MS Abstracts 04a-2g7

Cognitive deficits in Multiple Sclerosis (MS) are common and correlate with contemporary MRI Brain abnormalities, particularly Atrophy.

But, the ability of imaging early in the disease to predict later Cognitive Impairment remains to be determined.

Thirty Relapsing/Remitting MS patients recruited within three years of the onset of the disease, and in whom MRI had been performed at baseline and a year later, were assessed NeuroPsychologically five years later.

Imaging parameters accounting for significant variance in Cognitive performance were identified using multiple regressions, once confounding variables were controlled.

Patients performed significantly worse than expected on tests of Attention/Speed of Information Processing and half of them had experienced some decline in IQ in relation to premorbid estimates.

The rate of Global Brain Atrophy in the first year of the study accounted for significant variance in the overall Cognitive performance, and in Memory and Attention/Speed of Information Processing.

Poor performance on Attention tests was associated with high T₁-weighted Lesion Volume and reduced Magnetization Transfer Ratio (MTR) in Normal-Appearing White Matter (NAWM).

These results suggest that NeuroAxonal Loss was identified early in the disease, and its rate of progression, predicted Cognitive Impairment later in the disease.

NeuroAxonal loss is likely to affect Commissural and Association Fibers that subserve the Cognitive processes impaired in MS.

Background
Fatigue is a major problem in Multiple Sclerosis (MS), and its association with MRI features is debated.

Objective
To study the correlation between Fatigue and lesion load, White Matter (WM), and Gray Matter (GM), in MS patients independent of disability.

Methods
We studied 222 Relapsing/Remitting MS patients with low disability (scores < /=2 at the Kurtzke Expanded Disability Status Scale).

Lesion load, WM and GM were measured by fully automated, operator-independent, multi-parametric segmentation method. T₁ and T₂ lesion volume were also measured by a semi-automated method.

Fatigue was assessed by the Fatigue Severity Scale (FSS), and patients divided in high-Fatigue (FSS>/=5; n=197) and low-Fatigue groups (FSS < /=4; n=25).

Results
High-Fatigue patients showed significantly higher Abnormal White Matter Fraction (AWM-f), T₁ and T₂ lesion loads, and significant lower WM-f, and GM-f.

Multivariate analysis showed that high FSS was significantly associated with lower WM-f, and GM-f. Females and highly educated patients were significantly less fatigued.

Conclusion
These results suggest that among MS patients with low disability those with high-Fatigue show higher WM and GM Atrophy and higher lesion load.

And, that female sex and higher levels of education may play a protective role towards Fatigue.

Furthermore, they suggest that in MS, independent of disability, WM and Gray Matter Atrophy is a risk factor to have Fatigue.

Sixty, Relapsing/Remitting (RR) Multiple Sclerosis (MS) patients, who underwent treatment with Glatiramer Acetate (GA), Interferon-beta-1a (IFN-ß-1a), and ImmunoGlobulins (Igs) (20 per treatment group), were assessed for levels of Brain-Derived NeuroTrophic Factor (BDNF).

In the supernatants of unstimulated and stimulated Peripheral Blood MonoNuclear Cells (PBMCs) in the first year of treatment.

PhytoHemAgglutinin (PHA), Anti-OKT3 AntiBody, Myelin Basic Protein (MBP) and GA were used as stimuli. Cytokine responses by ELISPOT and LymphoProliferative Responses were also assessed.

The GA-treated MS patient group showed a progressive increase in BDNF levels, from baseline to month three; thereafter, the levels remained stable and significantly greater compared with baseline and controls (ANOVA = P < 0.001).

IFN-ß-1a had no effect on BDNF production, whereas Igs induced a slight decrease (ANOVA = P < 0.04).

ELISPOT analysis revealed a significant decrease of IFN-γ, an increase of InterLeukin-4 (IL-4) and IL-5 in GA-treated MS patients, and an increase of IL-10 in patients treated with IFN-ß-1a and GA.

No significant correlation was found between BDNF secretion in the supernatants of PBMCs and Cytokine response, lesional load, and measures of Atrophy.

Increased BDNF production related to GA treatment can have implications for understanding the mechanism of action of this ImmunoModulatory agent, in light of evidence suggesting its effects in promoting NeuroProtective Immunity in MS patients.

However, a clinically measurable effect, especially in terms of an impact on actual disease progression, remains to be established.

Although Axonal Loss has been observed in DeMyelinated Multiple Sclerosis (MS) lesions, there has been a major focus on understanding mechanisms of DeMyelination.

However, identification of markers for Axonal Damage and development of new imaging techniques has enabled detection of subtle changes in Axonal pathology and revived interest in the NeuroDegenerative component of MS.

Axonal Loss is generally accepted as the main determinant of permanent clinical disability.

However, the role of Axonal Loss early in disease or during Relapsing/Remitting disease is still under investigation.

As are the interactions and interdependency between inflammation, DeMyelination, NeuroDegeneration and NeuroProtection in the pathogenesis of MS.

Multiple Sclerosis is a chronic inflammatory disease of the CNS. Although progressive Brain Injury and diffuse inflammatory damage has been shown in the chronic phase of the disease.

Little is known about the molecular mechanisms underlying these pathological processes.

In order to identify these mechanisms, we have studied the gene expression profile in non-lesion containing tissue, the so-called Normal-Appearing White Matter (NAWM).

We performed differential gene expression analysis and quantitative RT-PCR on SubCortical White Matter from 11 Multiple Sclerosis and 8 control cases.

Differentially expressed genes were further analysed in detail by in situ hybridization and ImmunoFluorescence studies.

We show that genes known to be involved in AntiInflammatory and protective mechanisms such as STAT6, JAK1, IL-4R, IL-10, Chromogranin C and HIF-1alpha are consistently upregulated in the Multiple Sclerosis NAWM.

On the other hand, genes involved in ProInflammatory mechanisms, such as STAT4, IL-1beta and MCSF, were also upregulated but less regularly.

Immunofluorescence colocalization analysis revealed expression of STAT6, JAK1, IL-4R and IL-13R mainly in Oligodendrocytes, whereas STAT4 expression was detected predominantly in Microglia.

In line with these data, in situ hybridization analysis showed an increased expression in Multiple Sclerosis NAWM of HIF-1alpha in Oligodendrocytes and HLA-DRalpha in Microglia cells.

The consistency of the expression levels of STAT6, JAK1, JAK3 and IL-4R between the Multiple Sclerosis cases suggests an overall activation of the STAT6-signalling pathway in Oligodendrocytes.

Whereas the expression of STAT4 and HLA-DRalpha indicates the activation of ProInflammatory pathways in Microglia.

The upregulation of genes involved in anti-inflammatory mechanisms driven by Oligodendrocytes may protect the CNS environment and thus limit lesion formation.

Whereas, the activation of ProInflammatory mechanisms in Microglia may favor disease progression.

Altogether, our data suggests an endogenous inflammatory reaction throughout the whole White Matter of Multiple Sclerosis Brain, in which Oligodendrocytes actively participate.

This reaction might further influence and to some extent facilitate lesion formation.

Objective
To determine the functional and structural substrates of Motor Network Dysfunction in patients with Relapsing/Remitting Multiple Sclerosis (RRMS).

Methods
Using a 3-T scanner, in 12 right-handed RRMS patients and 14 matched controls, we acquired Diffusion Tensor (DT) MRI and functional MRI during the performance of a simple Motor Task with the right (R) hand.

Using DT MRI Tractography, we calculated DT-derived metrics from several Motor and NonMotor White Matter (WM) fiber bundles.

Functional connectivity analysis was performed using SPM2.

Results
Compared with control, MS patients had abnormal DT MRI metrics of all the WM bundles studied.

Compared with controls, MS patients had more significant activations of the left (L) Supplementary Motor Area (SMA), the L primary SensoriMotor Cortex (SMC), and the R Cerebellum.

They also had increased functional connectivity between the R primary SMC and the R Cerebellum (p = 0.01) and the L SMA and the L primary SMC (p = 0.04).

Coefficients of altered connectivity were correlated with structural MRI metrics of tissue damage of the CorticoSpinal and the DentatoRubroThalamic Tract (r values ranging from -0.73 to 0.85).

Conclusions
The correlations found between measures of functional connectivity and structural damage to some of the major Brain Motor White Matter bundles suggest:

An adaptive role of functional connectivity changes in limiting the clinical consequences of structural damage in patients with Relapsing/Remitting Multiple Sclerosis.

Combining measures of altered functional and structural connectivities of specific Brain Networks is a promising tool to elucidate the mechanisms responsible for clinical manifestations of CNS damage.

Purpose
To prospectively determine HemoDynamic changes in the Normal-Appearing White Matter (NAWM).

Of patients with Relapsing/Remitting Multiple Sclerosis (RR-MS) by using dynamic susceptibility contrast material-enhanced Perfusion Magnetic Resonance (MR) imaging.

Materials And Methods
Conventional MR imaging (which included acquisition of pre- and postcontrast transverse T₁-weighted, Fluid-Attenuated Inversion Recovery.

And T₂-weighted images) and dynamic susceptibility contrast-enhanced T₂*-weighted MR imaging were performed in 17 patients with RR-MS (five men and 12 women; median age, 38.4 years; age range, 27.6-56.9 years) and 17 control patients (seven men and 10 women; median age, 42.0 years; age range, 18.7-62.5 years).

Absolute Cerebral Blood Volume (CBV), absolute Cerebral Blood Flow (CBF), and Mean Transit Time (MTT).

Referenced to an arterial input function by using an automated method were determined in PeriVentricular, Intermediate, and SubCortical Regions of NAWM at the level of the Lateral Ventricles.

Least-squares regression analysis (controlled for age and sex) was used to compare Perfusion measures in each region between patients with RR-MS and control patients.

Repeated-measures analysis of variance and the Tukey honestly significant difference test were used to perform pairwise comparison of Brain Regions in terms of each Perfusion measure.

Results
Each region of NAWM in patients with RR-MS had significantly decreased CBF (P < .005) and prolonged MTT (P < .001) compared with the corresponding region in control patients.

No significant differences in CBV were found between patients with RR-MS and control patients in any of the corresponding areas of NAWM examined.

In control patients, PeriVentricular NAWM regions had significantly higher CBF (P =.03) and CBV (P =.04) than did Intermediate NAWM regions.

No significant regional differences in CBF, CBV, or MTT were found in patients with RR-MS.

Conclusion
The NAWM of patients with RR-MS shows decreased Perfusion compared with that of controls.

Copyright RSNA, 2004

Study Design
Double-blind, randomized, placebo-controlled, parallel-group clinical trial.

Objective
Assess safety and efficacy of Sustained-Release Fampridine in subjects with Chronic Spinal Cord Injury.

Setting
A total of 11 academic rehabilitation research centers in the United States.

Methods
A total of 91 subjects with Motor-incomplete Spinal Cord Injury (SCI), randomized to three arms:

Fampridine, sustained release, 25 mg b.i.d. (Group I), 40 mg b.i.d. (Group II), and placebo (Group III) for 8 weeks.

Outcome Measures
Patient diary questionnaire, Ashworth score, American Spinal Cord Injury Association International Standards, International Index of Erectile Function, Bladder and Bowel Management Questionnaires, and Clinician and Subject Global Impressions (Clinician Global Impression of change, Subject Global Impression (SGI)).

Safety was evaluated from adverse events, physical examinations, vital signs, ElectroCardiograms, and laboratory tests.

Results
In total, 78% of the subjects completed the study. More (13/30) discontinued from Group II than Group I (4/30) and Group III (3/31).

The most frequent adverse events across groups were Hypertonia, Generalized Spasm, Insomnia, Dizziness, Asthenia, Pain, Constipation, and Headache.

One subject in Group II experienced a Seizure. SCI changed significantly in favor of Group I (P = 0.02).

Subgroup analysis of subjects with baseline Ashworth scores > 1 showed significant improvement in Spasticity in Group I versus III (P = 0.02).

Conclusions
Group I showed significant improvement in SGI, and potential benefit on Spasticity.

The drug was well tolerated. Group II showed more adverse events and discontinuations.

Hypocretin-1 (Orexin-A) was administered to sleep-deprived (30–36 h) rhesus monkeys immediately preceding testing on a multi-image Delayed Match-To-Sample (DMS) Short-Term Memory task.

The DMS task used multiple delays and stimulus images and effectively measures Cognitive Deficits produced by sleep deprivation (Porrino et al., 2005).

Two methods of administration of Orexin-A were tested, IntraVenous injections (2.5–10.0 µg/kg, i.v.) and a novel method developed for nasal delivery via an atomizer spray mist to the nostrils (dose estimated 1.0 µg/kg).

Results showed that Orexin-A delivered via the IntraVenous and nasal routes significantly improved performance in sleep-deprived monkeys

However, the Nasal delivery method was significantly more effective than the highest dose (10 µg/kg) of IntraVenous Orexin-A tested.

The improvement in performance by Orexin-A was specific to trials classified as high versus low Cognitive Load as determined by performance difficulty under normal testing conditions.

Except for the maximum IntraVenous dose (10 µg/kg), neither delivery method affected task performance in alert non-sleep-deprived animals.

The improved performance in sleep-deprived animals was accompanied by Orexin-A related alterations in local Cerebral Glucose metabolism (CMRglc).

In specific Brain Regions shown previously to be engaged by the task and impaired by sleep deprivation (Porrino et al., 2005).

Consistent with the differential effects on performance, Nasal delivered Orexin-A produced a more pronounced reversal of sleep deprivation induced changes in Brain metabolic activity (CMRglc) than IntraVenous Orexin-A.

These findings provide strong evidence for the effectiveness of IntraNasal Orexin-A in alleviating Cognitive Deficits produced by loss of sleep.

Background And Purpose
Formation of lesions in Multiple Sclerosis (MS) shows pronounced short-term fluctuation of MR imaging HyperIntensity and size, a qualitatively known but poorly characterized phenomenon.

With the use of time-series modeling of MR imaging intensity, our study relates the short-term dynamics of new T₂ lesion formation to those of contrast enhancement and markers of long-term progression of disease.

Materials And Methods
We analyzed 915 examinations from weekly to monthly MR imaging in 40 patients with MS using a time-series model, emulating 2 opposing processes of T₂ prolongation and shortening, respectively.

Patterns of activity, duration, and residual HyperIntensity within new T₂ lesions were measured and evaluated for relationships to disability, Atrophy, and clinical phenotype in long-term follow-up.

Results
Significant T₂ activity was observed for 8 to 10 weeks beyond contrast enhancement.

Which suggests that T₂ MR imaging is sensitive to NonInflammatory processes such as Degeneration and repair.

Larger lesions showed longer subacute phases but disproportionally more recovery.

Patients with smaller average peak lesion size showed trends toward greater disability and proportional residual damage.

Higher rates of disability or Atrophy were associated with subjects whose lesions showed greater residual HyperIntensity.

Conclusion
Smaller lesions appeared disproportionally more damaging than larger lesions, with lesions in Progressive MS smaller and of shorter activity than in Relapsing/Remitting MS.

Associations of lesion dynamics with rates of Atrophy and disability and clinical subtype suggest that changes in lesion dynamics may represent a shift from inflammatory toward Degenerative Disease activity.

And greater proximity to a Progressive stage, possibly allowing staging of the progression of MS earlier, before Atrophy or disability develops.

Purpose Of Review
To discuss recent Neuro-Ophthalmic advances relevant to the management of Optic Neuritis and Multiple Sclerosis

Recent Findings
Major advances have occurred in the fields of Autoimmunity in Optic Neuritis, and in imaging the Retinal Nerve Fiber layer in both Optic Neuritis and Multiple Sclerosis

Summary
A proportion of cases of Optic Neuritis occur in patients who do not develop Multiple Sclerosis; the Optic Neuritis may be monophasic illness or recurrent.

In many recurrent cases who also have Myelitis (NeuroMyelitis Optica) a Serum AntiBody to Aquaporin-4 water channels has been detected.

It remains to be seen how many cases of recurrent Non-Multiple Sclerosis Optic Neuritis without Myelitis will be shown to be associated with this AutoAntiBody.

Optical Coherence Tomography has been shown to detect Axonal Loss in the Retina in both recovered Optic Neuritis and in Multiple Sclerosis without a past history of Optic Neuritis.

This is not a novel observation, but the technique may provide a quantitative measure of the loss of Optic Nerve Axons following the acute insult in Optic Neuritis, and chronically in Primary and Secondary/Progressive Multiple Sclerosis.

This is of particular interest in view of the evidence that it is Axonal Loss, rather than DeMyelination with preservation of Axons, that underlies disability in Multiple Sclerosis.

PeriVascular Microglia activation is a hallmark of inflammatory DeMyelination in Multiple Sclerosis (MS), but the mechanisms underlying Microglia activation and specific strategies to attenuate their activation remain elusive.

Here, we identify Fibrinogen as a novel regulator of Microglia activation and show that targeting of the interaction of Fibrinogen with the Microglia Integrin Receptor Mac-1 (alpha(M)beta(2).

CD11b/CD18) is sufficient to suppress Experimental Autoimmune Encephalomyelitis in mice that retain full Coagulation function.

We show that Fibrinogen, which is deposited PeriVascularly in MS plaques, signals through Mac-1 and induces the differentiation of Microglia to Phagocytes via activation of Akt and Rho.

Genetic disruption of Fibrinogen-Mac-1 interaction in Fibrinogen-gamma(390-396A) knock-in mice.

Or pharmacologically impeding Fibrinogen-Mac-1 interaction through IntraNasal delivery of a Fibrinogen-derived inhibitory Peptide (gamma(377-395)) attenuates Microglia activation and suppresses Relapsing Paralysis.

Because blocking Fibrinogen-Mac-1 interactions affects the ProInflammatory but not the ProCoagulant properties of Fibrinogen.

Targeting the gamma(377-395) Fibrinogen Epitope could represent a potential therapeutic strategy for MS and other NeuroInflammatory Diseases associated with Blood-Brain Barrier disruption and Microglia activation.