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.     

Brain MRI correlates of magnetization transfer imaging metrics in patients with multiple sclerosis.

Previous studies suggested that magnetization transfer ratio (MTR) histograms are highly correlated with other magnetic resonance imaging (MRI) measures and can be used as a reliable method for quantifying overall disease burden in multiple sclerosis (MS). However, the relative influence of burden and severity of macroscopic MS lesions and degree of brain atrophy on various MTR histogram parameters has not yet been fully elucidated. Aim of the present study was to investigate which MRI measure best predicts the values of MTR histogram parameters in MS patients. Forty-two MS patients underwent brain dual-echo. T1-weighted and magnetization transfer imaging (MTI) MRI scans. Hyperintense lesion load (LL) on proton density (PD)-weighted and hypointense LL on T1-weighted images were measured using a local thresholding technique. A measure of brain atrophy was derived from T1-weighted images by computing the volume of brain tissue segmented from a slab of five consecutive slices rostral to the velum interpositum. On MTI scans, MTR histogram analysis was performed for the whole brain and average lesion MTR was also calculated. PD-weighted LL, T1-weighted LL and brain volume were significantly correlated with several MTI-derived measures. When a multivariate analysis was performed, brain volume alone significantly predicted the values of all the MTR histogram-derived measures (P values ranged from 0.003 to 0.0002). The ratio between hypointense T1-weighted and hyperintense PD-weighted LL significantly predicted average lesion MTR (P<0.05). Our results confirm that MTR can be used as a reliable method to assess both the overall disease burden and the individual lesion intrinsic nature in MS patients. The significant influence of brain atrophy on MTR histogram parameters supports the concept that this method also provides information on the loss of brain parenchyma in MS.     

New hypointense lesions on MRI in relapsing-remitting multiple sclerosis patients

BACKGROUND: Preliminary observational studies with multiple sclerosis (MS) patients have reported strong correlations between an increase in hypointense lesion load (black holes) on T1-weighted spin echo images, and an increase in disability. OBJECTIVE: We assessed the relationship of hypointense lesions to the clinical course of disease among 50 relapsing-remitting MS patients in the controlled setting of a randomized clinical trial. METHODS: Fifty patients with relapsing-remitting disease were enrolled in a randomized double-blind two-arm (cladribine vs. placebo) clinical trial of 1-year duration. All patients had monthly clinical evaluations and MRIs over the course of the trial. Multivariate techniques were used to identify predictors of clinical severity from information on exacerbations, MRIs, baseline clinical parameters, and demographics. RESULTS: At baseline, clinical severity is weakly related to counts of black holes, with rank correlations between counts and clinical scores (EDSS and SNRS) of absolute magnitude 0.3. Rates of appearance of new black holes over the course of the trial are higher for patients with more severe disease at baseline (EDSS > or = 4) than for the less severe patients. Changes in clinical severity over the course of the trial are best predicted by baseline neurologic scores and numbers of exacerbations, with black holes adding no further improvement in prediction. CONCLUSIONS: Numbers of exacerbations seem more critical to short-term clinical outcomes in relapsing-remitting MS, as reflected by patients' clinical scores, rather than black holes. Various imaging methods and MRI indices capture complementary information relating to MS disease processes. The determination of which processes are affected by different drugs should lead to more effective treatment of MS patients.     

MRI relapses have significant pathologic and clinical implications in multiple sclerosis

MRI is extremely sensitive for detecting new inflammatory activity in the central nervous system of patients with multiple sclerosis (MS) that is often clinically silent. Each new lesion often leaves a permanent MS plaque, which is composed of varying degrees of demyelination, axonal loss, and gliosis. New large lesions have a greater risk of evolving into permanent T1-weighted hypointense lesions (black holes) that pathologically contain the greatest axonal loss and correlate more strongly with clinical disability than with overall lesion load on T2-weighted images. There is also an association between the severity of the total T2 lesion burden with cerebral atrophy and with diffuse changes in the normal-appearing brain tissue as determined by magnetization transfer imaging and magnetic resonance spectroscopy. To maintain normal clinical functioning, the brain may compensate by recruiting increased regions of cortex, as demonstrated by functional MRI (fMRI) studies. The degree of increased fMRI activation is proportional to the severity of T2 lesion load, up to a critical limit at which it appears that these compensatory mechanisms may fail. Therefore, new inflammatory activity, as detected by MRI, carries a risk of significant early pathologic damage and delayed yet permanent clinical disability.     

T1 lesion load and cerebral atrophy as a marker for clinical progression in patients with multiple sclerosis. A prospective 18 months follow-up study

We investigated the relationship between local tissue destruction, diffuse cerebral atrophy and clinical progression in patients with established multiple sclerosis (MS). Twenty-nine patients with MS (13 patients with relapsing--remitting and 16 with secondary progressive disease) were included in a prospective serial study. Cerebral volumes, T1 hypointense lesion volumes, T2 hyperintense lesion volumes at baseline and at 18 months follow-up, and the volume of monthly enhancing lesions from month 0 to month 9 were assessed on magnetic resonance imaging (MRI) brain scans using highly reproducible semi-automated quantitative techniques. The main outcome measures were the MRI parameters and disability on Kurtzkes' Expanded Disability Status Scale. There was a significant correlation between the change (increase) in T1 lesion volume and progressive cerebral atrophy, whereas no correlation between the T2 lesion volume and atrophy was seen over the same follow-up period. The change in T1 lesion volume correlated more strongly than did T2 lesion volume change with the change in disability. We conclude that hypointense abnormalities detected in T1-weighted brain scans and cerebral atrophy may be directly linked. Although one should bear in mind some potential for reversibility due to inflammatory, oedematous lesions, these MR measures are a useful marker of progressive tissue damage and clinical progression in established MS.     

Magnetisation transfer imaging in multiple sclerosis

Magnetisation transfer imaging (MTI) is a magnetic resonance imaging (MRI) technique that has a higher specificity than conventional T2-weighted scans to the heterogeneous pathological substrates of multiple sclerosis (MS) lesions. This review outlines the contribution of MTI in the study of lesion evolution and in the assessment of disease burden in MS. MTI studies of individual MS lesions confirm the pathological heterogeneity of T2-weighted MRI abnormalities and the potential role of unenhanced T1-weighted hypointensities as specific markers of localised severe white matter disruption. Correlative cross-sectional and longitudinal studies using MTI and gadolinium (Gd)-enhanced MRI reveal that MTI findings may vary in lesions with different patterns of enhancement, and that MTI abnormalities are closely related to the onset and recovery of blood-brain barrier disruption in new MS plaques. Measures obtained from MTI scans using whole-brain histogram analysis are highly correlated with the extent of MS abnormalities on conventional MRI scans and predict patients' clinical disability well, since they are sensitive to the amounts of both macro- and microscopic MS disease burden in the whole brain and in specific regions.     

Reproducibility of brain MRI lesion volume measurements in multiple sclerosis using a local thresholding technique: effects of formal operator training.

The assessment of lesion load (LL) on brain magnetic resonance imaging (MRI) scans from patients with multiple sclerosis (MS) is widely used to monitor disease evolution, natural or modified by treatments. In this study, we evaluated the effect of formal operator training on the intra- and inter-observer reproducibility of LL measurements obtained by several operators in a setting similar to that of clinical trials. Proton-density (PD)-weighted, unenhanced and enhanced T1-weighted brain MRI scans were obtained from 10 MS patients. Five naive technicians assessed LL on these images, using a semiautomated local thresholding technique for lesion segmentation and marked hardcopies as a reference. Measurements were performed twice before and twice after a 20-hour operator training. Mean intra-observer measurement coefficient of variations (COV) before and after the training were 3.1 and 1.6% for PD-weighted LL, 4.3 and 1.8% for unenhanced T1-weighted LL (p < 0. 001), 4.9 and 2.0% for enhanced T1-weighted LL (p = 0.002). Mean inter-observer COV were significantly reduced after training (from 10.0 to 5.6% for PD-weighted, from 11.0 to 7.3% for unenhanced T1-weighted and from 16.0 to 6.8% for enhanced T1-weighted LL). Our data indicate that LL assessment on serial MRI scans from MS patients performed by technicians, using a local thresholding technique for lesion segmentation, is characterized by low measurement variability which may be significantly improved by a short and cost-effective training.     

Magnetization transfer imaging to monitor the evolution of multiple sclerosis

Magnetization transfer imaging (MTI) is a magnetic resonance imaging (MRI) technique that is now used in multiple sclerosis (MS) studies, and is thought to have a higher pathological specificity than conventional T2-weighted imaging. This review outlines the major contributions given by MTI for the understanding of MS evolution.MTI studies of individual MS lesions confirm the pathological heterogeneity of T2-weighted MRI abnormalities and the potential role of unenhanced T1-weighted hypointensities as specific markers of localized severe white matter disruption. Correlative cross-sectional and longitudinal studies using MIT and gadolinium (Gd)-enhanced MRI reveal that MTI findings may vary in lesions with different patterns of enhancement, and that MTI abnormalities are closely related to the onset and recovery of blood-brain barrier disruption in new MS plaques. MTI lesion load (LL) is highly correlated with T2-weighted MRI lesion load, but it has a limited reliability as a measure of MS lesion burden. On the other hand, measures obtained from MT scans using whole-brain histogram analysis are highly correlated with the extent of MS abnormalities on conventional MRI scans, and predict patients' clinical disability well, since they are sensitive to both macro- and microscopic MS lesion burden in the whole brain and in specific regions.These data suggest that (a) MTI is sensitive to different stages of lesion pathology and pathological evolution in MS patients; and (b) MT histogram analysis can provide a more global assessment of MS lesion burden, since it encompasses both macro- and microscopic MS pathology.     

Comparison of MS clinical phenotypes using conventional and magnetization transfer MRI

OBJECTIVE: To identify differences in pathology between the principal clinical phenotypes of MS using conventional and magnetization transfer (MT) MRI. METHODS: T1-weighted and T2-weighted images as well as MT scans were obtained from 20 controls, 21 patients presenting with clinically isolated syndromes suggestive of MS, and 93 MS patients with relapsing-remitting, secondary progressive, benign, or primary progressive course. Metrics considered: hypointense T1 and T2 lesion volumes, average lesion MT ratio, average brain MT ratio, peak height and position from MT histograms. RESULTS: MS patients had lower MT metrics than controls. Patients with clinically isolated syndromes had MT measures similar to controls, whereas primary progressive MS patients had lower histogram peak height with normal peak position. Relapsing-remitting MS patients had lower MT measures, higher T2 lesion load and ratio of hypointense T1 to T2 lesion volumes than patients with clinically isolated syndromes, and lower MT ratio and peak height than benign MS patients. Benign MS patients were similar to controls and patients with clinically isolated syndromes. Secondary progressive MS patients had the lowest MT measures and highest lesion loads. CONCLUSIONS: Pathology in patients with clinically isolated syndromes is confined to modest tissue damage in the lesions seen on T2-weighted scans. Severe damage is important for the later development of disability. However, microscopic damage in normal-appearing white matter may be a major contributor to disability in primary progressive MS.     

Correlates of MS disability assessed in vivo using aggregates of MR quantities

OBJECTIVES: To assess the magnitude of the correlations between disability and composite MRI scores in patients with MS. METHODS: T2- and T1-weighted MRI, magnetization transfer imaging, diffusion tensor imaging, and MRS imaging scans of the brain from 23 patients with MS were obtained. T2 lesion volume, T1 lesion volume, brain magnetization transfer ratio, average brain diffusivity (D), and brain N-acetylaspartate/creatine ratio were measured. RESULTS: The correlations between the Expanded Disability Status Scale (EDSS) score and each of the MR quantities taken in isolation were not significant, with the exception of the correlation between EDSS and the NAA/creatine ratio (r = -0.50; p = 0.01). In contrast, three of the composite MR scores computed using regression models were strongly correlated with the EDSS scores (r range, 0.58 to 0.73; p range, 0.004 to 0.0001). The model that included T2 and T1 lesion volumes and brain D explained 34% of the EDSS variance; the model that included T2 and T1 lesion volumes and brain N-acetylaspartate/creatine ratio explained 36% of the EDSS variance; the model that included T1 lesion volume, brain D, and brain N-acetylaspartate/creatine ratio explained 53% of the EDSS variance. CONCLUSIONS: The results suggest that multiparametric MR models have the potential to provide powerful measures to monitor MS evolution.     

MRI correlates of cognitive dysfunction in multiple sclerosis patients

Studies with conventional magnetic resonance imaging (MRI) support the hypothesis that cognitive impairment in multiple sclerosis (MS) patients is related with the lesion burden. Patterns of frontal lobe cognitive decline were also found to be related with the corresponding regional lesion load, although the total lesion load on T2-weighted MRI scans of the brain seems to be more relevant in determining frontal lobe deficits. Other non-conventional MRI techniques with a higher specificity to the heterogeneous substrates of MS pathology, such as the assessment of hypointense lesion load on T1-weighted scans and the histogram analysis of magnetisation transfer ratio (MTR) maps, have recently been applied to MS cognitive studies. Results from these studies suggest that three factors play a role in the pathogenesis of MS dementia: the burden of MS lesions, the severity of the pathological damage within individual lesions and that of the normal-appearing white matter.     

MRI and magnetization transfer imaging changes in the brain and cervical cord of patients with Devic's neuromyelitis optica

OBJECTIVES: To assess MRI and magnetization transfer (MT) imaging changes in the brain and cervical cord from patients with Devic's neuromyelitis optica (DNO), and to compare them with those from patients with MS. BACKGROUND: In MS, MT imaging detects changes within the normal-appearing brain tissue (NABT). MS lesions in the cord usually are isointense on T1-weighted images. No study has investigated these two aspects in patients with DNO. METHODS: The authors obtained dual echo, fast fluid-attenuated inversion recovery, T1-weighted, and MT scans of the brain from 8 DNO patients, 10 MS patients, and 9 healthy volunteers. T2-weighted, short-tau inversion recovery, T1-weighted, and MT scans of the cervical cord also were obtained. The authors identified lesions visible on the different scans and quantified the volumes for those in the brain. MT ratio (MTR) histogram analysis of the NABT and of the entire cervical cord also was performed. RESULTS: No brain abnormalities were found on the T2-weighted scans from healthy volunteers and from seven DNO patients. No significant difference was found for any of the NABT-MTR histogram metrics between DNO patients and controls, whereas MS patients had a significantly lower histogram average MTR and peak height. No abnormalities were seen on any of the scans of the cervical cord from healthy volunteers. All DNO patients had a single lesion longer than two vertebral segments. Five of them were hypointense on T1-weighted scans. The authors identified 24 cord lesions from MS patients: 22 were shorter than two vertebral segments and none was hypointense. There was no difference in cervical cord MTR histogram metrics between DNO and MS patients. CONCLUSIONS: This study demonstrates that patients with Devic's neuromyelitis optica (DNO) and MS have different imaging characteristics of the brain and cervical cord. This provides further evidence that DNO is a clinical entity separate from MS.     

A conventional and magnetization transfer MRI study of the cervical cord in patients with MS

OBJECTIVE: To evaluate the contribution made by cervical cord damage, assessed using a fast short-tau inversion recovery (fast-STIR) sequence and magnetization transfer ratio (MTR) histogram analysis to the clinical manifestations of MS. BACKGROUND: Previous studies have failed to show significant correlations between the number and extent of T2 spinal cord lesions and the clinical status of patients with MS. Fast-STIR is more sensitive than T2-weighted imaging for detecting cervical cord MS lesions. MTR histogram analysis provides estimates of the overall disease burden in the cervical cord with higher pathologic specificity to the more destructive aspects of MS than T2-weighted scans. METHODS: We obtained fast-STIR and magnetization transfer (MT) scans from 96 patients with MS (52 with relapsing-remitting [RRMS], 33 with secondary progressive [SPMS], and 11 with primary progressive [PPMS] MS) and 21 control subjects. Dual-echo scans of the brain were also obtained and lesion load measured. Results: Eighty-one of the patients with MS had an abnormal cervical cord scan. Patients with SPMS had more cervical cord lesions and more images with visible cervical cord damage than did patients with RRMS or PPMS (p = 0.04). The entire cohort of patients with MS had lower average MTR of the cervical cord (p = 0.006) than control subjects. Compared to control subjects, patients with RRMS had similar cervical cord MTR histogram-derived measures, whereas those with PPMS had lower average MTR (p = 0.01) and peak height (p = 0.02). Patients with SPMS had lower histogram peak height than did those with RRMS (p = 0.03). The peak position and height of the cervical cord MTR histogram were independent predictors of the probability of having locomotor disability. We found no correlation between brain T2 lesion load and any of the cervical cord MTR histogram metrics. CONCLUSIONS: This study shows that the amount and severity of MS pathology in the cervical cord are greater in the progressive forms of the disease. An accurate assessment of cervical cord damage in MS gives information that can be used in part to explain the clinical manifestations of the disease.     

Has your patient's multiple sclerosis lesion burden or brain atrophy actually changed?

Changes in mean magnetic resonance imaging (MRI)-derived measurements between patient groups are often used to determine outcomes in therapeutic trials and other longitudinal studies of multiple sclerosis (MS). However, in day-to-day clinical practice the changes within individual patients may also be of interest In this paper, we estimated the measurement error of an automated brain tissue quantification algorithm and determined the thresholds for statistically significant change of MRI-derived T2 lesion volume and brain atrophy in individual patients. Twenty patients with MS were scanned twice within 30 min. Brain tissue volumes were measured using the computer algorithm. Brain atrophy was estimated by calculation of brain parenchymal fraction. The threshold of change between repeated scans that represented statistically significant change beyond measurement error with 95% certainty was 0.65 mL for T2 lesion burden and 0.0056 for brain parenchymal fraction. Changes in lesion burden and brain atrophy below these thresholds can be safely (with 95% certainty) explained by measurement variability alone. These values provide clinical neurologists with a useful reference to interpret MRI-derived measures in individual patients.     

Conventional magnetic resonance sequences in multiple sclerosis

The role of magnetic resonance imaging (MRI) in multiple sclerosis (MS) has received considerable attention in recent years. MRI has the potential to provide indices of disease activity and progression in clinical trials. Moreover, there is now widespread agreement that conventional MRI sequences are useful not only in diagnosing the disease but also in evaluating the natural course of the disease and the response to therapy. Conventional spin echo (CSE) sequences are widely accepted as sensitive techniques for the evaluation and quantification of brain MS lesions. Fast spin echo (FSE) sequences are now used as an alternative to CSE. They have the advantage of a considerable reduction in imaging time. Fast-fluid attenuation inversion recovery (fast-FLAIR) sequences, in which the signal from cerebrospinal fluid is suppressed, also provide a reliable means to evaluate the total lesion burden in patients with MS. Despite some limitations in the detection of infratentorial lesions, Fast-FLAIR sequences are useful in clinical studies. Compared with lesions load on conventional T2-weighted sequences, an increase in hypointense lesion load on CSE T1-weighted sequences correlates more strongly with increased disability in MS patients. This might be an additional useful MRI parameter to monitor disease progression in long-term studies. Gadolinium-enhanced T1-weighted images provide highly sensitive markers for detecting MRI activity, which represent the primary MRI endpoint for screening promising disease-modifying therapies, especially in phase II trials.     

MRI in multiple sclerosis: correlation with expanded disability status scale (EDSS).

Magnetic resonance (MR) imaging is very sensitive in showing disseminated MS lesions. Subclinical MR progression occurs frequently, explaining why MR is now used to monitor treatment, even without measurable consequences, of new MR lesions to the patient at this moment. In the light of this clinico-radiological paradox, the significance of MR in MS is discussed, particularly in relation with the expanded disability status scale (EDSS). Gadolinium-enhancing lesions correlate with the occurrence of relapses, CSF myelin breakdown products and, in patients with relapsing-remitting disease, with higher EDSS. However, the predictive value of the frequency of enhancement for changes in EDSS is only weak. For conventional T2-weighted MR imaging, the cross-sectional correlation with EDSS varies between 0.15 and 0.60, and is limited mainly by the inherent lack of tissues specificity of T2-weighted images. Both T1 black holes and magnetisation transfer (MT) parameters show a better correlation with EDSS; it should be noted that lesions in which those abnormalities are found go through an initial phase of enhancement as well. For T1 black holes, a correlation up to 0.81 has been reported for SP patients. Post-mortem studies show that black holes and low MT ratios are in vivo markers of axonal loss. Preliminary data indicate that progressive atrophy also correlates with progression on the EDSS scale. More should be learned about the fate of new MR lesion with regards to development of axonal loss, which at present is difficult to predict in the enhancing stage. The existence of escape mechanisms, including remyelination, make a simple correlation with EDSS extremely unlikely, and perhaps not even desirable. Nevertheless, while the clinical effect of a given new lesion may be difficult to ascertain, the absence of (new) MR lesions is prognostically favourable, as will be the degree to which new lesions are prevented by treatment.     

Serial MRI in multiple sclerosis: a prospective pilot study of lesion load, whole brain volume and thalamic atrophy.

Using serial magnetic resonance imaging (MRI), we investigated the relationship between diffuse cerebral atrophy, T1 and T2 lesion volumes, mean thalamic volumes and clinical progression in patients with established multiple sclerosis (MS). Eleven patients were included in this prospective serial study. Cerebral volumes, T1 hypointense lesion volumes, and T2 hyperintense lesion volumes at baseline and at up to 3 years follow-up were assessed on MRI brain scans. As a putative measure of cerebral atrophy mean thalamic volumes were also obtained. The outcome measures were the MRI parameters and disability on Kurtzke's expanded disability status scale (EDSS). Of the 11 patients 6 worsened clinically as measured by an increase of 0.5 or more on the EDSS. Cerebral atrophy occurred in 91% of patients and was independent of changes in lesion volumes and was not associated with disease progression as determined by the EDSS.     

White matter T(1) relaxation time histograms and cerebral atrophy in multiple sclerosis

T(1) relaxation time (T(1)) provides a quantitative magnetic resonance imaging (MRI) parameter for evaluating tissue damage in the brain. We aimed to measure T(1) in the white matter of patients with multiple sclerosis (MS) and study relationships with cerebral atrophy, T(2) lesion load and clinical parameters. Twenty-six patients with relapsing-remitting MS and sixteen healthy controls were scanned with dual-echo T(2)-weighted, 3-dimensional (3-D) magnetization-prepared rapid acquisition gradient echo and whole brain, multi-slice inversion recovery (IR) sequences. White matter masks were defined on axial T(1) map slices using semi-automated seed growing and normalized 'total white matter' T(1) histograms generated. Atrophy data was obtained using the Cavalieri method of modern design stereology. T(2) lesion volume was also determined using seed growing.T(1) histogram-derived measures (median, peak height, peak position and standard deviation) in MS patients were significantly different (p < 0.0001) from controls. Median T(1) correlated significantly with supratentorial (r = 0.42, p = 0.036), lateral ventricle (r = 0.55, p = 0.004), and T(2) lesion volumes (r = 0.84, p < 0.0001), but not with clinical parameters.Total white matter T(1) provides a robust, quantitative measure of global disease burden in MS, and also correlates significantly with cerebral atrophy. Serial studies are required to determine its potential role as a surrogate marker of disease progression.     

A multiparametric MRI study of frontal lobe dementia in multiple sclerosis

Previous studies achieved conflicting results when correlating magnetic resonance imaging (MRI) abnormalities and cognitive impairment in multiple sclerosis (MS) patients. Recently, the estimation of MS lesion load on T1-weighted images and the analysis of magnetization transfer ratio (MTR) histograms, increased the degree of the correlation between physical disability and MRI findings in MS. We assessed the relationship of conventional and non-conventional MRI-derived measures with frontal lobe dementia in MS. Dual echo, T1-weighted and MT MRI scans of the brain were obtained in 11 MS patients with and in 11 without frontal lobe dementia, matched for age, sex, education and disability. Total (TLL) and frontal (FLL) lesion loads were assessed from T2- and T1-weighted scans. MTR histogram analysis was performed for the whole brain, the frontal lobe and the cerebellum. Median TLL and FLL were significantly higher in cognitively impaired patients on both T2- and T1-weighted scans. The MRI measure that better discriminated the two groups of patients was T1-weighted TLL (median values were 19.1 ml for demented and 1.9 ml for non-demented patients, P=0.006). Average MTR, peak height and location of overall brain and frontal lobe histograms were significantly lower for cognitively impaired than for cognitively intact patients (P values ranged from 0.0001 to 0.001). Cerebellar MTR histogram metrics did not significantly differ in patients with and without cognitive decline. The presence of cognitive decline in MS is associated with the extent and pathological severity of brain MRI abnormalities.     

Correlations between monthly enhanced MRI Lesion rate and changes in T2 Lesion volume in multiple sclerosis

Magnetic resonance imaging (MRI) provides a powerful tool for assessing disease activity in multiple sclerosis (MS), and its role as a surrogate marker for monitoring treatment efficacy is now becoming established. The most commonly used MRI parameters in treatment trials are (1) monthly gadolinium-enhanced MRI, with the number of active lesions serving as the outcome measure, and (2) annual lesion load quantification, in which change in MS lesion volume provides the MRI endpoint. We evaluated clinical/MRI correlations and the relationship between these two markers of disease activity in 73 patients with clinically definite MS. Quantification of T2 lesion load was performed at study entry and exit, with a median study duration of 11 months (range, 9 to 14 months). Monthly postgadolinium T1-weighted images were acquired between these time points. Lesion load at study entry was significantly correlated with the baseline Expanded Disability Status Scale (EDSS) score, but no significant longitudinal correlation was demonstrated. The number of enhancing lesions on the entry scan was predictive of subsequent relapse rate over the study duration and also correlated with the subsequent enhancing lesion activity over the study period. A significant correlation was found between change in lesion load and disease activity on the monthly scans. Our results suggest that annual lesion load quantification provides an efficient measure of ongoing disease activity, and this supports its application as a surrogate marker of disease evolution in phase III treatment trials.