MS Abstracts 02b-2g4

Objective
To determine the effect of Donepezil in treating Memory and Cognitive Dysfunction in Multiple Sclerosis (MS).

Methods
This single-center double-blind placebo-controlled clinical trial evaluated 69 MS patients with Cognitive Impairment who were randomly assigned to receive a 24-week treatment course of either Donepezil (10 mg daily) or placebo.

Patients underwent NeuroPsychological assessment at baseline and after 24 weeks of treatment. The primary outcome was change in Verbal Learning and Memory on the Selective Reminding Test (SRT).

Secondary outcomes included other tests of Cognitive function, patient-reported change in Memory, and clinician-reported impression of Cognitive change.

Results
Donepezil-treated patients showed significant improvement in Memory performance on the SRT compared to placebo (p = 0.043).

The benefit of Donepezil remained significant after controlling for various covariates including age, Expanded Disability Status Scale, baseline SRT score, reading ability, MS subtype, and sex.

Donepezil-treated patients did not show significant improvements on other Cognitive tests, but were more than twice as likely to report Memory improvement than those in the placebo group (p = 0.006).

The clinician also reported Cognitive improvement in almost twice as many Donepezil vs placebo patients (p = 0.036).

No serious adverse events related to study medication occurred, although more Donepezil (34.3%) than placebo (8.8%) subjects reported unusual/abnormal dreams (p = 0.010).

Conclusions
Donepezil improved Memory in MS patients with initial Cognitive Impairment in a single center clinical trial.

A larger multicenter investigation of Donepezil in MS is warranted in order to more definitively assess the efficacy of this intervention.

Background
Long-term follow-up of the Optic Neuritis Treatment Trial (ONTT) cohort to evaluate Brain Magnetic Resonance Imaging (MRI) in patients who have not developed Clinically Definite Multiple Sclerosis.

Objective
To determine the proportion of patients with MonoSymptomatic Optic Neuritis who manifest new Brain MRI lesions without having developed Clinically Definite Multiple Sclerosis 10 to 14 years after enrollment in the ONTT.

Design, Setting & Participants
Observational study, fourteen clinical centers. One hundred eight ONTT patients who had not developed Clinically Definite Multiple Sclerosis 10 to 14 years after study enrollment.

Main Outcome Measure
Development of new T₂ lesions on follow-up Brain MRI.

Results
At least 1 T₂ lesion 3 mm or larger was observed on follow-up MRIs in 27 (44%) of 61 patients with normal baseline MRIs. Additional lesions (> or =3 mm) were present on follow-up MRIs in 26 (74%) of 35 patients with abnormal baseline MRIs.

Conclusions
A subset of patients with MonoSymptomatic Optic Neuritis manifest neither clinical signs nor MRI evidence of DeMyelination after more than 10 years of follow-up.

In other cases followed up for this length of time, MRI signal abnormalities may accumulate without causing new clinical manifestations of Multiple Sclerosis. This information is useful in counseling patients who develop first-episode Optic Neuritis.

Background & Purpose
In contrast to "Normal-Appearing" White Matter (NAWM) in patients with Multiple Sclerosis (MS), there are subtle, abnormal and diffuse signal intensity changes often seen on T₂-weighted MR images, which we have referred to as "Dirty-Appearing" White Matter (DAWM).

These areas of DAWM have slightly higher signal intensity than that of NAWM, but lower than that of lesion plaques. Our study was designed to determine the volumetric and Magnetization Transfer Ratio (MTR) features of DAWM in patients with MS.

Methods
Dual-Echo Fast Spin-Echo MR imaging and Magnetization Transfer imaging were performed in 22 patients with Relapsing/Remitting MS.

Slightly HyperIntense DAWM areas were manually outlined on the basis of T₂-weighted imaging findings. The volume and MTR of DAWM were calculated and compared with the volume and MTR of NAWM and T₂ lesion plaques.

Results
The average volume of DAWM (18.3 mL) was greater than the average volume of T₂ lesion plaques (11.0 mL, P =.04), and the mean MTR in DAWM (38.7%) differed significantly (P < .0001) from that in NAWM (40.7%) and plaques (33.3%).

There was a modest negative correlation between either mean MTR (r = -0.60; P =.003) of DAWM or peak height (r = -0.50; P =.02) of DAWM with T₂ lesion load.

Neither DAWM volume nor total T₂ abnormality (DAWM + plaques) volume correlates with the Expanded Disability Status Scale.

Conclusion
The results of this study indicate that MTR is able to differentiate DAWM from lesion plaques and NAWM and that DAWM might be a different pathologic process of the disease.

The notion and quantification of these subtle imaging findings of DAWM areas may improve our understanding of certain stages of disease progression and disease burden in patients with Relapsing/Remitting MS.

Cortical Gray Matter (cGM) develops a substantial burden of pathology in Multiple Sclerosis (MS). Previous cross-sectional studies have suggested a relationship between measures of Cortical Atrophy and Disability.

Our objective was to develop a method for automatically measuring the apparent cGM thickness as well as the integrity of the interface between cGM and SubCortical White Matter (GM/WM) both globally and regionally on T₁-weighted MRI.

And use this method in a longitudinal investigation of how these measures differed between patients with stable MS and patients with progressing disability.

Measurements were made over the whole Brain and for anatomically specified Cortical regions, both cross-sectionally at baseline and longitudinally on two MRI scans performed on average 1 year apart.

We found a higher average rate of apparent loss of cGM thickness across the whole Brain in the group that progressed over the interscan interval compared to the group that remained stable (progressing = -3.13 +/- 2.88%/year, stable = 0.06 +/- 2.31%/year, P = 0.002).

This difference was detected with regional measures in Parietal and PreCentral Cortex.

In contrast, change in the GM/WM interface integrity did not show detectable regional differences, although the group of MS patients whose disability progressed showed a significant decrease in GM/WM interface integrity compared to the stable group (P = 0.003).

Regional measures of apparent loss of cGM thickness enhance sensitivity to Cortical pathological changes. A measure of integrity offers a new index of disease-associated Cortical changes at the GM/WM interface.

The results suggest that progression of disability in MS is associated with the progression of MRI-detectable Cortical pathology.

This paper reports a study that was aimed to evaluate Executive Functions in Relapsing/Remitting Multiple Sclerosis patients.

The groups tested comprised 22 Relapsing/Remitting Multiple Sclerosis patients, and 22 Non-Brain damaged controls.

When one is engaged in two speeded tasks, not simultaneously but with some form of alternation, it is slower to respond to an item of task A if it was preceded by an item of task B, than when it was preceded by an item of task A.

Shifts between sets of Cognitive operations can be internally or externally generated. Endogenous task shift refers to advance preparation for the new task.

In the present study, we tested endogenous shift cost in Relapsing/Remitting Multiple Sclerosis patients. The results indicate a greater shift cost for patients than for Non-Brain damaged controls.

Multiple Sclerosis is an Inflammatory Disease of the CNS leading to the destruction of Oligodendrocytes (OLs), Myelin Sheaths and Axons. The mediators of tissue injury remain unknown.

Glutamate, which can be released by activated Immune Cells or produced within the CNS, has been implicated as a potential mediator of tissue injury in Multiple Sclerosis.

alpha-Amino-3-Hydroxy-5-Methyl-4- Isoxazole Proprionic Acid (AMPA) and Kainate are highly toxic when added to rodent OL cultures.

Using OLs derived from human adult surgical specimens, we investigated AMPA/Kainate Receptor expression and the effects of Receptor stimulation on the viability of human OLs.

We find that human adult OLs in vitro express low levels of Ionotropic Glutamate Receptors and are resistant to ExcitoToxicity mediated by high and sustained doses of AMPA or kainate, even when Receptor desensitization is blocked.

In contrast, rat OLs show strong AMPA receptor expression and are susceptible to ExcitoToxicity, as previously demonstrated.

Furthermore, we show in human Brain sections that OLs do not express AMPA receptors in situ and that Glial expression of AMPA Receptors is limited to Astrocytes.

The apparent lack of Glutamate Receptor expression on human OLs and their resistance to AMPA/Kainate Toxicity should be considered when postulating mechanisms of tissue injury in Multiple Sclerosis.

Objective
To investigate the relationship of CSF and the Serum Nitric Oxide metabolites Nitrite and Nitrate (NOx) to disease activity and progression in patients with Multiple Sclerosis (MS).

Methods
The study was divided into cross-sectional and follow-up. In the cross-sectional study, 20 patients with Relapsing/Remitting (RR), 21 with Secondary/Progressive (SP), and 10 with Primary/Progressive (PP) MS and 14 control subjects were included.

Patients were assessed on clinical (Expanded Disability Status Scale [EDSS], Ambulation Index [AI], 9-Hole Peg Test [9-HPT]) and MRI measurements.

In the follow-up study, 34 MS patients from the cross-sectional study agreed to be assessed again after an average of 3.0 +/- 0.5 years. NOx was measured using a vanadium-based assay.

Results
In the cross-sectional study, CSF NOx was raised in patients with RR-MS (p = 0.001) and PP-MS (p = 0.02) vs controls.

Higher CSF NOx levels were found in patients with mild disability (AI < or = 6.0; EDSS < or = 4.0; Multiple Sclerosis Severity Score [MSSS] < or = 4.8) vs patients with advanced disease (AI > 6.0 [p = 0.002]; EDSS > 4.0 [p = 0.02]; MSSS > 4.8 [p = 0.01]).

In the subgroup of patients having Gd-enhancing MRI lesions (n = 11), correlation between the volume of enhancement and CSF NOx was found (r = 0.74, p = 0.01).

In the follow-up study, patients with disability progression had higher baseline CSF NOx levels than those who were stable on EDSS (p = 0.02) or AI (p = 0.03). A positive correlation was found between baseline CSF NOx and the change in MR T₂-weighted lesion load (r = 0.4, p = 0.03).

Conclusions
CSF Nitrite and Nitrate levels were increased in mildly disabled patients with MS and found to correlate with the volume of Gd-enhanced lesions on MRI.

Raised baseline CSF NOx was associated with clinical and MRI progression in MS patients over 3-year follow-up.

We examined whether treatment with Daclizumab, a humanized Monoclonal Antibody specific for the InterLeukin-2 Receptor alpha chain, was safe and efficacious in Relapsing/Remitting and Secondary/Progressive Multiple Sclerosis patients.

Nineteen ambulatory patients with clinically active disease were treated for 5 to 25 months. Seventeen patients were not responding to other immunotherapies.

Daclizumab was generally well tolerated. Sustained clinical improvement (10 patients) or stabilization (9 patients) was observed. Daclizumab treatment produced significant reduction in Magnetic Resonance Imaging activity.

Ann Neurol 2004.

Background
In patients who present with Clinically Isolated Syndromes suggestive of Multiple Sclerosis, Interferon-ß-1a is effective in delaying evolution to clinically definite disease and in reducing MRI-measured disease activity.

We aimed to assess whether this drug can also reduce the rate of Brain Volume decrease in such patients enrolled in the ETOMS (Early Treatment Of Multiple Sclerosis) trial.

Methods
MRI data for Brain Volume measurements at baseline, month 12, and month 24 were available from 131, 111, and 112 patients assigned treatment (22 microg Interferon-ß-1a), and 132, 98, and 99 patients assigned placebo respectively.

Normalized Brain Parenchymal Volume (NBV) at baseline and percentage Brain Volume changes (PBVC) were measured with a fully-automated segmentation technique.

The primary endpoint was conversion to Clinically Definite Multiple Sclerosis due to clinical relapse. Analysis was by intention to treat.

Findings
41 (31%) of 131 patients on Interferon-ß-1a and 62 (47%) of 132 on placebo converted to Clinically Definite Multiple Sclerosis (odds ratio 0.52 [95% CI 0.31-0.86], p=0.0115).

Mean PBVC for patients on placebo was -0.83% during the first year, -0.67% during the second year, and -1.68% during the entire study period.

Respective values for treated patients were -0.62%, -0.61%, and -1.18%. The changes in Brain Volume were significant in both groups at all timepoints.

A significant treatment effect was detected for month 24 versus baseline values (p=0.0031). The number of new T₂ lesions formed during the first year correlated weakly with PBVC during the second year.

Interpretation
Early treatment with Interferon-ß-1a is effective in reducing conversion to Clinically Definite Multiple Sclerosis and in slowing progressive loss of Brain Tissue in patients with Clinically Isolated Syndromes.

The modest correlation between new lesion formation and Brain Volume decrease suggests that Inflammatory and NeuroDegenerative processes are, at least partly, dissociated from the earliest clinical stage of Multiple Sclerosis onwards.

Purpose
To determine whether voxel-based analysis of Magnetization Transfer Ratio (MTR) maps can provide evidence of a coherent pattern of Gray Matter (GM) macroscopic and microscopic tissue damage in patients at the earliest stage of Multiple Sclerosis (MS).

Materials And Methods
We acquired GM MTR maps in 18 patients with Clinically Isolated Syndrome Suggestive of MS (CISSMS), and 18 sex- and age-matched healthy controls.

We evaluated the clinical status of the patients using the MS Functional Composite Score and the Expanded Disability Status Scale.

A two-sample t-test (P < 0.0001, k=20, uncorrected for height threshold) was used to compare GM MTR maps from patients and controls on a voxel-by-voxel basis.

We then extracted data from regions with t-values above the statistical threshold to verify the significance of differences using a nonparametric Mann-Whitney U-test.

Results
A between-groups comparison of GM maps revealed large abnormalities in the Basal Ganglia, including the BiLateral Thalamus, BiLateral Lenticular Nucleus, BiLateral Head of Caudate, and protuberance, and smaller abnormalities in the Right Insula, Right BA 4, and Left BA 40.

The MTR measured in the Left Caudate and Right Insula was inversely correlated with duration following the first clinical event.

Conclusion
These results suggest that although MS is a multifocal DeMyelinating Disease that affects White Matter (WM), a pattern of tissue damage is present inside the GM involving predominantly Basal Ganglia at the earliest stage of the disease.

Objectives
To establish whether Magnetization Transfer Ratio (MTR) Histograms are sensitive to change in Normal-Appearing Gray Matter (NAGM) in early Relapsing/Remitting Multiple Sclerosis (RRMS) in the absence of significant Disability.

And to assess whether Gray or White Matter MTR measures are associated with clinical measures of impairment in early RRMS.

Methods
38 patients were studied (mean disease duration 1.9 years (range 0.5 to 3.7); median Expanded Disability Status Scale (EDSS) 1.5 (0 to 3)), along with 35 healthy controls.

MTR was determined from Proton Density weighted images with and without MT presaturation. SPM99 was used to generate Normal-Appearing White Matter (NAWM) and NAGM segments of the MTR map, and partial voxels were minimised with a 10 pu threshold and voxel erosions.

Mean MTR was calculated from the tissue segments. Atrophy measures were determined using a 3D fast spoiled gradient recall sequence from 37 patients and 17 controls.

Results
Mean NAGM and NAWM MTR were both reduced in early RRMS (NAGM MTR: 31.9 pu in patients v 32.2 pu in controls; p< 0.001; NAWM MTR: 37.9 v 38.3 pu, p = 0.001).

Brain Parenchymal Fraction (BPF) correlated with NAGM MTR, but when BPF was included as a covariate NAGM MTR was still lower in the patients (p = 0.009). EDSS correlated with NAGM MTR (r = 0.446 p = 0.005).

Conclusions
In early RRMS, Gray Matter MTR abnormality is apparent. The correlation with mild clinical impairment (in this essentially non-disabled cohort) suggests that NAGM MTR could be a clinically relevant surrogate marker in therapeutic trials.

Purpose
The purpose of this work was to determine the extent of disease and disease severity in the conventional MR Normal-Appearing Gray Matter (NAGM) and Normal-Appearing White Matter (NAWM).

In patients with Relapsing/Remitting (RR) and Secondary/Progressive (SP) Multiple Sclerosis (MS) utilizing quantitative Magnetization Transfer Ratio (MTR) Histogram analysis.

Method
Twenty-seven patients with MS (16 RR, 11 SP) and 16 healthy control subjects were studied. MTR was calculated in the totally segmented GM and WM without T₂ lesions in each group.

Results
Each of the RR and SP MS patient groups had significantly smaller MTR Histogram mean values in NAGM and NAWM than the healthy subjects (p < /= 0.0015).

SP MS patients had a significantly lower first quartile and MTR Histogram peak height for NAGM only (p < /= 0.004) when compared with both RR MS patients and healthy subjects.

The T₂ lesion load had a modest negative correlation with MTR values in both RR and SP MS, but only in NAGM.

Conclusion
Separate analysis of GM and WM MTR Histograms may allow better detection of subtle damage and better understanding of the natural history of MS disease and ultimately the response to therapeutics.