Gray Matter Damage In Multiple Sclerosis

Objective
To perform Voxel-wise assessments of Regional Brain Atrophy state and rate in subjects with Relapsing/Remitting (RR) Multiple Sclerosis (MS).

Background
Recently, attention has focused on defining the tissue compartments and regions within which Brain Atrophy occurs.

These regional measures of Brain Volume changes may help to better define the nature of the pathology underlying MS.

In this context, specific Regional measures of Gray Matter (GM) Volume changes can be obtained by using the Voxel-Based Morphometry (VBM) approach.

Methods
Fifty-nine subjects with RR MS underwent conventional MRI at baseline and after a mean follow-up period of 3 years.

Cross-sectionally, two VBM analyses (SPM-VBM, based on the Statistical Parametric Mapping software package, and FSL-VBM, based on the FMRIB Software Library tools) were performed to assess Cortical GM Volumes in RR MS patients compared to 25 age- and sex-matched Normal Controls (NC).

Longitudinally, FSL-VBM and the regional extension of the SIENA method (SIENAr) were both used to assess Regional Brain Atrophy rate in the RR MS patients and its relationship with increases in T₂-weighted White Matter (WM) Lesion Volume over the follow-up period.

Results
Widespread decrease in Cortical GM Volume was found in the RR MS patients compared to NC.

Both SPM-VBM and FSL-VBM showed similar involvement of Cortical Regions (Frontal, Temporal, Parietal, Occipital Lobes and Insula), with a close correlation between the numbers of significant Voxels obtained with the two different procedures (r=0.73, p < 0.001).

After 3-year follow-up, both FSL-VBM and SIENAr showed a further significant reduction in GM Volume in the Lateral Frontal and Parietal Cortices, bilaterally.

Regional Volume changes also appeared significantly pronounced in correspondence to the increase in T₂-weighted WM Lesion Volume over the follow-up period.

Conclusions
By using different methodologies, we showed similar widespread tissue loss in the Cerebral Cortex of patients with RR MS.

This Brain Tissue Loss further progresses over time, particularly in the Fronto-Parietal Cortex and seems to be partially dependent upon the increase of lesion load.

Objective
To determine the relation of Gray Matter (GM) and White Matter (WM) Brain Volumes, and WM lesion load, with clinical outcomes 20 years after first presentation with Clinically Isolated Syndrome suggestive of Multiple Sclerosis (MS).

Methods
Seventy-three patients were studied a mean of 20 years from first presentation with a Clinically Isolated Syndrome

33 of whom developed Relapsing/Remitting MS and 11 Secondary/Progressive MS, with the rest experiencing no further definite Neurological events), together with 25 healthy control subjects.

GM and WM Volumetric measures were obtained from three-dimensional T₁-weighted Brain Magnetic Resonance images using Statistical Parametric Mapping 2.

Results
Significant GM (p < 0.001) and WM Atrophy (p = 0.001) was seen in MS patients compared with control subjects.

There was significantly more GM, but not WM Atrophy, in Secondary/Progressive MS versus Relapsing/Remitting MS (p = 0.003), and Relapsing/Remitting MS versus Clinically Isolated Syndrome (p < 0.001).

GM, but not WM, Fraction correlated with Expanded Disability Status Scale (r(s) = -0.48; p < 0.001) and MS Functional Composite scores (r(s) = 0.59; p < 0.001).

WM lesion load correlated with GM (r(s) = -0.63; p < 0.001), but not with WM Fraction. Regression modeling indicated that the GM Fraction explained more of the variability in clinical measures than did WM lesion load.

Interpretation
In MS patients with a relatively long and homogeneous disease duration, GM Atrophy is more marked than WM Atrophy, and reflects disease subtype and Disability to a greater extent than WM Atrophy or lesions.

Ann Neurol 2008.

Objective
To investigate the medium-term evolution of Gray Matter (GM) damage in patients at presentation with Clinically Isolated Syndrome suggestive of Multiple Sclerosis (MS).

And, to assess whether it is associated with clinical disease activity during the initial stage of MS.

Methods
In 30 patients enrolled within three months from the onset of a Clinically Isolated Syndrome, conventional and Diffusion Tensor MRI scans of the Brain were acquired at baseline and after 3 years.

Percentage Brain Volume Change between baseline and follow-up scans was computed. Histograms of Mean Diffusivity and Fractional Anisotropy for the Normal-Appearing White Matter and Histograms of Mean Diffusivity for the GM were produced.

Results
Mean percentage Brain Volume Change was -1.04 % (p < 0.001 vs. null change).

GM Mean Diffusivity showed an increase at follow-up (p = 0.004), whose magnitude was greater, but not significantly, in patients who relapsed than in those who did not.

There was no correlation between on-study relapse rate and GM Mean Diffusivity changes over time.

Conclusions
In patients with Clinically Isolated Syndrome suggestive of MS, GM damage begins to accumulate during the initial stage of the disease, possibly as a consequence of GM lesion accumulation.

The magnitude of such a damage does not seem to be associated with the concomitant clinical activity.

Background
The presence and degree of Neuronal Degeneration already existing in patients at their initial presentation with a Clinically Isolated Syndrome suggestive of Multiple Sclerosis (CIS) is unclear.

And, Whole Brain or Whole Normalized Gray Matter analyses have not demonstrated significant Atrophy in CIS cohorts at clinical presentation.

Voxel-based analyses allow detection of Regional Atrophy throughout the Brain and therefore, may be sensitive to Regional Atrophy in CIS patients, and these changes may correspond with clinical disability.

Methods
We have used a modified Voxel-Based Morphometry (VBM) method to correct for lesion effects to analyze Regional Atrophy.

And, perform Voxel-wise correlations between volume and clinical metrics in forty-one untreated CIS patients at presentation compared to forty-nine healthy controls.

Results
Our results confirmed that there was no significant difference in Whole Normalized Gray Matter Volume between CIS and controls while VBM showed significant areas of BiLateral Thalamic, Hypothalamic, Putamen, and Caudate Atrophy.

Voxel-wise correlations with clinical measures showed that Cerebellar Volumes correlated with clinical Cerebellar function, Nine-Hole Peg Test scores, and MSFC, and the MSFC was also correlated with Putamen Volume.

Lastly, T₁ lesion volumes were found to correlate with Thalamic and Hippocampal Atrophy suggesting a link between White Matter lesions and Gray Matter degeneration at the earliest stages of Multiple Sclerosis.

Conclusions
Atrophy is present in CIS patients at presentations, particularly in the Thalamus, and other deep Gray Matter structures.

Furthermore, the correlations with clinical metrics suggest the importance of this Atrophy to clinical status and the correlation with T₁ lesion load suggests a possible role of Wallerian Degeneration.

N-AcetylAspartate/Creatine (NAA/Cr) ratios, assessed with Proton Magnetic Resonance Spectroscopy, are increasingly used as a surrogate marker for Axonal Dysfunction and Degeneration in Multiple Sclerosis (MS).

The purpose of this study was to test short-time reproducibility of NAA/Cr ratios in patients with clinically stable MS.

In 35 MS patients we analysed NAA/Cr ratios obtained with (1)H-MR Spectroscopic imaging at the Centrum Semiovale either with Lateral Ventricles partially included (group 1; n=15) or more Cranially with no Ventricles included (group 2; n=20).

To test short-term reproducibility of the NAA/Cr measurements, patients were scanned twice 4 weeks apart.

We determined mean NAA/Cr and Cho/Cr ratios of 12 Gray Matter and 24 White Matter Voxels. Mean NAA/Cr ratios of both the White and Gray Matter did not change after 4 weeks.

Overall 4-week reproducibility of the NAA/Cr ratio, expressed as coefficient of variation, was 4.8% for Gray matter and 3.5% for White Matter.

Reproducibility of Cranial scanning of the Ventricles was slightly better than with CerebroSpinal Fluid included.

Our study shows good short-term reproducibility of NAA/Cr ratio measurements in the Centrum Semiovale, which supports the reliability of this technique for longitudinal studies.

Background
There is growing evidence for the concept of Multiple Sclerosis (MS) as an Inflammatory NeuroDegenerative Disease, with a different pattern of Atrophy evolution in Gray Matter (GM) and White Matter (WM) tissue compartments.

Objective
We aimed to investigate the evolution of different MRI measures in early Relapsing/Remitting patients with MS and in Normal Controls (NCs) over 2 years.

We also evaluated the progression of these MRI measures in a subset of patients who were followed for up to 5 years.

Methods
Included in this study were 147 patients who participated in the combination ASA (Avonex Steroids Azathioprine) study and completed full treatment, clinical and MRI assessment at 0, 12 and 24 months.

A subgroup of 66 patients was followed for 36 months, 51 patients for 48 months and 43 patients for 60 months.

Mean age at baseline was 30.7 years, mean disease duration was 5.5 years, mean EDSS was 1.8 and mean annualised relapse rate before study entry was 1.7.

MRI scans were performed on a 1.5T scanner every 2 months for the first 2 years and thereafter once yearly for up to 5 years.

In addition to the MS group, 27 NCs were examined at months 0, 12 and 24 using the same MRI protocol.

Percentage Brain Volume Change (PBVC), GM Volume (GMV), WM Volume (WMV) and Peripheral Gray Volume (PGV) were measured annually using SIENA/X software.

T₂-HyperIntense lesion volume (LV), Lateral Ventricle Volume (LVV) and Third Ventricle Width (3VW) were also assessed annually.

Results
Over the period of 0-24 months, patients with MS lost significantly more GMV (-2.6% vs -0.72%, p < 0.001), PGV (-2.4% vs -1.03%, p < 0.001) and PBVC (-1.2% vs -0.22%, p < 0.001), and increased in LVV (+16.6% vs +0.55%, p < 0.003) and 3VW (+9.3% vs 0%, p = 0.003), when compared with NCs.

Within-person change in MRI measures for patients with MS over 5 years was -4.2% for PBVC, -6.2% for GMV, -5.8% for PGV, -0.5% for WMV (all p < 0.001), +68.7 for LVV (p < 0.001), +4% for 3VW (p < 0.001) and +42% for T₂-LV (p < 0.001).

Conclusions
Our study confirmed a different pattern of GM, WM and Central Atrophy progression over 2 years between patients with MS and NCs.

The study showed a different evolution of tissue compartment Atrophy measures in patients with MS, with faster decline in Cortical and deep GM regions, as well as PeriVentricular WM regions, over a 5-year period.

Objective
We used Voxel-Based Morphometry (VBM) to assess the pattern of Regional Gray Matter (GM) loss in patients with pediatric Multiple Sclerosis (MS).

And its relation with the Expanded Disability Status Scale (EDSS) score, disease duration, and the extent of T₂ Lesion Load (LL).

Methods
From 28 patients with pediatric Relapsing/Remitting MS (16 girls; mean age = 14.4 years, range = 7 to 16 years) and 21 matched controls, dual-echo and three-dimensional T₁-weighted Magnetization prepared rapid acquisition gradient echo sequences were acquired.

T₂ LL was measured using a local thresholding segmentation technique. Data were analyzed using an optimized VBM analysis and statistical parametric mapping.

Results
In pediatric patients with MS, mean Brain T₂ LL was 7.8 mL +/- 11.3. IntraCranial Volume did not differ between patients and controls.

Compared to controls, patients with pediatric MS had significant GM loss in the Thalamus, bilaterally, which was significantly correlated with T₂ LL (r = -0.80 for the Right Thalamus, r = -0.74 for the left Thalamus, p < 0.05, corrected for multiple comparisons).

No correlation was found between Thalamic GM loss, disease duration, and disability.

Conclusions
In patients with pediatric Multiple Sclerosis (MS), differently from what happens in adult-onset MS, Gray Matter (GM) Atrophy seems to involve the Thalamus only, with sparing of the Cortex and other deep GM Nuclei.

The correlation found between Atrophy and T₂ lesion load suggests TransSynaptic and Wallerian Degeneration as the most likely substrate of tissue loss in the Thalamus of these patients.

To assess Regional Gray Matter (GM) changes in a large cohort of Multiple Sclerosis (MS) patients with different clinical phenotypes, using Voxel-Based Morphometry (VBM) and their correlation with the extent of global and Regional T₂ Lesion Volumes (LV).

We acquired conventional MRI scans from 71 MS patients with different clinical phenotypes:
1. 26 with Relapsing/Remitting [RR] MS,
2. 27 with Secondary/Progressive [SP] MS and
3. 18 with Primary/Progressive [PP] MS),
4. 28 patients with a Clinically Isolated Syndrome (CIS) suggestive of MS, and
5. 21 controls

No GM loss was found in CIS patients.

Compared to CIS patients, those with RRMS had a significant GM loss in the Right Pre and PostCentral Gyri.

Compared to RRMS, SPMS patients had a significant GM loss in several regions of the Fronto-Parieto-Temporo-Occipital Lobes, the Cerebellum and Superior and Inferior Colliculus, bilaterally, and deep GM structures.

Compared to PPMS, SPMS patients had a significant GM loss in the Postcentral Gyrus, the Cuneus, the Middle Occipital Gyrus, the Thalamus, the Cerebellum, and the Superior and Inferior Colliculi.

In all MS groups, regional GM loss was strongly/moderately correlated with Brain T₂ LV.

In SPMS and PPMS patients, a correlation was found between Cortical regional GM loss and T₂ LV of the corresponding or adjacent lobes.

In MS patients, GM Volume Loss follows different patterns of regional distribution according to the clinical phenotype of the disease.

It is likely secondary to the presence and topography of focal WM Inflammatory-DeMyelinating lesions, and is more evident in the Progressive forms of the disease.

Background
NeuroAxonal Loss is a pathological substrate of disability in Progressive Multiple Sclerosis (MS) and can be estimated in vivo by measuring tissue Atrophy on Magnetic Resonance Imaging (MRI).

While there is some evidence that Brain Atrophy correlates better with disability than T₂ lesion load in Secondary/Progressive MS, the clinical relevance of Atrophy within specific regions of the Central Nervous System requires further evaluation.

Methods
Clinical and MRI examinations were performed in 117 subjects with Secondary/Progressive MS.

MRI analysis included measures of Normalized Brain Volume (NBV), Normalized Gray Matter (NGMV) and White Matter Volume (NWMV), Central Cerebral Volume (CCV), Spinal Cord Cross-Sectional Area (SCCA), and Brain T₂ and T₁ lesion volume.

Clinical assessments included the Expanded Disability Status Scale (EDSS) and MS Functional Composite (MSFC).

Results
All MRI measures correlated significantly with the MSFC score, with the strongest correlation being for the NBV (r = 0.47; P < 0.001).

NBV and SCCA were the only significant independent predictors of the MSFC score in a stepwise regression model containing all the MRI measures, and SCCA was the only MRI measure to show a significant association with the EDSS.

While NGMV had stronger correlations with the clinical variables than NWMV, NBV was more correlated with clinical impairment than either measure.

Conclusions
This data suggests that measures of Atrophy, particularly of the Whole Brain and Spinal Cord, are relevant and useful disease markers in Secondary/Progressive MS.

Multiple Sclerosis (MS) is an inflammatory disease of the Central Nervous System, predominantly, but not exclusively, involving the Normal-Appearing White Matter.

Until very recently we believed that nervous dysfunction in MS was completely depending on the accumulation of lesions in the White Matter of the CNS.

As a consequence, lesions seen by Magnetic Resonance Imaging (MRI) have been considered a potential surrogate end point in clinical trials assessing new MS treatments.

More recently, this concept have been challenged by the emerging evidences, mostly from pathological and MRI studies, that lesions may be located also in Gray Matter and that the White and Gray Matter not affected by lesions is abnormal.

The causes of this Normal-Appearing Gray and White Matter damage are still debated and there is the possibility that such damage is largely independent from the lesions.

There are accumulating evidences that the pathogenetic mechanisms in MS may differ in the early and in the late phases of the disease.

Early MS is associated with recruitment of systemically derived Immune Cell populations and inflammatory lesions. Late MS results characterized by a predominantly compartimentalized Immunological Response.

These recent modifications on our views of the MS pathogenesis and pathophysiology do have major implications on the therapeutic strategies, including the use of treatments aiming to enhance the recovery, such as Stem Cell therapy.

Objective
To determine Gray Matter (GM) Atrophy rates in Multiple Sclerosis (MS) patients at all stages of disease, and to identify predictors and clinical correlates of GM Atrophy.

Methods
MS patients and healthy control subjects were observed over 4 years with standardized Magnetic Resonance Imaging (MRI) and Neurological Examinations.

Whole-Brain, GM, and White Matter Atrophy rates were calculated.

Subjects were categorized by disease status and disability progression to determine the clinical significance of Atrophy. MRI predictors of Atrophy were determined through multiple regression.

Results
Subjects included 17 healthy control subjects, 7 patients with Clinically Isolated Syndromes, 36 patients with Relapsing/Remitting MS (RRMS), and 27 patients with Secondary/Progressive MS (SPMS).

Expressed as fold increase from control subjects, GM Atrophy rate increased with disease stage, from 3.4-fold normal in Clinically Isolated Syndromes patients converting to RRMS to 14-fold normal in SPMS.

In contrast, White Matter Atrophy rates were constant across all MS disease stages at approximately 3-fold normal.

GM Atrophy correlated with disability.

MRI measures of focal and diffuse tissue damage accounted for 62% of the variance in GM Atrophy in RRMS, but there were no significant predictors of GM Atrophy in SPMS.

Interpretation
Gray Matter tissue damage dominates the pathological process as MS progresses, and underlies Neurological disabillity.

Imaging correlates of Gray Matter Atrophy indicate that mechanisms differ in RRMS and SPMS.

These findings demonstrate the clinical relevance of Gray Matter Atrophy in MS, and underscore the need to understand its causes.

Ann Neurol 2008.

Multiple Sclerosis (MS) has been classically regarded as a White Matter disease. However, recent HistoPathological studies have convincingly shown that Gray Matter regions are also heavily affected.

Gray Matter damage starts early in the disease and substantially affects Clinico-Cognitive functioning.

Detection of Cortical Gray Matter lesions by use of standard MRI techniques has proved challenging, and more advanced techniques are needed. At present, the causes of Gray Matter damage are unclear.

We review several exciting new hypotheses on Gray Matter pathogenesis, including Meningeal inflammation as a cause of SubPial Cortical Damage.

But also selective vulnerability of Neuronal subpopulations, Growth Factor dysregulation, Glutamate ExcitoToxicity, Mitochondrial abnormalities, and the "use-it-and-lose-it" principle.

These hypotheses remain to be validated over the coming years, and could substantially affect our current views on MS pathogenesis.