MS Abstracts 01b-2g7

Objective
To investigate the effect of APOE epsilon4 on different Cognitive domains in a population of Greek patients with Multiple Sclerosis (MS).

Methods
A total of 125 patients with MS and 43 controls were included in this study and underwent NeuroPsychological assessment with Rao's Brief Repeatable Battery.

All patients with MS were genotyped for APOE. The effect of APOE epsilon4 on different Cognitive domains was investigated.

Results
Fifty-one percent of patients with MS were Cognitively Impaired. E4 carriers had a sixfold increase in the relative risk of impairment in Verbal Learning vs noncarriers (OR 6.28, 95% CI 1.74 to 22.69).

This effect was domain-specific and was not observed in other Cognitive domains assessed by the battery.

Conclusion
We found an association of APOE epsilon4 with impaired Verbal Learning in patients with Multiple Sclerosis.

We investigated the influence of age at disease onset on timing of the Progressive phase in 957 patients with Multiple Sclerosis (MS).

Age at onset powerfully predicts the probability of developing a Primary/Progressive form of the disease. Moreover, age at onset strongly determines the time to conversion to secondary progression for patients presenting with a Relapsing form.

This suggests that age at onset strongly influences the NeuroDegenerative component of MS.

Objective
To study the use of Auditory feedback for gait management and rehabilitation in patients with Multiple Sclerosis (MS).

Methods
An auditory feedback cue, responding to the patient's own steps in closed-loop, was produced by a wearable motion sensor and delivered to the patient through ear phones.

On-line (device on) and residual short-term therapeutic effects on walking speed and stride length were measured in fourteen randomly selected patients with gait disturbances predominantly due to Cerebellar Ataxia.

Results
Patients showed an average improvement of 12.84% on-line and 18.75% residually in walking speed.

Average improvement in stride length was 8.30% on-line and 9.93% residually. The improvement results are particularly noteworthy when compared with the lack of change in healthy control subjects.

Conclusions
Patients with MS using Auditory feedback cues showed improvement in walking abilities

A number of factors more or less unique to Multiple Sclerosis have suggested that this disease may be particularly amenable to cell-based reparative therapies.

The relatively focussed damage to Oligodendrocytes and Myelin at least in early disease implies that only a single population of cells need be replaced-and that the daunting problem of re-establishing connectivity does not apply.

The presence of significant though partial spontaneous Myelin repair in Multiple Sclerosis proves there to be no insurmountable barrier to ReMyelination intrinsic to the CNS:

The therapeutic challenge becomes that of supplementing this spontaneous process, rather than creating repair de novo.

Finally, the large body of available knowledge concerning the biology of Oligodendrocytes, and the success of experimental Myelin repair, have allowed cautious optimism that future prospects for such therapies are not unrealistic.

Nonetheless, particular and significant problems are not hard to list: the occurrence of innumerable lesions scattered throughout the CNS, Axon Loss, Astrocytosis, and a continuing inflammatory process, to name but a few.

Here we review the progress and the areas where difficulties have yet to be resolved in efforts to develop ReMyelinating therapies for Multiple Sclerosis.

MRI is extremely sensitive for detecting new inflammatory activity in the Central Nervous System of patients with Multiple Sclerosis (MS) that is often clinically silent.

Each new lesion often leaves a permanent MS plaque, which is composed of varying degrees of DeMyelination, Axonal Loss, and Gliosis.

New large lesions have a greater risk of evolving into permanent T₁-weighted HypoIntense lesions (Black Holes) that pathologically contain the greatest Axonal Loss.

And, correlate more strongly with clinical disability than with overall lesion load on T₂-weighted images.

There is also an association between the severity of the total T₂ lesion burden with Cerebral Atrophy.

And, with diffuse changes in the Normal-Appearing Brain Tissue as determined by Magnetization Transfer Imaging and Magnetic Resonance Spectroscopy.

To maintain normal clinical functioning, the Brain may compensate by recruiting increased regions of Cortex, as demonstrated by functional MRI (fMRI) studies.

The degree of increased fMRI activation is proportional to the severity of T₂ lesion load, up to a critical limit at which it appears that these compensatory mechanisms may fail.

Therefore, new inflammatory activity, as detected by MRI, carries a risk of significant early pathologic damage and delayed yet permanent clinical disability.

Purpose
To prospectively investigate whether T₁ changes in Normal-Appearing White Matter (WM) and Normal-Appearing Gray Matter (GM) in Multiple Sclerosis (MS) are global or regional and their relationship to disease type.

Materials And Methods
The institutional ethics review board approved study; written informed consent was obtained.

Whole-Brain T₁ maps were obtained in 67 patients with MS and 24 healthy control subjects with three-dimensional fast low-angle shot flip angle-array method, with correction for B(1) imperfections.

Analysis of variance was performed on T₁ Histogram parameters of global Normal-Appearing WM and GM. Regional mean T₁ values were analyzed with a multilevel approach.

Multiple linear regression analysis was performed to investigate associations with clinical disability and overall Atrophy. For patients, T₂ lesion load was determined.

Results
T₁ Histograms of Normal-Appearing WM had significantly higher peak positions for patients with MS (792 msec +/- 36 in Secondary/Progressive [SP] MS) than for control subjects (746 msec +/- 23) and were significantly broader and lower (all P < .001).

Histograms for Cortical Normal-Appearing GM were significantly shifted (peak positions, 1263 msec +/- 44 in control subjects and 1355 msec +/- 62 in patients with SP MS) (P < .001).

Histogram peak positions were significantly higher in SP MS than in Relapsing/Remitting (RR) and Primary/Progressive MS (P < .05). In SP disease, at least 31% of Normal-Appearing WM and 20% of Cortical Normal-Appearing GM were affected.

In MS, T₁ was significantly elevated in all Normal-Appearing WM and Cortical Normal-Appearing GM regions (all P < .01) but was elevated only in the Thalamus in deep GM (P < .05).

Cortical T₁ Histogram peak position was associated with clinical disability; T2 lesion load was not.

Conclusion
Results suggest that a global disease process affects large parts of both Normal-Appearing WM and GM in MS and effects are worse for SP MS than for RR MS.

(c) RSNA, 2006.

Background And Purpose
Disease activity in Normal-Appearing White Matter (NAWM) in Multiple Sclerosis (MS) has been demonstrated in vivo with T₁ relaxation time measurements.

We aimed to investigate the spatial distribution of T₁ increases in MS NAWM without a priori selection of specific regions.

Methods
Whole-Brain quantitative T₁ maps were measured in 67 patients with one of the 3 main clinical types of MS (13 Primary/Progressive [PP], 36 Relapsing/Remitting [RR], and 18 Secondary/Progressive [SP]) and in 23 healthy control subjects.

After registration to standard space and segmentation of NAWM, the maps were analyzed by using Voxel-based analyses with a cluster-based corrected P threshold of .05.

Results
Group mean T₁ relaxation times throughout NAWM increased when going from control subjects to PPMS to RR to SP MS.

In the RR and SP MS groups, the T₁ increases compared with control subjects were significant throughout the NAWM, without apparent preference for specific Brain regions.

In RR MS, 16% of NAWM voxels displayed a significant increase in T₁ compared with control subjects, and in SP, this fraction was 49%.

The comparison between RR MS and the subsequent phase SP MS revealed that, in these patients, disease progression occurs throughout the NAWM.

In patients with PP MS, the spatial extent of significant T₁ increases is limited. There were no correlations with clinical disability scales or Brain Volume in a substantial fraction of voxels.

Conclusion
This study demonstrates that in patients with RR MS and SP MS, NAWM disease processes have no regional preferences but can occur throughout the Brain.

Background/Purpose
Gray Matter involvement in Multiple Sclerosis (MS) is of growing interest with respect to disease pathogenesis.

Magnetization Transfer Imaging (MTI), an advanced MRI technique, is sensitive to disease in Normal-Appearing White Matter (NAWM) in patients with MS.

Design/Methods
We tested if MTI detected SubCortical (deep) Gray Matter abnormalities in patients with MS (n= 60) vs age-matched normal controls (NL, n= 20).

Magnetization Transfer Ratio (MTR) maps were produced from axial proton density, conventional spin-echo, 5 mm gapless slices covering the Whole Brain.

Region-of-interest-derived MTR Histograms for the Caudate, Putamen, Globus Pallidus, Thalamus, and NAWM were obtained. Whole Brain MTR was also measured.

Results
Mean whole brain MTR and the peak position of the NAWM MTR Histogram were lower in patients with MS than NL (P < .001) and mean Whole Brain MTR was lower in Secondary/Progressive (SP, n= 10) than Relapsing/Remitting (RR, n= 50, P < .001) patients.

However, none of the SubCortical Gray Matter Nuclei showed MTR differences in MS vs. NL, RR vs. SP, or SP vs. NL.

Conclusions
The MTI technique used in this cohort was relatively insensitive to disease in the deep Gray Matter Nuclei despite showing sensitivity for Whole Brain disease in MS.

It remains to be determined if other MRI techniques are more sensitive than MTI for detecting pathology in these areas.

Objective
To investigate whether patients with early Primary/Progressive Multiple Sclerosis show changes in T₁ relaxation time (T₁-RT) in Normal-Appearing White Matter (NAWM) and Normal-Appearing Gray Matter (NAGM) during 2 years and whether T₁-RT at baseline predicts disability.

Methods
Twenty-one patients and 12 control subjects were studied at baseline and after 2 years. Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) scores were assessed.

T₁ relaxation time Histograms of NAWM and NAGM were obtained in all subjects, and mean, peak height, and peak location of the Histograms were measured.

Paired t tests were used to compare baseline and 2-year histogram values in patients and control subjects.

To investigate whether T₁-RT predicted clinical changes, multiple linear regression analysis was used.

Patients showed increases in NAWM and NAGM T₁-RT mean and peak location during follow-up, and significant decreases in NAWM and NAGM peak height.

Baseline NAWM T₁-RT mean values and peak height predicted disability at 2 years, as measured with the Multiple Sclerosis Functional Composite score.

Conclusion
T₁ relaxometry is a good marker of disease progression and has prognostic potential in Primary/Progressive Multiple Sclerosis.

Background And Objective
Observational studies may provide additional information about the behavior of different drugs in the post-marketing period.

We present the data from a cohort of Secondary/Progressive Multiple Sclerosis (SPMS) patients treated with Interferon-beta-1b (IFN-ß-1b) at our MS clinic.

Methods
This was an independent, open-label, non-randomized, observational study.

Within the period 1998 to 2005, all patients with SPMS who started therapy with IFN-ß-1b at our center were studied.

Each patient was included in a follow-up protocol collecting demographic and baseline clinical data.

Results
We studied 146 SPMS patients with a median follow-up of 60 months. Over the total study period, 62.2% of patients had confirmed progression.

The analysis of the time to confirmed progression showed that patients with two or more relapses in the 2 years before IFN-ß-1b initiation, had a higher risk of disability increase than those patients with less than two relapses (p = 0.002).

Multiple regression analysis showed disease activity in terms of relapses as the only factor to predict increase of disability during the follow-up period.

A significant proportion of patients (36%) stopped treatment during the follow-up period. IFN-ß-1b was safe, although some unexpected adverse events were observed.

Conclusions
A higher disease activity before the beginning of treatment with IFN-ß-1b in SPMS patients with a given EDSS rank could identify those with faster disability progression after treatment initiation.

Introduction
Increasing evidence suggests relevant Cortical Gray Matter pathology in patients with Multiple Sclerosis (MS).

But how early this pathology begins; its impact on clinical disability and which Cortical areas are primarily affected needs to be further elucidated.

Methods
115 consecutive patients (10 Clinically Isolated Syndrome (CIS), 32 possible MS (p-MS), 42 Relapsing/Remitting MS (RR-MS), 31 Secondary/Progressive MS (SP-MS)), and 40 age/gender-matched Healthy Volunteers (HV) underwent a Neurological Examination and a 1.5 T MRI.

Global and regional Cortical Thickness (CTh) measurements, Brain Parenchymal Fraction and T₂ lesion load were analyzed.

Results
We found a significant global Cortical thinning in p-MS (2.22 +/- 0.09 mm), RR-MS (2.16 +/- 0.10 mm) and SP-MS (1.98 +/- 0.11 mm) compared to CIS (2.51 +/- 0.11 mm) and HV (2.48 +/- 0.08 mm).

The correlations between mean CTh and White Matter (WM) lesion load was only moderate in MS (r = -0.393, p = 0.03) and absent in p-MS (r = -0.147, p = 0.422).

Analysis of regional CTh revealed that the majority of Cortical areas were involved not only in MS, but also in p-MS.

The type of clinical picture at onset (in particular, Pyramidal Signs/Symptoms and Optic Neuritis) correlated with Atrophy in the corresponding Cortical areas.

Discussion
Cortical thinning is a diffuse and early phenomenon in MS already detectable at clinical onset. It correlates with clinical disability and is partially independent from WM inflammatory pathology.

In Multiple Sclerosis (MS), Oligodendrocyte and Myelin destruction lead to DeMyelination with subsequent Axonal Loss.

Experimental DeMyelination in rodents has highlighted the activation of the SubVentricular zone (SVZ) and the involvement of Progenitor Cells expressing the polysialylated form of Neural Cell Adhesion Molecule (PSA-NCAM) in the repair process.

In this article, we studied the distribution of early PSA-NCAM⁺ Progenitors in the SVZ and MS lesions in human postmortem Brains.

Compared with controls, MS SVZ showed a 2- to 3-fold increase in cell density and proliferation, which correlated with enhanced numbers of PSA-NCAM⁺ and Glial Fibrillary Acidic Protein-Positive (GFAP⁺) cells.

PSA-NCAM⁺ Progenitors mainly were Sox9⁺, and a few expressed Sox10 and Olig2, markers of Oligodendroglial specification.

PSA-NCAM⁺ Progenitors expressing Sox10 and Olig2 also were detected in DeMyelinated MS lesions.

In active and chronic active lesions, the number of PSA-NCAM⁺ progenitors was 8-fold higher compared with chronic silent lesions, shadow plaques, and Normal-Appearing White Matter.

In active and chronic active lesions, PSA-NCAM⁺ progenitors were more frequent in PeriVentricular lesions (30-50%) than in lesions remote from the Ventricular wall.

These data indicate that, as in rodents, activation of Gliogenesis in the SVZ occurs in MS and suggest the mobilization of SVZ-derived early Glial Progenitors to PeriVentricular lesions, where they could give rise to Oligodendrocyte Precursors.

These early Glial Progenitors could be a potential target for therapeutic strategies designed to promote Myelin repair in MS.