Disability in multiple sclerosis is related to normal appearing brain tissue MTR histogram abnormalities

BACKGROUND: Magnetization transfer ratio (MTR) histogram analysis provides a global measure of disease burden in multiple sclerosis (MS). MTR abnormalities in normal appearing brain tissue (NABT) provide quantitative information on the extent of tissue damage undetected by conventional T2-weighted (T2W) magnetic resonance imaging (MRI). AIMS: 1) To compare the MTR histograms from NABT across a broad spectrum of relapse onset MS patients, including relapsing-remitting (RR) MS (including newly diagnosed and benign subgroups) and secondary progressive (SP) MS. 2) To determine the relationship between clinical disability and NABT MTR histograms. METHODS: 2D spin echo magnetization transfer imaging was performed on 70 RRMS and 25 SPMS patients and compared with 63 controls. MTR histograms were acquired for NABT after extracting lesions and cerebrospinal fluid (CSF). T2W images were used to measure the brain parenchymal fraction (BPF) and T2 lesion load. RESULTS: MS patients had a disease duration ranging from 0.5 to 37 years and an Expanded Disability Status Scale (EDSS) score ranging from 0 to 8.5. There was a significant decrease in NABT mean MTR (+/- standard deviation) compared with controls (33.07 pu +/- 1.06 versus 34.26 pu +/- 0.47; P < 0.001) with an effect size of 2.56. The reduction in NABT mean MTR varied among patient groups from 4.9% for SPMS, 3% for all RRMS, 2.7% for early RRMS and 2.5% for benign MS, compared with controls. NABT mean MTR correlated significantly with T2 lesion load (r = -0.82) and BPF (r = 0.58). EDSS score correlated with NABT mean MTR (r = -0.43), BPF (r = -0.33) and with T2 lesion load (r = 0.59). Multivariate analysis using NABT MTR peak height, T2 lesion load and BPF combined only accounted for 38% of the variance in the EDSS (r = 0.62; P < 0.001). Disease duration accounted for an additional 14% of variance in the EDSS (r = 0.72; P < 0.001). CONCLUSIONS: There is evidence of diffuse abnormalities in NABT in addition to global brain atrophy in relapse onset MS patients, including those with recently diagnosed RRMS and benign MS. The abnormalities are greatest in patients with the more disabling SPMS. Atrophy, NABT and lesion abnormalities are all partly correlated; the processes marked by these MR measures all contribute to disability in MS, providing complementary information relevant to the complex pathological processes that occur in MS.     

The normal appearing grey matter in primary progressive multiple sclerosis

Background: In 10–15 % of patients with multiple sclerosis (MS), the clinical course is characterized by slow progression in disability without relapses (primary progressive (PP) MS). The mechanism of disability in this form of MS is poorly understood. Using magnetization transfer ratio (MTR) imaging, we investigated normal appearing white matter (NAWM) and normal appearing grey matter (NAGM) in PPMS and explored the relationship of MTR measures with disability. Methods: Thirty patients with PPMS and 30 age matched controls had spin echo based MTR imaging to study lesions and normal appearing tissues. The brain was segmented into NAWM and NAGM using SPM99 with lesions segmented using a semiautomated local thresholding technique. A 75 % probability threshold for classification of NAWM and NAGM was used to diminish partial volume effects. From normalized histograms of MTR intensity values, six MTR parameters were measured. Mean lesion MTR and T2 lesion volume were also measured. Disability was assessed using Kurtzke's expanded disability status scale (EDSS). Results: Compared with controls, patients exhibited a significant reduction in mean NAWM (p = 0.001) and NAGM (p = 0.004) MTR. Spearman's rank correlation of EDSS with the six MTR parameters in NAWM and NAGM, mean lesion MTR, and T2 lesion volume, was only significant with mean NAGM MTR (r = −0.41, p = 0.02), the 25th percentile of NAGM MTR intensity (r = −0.37, p = 0.05), and T2 lesion volume (r = 0.39, p = 0.04). Multiple regression analysis of the relationship between EDSS and 4 MR parameters representing each tissue type (mean NAWM MTR, mean NAGM MTR, mean lesion MTR, T2 lesion volume) showed that the association of EDSS with mean NAGM MTR remained significant. Conclusions: There appear to be significant abnormalities in the NAGM in PP MS. Further investigation of the pathological basis and functional significance of grey matter abnormality in PPMS is warranted. Received: 7 September 2001, Received in revised form: 3 January 2002, Accepted: 16 January 2002 Correspondence to D. H. Miller     

Magnetization transfer ratio measurement in multiple sclerosis normal-appearing brain tissue: limited differences with controls but relationships with clinical and MR measures of disease

We investigated the magnetization transfer ratio (MTR) of normal-appearing white (NAWM) and grey matter (NAGM) in a relatively large group of multiple sclerosis (MS) patients, and the relations of MTR changes with clinical disability. MTR was measured in 66 MS patients (12 PP, 35 RR, 19 SP) and 23 healthy controls, using a whole-brain 3D-FLASH technique corrected post-hoc for B1-induced variation. Histogram parameters of conservatively selected NAWM and cortical NAGM were analysed using Bonferroni-corrected ANOVA with age as covariate. Additionally, manually outlined regions of interest were analysed using a multilevel method. Lesions had low MTR (mean 22.7+/-6.9%), but NAWM exhibited limited changes: MTR histogram peak position was 32.8+/-1.0% in controls and 32.4+/-0.9% in MS patients, with a significant decrease compared to controls only in SPMS patients (31.9+/-1.1%, p=0.045). Cortical NAGM histograms did not differ significantly between patients and controls. In SPMS, regional mean MTR was significantly decreased in corpus callosum and hippocampus. MTR histogram parameters of NAGM and NAWM were correlated with EDSS and MSFC scores, with lesion volume and with normalized brain volume. We conclude that disease-induced MTR changes were small in MS NAWM and NAGM, but did correlate with clinical decline, lesion volume and overall cerebral atrophy.     

Brain atrophy and magnetization transfer ratio following methylprednisolone in multiple sclerosis: short-term changes and long-term implications

BACKGROUND: The short-term effect of corticosteroids on MRI measures of multiple sclerosis (MS) is not well understood and may have a significant impact when using these quantitative measures to evaluate disease activity and changes following other therapeutic interventions. OBJECTIVE: To determine the impact of a course of intravenous methylprednisolone (IVMP) on quantitative measures of disease activity and tissue injury in MS patients. METHODS: We prospectively measured brain parenchymal fraction (BPF), magnetization transfer ratio (MTR, lesional and whole brain), and lesion volumes on nine weekly brain MRI studies in ten MS patients receiving a course of IVMP. A group of nine MS patients not receiving IVMP served as controls. RESULTS: In comparison to untreated controls, BPF declined over the eight weeks following IVMP treatment (P <0.02). BPF decline was most prominent in patients with secondary progressive MS (SPMS, P <0.03), and was not seen in relapsing-remitting (RR) MS patients. Short-term change in BPF correlated with baseline BPF (r =0.62, P =0.05) and short-term change in lesional MTR (r = -0.55, P =0.03), but not with change in enhancing lesion volume. Short-term change in lesional MTR inversely correlated with baseline lesional and whole brain MTR (r = -0.79, P =0.04 for both). There was no significant difference between treated and control patients in measures of MTR or T2, T1 or enhancing lesion volumes. CONCLUSIONS: Patients with SPMS showed a greater decline in BPF following IVMP than RRMS patients. A correlation between changes in BPF and MTR suggest that these changes are secondary to altered water content within MS lesions. Differential response to a standardized therapeutic intervention in RRMS and SPMS suggests that responses to therapy may differ due to a fundamental pathologic difference between early and late stage MS.     

Magnetization transfer magnetic resonance imaging and clinical changes in patients with relapsing-remitting multiple sclerosis

BACKGROUND: Magnetization transfer (MT) magnetic resonance imaging (MRI) can provide in vivo quantitative estimates of microscopic tissue damage in normal-appearing white matter (NAWM) and gray matter (GM) from patients with multiple sclerosis (MS). OBJECTIVE: To determine whether a one-time MT MRI can provide markers of short-term disease evolution in patients with relapsing-remitting MS. DESIGN: Eighteen-month observational study. SETTING: Neuroimaging Research Unit, Scientific Institute and University Ospedale San Raffaele. PATIENTS: Twenty-two patients with untreated relapsing-remitting MS. MAIN OUTCOME MEASURES: Relapse rate; disability according to the Expanded Disability Status Scale (EDSS); dual-echo, 2-dimensional gradient echo with and without a saturation MT pulse and T1-weighted MRIs of the brain; and MT ratio (MTR) histograms for NAWM and GM. RESULTS: During the study period, 13 patients (59%) experienced 25 relapses. The median EDSS score was 1.25 (range, 0-3.5) at study entry and 1.75 (range, 0-3) at study exit. Significant, although moderate, correlations were found between average GM MTR values at baseline and EDSS changes during the study period (r = -0.44; P = .04). A trend was observed for the correlation between NAWM MTR values at baseline and the EDSS changes throughout 18 months (r = -0.42; P = .05). For the relation between EDSS changes and baseline GM MTR, the slope of the regression line was -0.5 (95% confidence interval, -1.0 to 0.0), indicating that a decrease in the baseline GM MTR of 1% predicted an increase in the EDSS score of 0.5 point throughout the 18 months. CONCLUSION: This study indicates that a "snapshot" MT MRI assessment detects subtle brain tissue changes that are associated with short-term disability accumulation in patients with relapsing-remitting MS.     

Evidence for grey matter MTR abnormality in minimally disabled patients with early relapsing-remitting multiple sclerosis

OBJECTIVES: To establish whether magnetisation transfer ratio (MTR) histograms are sensitive to change in normal appearing grey matter (NAGM) in early relapsing-remitting multiple sclerosis (RRMS) in the absence of significant disability; and to assess whether grey or white matter MTR measures are associated with clinical measures of impairment in early RRMS METHODS: 38 patients were studied (mean disease duration 1.9 years (range 0.5 to 3.7); median expanded disability status scale (EDSS) 1.5 (0 to 3)), along with 35 healthy controls. MTR was determined from proton density weighted images with and without MT presaturation. SPM99 was used to generate normal appearing white matter (NAWM) and NAGM segments of the MTR map, and partial voxels were minimised with a 10 pu threshold and voxel erosions. Mean MTR was calculated from the tissue segments. Atrophy measures were determined using a 3D fast spoiled gradient recall sequence from 37 patients and 17 controls. RESULTS: Mean NAGM and NAWM MTR were both reduced in early RRMS (NAGM MTR: 31.9 pu in patients v 32.2 pu in controls; p<0.001; NAWM MTR: 37.9 v 38.3 pu, p = 0.001). Brain parenchymal fraction (BPF) correlated with NAGM MTR, but when BPF was included as a covariate NAGM MTR was still lower in the patients (p = 0.009). EDSS correlated with NAGM MTR (r = 0.446 p = 0.005). CONCLUSIONS: In early RRMS, grey matter MTR abnormality is apparent. The correlation with mild clinical impairment (in this essentially non-disabled cohort) suggests that NAGM MTR could be a clinically relevant surrogate marker in therapeutic trials.     

Increasing normal–appearing grey and white matter magnetisation transfer ratio abnormality in early relapsing–remitting multiple sclerosis

Abnormalities within normal–appearing grey and white matter (NAGM and NAWM) occur early in the clinical course of multiple sclerosis (MS) and can be detected in–vivo using the magnetisation transfer ratio (MTR). To better characterize the rates of change in both tissues and to ascertain when such changes begin, we serially studied a cohort of minimally disabled, early relapsing–remitting MS patients, using NAGM and NAWM MTR histograms. Twenty–three patients with clinically definite early relapsing–remitting MS (mean disease duration at baseline 1.9 years), and 19 healthy controls were studied. A magnetisation transfer imaging sequence was acquired yearly for two years. Twenty–one patients and 10 controls completed followup. NAWM and NAGM MTR histograms were derived and mean MTR calculated. A hierarchical regression analysis, adjusting for brain parenchymal fraction,was used to assess MTR change over time. MS NAWM and NAGM MTR were significantly reduced in comparison with controls at baseline and, in patients, both measures decreased further during follow–up: (–0.10pu/year, p = 0.001 and –0.18pu/year, p < 0.001 respectively). The rate of MTR decrease was significantly greater in NAGM than NAWM (p = 0.004). Under the assumption that such changes are linear, backward extrapolation of the observed rates of change suggested that NAWM abnormality began before symptom onset. We conclude that increasing MTR abnormalities in NAWM and NAGM are observed early in the course of relapsing–remitting MS. It is now important to investigate whether these measures are predictive of future disability, and consequently, whether MTR could be used as a surrogate marker in therapeutic trials.     

Clinically benign multiple sclerosis despite large T2 lesion load: can we explain this paradox?

Magnetic resonance imaging (MRI) techniques such as magnetization transfer imaging and magnetic resonance spectroscopy (MRS) may reveal otherwise undetectable tissue damage in multiple sclerosis (MS) and can serve to explain more severe disability than expected from conventional MRI. That an inverse situation may exist where non-conventional quantitative MRI and MRS metrics would indicate less abnormality than expected from T2 lesion load to explain preserved clinical functioning was hypothesized. Quantitative MRI and MRS were obtained in 13 consecutive patients with clinically benign MS (BMS; mean age 44 +/- 9 years) despite large T 2 lesion load and in 15 patients with secondary progressive MS (SPMS; mean age 47 +/- 6 years) matched for disease duration. The magnetization transfer ratio (MTR), magnetization transfer rate (kfor), brain parenchymal fraction (BPF) and brain metabolite concentrations from proton MRS were determined. BMS patients were significantly less disabled than their SPMS counterparts (mean expanded disability status score: 2.1 +/- 1.1 versus 6.2 +/- 1.1; P < 0.001) and had an even somewhat higher mean T2 lesion load (41.2 +/- 27.1 versus 27.9 +/- 24.8 cm3; P = 0.19). Normal appearing brain tissue histogram metrics for MTR and kfor, mean MTR and kfor of MS lesions and mean BPF were similar in BMS and SPMS patients. Levels of N-acetyl-aspartate, choline and myoinositol were comparable between groups. This study thus failed to explain the preservation of function in our BMS patients with large T2 lesion load by a higher morphologic or metabolic integrity of the brain parenchyma. Functional compensation must come from other mechanisms such as brain plasticity.     

Significance of T2 lesions in multiple sclerosis: A 13-year longitudinal study

OBJECTIVE: To evaluate the relation between T2 lesions and disease severity in relapsing-remitting multiple sclerosis (MS). METHODS: This article describes a 13-year longitudinal study in 30 patients. RESULTS: Patients were 36.3 +/- 6.0 years old, had MS for 6.1 +/- 5.8 years, Expanded Disability Status Scale was 2.2 +/- 0.8, and brain parenchymal fraction (BPF) was 0.825 +/- 0.015 at study entry. At last visit, Expanded Disability Status Scale was 4.4 +/- 1.95, Multiple Sclerosis Functional Composite was -0.34 +/- 1.7, and BPF was 0.774 +/- 0.037. Baseline T2 lesion volume correlated with the BPF of the last visit (r = -0.66; p < 0.0001), magnetization transfer ratio (MTR) in normal-appearing brain tissue (r = -0.52; p = 0.004), and lesion MTR (r = -0.76; p < 0.0001). Change in T2 lesion volume in the first 2 years correlated with BPF of the last visit (r = -0.40; p = 0.03), normal-appearing brain tissue MTR (r = -0.44; p = 0.015), lesion MTR (r = -0.46; p = 0.018), Multiple Sclerosis Functional Composite scores (r = -0.50; p = 0.005), and Paced Auditory Serial Addition Task scores (r = -0.52; p = 0.003). Age was a significant covariate for clinical but not magnetic resonance imaging outcomes. INTERPRETATION: T2 lesions in relapsing-remitting MS correlate strongly with brain tissue loss and brain tissue integrity 13 years later, and with clinical disease severity, though age significantly impacts the clinical correlation. The results provide direct evidence for the disability threshold hypothesis in MS and support monitoring T2 lesions in relapsing-remitting MS.     

Abnormalities in normal appearing tissues in early primary progressive multiple sclerosis and their relation to disability: a tissue specific magnetisation transfer study

BACKGROUND: Patients with primary progressive multiple sclerosis (PPMS) often develop severe disability despite low levels of abnormality on conventional magnetic resonance imaging (MRI). This may relate to diffuse pathological processes occurring in normal appearing brain tissue (NABT) involving both white matter (NAWM) and grey matter (NAGM). Magnetisation transfer imaging (MTI) is capable of identifying these processes and may be particularly informative when applied to patients with early PPMS. AIM: To assess the relationship between abnormalities in NABT identified by MTI and disability and other radiological data in patients with early PPMS. METHODS: We studied 43 patients within 5 years of disease onset and 43 controls. The Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC) were scored. Magnetisation transfer ratios (MTR) of NABT, NAWM, and NAGM were calculated and the following MTR parameters were measured: mean, peak height, peak location, and MTR value at the 25th, 50th, and 75th percentiles. Proton density, T2, T1, and gadolinium enhancing lesion loads were also calculated. RESULTS: Differences were found between patients and controls in mean, peak height, and peak location of NAWM and NAGM (p < or = 0.001). Weak to moderate correlations were found between MTR parameters and disability in both NAWM and NAGM. Strong correlations between MTR parameters and lesion loads were found, particularly in NAWM. CONCLUSION: MTR abnormalities are seen in NAWM and NAGM in early PPMS and both are associated with disability. NAWM MTR abnormalities are more closely related to conventional MRI measures than those seen in NAGM.     

Cognitive impairment in relapsing-remitting multiple sclerosis can be predicted by imaging performed several years earlier

Cognitive deficits in multiple sclerosis (MS) are common and correlate with contemporary MRI brain abnormalities, particularly atrophy, but the ability of imaging early in the disease to predict later cognitive impairment remains to be determined. Thirty relapsing-remitting MS patients recruited within three years of the onset of the disease, and in whom MRI had been performed at baseline and a year later, were assessed neuropsychologically five years later. Imaging parameters accounting for significant variance in cognitive performance were identified using multiple regressions, once confounding variables were controlled. Patients performed significantly worse than expected on tests of attention/speed of information processing and half of them had experienced some decline in IQ in relation to premorbid estimates. The rate of global brain atrophy in the first year of the study accounted for significant variance in the overall cognitive performance, and in memory and attention/speed of information processing. Poor performance on attention tests was associated with high T1-weighted lesion volume and reduced magnetization transfer ratio (MTR) in normal-appearing white matter (NAWM). These results suggest that neuroaxonal loss was identified early in the disease, and its rate of progression, predicted cognitive impairment later in the disease. Neuroaxonal loss is likely to affect commissural and association fibres that subserve the cognitive processes impaired in MS.     

Absence of diffuse cervical cord tissue damage in early, non-disabling relapsing-remitting MS: a preliminary study

BACKGROUND: Magnetization transfer (MT) magnetic resonance imaging (MRI) can provide quantitative information about the severity of tissue damage in the cervical cord of patients with multiple sclerosis (MS). MT MRI-derived measures of cord damage are correlated with the severity of disease-related locomotor disability. OBJECTIVES: The objective of this study was to investigate whether MT MRI-detectable cervical cord damage is present in early relapsing-remitting (RR) MS. SUBJECTS AND METHODS: We studied 23 patients with 'early' RR MS (i.e., with a disease duration shorter than 5 years) and 10 age-matched healthy control subjects. During a single session, the following sequences were acquired using a 1.5 T scanner: (a) brain dual-echo turbo spin echo; (b) cervical cord fast short-tau inversion recovery; (c) cervical cord gradient echo, without and with MT pulse. Brain T2 lesion volume was measured. Cervical cord lesions were counted and normalized histograms of cord MT ratio (MTR) were produced. RESULTS: One or more cervical cord lesions were found in nine patients (39%). The average cord MTR and the mean histogram peak height values did not differ between patients and controls. There was no significant correlation between brain T2 lesion volume and cervical cord MTR histogram-derived metrics. CONCLUSIONS: Cervical cord tissue damage seems to be limited to macroscopic lesions in patients with early, non-disabling RR MS. Longitudinal studies are warranted to define the dynamics of MS-related cord damage accumulation over time later on in the course of the disease.     

Diffusion tensor imaging in early relapsing-remitting multiple sclerosis.

Diffusion tensor magnetic resonance imaging (DTI) indices are abnormal in patients with established multiple sclerosis (MS). The objective of this study was to examine the diffusion characteristics of MS lesions, normal appearing white matter (NAWM) and normal appearing grey matter (NAGM) in MS patients with early relapsing-remitting disease. A further objective was to investigate the relationship between three DTI parameters (fractional anisotropy (FA), mean diffusivity (MD) and volume ratio (VR)) and clinical outcome measures (Kurtzke expanded disability status scale (EDSS) and MS Functional Composite Measure) in early disease. DTI was performed in 28 patients and 27 controls. Analysis was carried out using a region of interest (ROI) approach. ROIs were placed in 12 NAWM and nine NAGM regions. Significant differences were found in FA, MD and VR between lesions and NAWM (P< 0.001 for all three DTI parameters). No significant differences were found between patients and controls when examining NAWM or NAGM, although there was a trend for abnormal NAWM FA and VR in some regions. No correlation was found between DTI parameters in lesions, NAWM or NAGM and the clinical outcome measures. The lack of significant DTI abnormality in the NAWM and NAGM may reflect a lack of pathological change or a limited sensitivity of DTI using ROI methodology. Previous studies have shown abnormalities in TI relaxation time, magnetisation transfer ratio (MTR) and N-Acetyl aspartate (NM) in this cohort of patients, and as such, DTI using a region of interest (ROI) approach may not be as sensitive as other MR techniques in detecting subtle changes in normal appearing brain     

Magnetization transfer ratio of the spinal cord in multiple sclerosis: relationship to atrophy and neurologic disability.

The authors compare the spinal cord magnetization transfer ratio (MTR) of multiple sclerosis (MS) patients to healthy volunteers, relate MTR to spinal cord atrophy, and relate these and other magnetic resonance (MR) imaging parameters to disability. Sixty-five patients with MS (14 relapsing remitting [RR], 34 secondary progressive [SP], and 17 primary progressive [PP] MS), and 9 healthy volunteers were studied using MR at 1.0 T. Disability of the patients was assessed using the expanded disability status scale (EDSS). Magnetic resonance parameters were upper spinal cord MTR, number of focal spinal lesions, presence of diffuse abnormalities, and spinal cord cross-sectional area (CSA). Correlations were assessed using Spearman's rank correlation coefficient (r). Magnetization transfer ratio was higher in the controls (median, 33%; range, 30%-38%) than in patients with MS (median, 30%; range, 16-36; p < 0.05). In patients with MS EDSS correlated with spinal cord MTR, albeit weakly (r = -0.25, p < 0.05). Correlation between EDSS and spinal cord CSA was better (SRCC = -0.40, p < 0.01). No correlation was found between MTR and CSA (r = 0.1, p = 0.4). Combining MTR with spinal cord CSA improved correlation with EDSS (r = -0.46, p < 0.001), suggesting an independent correlation between disability and these 2 MR parameters. Expanded disability status scale scores were higher in patients who had diffuse spinal cord abnormality regardless of focal lesions (median, 6; range, 1.5-7.5) than in patients without diffuse abnormalities (median, 3.5; range, 0-8; p < 0.01). CSA was lower in patients with diffuse spinal cord abnormality (median, 62; range, 46-89 mm2) than in patients without diffuse abnormalities (median, 73; range, 47-89 mm2; p < 0.01). MTR was slightly lower in patients with diffuse spinal cord abnormalities (median, 29; range, 21%-33%) than in patients without diffuse abnormalities (median, 31; range, 16-36; t-test, p < 0.05).     

Large-scale, multicentre, quantitative MRI study of brain and cord damage in primary progressive multiple sclerosis

Although the mechanisms underlying the accumulation of disability in primary progressive (PP) multiple sclerosis (MS) are still unclear, a major role seems to be played by 'occult' tissue damage. We investigated whether conventional and magnetization transfer (MT) MRI may provide complementary information for the assessment of PPMS severity. Conventional and MT MRI scans from 226 PPMS patients and 84 healthy controls were collected for centralized analysis. The expanded disability status scale (EDSS) score was rated at the time of MRI acquisition. T2 lesion volume, normalized brain volume (NBV) and cervical cord cross-sectional area (CSA) were measured. Magnetization transfer ratio (MTR) histograms from whole brain tissue, normal-appearing white matter and grey matter (NAGM) were also obtained. Mean NBV, CSA and MTR histogram-derived metrics showed significant inter-centre heterogeneity. After correcting for the acquisition centre, pooled average MTR and histogram peak height values were different between PPMS patients and controls for all tissue classes (P-values between 0.03 and 0.0001). More severe brain and cord atrophy and MT MRI-detectable NAGM damage were found in patients who required walking aids than in those who did not (P-values: 0.03, 0.001 and 0.016). A composite score of NBV, CSA, whole brain and NAGM MTR histogram peak height z-scores was correlated with patients' EDSS (r = 0.37, P 0.001). Magnetization transfer MRI might provide information complementary to that given by conventional MRI when assessing PPMS severity. Sequence-related variability of measurements makes the standardization of MT MRI acquisition essential for the design of multicentre studies.     

A comparative assessment of cerebral white matter by magnetization transfer imaging in early- and adult-onset multiple sclerosis patients matched for disease duration

A more favorable clinical course in early-onset (EO) multiple sclerosis (MS) than adult-onset (AO) disease is reported. Our aim was to assess white matter with/without lesions by magnetization transfer (MT) imaging in EO and AO MS patients matched for duration of the disease. Relapsing-remitting MS patients with disease onset at age ≤18 years and >18 years (n = 11 for each) were matched according to sex, age, disease duration, and 22 sex-and age-matched healthy subjects were studied with MT imaging. MT ratios (MTR) of manually outlined ROIs from T1-hypointense, T1-isointense lesions and perilesional normal appearing white matter (NAWM) as well as NAWM of the left frontal lobe of the patients and healthy subjects were calculated. MTR differences between two patient groups and control subjects, and correlation of MTR with EDSS, disease onset age, disease duration and relapse rate were analyzed statistically. In comparison with NAWM of the patients and healthy subjects, the greatest MTR reductions were observed in T1-hypointense lesions followed by T1-isointense lesions and perilesional NAWM, respectively, in EO and AO MS. Both groups’ NAWM MTR were reduced; greater and more significantly in EO patients. No correlation was found between MTR of any ROI and EDSS, duration of the disease, disease onset age, or relapse rate. Although normalization does not occur, abnormality of white matter in MS decreases as distance from the lesions increases. Greater NAWM abnormality in EO MS may relate to inherent myelin abnormalities and different repair/reorganization processes in this particular group.     

Grey matter magnetization transfer ratio independently correlates with neurological deficit in secondary progressive multiple sclerosis

Although there is substantial brain grey matter pathology in secondary progressive multiple sclerosis (MS), there has been limited investigation of its contribution to disability. This study investigated the correlation of magnetization transfer ratio (MTR) measures taken from brain grey matter, normal appearing white matter (NAWM) and lesions with neurological deficit and disability in 113 people with secondary progressive MS. In order to adjust for the potential effects of focal white matter lesions and global brain atrophy, T2 lesion volume and normalized brain volume (NBV) were also calculated for each subject. Clinical measures included the expanded disability status scale (EDSS) and the multiple sclerosis functional composite (MSFC) scores. Linear regression analysis was used to assess the age- and gender-adjusted correlation of MTR histogram mean, peak height and peak location with the MSFC and individual component measures. Logistic regression analysis was used to determine whether imaging measures could be used to predict if subjects were in the higher disability group (EDSS ≥ 6.5). Significant correlations were detected between MSFC composite and mean MTR in (i) normal appearing white matter (NAWM; r = 0.327, p < 0.0001), (ii) grey matter (r = 0.460, p < 0.0001) and (iii) lesions (r = 0.394, p < 0.0001). Although NBV and T2 lesion volume correlated significantly with MSFC, grey matter histogram mean emerged as the best predictor of MSFC score. None of the MRI measures significantly predicted higher EDSS. These results suggest that brain grey matter pathology plays an important role in determining neurological impairment. The apparent paucity of correlation between MRI measures and EDSS is likely to represent the relative insensitivity of the latter measure in this study group.     

Magnetization transfer imaging to monitor the evolution of MS: a 1-year follow-up study

OBJECTIVES: To assess the sensitivities of magnetization transfer imaging (MTI)-derived measures in detecting changes over time of macro- and microscopic lesion burdens in different MS phenotypes and to compare them with those of T2-weighted and T1-weighted lesion volumes. METHODS: A total of 96 patients were studied: 39 with relapsing-remitting MS (RRMS), 19 with secondary progressive MS (SPMS), nine with primary progressive MS, and nine with benign MS; 20 with clinically isolated syndromes suggestive of MS at presentation; and 20 healthy subjects. Brain T2-weighted, T1-weighted, and MTI scans were obtained at baseline and after 12 months. The authors measured T2-weighted and T1-weighted lesion volumes and average lesion MT ratio (MTR). The authors also derived MTR histograms from whole brain tissue (WBT) and normal-appearing brain tissue (NABT). RESULTS: In healthy control subjects, there was no significant change of any of the MTR histogram parameters. At follow-up, in the entire patient group, T2-weighted lesion volume significantly increased and average lesion MTR, WBT-MTR, NABT-MTR, and histogram peak positions significantly decreased. Patients with RRMS and SPMS had significantly higher changes in T2-weighted lesion volume and all the MTI-derived metrics compared with the other subgroups. MTI changes were more prominent (and significantly different) in patients with SPMS than in those with RRMS. Compared with patients with benign MS, patients with RRMS had significantly greater changes in T2-weighted lesion volume and WBT- and NABT-MTR metrics. Compared with patients with SPMS, patients with primary progressive MS had similar changes of T1-weighted and T2-weighted lesion volumes, but significantly lower changes of MTI-derived measures. CONCLUSIONS: MTI-derived measures are sensitive for detecting MS-related changes and might provide valuable outcome measures when assessing treatment effects in clinical trials of patients with MS.     

Cervical cord magnetization transfer ratio and clinical changes over 18 months in patients with relapsing-remitting multiple sclerosis: a preliminary study

BACKGROUND: Magnetization transfer ratio (MTR) permits the quantitative estimation of cervical cord tissue damage in patients with multiple sclerosis (MS). OBJECTIVE: To determine whether a single time-point MTR scan of the cervical cord is associated with short-term disease evolution in patients with relapsing-remitting (RR) MS. METHODS: Using a 1.5-T magnetic resonance imaging (MRI) system with a tailored cervical cord phased array coil, fast short-tau inversion recovery (fast-STIR) and MTR scans were obtained from 14 untreated patients with RRMS at baseline. Cervical cord MTR histograms were derived. Over the 18-month follow-up period, relapse rate was measured and disability assessed by the Expanded Disability Status Scale (EDSS) score. RESULTS: Average cervical cord MTR was correlated with relapse rate (r= -0.56, P=0.037). A moderate correlation (r values ranging from -0.33 to -0.36) between baseline cervical cord MTR metrics and EDSS changes over 18 months was also noted, albeit statistical significance was not reached (P = 0.26 and 0.21, respectively) perhaps because of the relatively small sample size. CONCLUSIONS: This study suggests that a 'snapshot' MT MRI assessment of the cervical cord may detect cervical cord tissue changes associated with short-term disease evolution in RRMS.     

A magnetization transfer histogram study of normal-appearing brain tissue in MS

OBJECTIVE: To evaluate 1) the ability of magnetization transfer ratio (MTR) histogram analysis to detect the extent of changes occurring outside MS lesions seen on conventional scans, 2) whether such changes vary in the different MS clinical phenotypes, 3) whether the changes are associated with the extent and severity of the macroscopic lesion load, and 4) the contribution to brain atrophy. METHODS: Dual-echo, T1-weighted, and MT scans of the brain were obtained from 77 patients with varying MS courses and 20 age- and sex-matched control subjects. To create MT histograms of the normal-appearing cerebral tissue, MS lesions were segmented from dual-echo scans, superimposed automatically, and nulled out from the coregistered and scalp-stripped MTR maps. Average MTR, peak height, and peak position were considered. T2 and T1 lesion loads, average lesion MTR, and brain volume were also measured. RESULTS: Average histogram MTR (p<0.0001) and peak position (p<0.0001) from patients with relapsing-remitting MS (RMMS) were lower than those from control subjects. Patients with primary progressive MS (PPMS) had lower average histogram MTR (p = 0.002) and histogram peak height (p = 0.01) than control subjects. Patients with secondary progressive MS (SPMS) had a lower peak height (p = 0.05) than those with RRMS. Average lesion MTR (p<0.0001) correlated highly with the histogram MTR. Average histogram MTR (p<0.0001) and T2 lesion load (p = 0.001) correlated highly with brain volume. CONCLUSIONS: The amount of microscopic changes account for an important fraction of the lesion load in MS. They may contribute to the development of brain atrophy and tend to be more evident in patients with secondary progressive MS.