Background
What currently appears to be irreversible Axonal loss in Normal-Appearing White Matter, measured by Proton Magnetic Resonance Spectroscopy is of great interest in the study of Multiple Sclerosis.

Our aim is to determine the Axonal damage in Normal-Appearing White Matter measured by Magnetic Resonance Spectroscopy and to correlate this with the functional disability measured by Multiple Sclerosis Functional Composite scale, Neurological Rating Scale, Ambulation Index scale, and Expanded Disability Scale Score.

Methods
Thirty one patients (9 male and 22 female) with Relapsing/Remitting Multiple Sclerosis and a Kurtzke Expanded Disability Scale Score of 0-5.5 were recruited from four hospitals in Andalusia, Spain and included in the study.

Magnetic resonance Spectroscopy scans and Neurological disability assessments were performed the same day.

Results
A statistically significant correlation was found (r = -0.38 p < 0.05) between disability (measured by Expanded Disability Status Scale Score) and N-AcetylAspartate (NAA/Cr ratio) levels in Normal-Appearing White Matter in these patients.

No correlation was found between the NAA/Cr ratio and disability measured by any of the other disability assessment scales.

Conclusions
There is correlation between Disability (measured by Expanded Disability Scale Score) and the NAA/Cr ratio in Normal-Appearing White Matter.

The lack of correlation between the NAA/Cr ratio and the Multiple Sclerosis Functional Composite score indicates that the Multiple Sclerosis Functional Composite is not able to measure irreversible disability and would be more useful as a marker in stages where Axonal Damage is not a predominant factor.

Background
The PathoPhysiological basis for differences in disability in patients with Multiple Sclerosis is unclear.

Methods
We used Magnetic Resonance Imaging to examine whether differences in Disability in cohorts of Multiple Sclerosis patients with similar T₂-weighted lesion load and disease duration were associated with a more destructive disease process in the more disabled patients.

Results
The Benign and severely disabled groups had similar Brain Atrophy metrics and similar decreases of the Neuronal marker, N-AcetylAspartate, in the Normal-Appearing White Matter of the Cerebrum on Magnetic Resonance Spectroscopy examination in vivo. The severely disabled cohort had more Spinal Cord Atrophy.

Conclusion
The dissociation of Spinal Cord Atrophy and Cerebral Atrophy between these two groups suggests that the difference between the more Benign and more disabled groups cannot be explained by a more aggressive pathological process that is affecting the entire NeuroAxis in a homogeneous fashion.

Lower levels of N-AcetylAspartate (NAA), a marker of Axonal Damage, have been found in the Normal-Appearing White Matter (NAWM) of Relapsing/Remitting Multiple Sclerosis (RRMS) patients with low physical disability.

However, its relation to the clinical status of these patients remains unclear.

We explored the association between NAA levels [normalized to Creatine (Cr), NAA/Cr] and a Cognitive feature that is not measured by the standard scales that address functional Disability [e.g. Expanded Disability Scale Score (EDSS)] in early RRMS.

Given that a considerable number of RRMS patients present Attentional Dysfunction early in the disease and assuming a functional-anatomical oriented guide:

It was hypothesized that patients with worse Attentional performance would show lower NAWM NAA/Cr values in the Locus Coeruleus Nuclei of the Pontine Ascendant Reticular Activating-System.

Proton Magnetic Resonance Spectroscopy (1H-MRS) examinations with concurrent clinical evaluation were acquired for 19 RRMS patients with a mean evolution time of 24 months (range 10-60) and mild disability (EDSS 0-3.5, median = 1).

1H-MRS was obtained with Spectroscopic imaging and measures were taken from the Right and Left HemiPons.

Attention was measured by means of the Dichotic Listening (DL) paradigm to increase the sensitivity of the testing to subtle Attentional Deficits. A consonant-vowel DL test was measured with and without Attentional instructions.

For the Attentional condition, the test was digitally manipulated to cue automatically to the Ear to be attended, thus allowing the obtention of both a Linguistic Lateralization Index (LI) and an index of integrity of Attentional Shifts (ASI).

Attentional Impairment was demonstrated in 47.3% of the patients. Pontine NAA/Cr levels accounted for 39% of the ASI variability (beta = 0.65, P < 0.002) but did not relate to the LI.

Moreover, when NAA/Cr levels were considered separately as Left and Right HemiPons values in a multivariate stepwise linear regression model, the right NAA/Cr ratio alone explained 43% of the ASI variability (beta = 0.68, P < 0.001).

Since the RRMS patients with greater Attentional Disturbances exhibited the lowest NAA/Cr levels, it is concluded that NAA provides a specific measure of pathological changes that are also relevant for Cognitive functions.

The use of both 1H-MRS and DL showed the connection between Axonal damage at Right Locus Coeruleus and Auditive Selective Attention Dysfunction in early-stage RRMS.

Objective
To compare the abnormalities shown by Magnetic Resonance Imaging of the Brain in three clinically distinct groups of patients with Multiple Sclerosis, and to correlate the extent of abnormality with the degree of clinical Disability in the three groups.

Design
All patients underwent Magnetic Resonance Imaging and full Neurological Examination, and their disability was scored according to the Expanded Kurtzke Disability State Scale (EDSS).

Setting & Patients
National Hospital for Nervous Diseases (Multiple Sclerosis NMR Research Group). Three groups of patients with confirmed Multiple Sclerosis:

• 12 patients with minimal disability despite a long (greater than 10 years) duration of illness (Benign MS)

• 16 who had developed progressive disability after a Relapsing/Remitting course (Secondary/Progressive MS)

• 13 who had had progressive disability from the onset of the disease (Primary/Progressive MS)

Main Outcome Measures
Number and size of lesions in 17 anatomically defined sites; total lesion load, estimated with an arbitrary scoring system weighted for the size of lesions; and disability score.

Results
Magnetic Resonance Imaging showed that all 41 patients had abnormalities.

These were extensive in the groups with Secondary/Progressive and Benign disease compared with the group with Primary/Progressive disease.

The lesions in the patients with Secondary/Progressive disease were larger and more confluent than those in the two other groups (p = 0.007).

Most lesions (85%) in the patients with Primary/Progressive disease were under 5 mm in diameter; this percentage was higher than that in the two other groups (p = 0.032).

Consequently, the patients with Primary/Progressive disease had the lowest mean lesion load (36.7); that in the patients with Benign disease was 52.7 and that in the patients with Secondary/Progressive disease 64.6 (p = 0.05).

No correlation existed between Disability and total Lesion Load.

The distribution of Brain lesions and of detectable Lesions of the Spinal Cord, and the frequency of Cortical Atrophy, were similar in all groups.

Conclusions
No relation was found between the degree of clinical disability and the extent of abnormality shown by Magnetic Resonance Imaging.

Patients with clinically Benign disease often had extensive abnormalities and those with Primary/Progressive disease had surprisingly few lesions.

Though Magnetic Resonance Imaging increases knowledge of the disease process in Multiple Sclerosis and is invaluable in diagnosis, it is not helpful in predicting Disability in individual patients.

The clinical features of relapses and progression largely define Multiple Sclerosis phenotypes. A Relapsing course is followed by chronic progression in some 80% of cases within 2 decades.

The relationship between these phases and long-term outcome remains uncertain. We have analyzed these clinical features within a well-studied natural history cohort with mean follow-up of 25 years.

For the entire cohort, median times to reach Disability Status Scale (DSS) 6, 8 and 10 were 12.7, 20.6 and 43.9 years, respectively.

Among 824 attack-onset patients, the great majority entered a Progressive phase with a mean time to progression of 10.4 years.

The effects of relapses often cloud the clinical onset of progression. However, there are circumstances where onset of progression is early, relatively discrete and identifiable at DSS of 2 or less.

Three subgroups allow for clarity of outcome comparison and they are:
1. Cases of Primary/Progressive (P/P) disease
2. Attack-onset disease where only a single attack has occurred before onset of progression (SAP)
3. Secondary/Progressive (S/P) disease where recovery from relapses allows recognition of the earliest clinical stages when progression begins

Here we compare survival curves in these three groups.

Among cohorts of SAP (n = 140), PP (n = 219) and SP (n = 146) where progression was stratified by DSS at its onset, there was no difference in time to DSS 6, 8 and 10.

These findings demonstrate that the Progressive course is independent of relapses either preceding the onset of relapse-free progression or subsequent to it.

Among SAP patients, the degree of recovery from the single defining exacerbation had no significant effect on outcome. The site of the original attack was not usually where progression began.

The relatively stereotyped nature of the Progressive phase seen in all Progressive phenotypes suggests regional and/or functional differential susceptibility to a process that appears degenerative in nature.

The highly prevalent distal CorticoSpinal Tract dysfunction in Progressive disease and the pathologically demonstrated selective Axonal Loss seen in this tract raises the possibility of a dying back central Axonopathy, at least in part independent of plaque location or burden.

Despite considerable individual variation, the progressive course of disability seen in groups of P/P, SAP and S/P-DSS2 is similarly stereotyped in quality and pace and may entail mechanisms common to all forms of Progressive Multiple Sclerosis.

The possibility that this is the primary process in some cases must be considered.

The NeuroPathology of Multiple Sclerosis is characterised by focal damage to White Matter.

However, tissue damage is also present in the Cortical Gray Matter, with a particularly high prevalence of Cortical DeMyelination being observed in Secondary/Progressive and Primary/Progressive forms of the disease.

The presence of Meningeal B-Cell follicle-like structures, which frequently appear during the Secondary/Progressive phase of disease, may be involved in the formation of these SubPial Cortical Lesions.

Diffuse White Matter inflammation accompanied by Axonal Damage can also be observed in Normal-Appearing White Matter and, again, this is more prominent in Chronic Progressive forms of Multiple Sclerosis than in acute stages of disease.

Axonal Damage is a particularly important component of the pathology of Multiple Sclerosis and appears to be a critical determinant of clinical outcome. Axons appear to become vulnerable to injury as a result of loss of their Myelin sheaths.

ReMyelination represents an important mechanism of tissue repair in Multiple Sclerosis and already occurs at an early stage of lesion development and in both White and Gray Matter lesions.

The extent of ReMyelination appears to be greater in Cortical Lesions and in lesions further from the Ventricles.

There is important heterogeneity between patients in terms of the extent of ReMyelination, which may reflect underlying differences in pathogenetic mechanisms between patients.

The pathological substrate of progressive disability in Multiple Sclerosis is hypothesized to be Axonal Loss.

Differences in the demographic, pathological and radiological features of patients with Primary/Progressive compared with Secondary/Progressive Multiple Sclerosis raise the question as to whether they actually represent separate clinical entities.

So far, large pathological studies comparing Axonal Damage between Primary/Progressive and Secondary/Progressive Multiple Sclerosis have not been reported.

In this clinico-pathological study we examined the Cervical Spinal Cord in patients with Primary and Secondary/Progressive Multiple Sclerosis.

Human Cervical Spinal Cord was derived at autopsy from 54 patients (17 Primary/Progressive, 30 Secondary/Progressive and 7 controls).

Tissue was stained ImmunoHistoChemically and examined to determine:
1. Tthe number of surviving CorticoSpinal Tract Axons
2. The extent of Gray and White Matter DeMyelination
3. The degree of inflammation inside and outside of lesions
4. The relationship between DeMyelination and Axonal Loss

Associated clinical data was used to calculate Expanded Disability Status Scale for each patient preceding death.

Motor disability in the Primary/Progressive and Secondary/Progressive groups was similar preceding death.

Secondary/Progressive Multiple Sclerosis patients showed considerably more extensive DeMyelination of both the White and Gray Matter of the Cervical Spinal Cord.

The total number of CorticoSpinal Axons was equally low in Primary/Progressive and Secondary/Progressive Multiple Sclerosis groups versus controls.

The reduction of Axonal Density in DeMyelinated regions compared to Normal-Appearing White Matter was significantly more extensive in Primary/Progressive versus Secondary/Progressive patients (33% reduction versus 16% reduction, P < 0.001).

These findings suggest Axonal Loss is the pathological substrate of progressive disability in both Primary/Progressive and Secondary/Progressive Multiple Sclerosis with a common plaque-centred mechanism.

More extensive Axonal Loss within areas of DeMyelination in Primary/Progressive Multiple Sclerosis could explain high levels of Axonal Loss observed in these patients despite low levels of DeMyelination.

Previous studies have established Regional Gray Matter (GM) Volume Loss in Multiple Sclerosis (MS) but the relationship between development of White Matter (WM) lesions and changes of Regional GM Volumes is unclear.

The present study addresses this issue by means of Voxel-Based Morphometry (VBM).

T₁-weighted three-dimensional Magnetic Resonance Imaging (MRI) data from MS patients followed up for 12 months were analyzed using VBM.

An analysis of covariance model assessed with cluster size inference (all corrected for multiple comparisons, p < 0.01) was used to compare GM Volumes between baseline and follow-up while controlling for age, gender, and disease duration.

Lesion burden, i.e. Volumes of T₁ HypoIntense and T₂ HyperIntense lesions and the number of new T₂ lesions at year one, was also determined.

Comparing all MS patients (n=211) longitudinally, GM volume remained unchanged during one year-follow-up.

Focusing on patients with Relapsing/Remitting MS (RRMS) (n=151), significant Cortical GM Volume reductions between baseline and follow-up scans were found:

In the Anterior and Posterior Cingulate, the Temporal Cortex, and Cerebellum.

Within the RRMS group, those patients with increasing T₂ and T₁ lesion burden (n=45) showed additional GM Volume Loss during follow-up in the Frontal and Parietal Cortex, and Precuneus.

In contrast, patients lacking an increase in WM lesion burden (n=44) did not show any significant GM changes.

The present study suggests that the progression of Regional GM Volume Reductions is associated with WM lesion progression and occurs predominantly in Fronto-Temporal Cortical Areas.

white Matter Tracts, which play a crucial role in the coordination of information flow between different regions of Gray Matter, are particularly vulnerable to Multiple Sclerosis.

Many studies have shown that the White Matter lesions in Multiple Sclerosis are associated with focal abnormalities of Gray Matter, but little is known about the alterations in the coordinated patterns of Cortical Morphology among regions in the disease.

Here, we used Cortical Thickness measurements from Structural Magnetic Resonance Imaging to investigate:

The relationship between the White Matter lesion load and the topological efficiency of Structural Cortical Networks in Multiple Sclerosis.

Network efficiency was defined using a 'small-world' network model that quantifies the effectiveness of information transfer within Brain Networks.

In this study, we first classified patients (n = 330) into six subgroups according to their Total White Matter lesion loads.

And identified Structural Brain Networks for each Multiple Sclerosis group by thresholding the corresponding Inter-Regional Cortical Thickness correlation matrix, followed by a network efficiency analysis with graph theoretical approaches.

The Structural Cortical Networks in Multiple Sclerosis demonstrated efficient small-world architecture regardless of the lesion load, an organization that maximizes the information processing at a relatively low wiring cost.

However, we found that the overall small-world network efficiency in Multiple Sclerosis was significantly disrupted in a manner proportional to the extent of Total White Matter lesions.

Moreover, regional efficiency was also significantly decreased in specific Brain regions, including the Insula and PreCentral Gyrus as well as regions of PreFrontal and Temporal Association Cortices.

Finally, we showed that the lesions also altered many Cortical thickness correlations in the Frontal, Temporal and Parietal Lobes.

Our results suggest that the White Matter lesions in Multiple Sclerosis might be associated with aberrant Neuronal Connectivity among widely distributed Brain regions.

And provide Structural (Morphological) evidence for the notion of Multiple Sclerosis as a Disconnection Syndrome.