MS Abstracts MRI2g3

Pathology and Magnetic Resonance Imaging (MRI) studies have provided evidence of widespread Axonal loss and reductions of Cerebral and Spinal Cord Volume in Multiple Sclerosis (MS).

Atrophy measures on MRI may be a useful surrogate marker of worsening disability in MS, but the published studies are of relatively short duration.

Change in Brain Volume (Atrophy) was measured over a four-year period in 20 patients with Relapsing/Remitting (RR) and 18 with Secondary/Progressive (SP) MS using three-dimensional (3D) MRI acquired during treatment trials of Interferon-ß-1a (Rebif).

Brain Parenchymal and Lateral Ventricle volume changes were determined and correlated with clinical measures.

Over four years, Brain Parenchymal Volume (Lateral Ventricles volume (r = 0.63, P = 0.004) and BPV change (r = -0.47, P = 0.037) were related to disability change, as measured by the Expanded Disability Status Scale.

Even though a small study and despite the possible confounding effects of Interferon treatment, this study demonstrated an association between measures of Cerebral Atrophy and worsening disability.

The data also provides evidence that Brain Atrophy can be detected early in the disease course and Central White Matter Atrophy as reflected by Ventricle enlargement appears to be a continuous process.

Background
The Spinal Cord is a common site of involvement in Multiple Sclerosis (MS) where pathology contributes substantially to locomotor disability.

Previous studies have demonstrated significant correlations between clinical disability and Cervical Cord Atrophy, but not with Cord T₂ lesion load.

We evaluate Cervical Cord pathology using, for the first time, quantitative T₁ relaxation time (T₁), which shows HistoPathological specificity for tissue damage in the Cerebral White Matter.

Method
Cervical Cord T₁ was compared in 15 MS patients [8 Relapsing/Remitting (RR), 7 Secondary/Progressive (SP)] and 6 healthy controls.

And related to normalized Upper Cervical Cord Area (UCCA), Cerebral White Matter T₁, T₂ lesion load and disability measures including the Expanded Disability Status Scale (EDSS), Ambulation Index (AI) and timed 25-foot walk.

T₁ maps of the Brain and Cervical Cord were acquired using a high-resolution, 3-dimensional fast low-angle shot sequence. Dual-echo sequences were also obtained.

Results
Median Cervical Cord T₁ [mean (standard deviation)] was significantly greater in RR [854 [28] ms] (p = 0.0006) and SP patients [927 [67] ms] (p < 0.0001) compared with controls [888 [61] ms], and in SP vs. RR patients (p = 0.002).

In the overall patient cohort, it correlated significantly with median Cerebral White Matter T₁ (r = 0.7, p = 0.0046), UCCA (r = -0.87, p < 0.0001), but not T₂ lesion loads.

Both median Cervical Cord T₁ and UCCA (respectively) correlated significantly with the EDSS (r = 0.55, p = 0.03; r = -0.54, p = 0.04), AI (r = 0.77, p = 0.001; r = -0.60, p = 0.02) and timed 25-foot walk (r = 0.56, p = 0.03; r = -0.55, p = 0.04).

Conclusion
Cervical Cord T₁ distinguishes between MS subgroups and could also prove a useful surrogate outcome measure in MS.

The relation of Cervical Cord T₁ to Cerebral White Matter T₁ suggests that Cord pathology may be influenced by tissue damage upstream.

Objective
To assess Cortical Gray Matter (GM) changes in MS and establish their relevance to clinical disability and to inflammatory changes of White Matter (WM) in patients with the Relapsing/Remitting (RR) and Primary/Progressive (PP) forms of the disease.

Methods
Conventional MRI examinations were obtained in patients with Definite MS who had either the RR or the PP form of the disease.

An automated analysis tool was used with conventional T₁-weighted MR images to obtain total and Cortical Brain Volumes normalized for head size.

Total Brain lesion load was estimated on conventional proton density and T₁-weighted MR images. The relationship between volumetric MR measures and scores of clinical disability was assessed.

Results
Normalized Cortical Volumes (NCV) were lower for both RR and PP MS patients than for normal control subjects (p < 0.001) but were similar between the two patient groups (p > 0.5).

NCV decreases in both patients groups were detected even in those patients with short disease duration (< 5 years; p < 0.001 in RR MS and p < 0.05 in PP MS) and minimal Brain lesion volume (< 5 mL; p < 0.0001 in RR MS and p < 0.005 in PP MS).

Measures of NCV in individual patients were negatively correlated with T₁-weighted lesion volume (r = -0.47, p < 0.001) and disease duration (r = -0.25, p < 0.05) only in the patients with RR MS.

NCV correlated with Expanded Disability Status Scale scores across all of the patients, but the strength of the correlation was stronger (p < 0.05) for PP (r = -0.64, p < 0.0001) than for RR (r = -0.27, p = 0.04) MS patients.

Conclusions
These data confirm substantial NeoCortical volume loss in MS patients and suggest that NeoCortical GM pathology may occur early in the course of the disease in both RR and PP MS patients and contribute significantly to Neurologic impairment.

Although a proportion of this NeoCortical pathology may be secondary to WM inflammation, the extent of the changes suggests that, especially in patients with PP MS, an independent NeuroDegenerative process also is active.

The aim of this study was to simultaneously measure in vivo volumes of Gray Matter (GM), normal White Matter (WM), Abnormal White Matter (aWM), and CerebroSpinal Fluid (CSF).

And to assess their relationship in 50 patients with Relapsing/Remitting Multiple Sclerosis (RR-MS) (age range, 21-59; mean EDSS, 2.5; mean disease duration, 9.9 years), using an unsupervised multiparametric segmentation procedure applied to Brain MR studies.

Tissue volumes were normalized to total IntraCranial Volume providing corresponding Fractional Volumes (fGM, faWM, fWM, and fCSF).

Subsequently corrected for aWM-related segmentation inaccuracies and adjusted to mean patients' age according to age-related changes measured in 54 normal volunteers (NV) (age range 16-70).

In MS patients aWM was 23.8 +/- 29.8 ml (range 0.4-138.8). A significant decrease in fGM was present in MS patients as compared to NV (49.5 +/- 3.2% vs 53.3 +/- 2.1%; P < 0.0001), with a corresponding increase in fCSF (13.0 +/- 3.8% vs 9.1 +/- 2.4%; P < 0.0001).

No difference could be detected between the two groups for fWM (37.5 +/- 2.6% vs 37.6 +/- 2.2%).

faWM correlated inversely with fGM (R = -0.434, P < 0.001 at regression analysis), and directly with fCSF (R = 0.473, P < 0.001), but not with fWM.

There was a significant correlation between disease duration and EDSS, while no relationship was found between EDSS or disease duration and Fractional Volumes.

Brain Atrophy in RR-MS is mainly related to GM loss, which correlates with faWM. Both measures do not appear to significantly affect EDSS, which correlates to disease duration.

Blood-Brain Barrier (BBB) HyperPermeability in Multiple Sclerosis (MS) is associated with lesion pathogenesis and has been linked to pathology in MicroVascular Tight Junctions (TJs).

This study quantifies the uneven distribution of TJ pathology and its association with BBB leakage.

Frozen sections from plaque and Normal-Appearing White Matter (NAWM) in 14 cases were studied together with White Matter from six Neurological and five normal controls.

Using single and double immunofluorescence and confocal microscopy, the TJ-associated protein Zonula Zonula Occludins-1 (ZO-1) was examined across lesion types and tissue categories, and in relation to Fibrinogen leakage.

Confocal image data sets were analyzed for 2198 MS and 1062 control vessels. Significant differences in the incidence of TJ abnormalities were detected between the different lesion types in MS and between MS and control White Matter.

These were frequent in oil-red O (ORO)(+) active plaques, affecting 42% of vessel segments, but less frequent in ORO(-) inactive plaques (23%), NAWM (13%), and normal (3.7%) and Neurological controls (8%).

A similar pattern was found irrespective of the vessel size, supporting a causal role for diffusible inflammatory mediators.

In both NAWM and inactive lesions, dual labelling showed that vessels with the most TJ abnormality also showed most Fibrinogen leakage.

This was even more pronounced in active lesions, where 41% of vessels in the highest grade for TJ alteration showed severe leakage.

It is concluded that disruption of TJs in MS, affecting both ParaCellular and TransCellular paths, contributes to BBB leakage.

TJ abnormality and BBB leakage in inactive lesions suggests either failure of TJ repair or a continuing pathological process.

In NAWM, it suggests either pre-lesion change or secondary damage. Clinically inapparent TJ pathology has prognostic implications and should be considered when planning disease-modifying therapy.

Copyright 2003 John Wiley & Sons, Ltd.

Magnetization Transfer (MT) imaging provides indirect information on tissue structure abnormalities in areas that otherwise may appear normal on conventional MRI.

We determined the evolution of MT changes in Normal-Appearing White Matter (NAWM) and lesion on serial examination of 9 Multiple Sclerosis (MS) patients and age matched controls.

The mean NAWM MT Ratio (MTR) was found to correlate strongly (R = 0.93) with the length of time since the patient's first clinical presentation and was well characterized by a linear decrease of -0.16%/year (p < 0.0001).

The time zero intercept of the NAWM MTR regression was 30.7 +/- 0.2%, not different from the average MTR of White Matter from controls (30.4 +/- 0.2 %).

An additional gradual decrease in NAWM MTR was observed 6 to 12 months before the appearance of a new lesion on conventional MRI, while a more precipitous decrease in MTR was seen 2 to 6 months before the lesion appeared.

Those lesions that exhibited pre-lesion MTR decreases showed less MTR recovery than lesions which had no pre-lesion MTR decrease.

The data suggest that the MTR of NAWM in MS undergoes a slow progressive decrease that starts at disease onset and accelerates rapidly in focal areas just prior to lesion appearance on conventional MRI.

Brain Atrophy is a proposed MRI marker of irreversible pathologic damage in Multiple Sclerosis (MS).

The Brain Parenchymal Fraction (BPF) is the ratio of Brain Parenchymal Volume to the total volume within the surface contour.

We developed a semiautomated measure of BPF using commercially available edge-finding and thresholding software (30-min analysis time per patient).

We measured BPF in 78 patients with MS and 17 healthy controls. BPF was lower in a cohort of patients with MS (n=50) (0.843+/-0.042, range 0.743-0.906) age-matched to controls (0.877+/-0.020, range 0.835-0.901) (p< 0.001).

BPF correlated inversely with Third Ventricular width (r=-0.785, p < 0.001), and total T₁ HypoIntense lesion volume (r=-0.347, p=0.011), but not with total T₂ HyperIntense lesion volume (r=-0.213, p=0.13).

BPF correlated negatively with Expanded Disability Status Scale (EDSS) score (r=-0.391, p=0.0006) and disease duration (r=-0.281, p=0.01).

Stepwise regression compared the relative abilities of MRI variables to predict clinical data.

By regression of age, BPF, Third Ventricular width, T₂ lesions, and T₁ lesions, BPF was the best predictor of disability score (R(2)=0.204, p< 0.001).

Third Ventricular width was the best predictor of disease duration (R(2)=0.316, p< 0.001).

None of the MRI variables differed between Relapsing/Remitting (RR) (n=60) and Secondary/Progressive (SP) (n=18) disease course (p>0.05).

The intrarater, interrater, and scan-rescan BPF variability (COV) was 0.31%, 0.34%, and 0.41% and the accuracy against a phantom was 99.1%.

We conclude that Whole-Brain Atrophy in MS can be reliably and readily quantified by a semiautomated approach. Longitudinal studies are warranted to determine if this method provides a sensitive biologic marker of the MS disease process.

Objective
Magnetic Resonance (MR) techniques are of value in following the pathological process of Multiple Sclerosis in vivo. They are widely applied to monitor the disease natural history and its modification by treatment.

However, serial studies of lesion measures have yielded generally disappointing correlations with the development of clinical disability. A potential explanation for this is the presence of abnormalities, beyond the visible lesions, in the Normal-Appearing White Matter (NAWM) and Gray Matter (NAGM).

Quantitative structural MR techniques, including measures of Magnetization Transfer, Diffusion, relaxation times and Spectroscopic metabolite concentrations, reveal that there are abnormalities in NAWM and NAGM.

These are present from clinical onset and become more pronounced with clinical progression, increasing disability and increasing lesion load.

Furthermore, functional MRI (fMRI) studies of Motor and Visual paradigms has identified a range of responses suggesting that Cortical plasticity exists.

Such modified responses are seen in the earliest stages of disease, and in the absence of visible lesions; but are more pronounced with disease progression, and increasing lesion load, and abnormality in the NAWM.

Limited reproducibility and sensitivity to change can pose methodological limitations for MR studies of NAWM and NAGM, especially when follow up intervals are relatively short.

While existing quantitative MR measures from Normal-Appearing tissues provide valuable information to understand the natural history and monitor treatment effects in MS; none of them fully or even predominantly accounts for the patient's functional state, nor can be relied on as a definitive surrogate measure of treatment effect.

Better resolution of the abnormalities is needed especially in Gray Matter where pathological foci are known to be abundant.

Studies correlating structural MR and fMRI parameters with measures of function in well defined anatomical pathways should further elucidate the pathogenic role of abnormality in the Normal-Appearing tissues.

In future, new imaging modalities are needed that provide a more specific measure of HistoPathological and Cellular aspects of the disease process in vivo.

The potential of MRI of the Spinal Cord as a diagnostic tool in MS has recently gained much interest. Dual echo spin echo MRI is most sensitive for the detection of Spinal Cord abnormalities, which range from multiple focal lesions to confluent areas of high signal intensity.

In some patients, commonly those with Primary/Progressive disease, diffuse areas of slightly increased signal intensity are found. Disappointingly, the relation between MRI findings and clinical disability is weak.

Studies relating MRI findings with HistoPathology have revealed substantial Axonal loss in the Spinal Cords of patients with MS, whether focal lesions are present or not.

Further, diffuse Cord Atrophy is found in advanced MS, which may reflect Axonal Loss.

In the diagnostic setting, Spinal Cord imaging is valuable. First, asymptomatic Spinal Cord lesions are very rare in disorders other than MS.

For example in a patient with equivocal Brain findings, such as an elderly patient with Vascular-Ischaemic lesions, a normal Spinal Cord examination can help rule out MS.

Second, presence of asymptomatic Spinal lesions may help confirm a diagnosis of MS when few or no Brain lesions are present.

Progression of disability in Multiple Sclerosis (MS) appears related to Axonal damage, which is at least in part associated with White Matter lesions.

Interferon-beta (IFN-ß) substantially reduces new inflammatory activity in MS and a recent report suggested that it may reverse a component of Axonal injury.

To test the generalizability of this conclusion, particularly in a population with relatively active disease, we used Magnetic Resonance Spectroscopy measures to test whether IFN-ß can reverse or arrest progression of Axonal injury in patients with MS.

Eleven patients with a history of active (median, 1.5 relapses/year) Relapsing/Remitting MS were treated with IFN-ß and responses to treatment were monitored.

With serial MRI and single voxel Magnetic Resonance Spectroscopic measurements of relative concentrations of Brain N-AcetylAspartate (NAA), a measure of Axonal integrity from a Central, predominantly White Matter Brain region.

IFN-ß treatment was associated with a significant reduction in relapse rate (p = 0.007) and White Matter water T₂ relaxation time (p = 0.047) over 12 months.

Also consistent with a treatment effect, White Matter T₂-HyperIntense lesion loads did not increase.

However, the Central White Matter NAA/Creatine ratio (NAA/Cr, which was reduced over 16 % in patients relative to healthy controls at the start of treatment), continued to decrease in the patients over the period of observation (mean 6.2 % decrease, p = 0.02).

For individual patients the magnitude of the NAA/Cr decrease was correlated with the frequency of relapses over the two years prior to treatment (r = -0.76, p = 0.006).

These data suggest that reduction of new inflammatory activity with IFN-ß does not invariably halt progression of Axonal injury.

Nonetheless, there appears to be a relationship between the rate of progression of Axonal injury and relapse rate over the previous two years.

The consequences of reduced inflammation on pathological progression relevant to disability therefore may be present, but substantially delayed. Alternatively, distinct mechanisms may contribute to the two processes.

Purpose
To examine the role of directional dependence of the Apparent Diffusion Coefficients in the evaluation of Normal-Appearing Brain regions of patients with Relapsing/Remitting Multiple Sclerosis.

Materials And Methods
The role of Diffusion Tensor eigenvalues was investigated in the Normal-Appearing Brain regions for 18 patients with Relapsing/Remitting Multiple Sclerosis and 15 age-matched normal controls.

Results
The Isotropic Apparent Diffusion was increased in all regions. However, reduced Anisotropy was significant only in regions with high Anisotropy, including the Corpus Callosum and the Internal Capsule.

And was due to increased Diffusion Tensor eigenvalues corresponding to Diffusion Transverse to the Fibers without significant increase along the Fibers.

This characteristic pattern of changes in Diffusion Tensor eigenvalues has been observed previously in cases of Wallerian Degeneration.

Low-Anisotropy regions corresponded to Gray Matter and Gray/White interface regions. Since Fiber Tract orientations are not determined for regions of low Anisotropy, this characteristic pattern of Diffusion change is not detectable in these regions.

Conclusion
Examination of Diffusion Tensor eigenvectors may provide insight into the changes observed in Diffusion and a signature of Wallerian Degeneration in the Normal-Appearing White Matter of Relapsing/Remitting Multiple Sclerosis patients.

Copyright 2003 Wiley-Liss, Inc.

Magnetic Resonance Imaging (MRI) is an important paraclinical tool for the diagnosis of Multiple Sclerosis (MS) and for monitoring its disease course.

The efficacy of most of the available MS disease-modifying treatments has been tested in clinical trials where MRI-derived quantities served as primary or secondary outcome measures.

However, conventional MRI measures (i.e., the number and volume of contrast-enhancing, the volumes of T₂-HyperIntense and T₁-HypoIntense lesions and the assessment of Brain Volume changes) are limited in terms of pathological specificity.

And, as a consequence, are modestly correlated with clinical measures of disease activity and have a modest prognostic value as predictors of MS evolution.

In the present review, we discuss the main factors potentially responsible for the so-called 'clinical MRI paradox' and how modern quantitative MR-based techniques might contribute to, at least partially, overcome it.

The lessons learned from MS trials suggest that future applications of MRI to assess MS evolution should rely upon the use of composite measures thought to reflect the various components of the disease, as well as on study protocols specifically designed on the individual trial characteristics.