Introduction
In Multiple Sclerosis (MS), Brain Atrophy measurement on Magnetic Resonance Imaging (MRI) reflects overall tissue loss, especially DeMyelination and Axonal loss.

We studied which factor contributes most to the development of Brain Atrophy extent and severity of lesions or damage of Whole Brain Tissue (WBT).

Methods
Eighty-six patients with MS [32 Primary/Progressive (PP), 32 Secondary/Progressive (SP)] and 22 Relapsing/Remitting (RR) were studied.

1. MRI included T₁- and T₂-weighted imaging to obtain HypoIntense T₁ lesion volume (T₁LV):
   • And two Brain Volume measurements:
2. The Parenchymal Fraction (PF; Whole Brain Parenchymal Volume/IntraCranial Volume)
   • As a marker of overall Brain Volume
3. The Ventricular Fraction (VF; Ventricular Volume/IntraCranial Volume)
   • As a marker of Central Atrophy
4. From Magnetization Transfer Ratio (MTR) Histograms, the relative peak height (rHp) was derived
   • As an index of damage of WBT
     • A lower peak height reflects damage of WBT

Results
Multiple Linear Regression analysis revealed that damage of WBT explains most of the variance of PF (standardized coeffcient beta = 0.59, p < 0.001 for WBT and beta = -0.19, p < 0.05 for T₁LV).

These findings are independent of disease phase; even in RR patients, damage of WBT plays a dominant role in explaining the variance in overall Brain Volume.

By contrast the variance in VF is explained by both T₁LV and damage of WBT (standardized coefficient beta = 0.43, p < 0.001 for T₁LV and beta =-0.38, p < 0.001 for WBT).

Conclusion
This study shows that overall Brain Volume (PF) is best explained by damage of WBT, supporting the significance of nonfocal pathology in MS in producing tissue loss.

Central Atrophy (VP) is determined by both lesion volume and damage of WBT. Our results underline the importance of nonfocal pathology even in the early (RR) phase of the disease.

Cognitive Impairment in Multiple Sclerosis (MS), generally in the form of the so-called SubCortical Dementia, results predominantly by the disruption of communication among Cortical and SubCortical areas, consequent to White Matter damage.

Studies with conventional Magnetic Resonance Imaging (MRI) demonstrated that Cognitive Impairment in MS patients is related to lesion burden, although the strength of this correlation is weak.

This can be partially explained by the poor pathological specificity of conventional MRI techniques and by damage in the Normal-Appearing White Matter (NAWM).

This interpretation is supported by studies using NonConventional MRI techniques, more specific to the heterogeneous substrates of MS pathology.

Such as, the assessment of HypoIntense lesion load on T₁-weighted scans, and the measurement of the Magnetization Transfer Ratio (MTR) of whole Brain, MS lesions and NAWM.

Other factors, such as the site of MS lesions and the presence of active inflammation, also seem to play an important role.

Neuronal damage seems to be a major source of disability in Multiple Sclerosis (MS) patients and at present Magnetic Resonance Imaging (MRI) is a sensitive method to evaluate lesion and disease activity.

We studied the potential correlation between changes in MS patients' disability after relapse, the degree of T₁ lesion HypoIntensity on MRI in vivo and Neuronal Apoptosis induced by CerebroSpinal Fluid (CSF) on Neuron cultures.

In this study, we included 24 MS patients with Relapsing disease. Clinical recovery from relapse was measured by the Expanded Disability Status Scale (EDSS).

T₁-weighted MRI studies were done according to established standards and Neuronal Apoptosis was induced by treatment of Neuronal cultures with CSF from patients while relapsing.

Recovery after relapse is inversely correlated with Neuronal Apoptosis (r=-0.725, p<0.0001).

A correlation was found between T₁ lesion HypoIntensity and a poor recovery from relapse (r=0.656, p=0.0005) and such HypoIntensity correlated strongly with Neuronal Apoptosis (r=-0.779, p<0.0001).

CSF from all patients with HypoIntense T₁ lesions caused significantly increased Neuronal Apoptosis.

Whereas, all CSF that did not induced such effects corresponded to patients without T₁ lesions.

The recovery from an acute MS relapse is significantly worse in patients with HypoIntense T₁ lesions in MRI and in those whose CSF damaged Neurons on cultures in vitro, phenomena that closely correlated each other.

Background
After the resolution of contrast enhancement, the majority of new MS lesions become IsoIntense with surrounding White Matter on T₁-weighted MRI.

Less commonly, a HypoIntense T₁ lesion develops, representing the development of more severe focal tissue damage.

Interferon-beta (IFN-ß) reduces both the number of new enhancing lesions and the duration of contrast enhancement.

Objective
To determine if IFN-ß affects the degree of tissue damage within new lesions and if its effects are related to lesion size.

Methods
One hundred twenty-five patients with Secondary/Progressive MS from seven European sites were randomized to receive either IFN-ß-1b or placebo.

Monthly, contrast-enhanced T₁-weighted MR images were acquired at baseline, at months 1 to 6, and at months 19 to 24.

The size of all new enhancing lesions developing between months 1 and 6 was recorded and their appearance at follow-up documented.

Results
In the first 6 months, fewer new enhancing lesions occurred in the IFN-ß-1b arm. This difference was greater for small (70% decrease) than for large (46% decrease) lesions.

HypoIntense T₁ lesions were more likely to form from large (25%) than from small (9%) enhancing lesions in both treatment arms.

Patients taking IFN-ß-1b developed fewer HypoIntense T₁ lesions; however, the proportion of enhancing lesions developing into HypoIntense T₁ lesions was similar in both arms.

Conclusion
IFN-ß-1b reduced the number of new enhancing lesions, with a greater effect on small lesions. However, when a new enhancing lesion did become established, treatment with IFN-ß-1b did not alter its subsequent course.

In patients with Primary/Progressive (PP) Multiple Sclerosis, Brain MRI lesion activity and burden are low, despite the presence of severe Neurological impairment.

On the contrary, the degree of Cord Atrophy and diffuse tissue damage in the Brain and Cervical Cord have been found to be associated with clinical disability.

Against this background, this study aimed at providing an in vivo indirect assessment of Brain and Cervical Cord pathology in a large cohort of PP Multiple Sclerosis patients, using conventional MRI and Magnetization Transfer Imaging (MTI).

Ninety-one PP Multiple Sclerosis patients, 36 Secondary/Progressive (SP) Multiple Sclerosis patients and 30 healthy controls underwent Brain and Cervical Cord MRI scans.

Using dual echo (Brain) or fast Short-Tau Inversion Recovery (Cervical Cord) MTI and T₁-weighted sequences.

For the Brain, T₂ HyperIntense and T₁ HypoIntense lesion volumes were calculated and the volume of the whole of the Brain tissue measured.

For the Cervical Cord, the number and burden of lesions and the Cross-Sectional Area were assessed.

MTI scans were post-processed and analyzed to obtain Magnetization Transfer Ratio (MTR) Histograms from the whole of the Brain and Cervical Cord tissue and from the Normal-Appearing Brain Tissue in isolation.

In PP Multiple Sclerosis patients, Brain, Normal-Appearing Brain Tissue and Cervical Cord MTR Histogram-derived metrics revealed the presence of diffuse tissue damage.

Whose characteristics did not significantly differ from those of SP Multiple Sclerosis patients, even though SP Multiple Sclerosis patients had higher MRI-visible lesion burdens.

None of the correlations between MRI or MTI measures obtained from the Brain and the Cord were significant.

PP Multiple Sclerosis patients' disability was significantly, albeit weakly associated with a composite MR model including measures of loss and intrinsic damage of Cervical Cord tissue.

Our data indicate the presence of a diffuse tissue damage undetectable by conventional MRI in PP Multiple Sclerosis patients, whose extent seems to match that of SP Multiple Sclerosis patients with similar levels of disability.

They also suggest that the severity of Multiple Sclerosis pathology in the Cervical Cord is one of the factors contributing to Neurological impairment in PP Multiple Sclerosis.

Objective
To characterize Whole-Brain Atrophy in Relapsing/Remitting MS (RRMS) patients over an 8-year period.

The specific goals of this study were to determine if Brain Atrophy is related to subsequent disability status and to identify MRI correlates of Atrophy progression.

Methods
A follow-up study was conducted to reassess patients from a phase III trial of Interferon-beta-1a (IFN-ß-1a) 8 years after randomization.

Clinical and MRI data from 172 patients followed over 2 years in the original trial were used as baseline data.

Follow-up data were obtained on 160 patients, including 134 patients with follow-up MRI examinations. Brain Atrophy was estimated by automated calculation of Brain Parenchymal Fraction.

The relation between Atrophy during the original trial and disability status at follow-up was determined.

Correlations were also determined between lesion measurements from the original trial and the Brain Parenchymal Fraction at follow-up.

Results
Brain Atrophy was correlated with subsequent disability status. Atrophy rate during the original trial was the most significant MRI predictor of disability status at follow-up.

Brain Atrophy at follow-up was related to lesion volumes measured during the original trial.

Conclusions
The relation between Atrophy progression and subsequent Neurologic Disability Status suggests that Atrophy progression during RRMS is clinically relevant.

Therefore, Atrophy progression may be a useful marker for disease progression in clinical trials.

The relation between lesions and subsequent Atrophy indicates that Brain Atrophy may be related to focal tissue damage at earlier points in time, but important predisposing or other factors contributing to Atrophy remain undefined.

Background
Diffusion Tensor Imaging (DTI) of Brain Tissue measures the Apparent Diffusion Coefficient (ADC), or Isotropic Diffusion, and Anisotropy, or Diffusion as influenced by tissue structure.

We hypothesized that HyperIntensities, when compared with normal tissue by DTI, would show evidence of damage through an increased ADC and decreased Anisotropy.

We also hypothesized that DTI changes in HyperIntensities would be similar between Depressed subjects and control subjects.

Methods
Fourteen Depressed geriatric patients and nineteen control subjects received DTI.

The ADC and Anisotropy of normal tissue from standard regions were compared with HyperIntensities from these regions. The Students' t test compared individual regions and averaged White Matter results.

Results
HyperIntensities showed higher ADC and lower Anisotropy than normal regions. Gray Matter exhibited similar trends. There was no significant difference in Diffusion characteristics of HyperIntensities between subjects and control subjects.

Conclusions
HyperIntensities damage the structure of Brain Tissue, and do so comparably in Depressed subjects and control subjects.

Purpose
To determine the Fractional Brain Tissue Volume changes in the Gray Matter and White Matter of patients with Relapsing/Remitting Multiple Sclerosis (MS) and to correlate these measurements with clinical disability and total lesion load.

Materials And Methods
Thirty patients with Relapsing/Remitting MS and 25 healthy control subjects underwent Magnetic Resonance Imaging.

Fractional Brain Tissue Volumes (tissue volume relative to Total IntraCranial Volume) were obtained from the total segmented Gray Matter and White Matter in each group and were analyzed.

Results
The Fractional Volume of White Matter versus that of Gray Matter was significantly lower (-6.4%) in patients with MS (P < .0001) than in control subjects.

Neither Gray Matter nor White Matter Fractional Volume measurements correlated with Clinical Disability in the patients with MS.

Conclusion
Loss of Brain Parenchymal Volume in patients with Relapsing/Remitting MS is predominantly confined to White Matter.

Analysis of Fractional Brain Tissue Volumes provides additional information useful in characterizing MS and may have potential in evaluating treatment strategies.

This study investigates water Diffusion changes in Wallerian Degeneration.

We measured indices derived from the Diffusion Tensor (DT) and T₂-weighted signal intensities in the Descending Motor Pathways of patients with small chronic Lacunar Infarcts of the Posterior Limb of the Internal Capsule on one side.

We compared these measurements in the healthy and lesioned sides at different levels in the BrainStem caudal to the primary lesion.

We found that secondary White Matter degeneration is revealed by a large reduction in Diffusion Anisotropy only in regions where Fibers are arranged in isolated bundles of parallel Fibers, such as in the Cerebral Peduncle.

In regions where the Degenerated Pathway crosses other Tracts, such as in the rostral Pons, paradoxically there is almost no change in Diffusion Anisotropy, but a significant change in the measured orientation of Fibers.

The trace of the Diffusion Tensor is moderately increased in all affected regions. This allows one to differentiate secondary and primary Fiber loss where the increase in trace is considerably higher.

We show that DT-MRI is more sensitive than T₂-weighted MRI in detecting Wallerian Degeneration. Significant Diffusion abnormalities are observed over the entire trajectory of the affected Pathway in each patient.

This finding suggests that mapping Degenerated Pathways noninvasively with DT-MRI is feasible. However, the interpretation of water Diffusion data is complex and requires a priori information about Anatomy and architecture of the Pathway under investigation.

In particular, our study shows that in regions where Fibers cross, existing DT-MRI-based Fiber tractography algorithms may lead to erroneous conclusion about Brain connectivity.

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.

Magnetic Resonance Imaging (MRI) plays an ever-expanding role in the evaluation of Multiple Sclerosis (MS).

This includes its sensitivity for the diagnosis of the disease and its role in identifying patients at high risk for conversion to MS after a first presentation with selected Clinically Isolated Syndromes.

In addition, MRI is a key tool in providing primary therapeutic outcome measures for Phase I/II trials and secondary outcome measures in Phase III trials.

The utility of MRI stems from its sensitivity to longitudinal changes including those in overt lesions and, with advanced MRI techniques, in areas affected by diffuse occult disease (the so-called Normal-Appearing Brain Tissue).

However, all current MRI methodology suffers from limited specificity for the underlying histopathology.

Conventional MRI techniques, including lesion detection and measurement of atrophy from T₁- or T₂-weighted images, have been the mainstay for monitoring disease activity in clinical trials.

In which the use of Gadolinium with T₁-weighted images adds additional sensitivity and specificity for areas of acute inflammation.

Advanced imaging methods including Magnetization Transfer, Fluid Attenuated Inversion Recovery, Diffusion, Magnetic Resonance Spectroscopy, Functional MRI, and nuclear imaging techniques have added to our understanding of the pathogenesis of MS.

And, may provide methods to monitor therapies more sensitively in the future.

However, these advanced methods are limited by their cost, availability, complexity, and lack of validation. In this article, we review the role of conventional and advanced imaging techniques with an emphasis on NeuroTherapeutics.