MS Abstracts 06a-2g5

  1. Prediction of longitudinal Brain Atrophy in Multiple Sclerosis by Gray Matter Magnetic Resonance Imaging T2 HypoIntensity
    Arch Neurol 2005 Sep;62(9):1371-6

  2. Cerebellar dysfunction in Multiple Sclerosis: evidence for an acquired channelopathy
    Prog Brain Res 2005;148:353-65

  3. MRI evidence for Multiple Sclerosis as a diffuse disease of the Central Nervous System
    J Neurol 2005 Oct;252 Suppl 5:v16-v24

  4. Inflammatory DeMyelination is not central to the pathogenesis of Multiple Sclerosis
    J Neurol 2005 Oct;252 Suppl 5:v10-v15

  5. Mitochondrial dysfunction as a cause of Axonal degeneration in Multiple Sclerosis patients
    Ann Neurol 2006 Mar;59(3):478-89

  6. NeuroTrophic Factors in Relapsing/Remitting and Secondary/Progressive Multiple Sclerosis patients during Interferon-beta therapy
    Clin Immunol 2006 Jan;118(1):77-82

  7. Ocular manifestations of Multiple Sclerosis
    Curr Opin Ophthalmol 2005 Oct;16(5):315-20

  8. Glucosamine abrogates the acute phase of Experimental Autoimmune Encephalomyelitis by induction of th2 response
    J Immunol 2005 Dec 1;175(11):7202-8

  9. Benefits of high-dose, high-frequency Interferon-ß-1a in Relapsing/Remitting Multiple Sclerosis are sustained to 16 months: Final comparative results of the EVIDENCE trial
    J Neurol Sci 2005 Dec 15;239(1):67-74

  10. Metabolite changes in early Relapsing/Remitting Multiple Sclerosis A two year follow-up study
    J Neurol 2005 Nov 24

  11. Age-related gadolinium-enhancement of MRI Brain lesions in Multiple Sclerosis
    J Neurol Sci 2005 Dec 15;239(1):95-9

  12. Neuropsychiatric symptoms in patients with Multiple Sclerosis
    Acta Psychiatr Scand 2005 Dec;112(6):463-8


Prediction of Longitudinal Brain Atrophy In Multiple Sclerosis By Gray Matter Magnetic Resonance Imaging T2 HypoIntensity

Bermel RA, Puli SR, Rudick RA, Weinstock-Guttman B, Fisher E, Munschauer FE 3rd, Bakshi R
Arch Neurol 2005 Sep;62(9):1371-6
University at Buffalo, State University of New York, Buffalo NeuroImaging Analysis Center, USA
PMID# 16157744

Gray Matter Magnetic Resonance Imaging T2 HypoIntensity, a marker of Iron deposition, is associated with clinical impairment and Brain Atrophy in cross-sectional studies of Multiple Sclerosis.

Treatment with intramuscular Interferon-ß-1a limits Brain Atrophy in the second year of treatment.

Objective & Design
To test whether T2 HypoIntensity predicts Brain Atrophy and whether Interferon affects this relationship. Post hoc analysis.

Setting & Patients
A multicenter treatment trial conducted at tertiary care comprehensive Multiple Sclerosis centers. Patients with Multiple Sclerosis who took part in a 2-year clinical trial in which they received intramuscular Interferon-ß-1a (30 mug/wk) or placebo.

Main Outcome Measures
Deep Gray Matter T2 HypoIntensity, Brain Parenchymal Fraction (BPF), and total T2, Gadolinium-enhancing, and T1 lesion volumes.

T2 HypoIntensity in various Gray Matter areas correlated with baseline BPF (r = 0.19-0.39; P = .001-.03).

In placebo-treated patients (n = 68), baseline T2 HypoIntensity predicted the change in BPF in the first year and throughout 2 years (r = 0.26-0.42; P< .001-.03).

T2 HypoIntensity was chosen in regression modeling as the best predictor of BPF change at the 1-year (R(2) = 0.23; P = .002) and 2-year (R(2) = 0.33; P< .001) time points after accounting for all Magnetic Resonance Imaging variables.

In the interferon group (n = 65), no relationship existed between baseline T2 HypoIntensity and BPF change.

Gray Matter T2 HypoIntensity predicts the progression of Brain Atrophy in placebo- but not Interferon-ß-1a-treated patients. This predictive effect is seen as early as the first year.

We hypothesize that Interferon-ß may exert its effect on Brain Atrophy in part by reducing a cascade of events that involve Iron deposition as a mediator of NeuroToxicity or as a disease epiphenomenon.


Cerebellar Dysfunction In Multiple Sclerosis: Evidence For An Acquired Channelopathy

Waxman SG
Prog Brain Res 2005;148:353-65
Yale University School of Medicine, Department of Neurology and PVA/EPVA Center for NeuroScience Research, New Haven, CT 06510 and Rehabilitation Research Center, VA Hospital, West Haven, CT 06516, USA
PMID# 15661203

Cerebellar dysfunction in Multiple Sclerosis (MS) is a significant contributor to disability, is relatively refractory to symptomatic therapy, and often progresses despite treatment with disease-modifying agents.

Thus, there is a need for better understanding of its pathophysiology. This chapter reviews a growing body of evidence which suggests that mis-tuning of Purkinje Cells, due to expression of an abnormal repertoire of Sodium Channels, contributes to Cerebellar Deficits in MS.

Within the normal Nervous System, Sodium Channel Na(v)1.8 is expressed in a highly specific manner within Spinal Sensory and Trigeminal Neurons.

And, is not present within Purkinje Cells, Na(v)1.8 mRNA and protein are, however, expressed within Purkinje Cells both in models of MS (Experimenal Autoimmume Encephalomyelitis; EAE), and in postmortem tissue from humans with MS.

    Expression of Na(v)1.8 within Purkinje Cells in vitro alters ElectroGenesis in these cells in several ways by:
  1. Increasing duration and amplitude of Action Potentials
  2. Decreasing the proportion of Action Potentials that are conglomerate and the number of spikes per conglomerate Action Potential
  3. Supporting sustained, pacemaker-like impulse trains in response to depolarization, which are not seen in the absence of Na(v)1.8

Similar changes are observed in recordings from Purkinje Cells in vivo from mice with EAE. Taken together, these results suggest that expression of Na(v)1.8 within Purkinje Cells distorts their pattern of firing in MS


MRI Evidence For Multiple Sclerosis As A Diffuse Disease Of The Central Nervous System

Filippi M, Rocca MA
J Neurol 2005 Oct;252 Suppl 5:v16-v24
Scientific Institute and University Ospedale San Raffaele, NeuroImaging Research Unit, Dept. of Neurology, Via Olgettina 60, 20132, Milan, Italy
PMID# 16254697

The classical view of MS as a chronic Inflammatory Demyelinating Disease leading to the formation of focal Central Nervous System (CNS) White Matter (WM) lesions has been recently challenged by pathological studies and by the extensive application of modern MRI-based techniques.

There is now overwhelming evidence supporting the following statements:*

MS causes widespread tissue damage in the Normal-Appearing White Matter (NAWM) of the Brain and Spinal Cord, whose extent and severity is more strictly associated to the clinical manifestations of the disease, than the extent of focal pathology.

Discrete, macroscopic lesions are just the tip of the iceberg of MS pathology.*

Gray Matter (GM) damage is a consistent feature of all MS phenotypes, which is progressive from the start of the Relapsing/Remitting phase of the disease.

As is the case for WM, GM damage is also a mixture of focal lesions and diffuse pathology.

High-field strength MR scanners are improving our ability to image focal GM lesions and modern MR-based techniques are enabling us to quantify in vivo the extent and severity of GM pathology, which have been shown to correlate only moderately with the amount of WM changes.

At least part of GM pathology in MS is not secondary to retrograde degeneration of fibers traversing WM lesions.* The NeuroDegenerative component of the disease is not a late phenomenon and it is not completely driven by inflammatory DeMyelination.

In fact, NeuroDegeneration occurs very early in the course of MS and the correlation between MRI measures of inflammation and NeuroDegeneration is weak in all disease phases.

The interplay of inflammation and NeuroDegeneration is a complex and still poorly understood phenomenon. At least part of MS-related NeuroDegeneration is not directly driven by Wallerian Degeneration.*

Functional Cortical changes can be seen in virtually all MS patients and are likely to play a central role in the ability of the MS Brain to respond to tissue injury and, hence, limit the functional consequences of structural damage.

MS disability is not just the result of tissue destruction but rather a balance between tissue destruction, tissue repair and adaptive Cortical reorganization.

All of this calls for the concept of MS as a focal, Inflammatory DeMyelinating, WM disease to be reexamined and to start viewing MS as a diffuse CNS disease with an important NeuroDegenerative component. This is central for identifying novel and effective treatment strategies.


Inflammatory DeMyelination Is Not Central To The Pathogenesis Of Multiple Sclerosis

Bruck W
J Neurol 2005 Oct;252 Suppl 5:v10-v15
University Hospital Georg-August-University, Dept. of Neuropathology, Robert-Koch-Str. 40, 37075, Gottingen, Germany
PMID# 16254696


Multiple Sclerosis is a disease of the Central Nervous System that destroys Myelin, Oligodendrocytes, Neurons and Axons.

Historically considered to be caused by an Autoimmune process mainly affecting Myelin and Oligodendrocytes in the White Matter, recent data provide evidence that a generalized, diffuse NeuroDegenerative process plays an important role in the pathogenesis of MS.

There is a high density of Axonal transections in active DeMyelinating lesions, but also persistent low-level Axonal damage in inactive plaques and diffuse Axonal and Neuronal loss throughout the Nervous System.

Initial Axonal injury appears to be closely related to inflammation, but is not restricted to the lesions themselves. Damage may be propagated throughout the Nervous System by Anterograde Wallerian, Retrograde or TranSynaptic degeneration.

Cumulative tissue loss in the Gray and White Matter, especially of Axons, is important and probably the principal determinant of accumulation of irreversible Neurological Disability and of conversion to a progressive disease course.


Mitochondrial Dysfunction As A Cause Of Axonal Degeneration In Multiple Sclerosis Patients

Dutta R, McDonough J, Yin X, Peterson J, Chang A, Torres T, Gudz T, Macklin WB, Lewis DA, Fox RJ, Rudick R, Mirnics K, Trapp BD
Ann Neurol 2006 Mar;59(3):478-89
Lerner Research Institute, Department of NeuroSciences
PMID# 16392116

Degeneration of chronically DeMyelinated Axons is a major cause of irreversible Neurological disability in Multiple Sclerosis (MS) patients.

Development of NeuroProtective therapies will require elucidation of the molecular mechanisms by which Neurons and Axons degenerate.

We report UltraStructural Changes that support Ca2+-mediated destruction of chronically DeMyelinated Axons in MS patients.

We compared expression levels of 33,000 characterized genes in postmortem Motor Cortex from six control and six MS Brains matched for age, sex, and postmortem interval.

As reduced energy production is a major contributor to Ca2+-mediated Axonal Degeneration, we focused on changes in Oxidative PhosPhorylation and inhibitory NeuroTransmission.

Compared with controls, 488 transcripts were decreased and 67 were increased (p < 0.05, 1.5-fold) in the MS Cortex.

Twenty-six nuclear-encoded Mitochondrial genes and the functional activities of Mitochondrial Respiratory Chain complexes I and III were decreased in the MS Motor Cortex.

Reduced Mitochondrial Gene expression was specific for Neurons. In addition, pre-synaptic and postsynaptic components of GABAergic NeuroTransmission and the density of Inhibitory InterNeuron processes also were decreased in the MS Cortex.

Our data supports a mechanism whereby reduced ATP production in DeMyelinated segments of Upper Motor Neuron Axons impacts Ion homeostasis, induces Ca2+-mediated Axonal Degeneration, and contributes to progressive Neurological disability in MS patients.

Ann Neurol 2006.


NeuroTrophic Factors In Relapsing/Remitting And Secondary/Progressive Multiple Sclerosis Patients During Interferon-beta Therapy

Caggiula M, Batocchi AP, Frisullo G, Angelucci F, Patanella AK, Sancricca C, Nociti V, Tonali PA, Mirabella M
Clin Immunol 2006 Jan;118(1):77-82
Institute of Neurology, Catholic University, Largo Gemelli 8, 00168 Rome, Italy; Fondazione Pro Iuventute Don Carlo Gnocchi, Rome, Italy
PMID# 16275091

Although Interferon-beta (IFN-ß) is a widely used disease-modifying therapy in Multiple Sclerosis (MS), the mechanisms responsible for its effects are not fully understood.

Some studies demonstrated that IFN-ß induces Nerve Growth Factor (NGF) secretion by Astrocytes and by Brain Endothelial Cells.

In this study, we determined the production of various NeuroTrophins:

  • Brain-Derived NeuroTrophic Factor, (BDNF)
  • NGF
  • Glial Cell line-derived NeuroTrophic Factor
    • NeuroTrophin 3
    • Neurotrophin 4

By Peripheral Blood Mononuclear Cells (PBMCs) in Relapsing/Remitting (RR) and Secondary/Progressive (SP) MS patients during IFN-ß treatment.

There were no main variations in NeuroTrophin production either among all MS patients globally considered or in the group of SPMS subjects.

Instead, in the group of RRMS patients who did not present clinical exacerbation of disease up to the end of the study, we found a significant increase in BDNF production as from 6 months after starting therapy.


Ocular Manifestations Of Multiple Sclerosis

Chen L, Gordon LK
Curr Opin Ophthalmol 2005 Oct;16(5):315-20
University of California, Jules Stein Eye Institute, Ocular Inflammatory Disease Center, Los Angeles, USA, and Greater Los Angeles VA Healthcare System, Los Angeles, California, USA, and Shenzhen Eye Hospital, Shenzhen, Guangdong, PR China
PMID# 16175046

Purpose Of Review
Multiple Sclerosis is an Autoimmune DeMyelinating Disorder of the Nervous System that is commonly manifested by Visual System involvement and that may initially present with Ophthalmologic symptoms.

This paper reviews recent findings regarding the Ocular manifestations in Multiple Sclerosis.

Recent Findings
Manifestations of Multiple Sclerosis in the eye include both the Afferent and Efferent Visual Pathways.

Optic Neuritis, the most common Ocular manifestation of Multiple Sclerosis, may be the initial clinical disease manifestation.

Recent long-term follow-up data show that most patients with DeMyelinating Optic Neuritis have an excellent prognosis for recovery of central Visual Acuity.

Evidence is emerging, however, for significant and broad reduction in both contrast sensitivity and color perception in Multiple Sclerosis patients despite near-normal Visual Acuities.

Ocular motor deficits in Multiple Sclerosis include InterNuclear Ophthalmoplegia and Nystagmus, resulting in Diplopia, Oscillopsia, Blurred Visual, Loss of Stereopsis, and reading fatigue.

Multiple Sclerosis also may be associated with Ocular Inflammatory Diseases, in particular Pars Planitis and Retinal Periphlebitis.

Ocular findings may be initial manifestations of Multiple Sclerosis and may predict additional DeMyelinating events.

Recognizing these syndromes and signs will help clinicians to properly evaluate the patient, formulate an appropriate differential diagnosis, be able to discuss the prognosis with the patient, and help develop an effective therapeutic plan.


Glucosamine Abrogates The Acute Phase Of Experimental Autoimmune Encephalomyelitis By Induction Of th2 Response

Zhang GX, Yu S, Gran B, Rostami A
J Immunol 2005 Dec 1;175(11):7202-8
Thomas Jefferson University, Department of Neurology, Philadelphia, PA 19107
PMID# 16301624

Glucosamine, a natural Glucose derivative and an essential component of glycoproteins and proteoglycans, has been safely used to relieve OsteoArthritis in humans.

Recent studies have shown that Glucosamine also possesses ImmunoSuppressive properties and is effective in prolonging graft survival in mice.

Whether this reagent is effective in human Multiple Sclerosis (MS), an inflammatory DeMyelination in the CNS, is not known. We thus investigated the therapeutic effect of Glucosamine on Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS.

We demonstrated that oral, i.p., or i.v. administration of Glucosamine significantly suppressed acute EAE, with reduced CNS inflammation and DeMyelination.

A significant, albeit not strong, blockade of Th1 response and an up-regulation of Th2 Cytokines (IL-5 and IL-10) are observed in the Splenocytes of Glucosamine-treated mice.

Glucosamine also regulates IL-5 and IL-10 in vitro. As Glucosamine is able to effectively suppress acute EAE, has low or absent toxicity, and has been safely used in humans orally.

Our study suggests a potential use for this drug alone or in combination with other disease-modifying immunotherapies to enhance their efficacy and reduce their doses in MS and possibly other Autoimmune Disorders.

Furthermore, because Glucosamine functions not simply as an ImmunoSuppressant, but as a mild ImmunoModulator, administration of Glucosamine provides a novel ImmunoRegulatory approach for Autoimmune Disorders.


Benefits Of High-Dose, High-Frequency Interferon-ß-1a In Relapsing/Remitting Multiple Sclerosis Are Sustained To 16 Months: Final Comparative Results Of The EVIDENCE trial

Panitch H, Goodin D, Francis G, Chang P, Coyle P, O'connor P, Li D, Weinshenker B; for the EVIDENCE (EVidence of Interferon Dose-response: European North American Comparative Efficacy) Study Group and the University of British Columbia MS/MRI Research Group
J Neurol Sci 2005 Dec 15;239(1):67-74
University of Vermont College of Medicine, Neurology Health Care Service, 1 South Prospect Street, Burlington, VT 05401, USA
PMID# 16169561

The EVIDENCE trial demonstrated that Interferon-ß-1a (IFN-ß-1a) , 44 mcg subcutaneously (sc) three times weekly (tiw) (Rebif(R)), was significantly more effective than IFN-ß-1a, 30 mcg intramuscularly (im) once weekly (qw) (Avonex(R)).

In reducing relapses and Magnetic Resonance Imaging (MRI) activity in patients with Relapsing/Remitting Multiple Sclerosis at both 24 and 48 weeks of therapy.

We now present final comparative data on these patients, showing that the superior efficacy of IFN-ß-1a, 44mcg sc tiw, for relapse measures and MRI activity, compared with IFN-ß-1a, 30mcg im qw, was sustained for at least 16 months.

The development of AntiBodies to IFN was associated with reduced efficacy on MRI measures and fewer IFN-related adverse events, but did not have an impact on relapse outcomes.


Metabolite Changes In Early Relapsing/Remitting Multiple Sclerosis A Two Year Follow-Up Study

Tiberio M, Chard DT, Altmann DR, Davies G, Griffin CM, McLean MA, Rashid W, Sastre-Garriga J, Thompson AJ, Miller DH
J Neurol 2005 Nov 24
Institute of Neurology, NMR Research Group, Queen Square, London WC1N 3BG, UK
PMID# 16307201

Previous in vivo Proton Magnetic Resonance Spectroscopic Imaging (1H-MRS) studies have found reduced levels of N-Acetyl-Aspartate (NAA) in Multiple Sclerosis (MS) lesions, the surrounding Normal-Appearing White Matter (NAWM) and Cortical Gray Matter (CGM), suggesting Neuronal and Axonal Dysfunction and loss.

Other metabolites, such as myoInositol (Ins), Creatine (Cr), Choline (Cho), and Glutamate plus Glutamine (Glx), can also be quantified by 1H-MRS, and studies have indicated that concentrations of these metabolites may also be altered in MS.

Relatively little is known about the time course of such metabolite changes. This preliminary study aimed to characterise changes in total NAA (tNAA, the sum of NAA and N-Acetyl-Aspartyl-Glutamate), Cr, Cho, Ins and Glx concentrations in NAWM and in CGM, and their relationship with clinical outcome, in subjects with clinically early Relapsing/Remitting MS (RRMS).

Twenty RRMS subjects and 10 healthy control subjects underwent 1H-MRS examinations yearly for two years. Using the LCModel, tNAA, Cr, Cho, Ins and Glx concentrations were estimated both in NAWM and CGM.

At baseline, the concentration of tNAA was significantly reduced in the NAWM of the MS patients compared to the control group (-7%, p = 0.003), as well as in the CGM (-8.7%, p = 0.009).

NAWM tNAA concentrations tended to recover from baseline, but otherwise tissue metabolite profiles did not significantly change in the MS subjects, or relatively between MS and healthy control subjects.

While Neuronal and Axonal damage is apparent from the early clinical stages of MS, this study suggests that initially it may be partly reversible.

Compared with other MR imaging measures, serial 1H-MRS may be relatively less sensitive to progressive pathological tissue changes in early RRMS.


Age-Related Gadolinium-Enhancement Of MRI Brain Lesions In Multiple Sclerosis

Tortorella C, Bellacosa A, Paolicelli D, Fuiani A, Di Monte E, Simone IL, Giaquinto P, Livrea P, Trojano M
J Neurol Sci 2005 Dec 15;239(1):95-9
San Paolo Hospital, NeuroPhysioPathology Unit, Bari, Italy
PMID# 16209877

There is evidence that inflammatory processes in Multiple Sclerosis (MS) are age-dependent. In this study we evaluated the impact of aging on gadolinium (Gd) enhancement of Brain Magnetic Resonance Imaging (MRI) lesions in MS patients.

Pre- and post-contrast MRI scans, acquired using a standardized procedure by the same MRI scanner, at least 1 month far from clinical relapse or steroid treatment, were examined in 200 disease-modifying treatment free MS patients.

Seventy-three patients (36.5%) showed at least one enhancing lesion.

Age at MRI examination (p=0.0001), disease duration (p=0.002) and EDSS score were significantly (p=0.02) lower, whereas relapse rate in the preceding 2 years was higher (p=0.003) in patients with enhancing lesions than in patients with unenhancing scans.

Multivariate logistic analysis showed that current age was the variable better predicting Gd enhancement (p=0.004).

The odds ratios were 0.95 (CI: 0.92-0.98) for each year of patient's age and 0.64 (CI: 0.48-0.87) for each age decade. The main changes in enhancement risk occurred after 35 years of age.

Multivariate Poisson regression model showed that relapse rate in the preceding 2 years (p < 0.0001) and current age (p=0.0003) were the best predictors of the number of enhancing lesions.

This information can be used to increase the statistical power of clinical trials using Gd-enhancing lesions as an outcome measure.


NeuroPsychiatric Symptoms In Patients With Multiple Sclerosis

Figved N, Klevan G, Myhr KM, Glad S, Nyland H, Larsen JP, Harboe E, Omdal R, Aarsland D
Acta Psychiatr Scand 2005 Dec;112(6):463-8
Stavanger University Hospital, Section of Geriatric Psychiatry, Stavanger, Norway
PMID# 16279876

To explore the range of psychiatric symptoms in patients with Multiple Sclerosis (MS) and their association with Neurological disability.

Patients diagnosed with MS during 1998-2000 in Rogaland and Hordaland counties, western Norway, were included.

Psychiatric symptoms were assessed by the Neuropsychiatric Inventory (NPI). Patients with Systemic Lupus Erythematosus (SLE) served as controls.

Eighty-six of 93 eligible MS patients were included, and 80% showed at least one psychiatric symptom. The most frequent symptoms were depression (59%), sleep disturbance (48%), irritability/emotional lability (42%), and apathy (31%).

Depression was associated with higher disability score. MS patients showed significantly higher NPI irritability score (P = 0.002), appetite disturbance score (P < 0.001), and apathy score (P = 0.01) than SLE patients.

Neuropsychiatric symptoms occur frequently in patients with MS. Irritability and apathy are independent of disability and chronic disease and represent unique disease manifestations.

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