MS Abstracts 01d-2g3

Background And Purpose
The T₂-weighted MR imaging total lesion volume and Expanded Disability Status Scale (EDSS) score are two common measures of Relapsing/Remitting Multiple Sclerosis disability and pathologic abnormality.

Because the Whole Brain N-AcetylAspartate concentration is considered to be a new marker of the disease burden, the purpose of this study was to evaluate the relationship among these three measures.

Methods
The Whole-Brain N-AcetylAspartate concentration and T₂-weighted lesion volume were quantified by using MR imaging and Proton MR Spectroscopy in:

49 patients with Relapsing/Remitting Multiple Sclerosis (36 female and 13 male patients; average age, 39 years; age range, 24-55 years; average EDSS score, 2; range of EDSS scores, 0-6).

Correlations among Whole-Brain N-AcetylAspartate concentrations, T₂-weighted lesion volumes, and EDSS scores were obtained.

Results
No correlation was found between Whole-Brain N-AcetylAspartate levels and either T₂-weighted lesion volumes or EDSS scores.

A weak correlation was found between the EDSS scores and T₂-weighted lesion volumes (P =.043, r(s) = 0.292).

Conclusion
Despite the lack of correlation between Whole-Brain N-AcetylAspartate concentration and the clinical Disability reflected in the EDSS score, only the former evaluates the global Neuronal Cell Disease in the entire Brain, including those lesions that are occult (invisible) to conventional imaging techniques.

Objective
To assess Axonal Damage and its contribution to disability at different stages of Multiple Sclerosis (MS).

Background
Recent in vivo imaging and in situ pathologic studies have demonstrated that substantial Axonal damage accompanies the inflammatory lesions of MS.

However, the relation of Axonal Damage to the duration of MS and its contribution to disability at different stages of the disease remain poorly defined.

Design
We performed Proton Magnetic Resonance Spectroscopic imaging in 88 patients with a wide range of clinical disability and disease duration to measure N-AcetylAspartate (NAA).

An index of Axonal integrity relative to Creatine (Cr), in a large Central Brain Volume that included mostly Normal-Appearing White Matter on Magnetic Resonance imaging.

Results
We observed that the NAA/Cr values were abnormally low in the early stages of MS, even before significant disability (measured using the Expanded Disability Status Scale [EDSS]) was evident clinically.

And declined more rapidly with respect to EDSS at lower than at higher EDSS scores (P< .001).

The correlation of NAA/Cr values with EDSS score was significantly (P<.03) stronger in patients with mild disability (EDSS score < 5, Spearman rank order correlation = -0.54, P< .001).

Than in patients with more severe disability (EDSS score > /=5, Spearman rank order correlation = -0.1, P< .9).

When similar analyzes were performed in patients with MS grouped for duration of disease, the subgroup with early disease duration (< 5 years) also showed Central Brain NAA/Cr resonance intensity ratios significantly lower than healthy controls (P< .001).

Conclusion
Cerebral Axonal Damage begins and contributes to disability from the earliest stages of the disease.

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 (), 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 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 , 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.

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, Edematous lesions, these MR measures are a useful marker of progressive tissue damage and clinical progression in established MS.

Patients with Multiple Sclerosis (MS) can benefit from treatment with Interferon-ß-1b. However, the mechanisms of action of this drug are incompletely understood and effects of Interferon-ß-1b on Axonal injury are not known.

A measure of Axonal injury can be obtained in vivo using Magnetic Resonance Spectroscopy to quantify the resonance intensity of the Neuronal marker, N-AcetylAspartate (NAA).

In a small pilot study, we performed combined Magnetic Resonance Imaging and Magnetic Resonance Spectroscopic imaging on 10 patients with Relapsing/Remitting MS before and 1 year after starting treatment with subcutaneous Interferon-ß-1b.

Resonance intensities of NAA relative to Creatine (Cr) were measured in a large, central Brain Volume.

These measurements were compared with those made in a group of 6 untreated patients selected to have a similar range of scores on the Expanded Disability Status Scale and mean NAA/Cr at baseline.

NAA/Cr in the treated group [2.74 (0.16), mean (SD)] showed an increase of 5.5% 12 months after the start of therapy [2.89 (0.24),p = 0.05], while NAA/Cr in the untreated group decreased.

But not significantly [2.76 (0.1) at baseline, 2.65 (0.14) at 12 months,p > 0.1]. NAA/Cr had become significantly higher in the treated group at 12 months than in the untreated group (p = 0.03).

Our data suggest that, in addition to losing Axons, patients with chronic Multiple Sclerosis suffer from chronic, sublethal Axonal injury that is at least partially reversible with Interferon-ß-1b therapy.

Objective
Axonal Damage is an important feature of MS pathology and the likely substrate of development of progressive disability. Brain Volume measurement on MRI can be used as an overall marker of tissue damage and Axonal loss.

The authors studied the relation of Brain Volume measurements with the MS Functional Composite (MSFC) in an attempt to improve the ClinicoRadiologic association.

Methods
In 137 patients with MS (80 Relapsing/Remitting [RR], 36 Secondary/Progressive [SP], and 21 Primary/Progressive [PP]) and 12 healthy controls, a Brain MRI scan was obtained.

Patients also underwent MSFC and Expanded Disability Status Scale (EDSS) assessments.

MRI analysis included determination of:
1. HypoIntense T₁ & T₂-weighted lesion load
2. Two Brain Volume measurements:
   • Parenchymal fraction (PF):
     • Whole Brain Parenchyma/IntraCranial volume
   • Ventricular Fraction (VF):
     • Ventricular volume/Whole Brain Parenchyma

Results
The median PF was smaller and the median VF larger in the patient group (0.81 for PF and 0.029 for VF) than in the control group (0.87 for PF, p < 0.001; and 0.013 for VF, p < 0.01).

For the patient population, moderate correlations were found between Brain Volume measurements and MSFC (0.36 for PF and -0.40 for VF).

Patients with short disease duration showed a correlation of MSFC with both Brain and lesion volume measurements on MRI, whereas patients with long disease duration only showed a correlation with Brain Volume measurements.

Conclusion
Brain Volume measurements are correlated with disability as assessed by the MSFC.

Although in the early phase of the disease the amount of focal DeMyelination is important, the residual Brain Volume seems to be more relevant in determining disability in later phases of the disease.

Context
HypoIntense lesions on T₁-weighted Spin-Echo Magnetic Resonance images (T₁ lesions) represent destructive Multiple Sclerosis (MS) lesions, consisting of Axonal loss and Matrix destruction.

These lesions are being used as a secondary outcome measure in Phase III clinical trials. Clinical determinants of T₁ lesions may differ between subgroups of patients with MS and subsequently may have implications for the selection of patients for clinical trials.

Objective
To determine if clinical characteristics of patients with MS are related to T₁ lesion volume.

Design
A survey of 138 patients with MS (52 with Relapsing/Remitting MS, 44 with Secondary/Progressive MS, and 42 with Primary/Progressive MS).

Setting
The Magnetic Resonance Center for Multiple Sclerosis Research, University Hospital "Vrije Universiteit," Amsterdam, the Netherlands.

Main Outcome Measures
Type of MS, Expanded Disability Status Scale (EDSS) score, sex, age at first symptoms, and T₁ lesion volume.

Results
Patients with Secondary/Progressive MS have the highest T₁ lesion volume.

Patients with Relapsing/Remitting MS have a lower T₁/T₂ ratio than patients with Secondary/Progressive MS and patients with Primary/Progressive MS.

In patients with Relapsing/Remitting MS and Secondary/Progressive MS, T₁ lesion volume relates to disease duration and EDSS score, while in patients with Primary/Progressive MS sex is important.

A trend toward higher T₁ lesion volume was shown for male patients with Primary/Progressive MS when compared with female patients with Primary/Progressive MS (1.0 cm(3) vs 0.3 cm(3), P=.03);

A trend toward higher T₁ lesion volume was found with age at onset in patients with Relapsing/Remitting MS and in patients with Primary/Progressive MS.

Conclusions
In patients with MS different clinical characteristics associate with T₁ lesion volume, suggesting a more destructive type of lesions in certain subgroups.

A possible sex difference in (destructive) lesion development on Magnetic Resonance Imaging should be evaluated in more detail, preferably in a cohort.

The Brain Water Fraction (R), the Brain water transverse relaxation time (T₂), the Atrophy index (alpha) and the absolute concentration of the principal Brain metabolites (NAA, Cho and Cr) were measured.

By localized Proton Magnetic Resonance Spectroscopy in the Occipito-Parietal Cortex (mainly Gray Matter), of 15 Relapsing/Remitting (RR) Multiple Sclerosis (MS) patients, 15 Secondary/Progressive (SP) MS patients and 8 healthy subjects.

Significantly lower values of N-AcetylAspartate (NAA), Creatine (Cr) and the NAA/Cr ratio in the Occipito-Parietal Cortex were detected in SP MS patients than in R-R MS and control subjects (p < 0.01).

Moreover, MS patients showed shorter T₂ water relaxation times and reduced Brain water fraction compared with controls.

Higher Atrophy indices were also detected in the mainly Occipito-Parietal Gray Matter of MS patients, particularly in those with the Progressive form.

These findings suggest that the pathological process in MS is not limited to either White Matter lesions or Normal-Appearing White Matter.

But extends into the Cortical Gray Matter (Occipito-Parietal), particularly in the Progressive form of the disease. This can involve changes in Neural metabolism or Neural shrinkage and Neuron loss.

The significant increase in Atrophy indices could be the expression of the relatively higher CerebroSpinal Fluid signal from the Occipito-Parietal Cortex, even in the absence of obvious Cortical Atrophy.

Purpose
To quantify the rate of concentration decline of Neuronal marker N-AcetylAspartate (NAA) in the entire Brain of patients with Relapsing/Remitting Multiple Sclerosis (MS) in relation to healthy age-matched control subjects.

Materials And Methods
Whole-Brain NAA (WBNAA) concentration was quantified in 49 patients with Relapsing/Remitting MS by using Magnetic Resonance (MR) imaging and Proton MR Spectroscopy.

It was statistically analyzed by using Spearman rank correlation coefficients to test the intragroup relationship between WBNAA and Expanded Disability Status Scale (EDSS) score and Mann-Whitney analyzes.

To test for differences between subgroups' EDSS scores versus previously published WBNAA values for healthy subjects, disease duration, and age.

Results
Analyzes indicated three subgroups of WBNAA dynamics:
1. Ten patients' conditions were "stable,"
   exhibiting an insignificant change of about 0% (0.02/14.37) per year, of clinically definite disease duration (P =.54)
2. 27 patients showed "moderate" decline,
   -2.8% (-0.34/12.18) per year (P <.01)
3. 12 patients experienced "rapid" decline,
   -27.9% (-3.39/12.14) per year (P <.01).

No correlation was found between WBNAA deficit, EDSS score, and age.

Conclusion
Ascertaining an individual's NAA concentration dynamics might enable early forecast of disease course, reflect disease severity and thus influence treatment decisions.

And improve clinical trial efficiency by allowing selection of candidates on the basis of WBNAA dynamics in addition to clinical status.

Objectives
The objective was to correlate Magnetic Resonance Imaging (MRI) T₂-weighted lesion load and measures of White Matter Atrophy in the Brain to disability in a population-based sample of patients with Multiple Sclerosis (MS).

Material And Methods
A well defined cohort of patients was drawn at random from the general MS population by using the Danish Multiple Sclerosis Registry.

A semi-automated local thresholding technique was used to quantify T₂-weighted lesions on MRI.

Whereas manual tracing was applied to measure the Corpus Callosum Brain Ratio (CCR) and the Ventricle Brain Ratio (VBR).

Results
A sample of 86 patients with a mean age of 43.3 years (SD 4.3), mean disease duration of 13.6 years (SD 4.4) and a median Expanded Disability Status Score (EDSS) of 6.0 was identified.

The correlation between total lesion area of the Brain (TLA) and Disability (EDSS) for the whole sample was moderate (Spearman rank correlation coefficient r=0.48, P<0.001).

Also correlations of CCR and VBR to disability (r=0.32-0.46) were significant.

Conclusions
Correlations of TLA and disability in this study were rather strong.

Hence, T₂-weighted MRI lesion load in the Brain still plays an important role as a surrogate marker of disease and as a secondary outcome measure in Phase III Treatment Trials.

MRI is the most powerful imaging technique in managing patients with suspected or confirmed Multiple Sclerosis (MS). However, conventional MRI variables show nonspecific abnormalities weakly correlated with clinical progression of the disease.

New techniques, now routinely available, offer better characterization of the PathoPhysiology.

We combined conventional MRI, including lesion load, contrast enhancement and "black holes" with Magnetization Transfer and Diffusion-weighted imaging and localized Proton MR Spectroscopy (MRS) to study their relationship with disability, course and duration of MS.

The variables that were the most significantly linked to the course of the disease (Relapsing/Remitting versus Secondary/Progressive) were lesion load, mean overall Magnetization Transfer Ratio and Apparent Diffusion Coefficient (MGADC).

The percentage of ADC in (PADCIMD), and out of (PAD-COMD) modal distribution, and the ratio N-AcetylAspartate and Creatine-containing compounds on MRS of the Centrum Semiovale.

MGADC and PADCIMD were the independent factors most related to disability and duration of disease.

Combining MRI techniques is clinically relevant and feasible for studies of MS and may be applied to other diseases of the Central Nervous System.