional behavior. Linear regression analysis between monoexponential T2 relaxation time and MTR measurements demonstrated excellent correlation for DWM(r=–0.78, p<0.0001), very good correlation for black-hole lesions(r=-0.71, p=0.002), good correlation for isointense lesions(r=–0.60, p=0.005), moderate correlation for mildly hypointense lesions(r=–0.34, p=0.007), and non-significant correlation for homogeneous enhancing plaques, NAWM, and NWM. Biexponential T2 relaxation-time behavior is seen in only very few lesions (mainly on plaques with high degree of demyelination and axonal loss). A strong correlation between MTR and monoexponential T2 values was found in regions where either inflammation or demyelination predominates; however, when both pathological conditions coexist, this linear relationship is lost.     

Texture analysis of magnetization transfer maps from patients with clinically isolated syndrome and multiple sclerosis

Purpose

To investigate the behavior of texture parameters derived from the gray level co‐occurrence matrix from gray matter (GM) and white matter (WM) (with lesions removed) segments of magnetization transfer ratio maps from controls and patients.

Materials and Methods

Magnetization transfer ratio maps from 23 controls and patients with either a clinically isolated syndrome (CIS) (38 patients) or clinically definite multiple sclerosis (MS) (35) were scanned and texture parameters extracted. The texture parameters were compared between the groups and correlated with clinical measures of disability in the MS patients to investigate any association with disease severity.

Results

No significant differences were found between the texture parameters from controls and CIS patients; however, several parameters differ between MS patients and the two other groups, particularly in the GM, but also in the WM. The expanded disability status score and timed walk test correlate with GM texture measures, while the Paced Auditory Serial Addition Test 3 score, a cognitive measure, correlates with WM texture. Texture abnormalities were seen in MS WM and GM, indicating tissue damage beyond classical WM lesions, the abnormalities being more evident in GM.

Conclusion

The findings highlight potential for texture analysis measures in classifying central nervous system demyelinating diseases that warrants further investigation. J. Magn. Reson. Imaging 2009;30:506–513. © 2009 Wiley‐Liss, Inc.     

Power efficient on-resonance saturation pulses for magnetization transfer in magnetic resonance imaging

A family of new on-resonance saturation pulses for magnetization transfer in MRI is proposed. These pulses can be represented as a product of a shaped function and a cosine function. The shaped function can have many different forms, one of which is a Gaussian function. The experimental results on a 1.0 T whole body scanner show that the new on-resonance pulses are more efficient for magnetization transfer than either on-resonance binomial sequence pulses or offresonance Gaussian pulses at the same power level.     

Serial gadolinium-enhanced magnetic resonance imaging in patients with multiple sclerosis treated with mitoxantrone

Serial gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) was used to monitor the effect of mitoxantrone in ten patients with rapidly deteriorating multiple sclerosis (MS). MRI was performed as a baseline and thereafter at 1,3,6,9,12 and 24 months. The total number of Gd-enhancing lesions diminished from 169 at baseline to 10 after 1 year and to 5 after 2 years. This reduction and the percentage of follow-up MRI studies showing no Gd enhancement were more pronounced than in other MRI studies of the natural course of MS. Measured with quantitative neurological scales, only one patient showed deterioration after 2 years; nevertheless, the changes in MRI were much more marked than those observed clinically. Serial Gd-MRI therefore, seems necessary for documenting efficacy in future therapeutic trails.     

Quantification of magnetization transfer rate and native T1 relaxation time of the brain: correlation with magnetization transfer ratio measurements in patients with multiple sclerosis

The purpose of this paper is to perform quantitative measurements of the magnetization transfer rate (Kfor) and native T1 relaxation time (T1free) in the brain tissue of normal individuals and patients with multiple sclerosis (MS) by means of multiple gradient echo acquisitions, and to correlate these measurements with the magnetization transfer ratio (MTR). Quantitative magnetization transfer imaging was performed in five normal volunteers and 12 patients with relapsing–remitting MS on a 1.5 T magnetic resonance (MR) scanner. The T1 relaxation time under magnetization transfer irradiation (T1sat) was calculated by means of fitting the signal intensity over the flip angle in several 3D spoiled gradient echo acquisitions (3°, 15°, 30°, and 60°), while a single acquisition without MT irradiation (flip angle of 3°) was utilized to calculate the MTR. The Kfor and T1free constants were quantified on a pixel-by-pixel basis and parametric maps were reconstructed. We performed 226 measurements of Kfor, T1free, and the MTR on normal white matter (NWM) of healthy volunteers (n=50), and normal-appearing white matter (NAWM) and pathological brain areas of MS patients (n=120 and 56, respectively). Correlation coefficients between Kfor–MTR, T1free–MTR, and T1free–Kfor were calculated. Lesions were classified, according to their characteristics on T1-weighted images, into isointense (compared to white matter), mildly hypointense (showing signal intensity lower than white matter and higher than gray matter), and severely hypointense (revealing signal intensity lower than gray matter). Dirty white matter (DWM) corresponded to areas with diffused high signal, as identified on T2-weighted images. Strong correlation coefficients were obtained between MTR and Kfor for all lesions studied (r²=0.9, p<0.0001), for mildly hypointense plaques (r²=0.82, p<0.0001), and for DWM (r²=0.78, p=0.0007). In contrast, comparison between MTR and T1free values yielded rather low correlation coefficients for all groups assessed. In severely hypointense lesions, an excellent correlation was found between Kfor and T1free measurements (r²=0.98, p<0.0001). Strong correlations between Kfor and T1free were found for the rest of the subgroups, except for the NAWM, in which a moderate correlation was obtained (r²=0.5, p<0.0001). We conclude that Kfor and T1free measurements are feasible and may improve our understanding of the pathological brain changes that occur in MS patients.