Proton MR Spectroscopy In Multiple Sclerosis Abstracts - 01

Magnetic Resonance Imaging (MRI) is the most important paraclinical measure for assessing and monitoring the pathologic changes implicated in the onset and progression of Multiple Sclerosis (MS).

Conventional MRI sequences, such as T₁-weighted Gadolinium (Gd) enhanced and Spin-Echo T₂-weighted imaging, only provide an incomplete picture of the degree of inflammation and underlying NeuroDegenerative changes in this disease.

Two- and Three-Dimensional Fluid-Attenuated Inversion Recovery and Double Inversion Recovery sequences allow better identification of Cortical, PeriVentricular and InfraTentorial lesions.

Ultra-high field strength MRI has the potential to detect Subpial Cortical and deep Gray Matter lesions. Unenhanced T₁-weighted imaging can reveal HypoIntense Black Holes, a measure of chronic NeuroDegeneration.

Magnetization Transfer Imaging (MTI) is increasingly used to characterize the evolution of MS lesions and Normal-Appearing Brain Tissue.

Evidence suggests that the dynamics of MTI Magnetization Transfer changes correlate with the extent of DeMyelination and ReMyelination.

Magnetic Resonance Spectroscopy, which provides details on tissue biochemistry, metabolism, and function, also has the capacity to reveal NeuroProtective mechanisms.

By measuring the motion of water, Diffusion Imaging can provide information about the orientation, size, and geometry of tissue damage in white and Gray Matter.

These advanced non-conventional MRI techniques relate better to clinical Impairment, disease progression, accumulation of Disability, and have the potential to detect NeuroProtective effects of treatment.

Although detecting the status of Neuronal integrity using MRI techniques continues to improve, a "gold standard" model remains to be established.

Proton MR Spectroscopy (MRS) allows noninvasive characterization of Chemical-pathologic changes in the Brain.

In patients with Multiple Sclerosis (MS), proton MRS reveals Chemical pathology in focal inflammatory lesions as well as in regions of the Brain that are not associated with structural abnormalities on conventional MRI.

In MS studies, it has been particularly useful as a method for the assessment of NeuroDegeneration based on decreases in the levels of the Neuro-Axonal marker compound, N-AcetylAspartate.

Also, MRS has provided evidence of Chemical pathology and repair involving Non-Neuronal Brain Cells based on changes in metabolites, including Choline, myo-Inositol, Glutamate, and GABA.

Despite its greater pathologic specificity for Axonal integrity compared to conventional MRI, MRS has been used only infrequently in clinical trials.

This prompted us to review current MRS clinical applications in MS, discuss the potential and limitations of the technique, and suggest recommendations for the application of MRS to clinical trials.

Background And Purpose
Proton MR Spectroscopy ((1)H-MR Spectroscopy) is a well-established method for the in vivo investigation of the Normal-Appearing White Matter (NAWM) in patients with Multiple Sclerosis (MS).

Metabolic changes in NAWM are of special interest in patients with Clinically Isolated Syndromes (CIS) suggestive of MS regarding further prognostic classifications.

The purpose of this study was to investigate metabolic alterations in NAWM in patients with CIS with use of high-field (1)H-MR Spectroscopy and to compare the results to those in patients with an early course of MS.

Materials And Methods
With use of a 3T whole-body MR imaging system, single-Voxel (1)H-MR Spectroscopy (PRESS; TR: 2000 ms; TE: 38 ms and 140 ms) of the Parietal NAWM was performed in 20 control subjects, 36 patients with CIS, and 12 patients with MS.

Metabolite ratios and concentrations of N-AcetylAspartate (tNAA), myo-Inositol (mIns), Choline, and total Creatine (tCr) were determined.

Results
Compared with the control group, mean NAWM mIns concentrations were significantly elevated in the MS group (4.56 mmol/L versus 3.75 mmol/L, P = .02).

But not in the CIS group (4.04 mmol/L, P = .44). The higher concentration of mIns in the MS group was also reflected in the increased Ins/tCr ratio (P = .02).

The mean NAWM tNAA was significantly decreased in both patient groups compared with the control group (CIS, 13.42 mmol/L, P = .02; MS, 12.77 mmol/L versus 14.51 mmol/L, P = .008).

Conclusions
A significant increase of the activity of the Glial Cells can only be observed in patients with an established diagnosis of MS but not in patients with CIS.

Axonal Damage occurs already during the first DeMyelinating episode in patients with CIS as well as in patients with definite MS.

In the last decade, the use of Magnetic Resonance Imaging (MRI) has led to a re-evaluation of the pathogenesis and the natural history of Multiple Sclerosis (MS).

This has been driven to a significant degree by results of Proton Magnetic Resonance Spectroscopy (1H-MRS) studies.

By providing evidence of early NeuroDegeneration (based on levels of N-AcetylAspartate), results of 1H-MRS studies have led to a reconsideration of the role of Axonal Damage in MS.

By measuring Brain changes of metabolites such as Choline and myo-Inosol, 1H-MRS has confirmed the importance of assessing Myelin damage and repair.

However, despite the pathological specificity of 1H-MRS and the relatively large number of clinical 1H-MRS studies on patients with MS:

Measures provided by this MR technique are not used routinely for assessing and monitoring MS patients. This is due to technical difficulties and limitations that are at present not entirely solved.

We will review here the most relevant results in MS studies that have used 1H-MRS measures, the clinical importance of these results and the pending issues that need to be solved for a larger and more reliable use of 1H-MRS in clinical MS studies.

Besides focal White Matter lesions, Multiple Sclerosis Brain Tissue also displays abnormalities in the Gray Matter and the Normal-Appearing White Matter.

Recent advances in Magnetic Resonance Imaging studies of both types of tissue are discussed.

Herein, Normal-Appearing White Matter abnormalities are being found in Quantitative Magnetic Resonance investigations, consistent with a limited degree of Axonal Damage and/or DeMyelination.

And an increase of Glial Cells, but the specific nature of the HistoPathological changes underlying the Quantitative Magnetic Resonance abnormalities remains unclear.

Gray Matter studies have demonstrated that much of the disease process remains undetected by Conventional Magnetic Resonance Imaging.

Although newly developed techniques, such as 3D Double-Inversion Recovery, may greatly improve detection of Cortical pathology.

It remains important to investigate the resultant effects on the Cortical Tissue alongside this.

By studying integrity of Normal-Appearing Cortical Tissue through quantitative Magnetic Resonance studies, as well as the net NeuroDegenerative effect through measurements of Cortical thickness and Cortical Atrophy (rates).

To improve our understanding of Normal-Appearing White and Gray Matter changes, their mutual relations, and their relations to clinical changes, further in vivo Magnetic Resonance Imaging studies are required.

Specifically, it is proposed that more spatially specific investigations, ideally utilizing subject-specific anatomical information from.

For example, Diffusion fiber-tracking techniques, could be used to gain more insight into the relations between Normal-Appearing White Matter changes, Cortical changes, Magnetic Resonance visible focal-lesions, and Physical and Cognitive deficits.

Objective
To assess the relationship between the Spectroscopically measured Axonal Damage in the Normal-Appearing White Matter of the BrainStem.

The total Brain T₂-HyperIntense Lesion Volume (T₂LV), and disability in patients with early Relapsing/Remitting Multiple Sclerosis (RRMS).

Methods
Forty-three RRMS patients and 10 sex- and age-matched healthy controls were prospectively studied for 2 years.

T₂-weighted Magnetic Resonance (MR) images and Proton MR Spectroscopy were acquired at the time of recruitment and at year 2.

BrainStem was considered, where large tracts join together, as a suitable region to detect early Axonal Damage.

The T₂LV was calculated with a semiautomatic program.

N-AcetylAspartate (NAA), Creatine (Cr), and Choline (Cho) resonances areas were integrated with the jMRUI program, and the ratios were calculated for the sum of the Volume Elements represented at BrainStem.

Results
The basal NAA/Cho ratio was significantly decreased in patients compared with controls.

After 2-year follow-up, there was a decrease in the NAA/Cho (-9%; p = 0.002) and NAA/Cr (-13%; p = 0.001) ratios.

And, an increase in the T₂LV (19%; p = 0.043) in Multiple Sclerosis patients, whereas control subjects had no significant metabolic changes.

Significant NAA/Cr ratio decreases were observed in both patients, with and without relapses, whereas T₂LV only increased in patients with relapses.

The final Expanded Disability Status Scale (EDSS) score correlated with T₂LV at baseline.

But, no significant correlations were found between metabolic values, T₂LV change, or EDSS score over the study period.

Conclusions
Our data reveal an early and progressive Axonal Damage in Relapsing/Remitting Multiple Sclerosis.

Axonal loss and T₂ lesion volume seem to be at least partly dissociated processes in early stages of the disease.

MRI is the most important paraclinical measure for assessing and monitoring the pathologic changes implicated in the onset and progression of Multiple Sclerosis (MS)

Conventional MRI sequences, such as T₁-weighted Gadolinium-enhanced and Spin-Echo T₂-weighted imaging, are unable to provide full details about the degree of inflammation and underlying NeuroDegenerative changes.

Newer nonconventional MRI techniques have the potential to detect clinical impairment, disease progression, accumulation of disability, and the NeuroProtective effects of treatment.

Unenhanced T₁-weighted imaging can reveal HypoIntense black holes, a measure of chronic NeuroDegeneration.

Two- and Three-dimensional Fluid-Attenuated Inversion Recovery sequences allow better identification of Cortical lesions.

Ultrahigh-field strength MRI has the potential to detect Subpial Cortical and deep Gray Matter lesions.

Magnetization Transfer Imaging is increasingly used to characterize the evolution of MS lesions and Normal-Appearing Brain Tissue.

Evidence suggests that the dynamics of Magnetization Transfer changes correlate with the extent of DeMyelination and ReMyelination.

Magnetic Resonance Spectroscopy, which provides details on tissue BioChemistry, metabolism, and function, also has the capacity to reveal NeuroProtective mechanisms.

By measuring the motion of water, Diffusion Imaging can provide information about the orientation, size, and geometry of tissue damage in white and Gray Matter.

Functional MRI may help clarify the Brain's plasticity-dependent compensatory mechanisms in patients with MS.

High-resolution MicroAutoRadiography and new contrast agents are proving to be sensitive means for characterizing molecular markers of disease activity, such as activated Microglia and Macrophages.

Optical Coherence Tomography, a new research technique, makes it possible to investigate relevant physiologic systems that provide accurate measures of tissue changes secondary to the MS disease process.

Although detecting the status of Neuronal integrity using MRI techniques continues to improve, a "gold standard" model remains to be established.

Backgrounds
Atrophy of Corpus Callosum (CC), a White Matter structure linking the two Hemispheres, is commonly observed in Multiple Sclerosis (MS).

However, the occurrence and processes leading to this alteration are not yet determined.

Goal And Methods
To better characterize the onset and progression of CC Atrophy from the early stage of MS.

We performed a two-year follow-up Magnetic Resonance Imaging/Magnetic Resonance Spectroscopic Imaging (MRI/MRSI) exploration of CC in 24 patients with Clinically Isolated Syndrome.

These patients were explored using the same protocol at month (M)6, M12 and M24.

MRI/MRSI techniques were applied to measure CC volume, and relative concentrations of N-AcetylAspartate (NAA), Creatine/PhosphoCreatine (Cr) and Choline-containing compounds (Cho).

A group of matched controls was also explored.

Results
Atrophy of CC, not present at baseline, was observed at M12 and progressed over the second year (M24).

At baseline, a decrease in relative NAA level was observed in the Anterior and Posterior Body of CC, with normalization during the follow-up period.

In the Anterior Body, an increase in relative Cho level was observed, with normalization at M6.

Normal relative Cr levels were observed at all time points in all sub-regions. The rate of CC Atrophy was correlated with the change in the Expanded Disability Status Scale (EDSS) during the follow-up period.

Conclusion
These results suggest that CC Atrophy appears over a period of one year after the first acute inflammatory episode, and that this Atrophy is accompanied, especially in the Anterior Body of CC.

By a normalization of the relative Cho levels, marker of acute inflammation, and NAA levels, marker of Neuronal Dysfunction and/or Loss.

Many MR Spectroscopy (MRS) studies of Multiple Sclerosis (MS) have focussed on metabolism in Normal-Appearing White Matter (NAWM) and in White Matter Lesions (WML).

In this study, eight patients suffering from Primary or Secondary/Progressive MS (PPMS/SPMS) and seven patients with Relapsing/Remitting MS (RRMS) were examined by 1H-MRSI to assess metabolite levels in Gray Matter (GM) as well.

1H-MRS Chemical-shift imaging of a Cerebral Volume of interest of 8x8x2 cm(3) above the Lateral Ventricles.

Revealed differences between the metabolite concentrations in the three groups varying from almost significant [NAWM, Choline (Cho); P=0.0547] to highly significant [GM, N-AcetylAspartate (NAA); P=0.0003].

In PPMS/SPMS patients, the decreases in Choline, Creatine (Cr) and N-AcetylAspartate compared with six healthy controls were significant in GM and to a lesser extent, in NAWM.

No significant differences in metabolite concentrations were found between RRMS and controls. In WML, all metabolites were reduced compared with White Matter in controls (Cho: P=0.0020; Cr and NAA: P<0.0001, both).

In conclusion, the concentrations of Cho, Cr and NAA are reduced in PPMS/SPMS patients, especially in GM and in WML.

Despite contrary observations in previous studies, increases in the concentrations of Cr and/or Cho were not observed.

MR Spectroscopy (MRS) provides information about Neuronal Loss or dysfunction by measuring decreases in N-AcetylAspartate (NAA), a metabolite widely believed to be a marker of Neuronal viability.

In Multiple Sclerosis (MS), Whole-Brain NAA (WBNAA) has been suggested as a marker of disease progression and treatment efficacy in treatment trials.

And, the ability to measure NAA loss in specific Brain regions early in the evolution of this disease may have prognostic value.

Most Spectroscopic studies to date have been limited to single Voxels or nonlocalized measurements of WBNAA only, and longitudinal studies have often been hampered by standardization and reproducibility problems.

Multi-slice Echo-Planar Spectroscopic Imaging (EPSI) is presented as a promising alternative to single-Voxel or nonlocalized Spectroscopy for obtaining global metabolite estimates in MS.

In the same session, measurements of metabolites in specific Brain areas chosen after image acquisition (e.g., Normal-Appearing White Matter (NAWM), Gray Matter (GM), and lesions) can be obtained.

The identification and exclusion of regions that are inadequate for Spectroscopic evaluation in global assessments can significantly improve quality and reproducibility, as demonstrated by a low within-subject variance in healthy controls.

The reproducibility of the technique makes it a promising tool for future longitudinal Spectroscopic studies of MS.

Copyright 2005 Wiley-Liss, Inc.

Proton Magnetic Resonance Spectroscopy(1H-MRS), which provides bioChemical information in not only visible lesions on conventional MR imaging, but also Normal-Appearing White Matter (NAWM).

It has extended the genesis of Multiple Sclerosis (MS) in several important directions:
1. Serial 1H-MRS studies reveal dynamic regional bioChemical alterations in plaques during the course of the illness
2. Axonal Damage may occur at early stage
3. Neuronal loss can be substantial in the Gray Matter
4. NAWM shows widespread BioChemical involvement prior to detection on MRI
5. Severities of NeuroAxonal involvement significantly correlate with Neurological dysfunction

1H-MRS will provide more detailed information than conventional MRI, and could be beneficial in monitoring effects of therapeutic interventions in MS.

We studied 24 patients with Multiple Sclerosis (MS) by Proton Magnetic Resonance Spectroscopic Imaging (1H-MRSI) to assess the NeuroChemical pathology of the White-Matter Lesions (WML) and Normal-Appearing White Matter (NAWM).

Our 1H-MRSI technique allowed simultaneous measurement of N-AcetylAspartate (NAA), Choline-containing compounds (Cho), and Creatine plus PhosphoCreatine (Cr) signal intensities from four 15-mm slices divided into 0.84 ml single-volume elements.

In WML we found significantly lower NAA/Cr and NAA/Cho ratios and a significantly higher Cho/Cr ratio than in NAWM or control White Matter.

In NAWM, NAA/Cr and Cho/Cr were significantly lower than in control White Matter. 1H-MRS was compatible with damage to Myelin in WML, and with Axonal Damage and/or dysfunction in WML and NAWM.

These findings extend data on involvement of NAWM in MS beyond the abnormalities visible on MRI.