MS Abstracts 01b-2g3

There is evidence that the clinical course of Multiple Sclerosis is age related. The present study evaluated the relationship between age and rate of disability progression in a large hospital-based cohort of definite cases of Multiple Sclerosis (n= 1,463).

Patients were followed every 6 to 12 months for a total period of observation of 11,387.8 person-years. Expanded Disability Status Scale scores increased significantly with increasing current age and longer duration of disease (p=0.007).

Median times to reach Expanded Disability Status Scale scores of 4.0 and 6.0, assessed using an extended Kaplan-Meier method with age as a categorical time-varying covariate, were significantly longer among patients aged 20 to 35 years compared with patients aged 36 to 50 and 51 to 65 years (p < 0.0001).

Significant associations were observed between mean Expanded Disability Status Scale scores and age at disease onset, current age, and the interaction of age at disease onset and current age (p < 0.001).

Current age had a greater effect (59% of variability in the model) on disease severity than did age at disease onset.

Furthermore, a multiplicative effect on Expanded Disability Status Scale (EDSS) score was observed for age at disease onset and current age combined, indicating a faster rate of disease progression in older patients.

In conclusion, the results of the current study demonstrate the impact of age on rate of disability progression in Multiple Sclerosis and suggest that an age-adjusted progression index may be a more relevant criterion for defining differences between Multiple Sclerosis groups.

Background And Purpose
Persistent T₁-HypoIntense lesions ("Black Holes") are thought to represent permanent damage of Brain Parenchyma.

We attempted to ascertain whether the metabolic profiles of these HypoIntense areas support this hypothesis and whether these profiles correlate with these HypoIntense findings.

Methods
Four patients with Relapsing/Remitting Multiple Sclerosis and four matched control volunteers underwent MR imaging and 3D proton MR Spectroscopy.

Absolute levels of N-AcetylAspartate (NAA), Creatine, and Choline (Cho) were obtained in 0.19 cm(3) Voxels containing 14 T₁-HypoIntense lesions (average volume, 0.4 cm(3); range, 0.2-1.0 cm(3)) in patients.

Metabolite levels were analyzed, by using Pearson correlation, against their respective lesions' HypoIntensity relative to the surrounding Apparently-Normal White Matter.

Results
Moderate correlation, r = 0.56, was found between the NAA level and MR imaging HypoIntensity.

Of the 14 lesions studied, 12 were deficient in NAA and 11 had excess Cho compared with corresponding Brain regions in control volunteers.

Only one lesion was significantly deficient in all three metabolites, indicative of total damage or Matrix Loss.

Conclusion
No relationship was found between the HypoIntensity of the lesions and their metabolic profile.

Specifically, lesions with the same HypoIntensity on T₁-weighted MR images were metabolically variable (ie, displayed disparate metabolite levels and behavior).

Also, although 86% of the lesions exhibited abnormally low NAA, 71% also had increased Cho.

This indicates that although Neuronal damage had already occurred (lower NAA), these lesions were still "smoldering" with active membrane turnover (high Cho), most likely because of De- and ReMyelination, indicative of shadow plaques (ReMyelinated lesions).

Consequently, Relapsing/Remitting HypoIntense lesions represent neither final-stage nor static pathologic abnormality.

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 Gray Matter (NAGM).

In MS patients with early Relapsing/Remitting disease, a further objective was to investigate the relationship between three DTI parameters:

1. Fractional Anisotropy (FA)
2. Mean Diffusivity (MD)
3. Volume Ratio (VR)) and

Clinical Outcome Measures:
1. Kurtzke Expanded Disability Status Scale (EDSS)
2. 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 T₁ relaxation time, Magnetization Transfer Ratio (MTR) and N-AcetylAspartate (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.

Background
After the resolution of contrast enhancement, the majority of new MS lesions become IsoIntense with surrounding White Matter on T₁-weighted MRI.

Less commonly, a HypoIntense T₁ lesion develops, representing the development of more severe focal tissue damage.

Interferon-beta (IFN-ß) reduces both the number of new enhancing lesions and the duration of contrast enhancement.

Objective
To determine if IFN-ß affects the degree of tissue damage within new lesions and if its effects are related to lesion size.

Methods
One hundred twenty-five patients with Secondary/Progressive MS from seven European sites were randomized to receive either IFN-ß-1b or placebo.

Monthly, contrast-enhanced T₁-weighted MR images were acquired at baseline, at months 1 to 6, and at months 19 to 24. The size of all new enhancing lesions developing between months 1 and 6 was recorded and their appearance at follow-up documented.

Results
In the first 6 months, fewer new enhancing lesions occurred in the IFN-ß-1b arm. This difference was greater for small (70% decrease) than for large (46% decrease) lesions.

HypoIntense T₁ lesions were more likely to form from large (25%) than from small (9%) enhancing lesions in both treatment arms.

Patients taking IFN-ß-1b developed fewer HypoIntense T₁ lesions; however, the proportion of enhancing lesions developing into HypoIntense T₁ lesions was similar in both arms.

Conclusion
IFN-ß-1b reduced the number of new enhancing lesions, with a greater effect on small lesions. However, when a new enhancing lesion did become established, treatment with IFN-ß-1b did not alter its subsequent course.

Background
The recently completed placebo-controlled multicenter randomized trial of Interferon-ß-1b (Betaferon) in 718 patients with Secondary/Progressive MS shows significant delay of disease progression and reduction of relapse rate.

This study provides an opportunity to assess the level of relationship between clinical and MRI outcomes in this cohort of patients with Secondary /Progressive MS.

Methods
Brain T₂-weighted lesion volume was measured annually in all available patients, with visual analysis to identify any new or enlarging (active) T₂ lesions at each annual time point.

A subgroup of 125 patients had monthly Gadolinium-enhanced, T₁-weighted imaging at months 0 to 6 and 18 to 24. Relapses were documented and Expanded Disability Status Scale (EDSS)was measured every 3 months.

Results
For the annual MRI outcomes, a significant but modest correlation was identified between the change in T₂ lesion volume from baseline to the final scan and the corresponding change from baseline in EDSS (r = 0.17, p < 0.0001).

There were significant correlations between the cumulative number of active T₂ lesions and 1) change in EDSS (r = 0.18, p < 0.0001) and 2) relapse rate (r = 0.24, p < 0.0001).

In the subgroup of 125 patients undergoing monthly imaging, MRI lesion activity was correlated with relapse rate over months 0 to 24 (r = 0.24, p = 0.006) but not with change in EDSS.

Conclusions
These results confirm that the clinical-MRI relationships previously identified in Relapsing/Remitting MS still are apparent in the Secondary/Progressive phase of the disease and support the use of MRI as a relevant outcome measure.

In view of the relatively modest nature of the correlations, it seems unwise to rely on such MRI measures alone as primary efficacy variables in Secondary/Progressive MS trials.

Brain Atrophy measured by MRI is a potentially useful tool for monitoring disease progression in Multiple Sclerosis. The location, extent and mechanisms of Brain Atrophy in early disease are not well documented.

Using quantitative MRI, this study investigated whole Brain, Gray and White Matter Atrophy in Clinically Early Relapsing/Remitting Multiple Sclerosis and its relationship to lesion measures.

Data came from 27 normal control subjects (14 females and 13 males, mean age 36.1 years) and 26 subjects with Clinically Definite Multiple Sclerosis (18 females and eight males, mean age 35.1 years, mean delay from first symptom to scan 1.8 years, median Expanded Disability Status Scale score 1.0).

All had three-dimensional Fast Spoiled Gradient Recall (3D FSPGR), T₁-weighted pre- and post-Gadolinium-enhanced and T₂-weighted scans.

The 3D FSPGR images were automatically segmented into Gray and White Matter and CerebroSpinal Fluid using SPM99.

3D FSPGR HypoIntense, T₂HyperIntense , T₁ HypoIntense.

And, T₁ post-Gadolinium-enhancing lesion volumes were determined by semi-automatic lesion segmentation.

The SPM99 output was combined with the 3D FSPGR lesion segmentations to quantify tissue volumes as fractions of total IntraCranial volumes.

Producing values for the Brain Parenchymal Fraction (BPF), White Matter Fraction (WMF) and Gray Matter Fraction (GMF).

Comparing Multiple Sclerosis with control subjects, BPF, GMF and WMF were significantly reduced (P < 0.001 for all tissue fractions).

Using Pearson correlations, T₂ HyperIntense and T₁ HypoIntense lesion volumes were inversely related to BPF (T₂ r = -0.78, P < 0.001; T₁ r = -0.59, P = 0.002).

And GMF (T₂ r = -0.73, P < 0.001; T₁ r = -0.53, P = 0.006), but not WMF (T₂ r = -0.30, P = 0.134; T₁ r = -0.26, P = 0.199).

T₁ post-Gadolinium-enhancing lesion volumes were not correlated with any fractional volumes. These results indicate that significant Brain Atrophy, affecting both Gray and White Matter, occurs early in the clinical course of Multiple Sclerosis.

The lack of correlation between lesion load measures and WMF suggests that pathological changes in White Matter may occur by mechanisms which are at least partly independent from overt lesion genesis in early Multiple Sclerosis.

Objective
To explore the potential usefulness of two new Magnetic Resonance Imaging (MRI) analysis techniques for assessment of progressive Cerebral Atrophy and T₂ lesion activity.

In Primary/Progressive Multiple Sclerosis (PPMS), and thereby assess the relationship between MRI activity and Atrophy in this patient group.

Background
Measurements of Cerebral Atrophy and net change in T₂ lesion volumes are currently used as surrogate markers of disease progression in Multiple Sclerosis (MS).

However, manual implementation of these techniques is time-consuming and the pathological specificity of T₂ lesion change is low.

Advances in serial scan registration have facilitated the development of a new, fully-automated technique to measure Cerebral volume (SIENA; Structural Image Evaluation, using Normalization, of Atrophy), and a technique to measure the total new T₂ lesion volume selectively (MRI difference imaging).

Method
SIENA measures changes in Cerebral size based on sub-voxel detection of shifts in edge contours.

The lesion difference imaging method measures differences in lesion volumes over time as defined by a semi-automated outlining technique.

The two new methods were validated against the T₂ lesion volume contour technique and a previously described measure of partial Brain Volume (which uses six slices centred on the presumed area of greatest change around the Lateral Ventricles).

All were applied to serially acquired MR images from a cohort of 39 patients with PPMS, who also underwent scoring on the expanded disability status scale (EDSS) twice, two years apart.

Results
The two measures reflecting Cerebral Atrophy correlated strongly (r = 0.58, p < 0.001). T₂ lesion load measurements using the two techniques correlated very highly (r = 0.999, p < 0.001).

91% of the total new T₂ lesion volume was from enlargement of pre-existent lesions and only 9 % from new, discrete, lesions.

No relationship was seen between the traditional measure of net gain in T₂ lesion load and either measure of Atrophy.

However, the fully-automated measure of total new T₂ load correlated with both measures of Atrophy (SIENA technique, r= -0.37, p= 0.02; six slice measure, r = -0.41, p = 0.01). There was no relationship between the MRI measures and changes in the EDSS.

Conclusion
Both of the new image analysis techniques appear to be promising as sensitive markers for disease progression in PPMS.

The correlation of total new T₂ lesion volume with the progression of Cerebral Atrophy (which is known to be a consequence of Axonal loss in Progressive Disease).

Compared with a lack of correlation with the traditional net gain in T₂ lesion load is interesting and suggests that the total new T₂ lesion volume may ultimately be the most useful measure.

Background
In Multiple Sclerosis (MS), pathological changes have been found both in macroscopic lesions and Normal Appearing Tissue.

Magnetization Transfer Ratio (MTR) and T₁ relaxation time are abnormal in Normal-Appearing Tissues in established MS. This study used these MR techniques in early MS to study Normal Appearing Tissues and lesions.

The purpose was to determine whether abnormalities are already detectable in Normal-Appearing Tissues in early MS, and if so how they correlate with lesion characteristics.

Methods
Twenty two patients with early Relapsing/Remitting (RR) MS (median disease duration 2 years, range 7 months-3 years) and 11 age-matched controls were studied.

MTR and T₁ relaxation times were measured in 9 regions of Normal Appearing White Matter (NAWM) and 7 of Normal-Appearing Gray Matter (NAGM). Gadolinium enhancing, T₁-HypoIntense and T₂ lesion loads were measured in all patients.

Results
When all regions were combined, there was a significant difference between patient and control NAWM for both T₁ and MTR; T₁ was abnormal in 6/9 and MTR in 3/9 NAWM regions.

Global assessment of NAGM revealed a significant difference between patients and controls for Ti but not for MTR; T₁ was significantly abnormal only in frontal NAGM.

There was no significant correlation between NAWM T₁ or MTR and any of the lesion load measurements.

Conclusions
This study reveals quantitative MR abnormalities in both NAWM and NAGM in early RR MS, with more extensive changes in the former.

The lack of correlation between NAWM and lesion abnormalities suggests that they have developed by at least partly independent mechanisms. T₁ may be more sensitive than MTR in detecting subtle pathological changes in NAWM and NAGM.

This study documents changes in clinical and Magnetic Resonance Imaging (MRI) characteristics in a large cohort of patients with Primary and Transitional/Progressive Multiple Sclerosis (PP and TPMS) over 2 years.

Patients with PPMS and TPMS were recruited from six European centres and underwent clinical and MRI examination at three time points: baseline, year one and year two.

Of the 190 patients recruited clinical data were available on 125 patients (66%, five centers) and MRI data were available on 113 patients (59%, four centres) at 2 years.

Significant increases were seen in T₂ load and T₁ HypoIntensity, while Brain and Cord volume decreased.

In PPMS significantly higher lesion loads were found in those who presented with Non-Cord Syndromes when compared to Cord presentation.

And, there was a trend to greater Brain Atrophy in those who deteriorated clinically over the course of the study compared to those who remained stable. Significant Cord Atrophy was only seen in those with a Cord presentation.

Measurable changes in MRI parameters can be detected in PPMS patients over a relatively short period of time. MRI quantification is likely to be useful in elucidating disease mechanisms in PPMS and in the execution of clinical trials.

Ten to fifteen percent of patients with Multiple Sclerosis (MS) have a condition that is Progressive from onset without a preceding Relapsing/Remitting phase: this is known as Primary/Progressive Multiple Sclerosis (PPMS).

Patients with PPMS tend to be older, often present with motor symptoms and, in contrast to Relapsing MS, are as likely to be male as female.

The conventional Magnetic Resonance Imaging (MRI) characteristics of PPMS include a tendency to lower lesion loads and lower rate of new lesion formation.

In common with Relapsing MS, the relation between conventional MRI abnormalities and clinical condition is poor.

Studies using newer MRI techniques, such as Magnetization Transfer Imaging (MTI), Diffusion-Weighted Imaging (DWI), Magnetic Resonance Spectroscopy (MRS), and Functional MRI (fMRI), have also been carried out.

These techniques are sensitive to a wider range of abnormalities within tissue, and their increased pathological specificity may be helpful in clarifying the underlying pathology of the condition.

There is a large historical database of dual-echo Conventional Spin-Echo (CSE) Magnetic Resonance images in Multiple Sderosis (MS).

If new analysis techniques can be developed then this database could provide valuable information.

We have investigated a technique in which the Late Echo of a Dual-Echo data set is subtracted from the corresponding Early Echo-yielding images, which appear qualitatively similar to T₁-weighted images.

This study investigated whether the HypoIntense lesions on the 'pseudo-T₁' images (created as described above) were related to HypoIntense lesions on conventional T₁-weighted images.

The HypoIntense lesion areas were measured by a blinded observer using a computer-assisted contouring technique applied to pseudo-T₁.

And T₁-weighted CSE images obtained from 17 patients with Secondary/Progressive MS (SPMS).

The mean HypoIntense lesion area from T₁-weighted images was 2218 +/- 2072 mm2, compared to 1426 +/- 1353 mm2 from pseudo-T₁ images (p = 0.008).

There was, however, a strong correlation between the values obtained from the two sets of images (r = 0.93, p < 0.001).

The strong correlation between the values obtained from the two sets of images suggests that pseudo-T₁ images may be useful to investigate a subgroup of more destructive lesions in MS from historical databases and in future prospective studies when imaging time is limited.