MS Abstracts MRI2g2

Rationale And Objectives
To measure T₂ relaxation times of normal White and Gray Matter using a novel CPMG sequence and investigate if any correlation exists between Magnetization Transfer Ratio (MTR) and T₂ relaxation-related parameters.

Materials And Methods
Seventeen normal volunteers participated on this study. A single-slice 32-echo sequence was used to calculate the T₂ relaxation time of Frontal and Occipital White Matter and Cortical Gray Matter.

T₂ relaxation analysis included MonoExponential and BiExponential fitting whereas an F test was used to determine if BiExponential fitting was statistically more accurate than MonoExponential fitting.

Short and long T₂ constants were calculated as well as the signal fractions of each pool.

MTR calculations were based on a three-dimensional gradient echo (3D FFE) Proton Density weighted sequence with and without an on-resonance composite prepulse.

MTR and T₂ relaxation times were calculated and linear regression analysis was applied.

Results
BiExponential fitting was more accurate comparing with MonoExponential fitting in all WM and GM regions (F > 2.47, P < 0.01).

Mean values of short T₂ constant for Frontal White Matter (fWM), Occipital White Matter (oWM) and Gray Matter (GM) were 8.10, 9.36, and 22.23 milliseconds, respectively.

Whereas the mean values of long T₂ constant were 85.1, 93.02, and 118.72 milliseconds, respectively.

Mean Restricted Water Percentages (RWP)- corresponding to the signal fraction of the protons with short T₂-for the fWM, oWM, and GM were 22.01%, 23.36%, and 18.7%.

Mean Free Water Percentages (FWP)-corresponding to the signal fraction of the protons with long T₂-for the fWM, oWM and GM were 77.99%, 76.64%, and 81.3%. Mean MTR values for fWM, oWM and GM were 68.4%, 68.2%, and 61.3%, respectively.

No significant correlation was found in fWM and oWM between MTR and RWP, short and long T₂ components.

While a moderate correlation existed in GM between MTR and RWP (r = 0.57; P = 0.02), MTR and short T₂ component (r = -0.69; P = 0.004) and MTR and long T₂ component (r = -0.62; P = 0.012).

Conclusions
Two proton pools with different T₂ decay characteristics can be separated in normal Gray and White Matter when using a multiecho sequence with short echo spacing.

MTR and T₂ relaxation times were significantly correlated in Gray Matter and the combination of both types of measurements may be helpful in studying Myelin related disorders.

Objective
To use both whole-Brain and Normal-Appearing Brain Tissue (NABT) T₁ relaxation time Histograms to investigate abnormalities in early Relapsing/Remitting (RR) Multiple Sclerosis (MS).

Background
In patients with established MS, both lesions and NABT exhibit an increase in T₁ relaxation time. By using T₁ Histogram analysis, it is hoped that such changes in early disease can be detected.

Method
Twenty-seven patients and 14 age- and sex-matched controls underwent Magnetic Resonance Imaging (MRI) of the Brain, which included the following sequences:

1. Proton Density (PD)- and T₂-weighted Fast Spin Echo (FSE) to measure T₂ lesion load

2. PD- and T₁-weighted gradient echos from which T₁ relaxation was calculated

3. T₁-weighted SE imaging pre- and post-triple dose (0.3 mmol/kg) Gadolinium (Gd-DTPA) to measure T₁ HypoIntense and Gadolinium-enhancing lesion loads, respectively

All patients had RR MS with disease duration < 3 years (median 1.7 years).

Statistical Parametric Mapping (SPM) 99 was used to segment Brain from CerebroSpinal Fluid (CSF), and lesions were segmented using a local thresholding technique.

Results
Both whole-Brain and NABT Histograms were abnormal for all six T₁ Histogram parameters that were measured.

For NABT, the mean T₁ was 1,027 (+/- 74) ms in patients and 969 (+/- 41) ms in controls (p=0.003).

There was little difference between the global and NABT Histograms, which indicates that most of the whole-Brain Histogram abnormality derives from Normal-Appearing Tissues.

There was a correlation between the Nine-Hole Peg Test and NABT T₁ measures.

Conclusion
There are widespread abnormalities of NABT in early RR MS, which were sensitively detected by T₁ relaxation time Histogram analysis.

As such, T₁ Histogram analysis appears promising for studying the natural history of early RR MS, and in the monitoring of response to treatment.

In some rare cases, DeMyelinating plaques appear on contrast-enhanced T₁-weighted images as PseudoTumoral, Cyst-like lesions (HypoIntense, Ring Enhancing).

Serial proton MR Spectroscopy, T₂ relaxometry and Magnetization Transfer Ratios (MTR) were performed on three PseudoTumoral DeMyelinating lesions to obtain information about their pathological basis.

Baseline and 1-month MTR and T₂ values were similar to those of CerebroSpinal Fluid, while Spectra showed Lactate, Lipids and Choline.

Three-month and 1 year exams showed recovery of MTR, T₂ and N-AcetylAspartate, approaching the ContraLateral values, while Creatine and Choline were normal or surpassed ContraLateral values. Lipids and Lactate gradually disappeared.

These results suggest that PseudoTumoral, cyst-like, ring-enhancing lesions may be characterized by an accumulation of Edema in the ExtraCellular Space with an almost complete absence of cells.

Reduction of the Edema allows restoration of the tissue to its original location, indicating that cellular destruction was less important than was expected after the first exam.

Thus, the evolution of this kind of lesion should be kept in mind when considering lesion volume from T₁-weighted images as a marker of disability or irreversible cellular destruction in MS.

Copyright 2002 John Wiley & Sons, Ltd.

Clinically Isolated Syndromes (CIS) are events suggestive for emerging Multiple Sclerosis (MS). A majority of patients develop MS within months or years while others remain clinically isolated.

The goal of this study was to investigate whether BioChemical metabolites detectable by ₁H Magnetic Resonance Spectroscopy (MRS) may serve to distinguish between these two groups.

We investigated 41 patients 14 years after presentation with a CIS and 21 controls with combined quantitative short echo ₁H MRS and Magnetic Resonance Imaging (MRI) and assessed disability according to the Expanded Disability Status Scale (EDSS). At follow-up, 32 had developed MS, and 9 still had CIS.

Compared with controls, MS patients demonstrated significantly higher concentrations of Myo-Inositol (Ins) in Normal-Appearing White Matter (NAWM) and lesions.

Lesions also demonstrated a reduced N-Acetyl-Aspartate (NAA) level and an increase in Choline-containing compounds (Cho).

The NAWM Ins concentration was correlated with EDSS (r = 0.48, p = 0.005). MS Normal-Appearing Cortical Gray Matter (CGM) exhibited a decreased NAA. Patients who remained CIS did not differ significantly from controls in any MRS measure.

Metabolite changes in Normal-Appearing White and Gray Matter in MS indicate diffuse involvement of the entire MS Brain, which was not seen in the persisting CIS patients. Elevated Ins in MS NAWM appeared functionally relevant it may indicate Glial Cell proliferation or Gliosis.

The aim of this study was to investigate changes of Brain Volume as measured by Magnetic Resonance Imaging (MRI) in Relapsing/Remitting Multiple Sclerosis (MS) patients under treatment with Interferon-ß-1a.

Moreover, the relationship between Brain Volume changes and standard MR or clinical outcome variables was determined.

After a 6-month pretreatment period, 52 patients with Relapsing/Remitting MS were assigned to receive Interferon-ß-1a (Rebif-Serono) during a 24-month treatment period.

MRI scans were performed monthly during the 6-month pretreatment period and for the first 9 months of the treatment period.

A final MRI scan was also performed at the end of the 12- and 24-month treatment period. Over 24 months of IFN-ß-1a treatment, a significant decrease of HyperIntense lesion volume was found (-18.0%; p<0.0001) compared to the last pretreatment scan.

While T₁ HypoIntense volume showed a slight nonsignificant increase (+2.2%), and Brain Volume showed a significant decrease (-2.2%; p<0.0001).

The mean volume of enhancing lesions over the 6-month pretreatment period was significantly related to absolute (p=0.02; r=-0.32) and per cent change (p=0.03; r=-0.30) of Brain Volume during 24-month treatment period.

No correlations between changes in Brain Volume and changes in T₂ HyperIntense volume or T₁ HypoIntense volume were observed.

Neither was there a relationship between Brain Volume and changes of Expanded Disability Status Scale (EDSS) or frequency in clinical relapses.

Of the group in whom was detected a significant decrease of Brain Volume, 13 out of 26 (50%) had a sustained change in EDSS.

While in the group that did not have a significant decrease of Brain Volume, only 3 out of 26 (11.5%) had a sustained EDSS change (p=0.02).

In this study a decrease of Brain Volume was found in Relapsing/Remitting MS patients treated with IFN-ß-1a over 2 years.

The only parameter that predicted Brain Volume decrease by 2 years of IFN-ß-1a treatment was the mean volume of enhancing lesions over the 6-month pretreatment period.

Previous studies have established the clinical relevance of HypoIntense lesions ("black holes") on T₁-weighted MRI as a surrogate marker for pathological change [36].

In contrast to measuring the volume of "black holes", the direct measurement of T₁ values allows an objective assessment of the changes contributing to HypoIntensity both in the focal lesions and in the Normal Appearing White Matter (NAWM).

The aims of this study were to:

1. Determine the relationship between T₁ values in the NAWM and in discrete lesions
2. Test the relationship between White Matter T₁ changes and measures of disability
3. Determine whether pathology leading to T₁ change occurred in Thalamic Gray Matter of patients with Multiple Sclerosis

24 patients with Clinically Definite Multiple Sclerosis (13 with Relapsing/Remitting Multiple Sclerosis and 11 with Secondary/Progressive Multiple Sclerosis) and 11 controls participated.

White Matter T₁ Histograms and mean T₁ values for the Thalamus were generated from Whole Brain T₁ relaxation time maps measured using a novel Echo-Planar imaging based MRI sequence at ₃Tesla.

Tissue segmentation based on T₂- and T₁-weighted images allowed independent study of changes in lesions and NAWM.

White Matter T₁ Histograms from the patient group showed a reduced peak height and a shift towards higher T₁ values (p = 0.028) relative to controls.

The mean Thalamic T₁ was greater for Secondary/Progressive patients than for healthy controls (p = 0.03). Mean White Matter T₁ values correlated significantly with disability (r = 0.48, p = 0.02).

The mean T₁ value in the T₁-HypoIntense lesions correlated strongly with the mean T₁ value in the NAWM (r = 0.80, p < 0.001).

No significant relationship was found between mean White Matter T₁ value and Cerebral volume (r = -0.23, p = 0.31).

The T₁ measurements extend previous observations suggesting that changes in the NAWM occur in parallel with pathology in lesions of MS.

T₁ measurements of either the total or NAWM therefore may provide a potentially observer- and scanner- independent marker of pathology relevant to disability in MS.

Conventional MRI (cMRI) is limited in its ability to provide specific information about pathology in MS.

Measures commonly derived from cMRI include T₂ lesions, T₁-enhanced lesions, Atrophy, and possibly T₁-HypoIntense lesions, which have been extensively investigated in many clinical trials.

Better MRI measures are needed to advance our understanding of MS and design ideal clinical trials.

This article reviews the strengths and weaknesses of the major MRI-based methods used to monitor MS evolution and submits that:

• Metrics derived from Magnetization Transfer MRI, Diffusion-weighted MRI, and Proton MRS should be implemented to achieve reliable specific in vivo quantification of MS pathology
  

• Targeted multiparametric MRI protocols rather than generic application of cMRI should be used in all possible clinical circumstances and trials

• Reproducible quantitative MR measures should ideally be used for the assessment of patients but are essential for clinical trials

To assess the applicability of Magnetic Resonance Spectroscopy (Spectroscopy) for long-term follow-up of Neurological Diseases.

A longitudinal 1H-MRS study at 3 T was carried out on ten patients having Relapsing/Remitting Multiple Sclerosis (MS) who, after baseline examination, received Interferon-beta (IFN-ß-1b).

At 8-20 examinations within up to 34 months absolute concentrations of N-AcetylAspartate (NAA), total Creatine (tG), and Choline-containing compounds (tCho) were determined in a large non-enhancing lesion and ContraLateral Normal Appearing White Matter (NAWM).

MR Spectra were analyzed using a novel time domain-frequency domain method including non-parametric background characterization.

For comparison at baseline, ten healthy controls were examined. The concentrations of tCho and tCr were found to be higher in MS Brain than in control Brain.

Besides a non-significantly lower NAA concentration in lesions there were no concentration differences between lesions and NAWM. Over the follow-up period the measured metabolite concentrations exhibited a high variability.

Most concentrations remained within this scatter, and statistical tests revealed significant fluctuations in the levels of metabolites in one case only.

This stability of the metabolite concentrations over time might result from IFN therapy as for the spontaneous course of Relapsing/Remitting MS decreasing metabolite (NAA/tCr) ratios have been reported.

The results further suggest that future treatment trials intending to use metabolite concentrations as a secondary outcome indicator use even longer observation periods.

And, besides group analysis of large cohorts, investigate the time behavior of selected single cases. The biochemical abnormalities found in NAWM emphasize the importance of analyzing both lesion and NAWM.

In Relapsing/Remitting (RR) Multiple Sclerosis (MS), conventional Magnetic Resonance Imaging (MRI) has proved to be a valuable tool to assess the lesion burden and activity over time.

However, conventional MRI cannot characterize and quantify the tissue damage within and outside such lesions and only can provide some gross measures reflecting the presence of irreversible tissue damage, such as the load of T₁ "Black Holes" and the severity of Brain or Cord Atrophy.

Other MR-based techniques, including Cell-Specific imaging, Magnetization Transfer (MT) MRI (MT-MRI), Diffusion-Weighted (DW) MRI (DWI-MRI), Proton Magnetic Resonance Spectroscopy (1H-MRS), and Functional MRI (fMRI), have the potential to overcome this limitation.

And, consequently, to provide additional information about the nature and the extent of MS tissue damage, which would inevitably remain undetected when only a conventional MRI is obtained.

Cell-Specific imaging should result in a better definition of the cellular mechanisms associated with MS inflammation.

Metrics derived from MT- and DW-MRI can quantify the structural changes occurring within and outside lesions visible on conventional MRI scans.

1H-MRS could add information on the biochemical nature of such changes.

fMRI is a promising technique to assess the mechanisms of Cortical reorganization, which may limit the consequences of an MS-related injury.

The application of these MR techniques to the study of RRMS is likely to provide useful insights into the PathoPhysiology of this disease and to improve our ability to assess the efficacy of experimental treatments.

Background
Diffusion-Tensor Magnetic Resonance Imaging is sensitive to the more destructive aspects of Multiple Sclerosis (MS) evolution occurring outside and within T₂-visible lesions.

And, as a consequence, holds promise for providing a more complete picture of Primary/Progressive (PP) MS-related tissue damage than conventional Magnetic Resonance Imaging.

Objective
To improve our understanding of PPMS by assessing the extent of occult pathological features in the Normal-Appearing White and Gray Matter of the Brain using Diffusion-Tensor Magnetic Resonance Imaging.

Methods
Ninety-six patients with PPMS, 47 patients with Secondary/Progressive (SP) MS, and 44 healthy control subjects were studied.

T₂-HyperIntense and T₁-HypoIntense lesion volumes were calculated, and the volume of the Whole Brain Tissue was measured.

Diffusion-Tensor Magnetic Resonance Imaging scans were postprocessed and analyzed to obtain the Mean Diffusivity and Fractional Anisotropy Histograms from the Brain and from the Normal-Appearing White and Gray Matter in isolation.

Results
The mean T₂-HyperIntense and T₁-HypoIntense lesion volumes were lower in patients with PPMS than in patients with SPMS, while the mean absolute Brain Volumes were similar in the 2 groups.

The average lesion Diffusivity was significantly higher in patients with SPMS than in patients with PPMS (P < .001).

Histogram-derived metrics of the Brain tissue and Normal-Appearing White and Gray Matter were significantly different between patients with PPMS and healthy subjects (range, P =.004 to < .001).

Average Diffusivity values were significantly higher in patients with SPMS than in patients with PPMS for all the tissues studied (range, P =.001 to < .001).

Fractional Anisotropy Histogram-derived quantities did not significantly differ between the 2 patient groups (range, P =.94 to.03).

Conclusion
This study confirms that, in patients with PPMS, Normal-Appearing White (NAWM) and Gray Matter (NAGM) are not spared by disease-related pathological processes, although they are affected to a lesser degree than in patients with SPMS.

T₁ relaxation time (T₁) provides a quantitative Magnetic Resonance Imaging (MRI) parameter for evaluating tissue damage in the Brain.

We aimed to measure T₁ in the White Matter of patients with Multiple Sclerosis (MS) and study relationships with Cerebral Atrophy, T₂ lesion load and clinical parameters.

Twenty-six patients with Relapsing/Remitting MS and sixteen healthy controls were scanned with dual-echo T₂-weighted, 3-dimensional (3-D) Magnetization-prepared Rapid Acquisition Gradient Echo and Whole Brain, multi-slice Inversion Recovery (IR) sequences.

White Matter masks were defined on axial T₁ map slices using semi-automated seed growing and normalized 'total White Matter' T₁ Histograms generated.

Atrophy data was obtained using the Cavalieri method of modern design stereology. T₂ lesion volume was also determined using seed growing.

T₁ Histogram-derived measures (median, peak height, peak position and standard deviation) in MS patients were significantly different (p < 0.0001) from controls.

Median T₁ correlated significantly with:
1. SupraTentorial (r = 0.42, p = 0.036)
2. Lateral Ventricles (r = 0.55, p = 0.004)
3. T₂ Total Lesion Volumes (r = 0.84, p < 0.0001)
   • But not with clinical parameters

Total White Matter T₁ provides a robust, quantitative measure of global disease burden in MS, and also correlates significantly with Cerebral Atrophy.

Serial studies are required to determine its potential role as a surrogate marker of disease progression.