MS Abstracts 03b-2g4

Multiple Sclerosis (MS) is a chronic disease of the CNS that most commonly affects young adults.

It is usually characterized in the early years by acute relapses followed by partial or complete remission; in later years progressive and irreversible disability develops.

Because of the protracted and unpredictable clinical course, biological surrogate markers are much needed to make clinical trials of potential disease-modifying treatments more efficient.

Magnetic Resonance (MR) outcome measures are now widely used to monitor treatment outcome in MS trials.

Areas of multifocal inflammation are detected with a high sensitivity as new areas of Gadolinium enhancement and T₂ abnormality, and these may be considered as surrogate markers for clinical relapses.

However, progressive disability is not clearly related to inflammatory lesions but rather to a progressive and diffuse process with increasing NeuroAxonal Loss.

MR surrogate measures for NeuroAxonal Loss include Atrophy (tissue loss in Brain and Spinal Cord), N-AcetylAspartate, and T₁ HypoIntense lesions.

Diffuse abnormality in Normal-Appearing Brain Tissue may also be monitored using Magnetization Transfer Ratio and other quantitative MR measures.

For treatment trials of new agents aimed at preventing disability, measures of NeuroAxonal damage should be acquired, especially Atrophy, which occurs at all stages of MS and which can be quantified in a sensitive and reproducible manner.

Because the MR surrogates for NeuroAxonal Loss are not yet validated as predicting future disability, definitive trials should continue to monitor an appropriate disability endpoint.

Multiple Sclerosis (MS) has traditionally been viewed as an Inflammatory DeMyelinating White Matter (WM) Disease of the Central Nervous System. However, recent pathology and MRI studies have shown lesions in the Gray Matter (GM) as well.

To ascertain the extent of GM involvement, we obtained with nonlocalizing proton MR Spectroscopy the concentration of N-AcetylAspartate (NAA), a metabolite found almost exclusively in Neuronal Cells, T₂-lesion loads.

And, GM and WM fractions in the entire Brain of 71 Relapsing/Remitting (RR) MS patients (51 women, 20 men, 25-55 years old) and 41 healthy controls (27 women, 14 men, 23-55 years old).

The average Whole Brain NAA (WBNAA) difference between the patients and the controls was -2.9 mM (-22%, P < 0.0001); range: +1.2 to -7.8 mM (+8% to -63%). The patients' median T₂ Lesion Volume was 5.5 (range: 0.140-28) cm(3).

GM and WM comprised 50.4 +/- 3.8% and 30.4 +/- 5.0% (mean +/- standard deviation), respectively, of the total Brain Volume in the patients; 53.8 +/- 3.7% and 35.4 +/- 4.7% in the controls.

Because WM and GM constitute approximately 40% and 60% of the Brain Parenchyma, respectively, and the NAA concentration in the former is 2/3 of the latter, WBNAA loss greater than 40% x 2/3 = 27% cannot be explained in terms of WM (Axonal) Pathology alone.

And, must include widespread GM (Neuronal) Deficits. Therefore, the concept of MS, even at its earlier stages, as a WM disease might need to be re-examined.

This study used a model for Magnetization Transfer (MT) to estimate two underlying parameters: the Macromolecular Proton Fraction (f) and the bound pool T₂ (T₂b) in patients with Multiple Sclerosis (MS).

Sixty patients with Clinically Definite MS and 27 healthy controls were imaged using:

1. A dual echo fast spin echo sequence
2. A MT sequence (with ten MT power and offset frequency combinations)
3. Proton density and T₁ weighted sequences (for T₁ relaxation time estimation)

Fourteen Normal-Appearing White Matter (NAWM) regions of interest (ROI) and six Normal-Appearing Gray Matter (NAGM) ROIs were outlined in all subjects.

Lesions were also contoured in subjects affected by MS. The model was fitted to the data leading to estimates of T₂b and f.

Results showed that T₂b was increased in lesions whereas f was reduced. In NAWM, f was decreased while T₂b was only increased in Secondary/Progressive MS.

NAWM f correlated modestly with disability. Further studies are needed to investigate the pathological basis of the abnormalities observed.

Background
There is little information available on Gray and White Matter (GM and WM) Atrophy in Primary/Progressive Multiple Sclerosis (PPMS) and on their relationships with clinical and other Magnetic Resonance Imaging (MRI) measures.

Aim
To evaluate disease progression in the early phase of PPMS, focusing on Axonal Loss as assessed by Volumetric MRI measures of WM and GM.

And, to determine their relationships with clinical outcomes and lesion load measures.

Methods
Forty-three patients with PPMS within 5 years of symptom onset and 45 control subjects were studied.

Three-dimensional Brain scans were acquired and segmented into WM, GM, and CerebroSpinal Fluid (CSF) using SPM99.

Brain Parenchymal (BPF), WM (WMF), and GM Fractions (GMF) normalized against Total IntraCranial Volumes were estimated.

T₂-weighted (T₂) and enhancing lesion loads were also determined. Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) scores were recorded in all patients.

Results
There were significant differences between patients and controls in BPF, WMF, and GMF values (P < 0.001). BPF (r = -0.469; P = 0.002) and WMF (r = -0.532; P < 0.001) but not GMF (r = -0.195; P = 0.2) correlated with EDSS scores.

PF (r = 0.518; P = 0.001), WMF (r = 0.483; P = 0.001), and GMF (r = 0.337; P = 0.031) correlated with MSFC scores. Correlations with enhancing lesion and T₂ loads were only significant for BPF and WMF.

Conclusions
Brain Atrophy is seen in the early stages of PPMS and affects both GM and WM. WM Atrophy appears more closely related to clinical outcome and WM focal damage than GM Atrophy in this patient group.

Mild Cognitive Impairment (MCI) is considered to be a transitional stage between normal aging and Dementia. In Alzheimer's Disease (AD), White Matter structural pathology is due to Wallerian Degeneration and Central Angiopathy.

However, in MCI patients, the presence and extent of White Matter alterations as a possible correlate of Impaired Memory Function and as predictor of subsequent progression to AD is not clarified yet.

Diffusion Tensor Imaging (DTI) reveals the UltraStructural integrity of Cerebral White Matter Tracts. Therefore, it could detect pathological processes that modify tissue integrity in patients with MCI.

In our prospective study, conventional and Diffusion Tensor MR scans were obtained from 14 patients with MCI, 19 patients with AD, and 10 healthy controls.

Mean Diffusivity (MD) and Fractional Anisotropy (FA) were measured in Temporal, Frontal, Parietal and Occipital White Matter regions as well as in the Corpus Callosum (Genu and Splenium) and the Hippocampus.

MCI patients showed higher MD values in the Left Centrum Semiovale (p = 0.013; Right: p = 0.026), in the Left Temporal (p = 0.006), the Right temporal (p = 0.014) and the Left Hippocampal (p = 0.002) region.

As compared to the control group, FA values of MCI patients and controls did not differ significantly in any region.

Compared to controls, AD patients had increased MD values in the Left Centrum Semiovale (p = 0.012), the Left Parietal (p = 0.001), the Right Parietal (p = 0.028), the Left Temporal (p = 0.018), the Right Temporal (p = 0.011) and the Left Hippocampal region (p = 0.002).

Decreased FA values were measured in the Left Temporal Area (p = 0.017) and in the Left Hippocampus (p = 0.031) in AD patients compared to controls. FA and MD values did not differ significantly between AD and MCI patients.

Elevated MD values indicating Brain tissue alterations in MCI patients were found in regions that are typically involved in early changes due to AD, particularly the Left Hippocampus.

The sensitivity of distinguishing MCI patients from controls was 71.4% (with a specificity set at 80%).

Therefore, the DTI technique validates the MCI concept, and Diffusion Tensor MR measurement can be a helpful tool to quantify MCI pathology in vivo.

Copyright 2004 S. Karger AG, Basel

Diffusion Tensor Magnetic Resonance Imaging (DTI) reveals measurable abnormalities in Normal-Appearing Brain Tissue (NABT) in established Multiple Sclerosis (MS). However, it is unclear how early this occurs.

Recent studies have employed Whole Brain Histogram analysis to improve sensitivity, but concern exists regarding reliability of Tissue/CerebroSpinal Fluid Segmentation and possible intersubject Brain Volume differences, which can introduce partial volume error:

To address this, 28 early Relapsing/Remitting MS subjects [median disease duration 1.6 years; median Expanded Disability Status Scale (EDSS) score 1.5].

And 20 controls were compared with Whole Brain Histogram analysis using an automated segmentation algorithm to improve reproducibility.

Brain Parenchymal Volumes (BPV) were estimated for each subject in the analysis. The mean, peak height and peak location were calculated for DTI Parameters [Fractional Anisotropy (FA), Mean Diffusivity and Volume Ratio].

An increased FA peak height in MS subject NABT was observed (P = 0.02) accounting for age, gender and BPV. Removing BPV revealed additional abnormalities in NABT.

The main conclusions are:
1. A peak height is increased in NABT in early MS
2. Partial volume edge effects may contribute to apparent NABT Histogram abnormalities
3. Correction for Brain Volume differences should reduce potential partial volume edge effects

To elucidate the impact of Myelinating Schwann Cells on the molecular architecture of the Nodes of Ranvier, we investigated the Nodal expression of Voltage-gated Sodium Channel (VGSC) Isoforms.

And, the localization of ParaNodal and JuxtaParaNodal membrane proteins in a severely affected Schwann Cell mutant, the mouse deficient in Myelin protein zero (P0).

The abnormal Myelin formation and compaction was associated with immature Nodal cluster types of VGSC.

Most strikingly, P0-deficient Motor Nerves displayed an ectopic Nodal expression of the Na(v)1.8 isoform, where it is coexpressed with the ubiquitous Na(v)1.6 channel.

Furthermore, Caspr was distributed asymmetrically or was even absent in the mutant Nerve Fibers.

The Potassium Channel K(v)1.2 and Caspr2 were not confined to JuxtaParaNodes, but often protruding into the ParaNodes.

Thus, deficiency of P0 leads to dysregulation of Nodal VGSC isoforms and to altered localization of ParaNodal and JuxtaParaNodal components of the Nodal complex.

Background And Purpose
Multiple biomarkers are used to quantify the severity of Traumatic Brain Injury (TBI) and to predict outcome. Few are satisfactory.

CT and conventional MR imaging underestimate injury and correlate poorly with outcome.

New MR imaging techniques, including Diffusion Tensor Imaging (DTI), can provide information about Brain UltraStructure by quantifying Isotropic and Anisotropic Water Diffusion.

Our objective was to determine if changes in Anisotropic Diffusion in TBI correlate with acute Glasgow Coma Scale (GCS) and/or Rankin scores at discharge.

Methods
Twenty patients (15 male, five Female; mean age, 31 years) were evaluated.

Apparent Diffusion Coefficients (ADCs) and Fractional Anisotropy (FA) values were measured at multiple locations and correlated with clinical scores. Results were compared with those of 15 healthy control subjects.

Results
ADC values were significantly reduced within the Splenium (Delta18%, P =.001). FA values were significantly reduced in the Internal Capsule (Delta14%; P < .001) and Splenium (Delta16%; P =.002).

FA values were significantly correlated with GCS (r = 0.65-0.74; P < .001) and Rankin (r = 0.68-0.71; P < .001) scores for the Internal Capsule and Splenium.

The correlation between FA and clinical markers was better than for the corresponding ADC values. No correlation was found between ADC of the Internal Capsule and GCS/Rankin scores.

Conclusion
DTI reveals changes in the White Matter that are correlated with both acute GCS and Rankin scores at discharge. DTI may be a valuable biomarker for the severity of tissue injury and a predictor for outcome.