Roemer SF, Parisi JE, Lennon VA, Benarroch EE, Lassmann H, Bruck W, Mandler RN, Weinshenker BG, Pittock SJ, Wingerchuk DM, Lucchinetti CF
Brain 2007 Feb 4
Mayo Clinic College of Medicine, Laboratory Medicine and Pathology and Immunology, Departments of Neurology, Rochester, MN, USA; National Institutes of Health, Center for the Clinical Trials Network, Bethesda; Mayo Clinic College of Medicine, Department of Neurology, Scottsdale, AZ, USA; Center for Brain Research, Medical University of Vienna, Vienna; Georg-August University, Institute for Multiple Sclerosis Research, Austria and Department of NeuroPathology, Gottingen, Germany
NeuroMyelitis Optica (NMO) is an Inflammatory DeMyelinating Disease that typically affects Optic Nerves and Spinal Cord. Its pathogenic relationship to Multiple Sclerosis (MS) is uncertain.
Unlike MS, NMO lesions are characterized by deposits of IgG and IgM co-localizing with products of Complement activation in a VasculoCentric pattern around thickened hyalinized blood vessels.
Suggesting a pathogenic role for Humoral Immunity targeting an Antigen in the PeriVascular Space.
A recently identified specific Serum AutoAntibody biomarker, NMO-IgG, targets Aquaporin-4 (AQP4).
The most abundant water channel protein in the CNS, which is highly concentrated in Astrocytic foot processes.
We analyzed and compared patterns of AQP4 ImmunoReactivity in CNS tissues of nine patients with NMO, 13 with MS, nine with Infarcts and five normal controls.
In normal Brain, Optic Nerve and Spinal Cord, the distribution of AQP4 expression resembles the VasculoCentric pattern of Immune complex deposition observed in NMO lesions.
In contrast to MS lesions, which exhibit stage-dependent loss of AQP4, all NMO lesions demonstrate a striking loss of AQP4 regardless of the stage of DeMyelinating activity, extent of tissue Necrosis, or site of CNS involvement.
We identified a novel NMO lesion in the Spinal Cord and Medullary Tegmentum extending into the area postrema.
Characterized by AQP4 loss in foci that were Inflammatory and Edematous, but neither DeMyelinated nor Necrotic.
Foci of AQP4 loss coincided with sites of intense VasculoCentric Immune Complex deposition.
These findings strongly support a role for a Complement activating AQP4-specific AutoAntibody as the initiator of the NMO lesion, and further distinguish NMO from MS.
Limmroth V, Malessa R, Zettl UK, Koehler J, Japp G, Haller P, Elias W, Obhof W, Viehover A, Meier U, Brosig A, Hasford J, Putzki N, Kalski G, Wernsdorfer C
J Neurol 2007 Feb 1
for the QUASIMS Study Group
University of Colognen, Cologne City Hospitals, Dept. of Neurology, Ostmerheimerstr. 200, 51109, Cologne, Germany
Interferon-beta (IFN-ß) preparations are the most frequently prescribed therapies for patients with Relapsing Multiple Sclerosis (MS). Several open-label observational studies report similar efficacy among IFN-ß preparations.
The Quality Assessment in Multiple Sclerosis Therapy (QUASIMS) study is a large, open-label observational study designed to compare the effectiveness and tolerability of available IFN-ß preparations.
As disease-modifying therapies for Relapsing MS across a wide range of clinical practice settings.
This retrospective, controlled cohort study was conducted by chart review at 510 sites in Germany, Austria, and Switzerland.
Enrolled patients had received one of the four available IFN-ß preparations/dosing regimens (intramuscular IFN-ß-1a 30 microg 1x/week [Avonex((R))], subcutaneous (SC) IFN-ß-1a 22 or 44 microg 3x/week [Rebif((R))], or SC IFN-ß-1b 250 microg 3.5x/week [Betaferon/Betaseron((R))]) for >/= 2 years.
Preplanned outcomes at 1 and 2 years included change from baseline Expanded Disability Status Scale (EDSS) score, percentage of progression-free patients (< 1.0 EDSS point), annualized relapse rate (RR), percentage of relapse-free patients, and reasons for therapy change.
Of 4754 evaluable patients, 3991 (84%) received IFN-ß as initial therapy.
There were no significant differences among IFN-ßs when used as initial or follow-up therapy on almost all outcome variables.
Relapse rate was consistently higher and percentage of relapse-free patients consistently lower for all products used as follow-up versus initial therapy.
Results of QUASIMS showed similar effectiveness among IFN-ß products. Benefits were consistently superior when IFN-ß was used as initial rather than follow-up therapy.
Our results suggest that patients do not benefit in terms of disease outcome from switching between IFN-ß preparations/dosing regimens.
Assessing Atrophy Of The Major White Matter Fiber Bundles Of The Brain From Diffusion Tensor MRI Data
Pagani E, Horsfield MA, Rocca MA, Filippi M
Magn Reson Med 2007 Aug 30;58(3):527-534
Scientific Institute and University Ospedale San Raffaele, NeuroImaging Research Unit, Department of Neurology, Milan, Italy
Brain Atrophy is a typical feature of many Neurological conditions. Therefore, quantitative evaluation and spatial characterization of Atrophy are potentially useful for monitoring the evolution of Central Nervous System (CNS) disorders.
In this study, a method for measuring Atrophy of the major White Matter (WM) fiber bundles in the Brain using Diffusion Tensor (DT) MRI data is developed.
To this end, an atlas was created from sets of Diffusion Anisotropy images from normal subjects, and the deformations necessary to match single subject Anisotropy images to this atlas were then computed.
Because Diffusion Anisotropy images were used, this approach should be sensitive to fiber bundle volume changes in the same way that using T1-weighted images allows Gray Matter volume changes to be measured.
The Jacobian determinant of the deformation field for each subject was then used as a measure of contraction or expansion of the tissue at each image voxel.
An overview of the nonlinear registration problem is given; then an optimization of the parameters for the chosen algorithm is performed and the method for producing the atlas is described.
The effectiveness of the method was then tested on data from five patients with Multiple Sclerosis (MS) and two patients with Amyotrophic Lateral Sclerosis (ALS).
Magn Reson Med 58:527-534, 2007. (c) 2007 Wiley-Liss, Inc.
Galimberti D, Scalabrini D, Fenoglio C, Comi C, De Riz M, Venturelli E, Lovati C, Mariani C, Monaco F, Bresolin N, Scarpini E
Eur J Neurol 2007 Feb;14(2):162-7
University of Milan, IRCCS Ospedale Maggiore Policlinico, Dino Ferrari Center, Department of Neurological Sciences, Milan, Italy
CXCL10 (Interferon-gamma-inducible protein-10) levels are increased in CerebroSpinal Fluid of Multiple Sclerosis (MS) patients with symptomatic attacks of Inflammatory DeMyelination, supporting a role for this molecule in MS pathogenesis.
Two hundred and twenty-six patients with MS and 235 controls were genotyped for G --> C and T --> C single nucleotide polymorphisms (SNPs) in exon 4 of CXCL10 gene.
Haplotypes were tested for association and correlated with clinical variables. The two SNPs studied were in complete linkage disequilibrium. None of the determined haplotypes was associated with MS.
However, carriers of the GGTT haplotype (defined as wild type, according to the sequence in National Centre for Biotechnology Information (NCBI) database) had a significantly lower progression index than non-carriers (P = 0.016).
Furthermore, amongst patients who had an initial Relapsing/Remitting (RR) course of the disease, the time between onset and second episode was significantly longer in GGTT carriers (P = 0.021).
Considering Secondary/Progressive (SP)-MS patients, the time between the initial RR form and the subsequent worsening to SP was longer in this group (P = 0.08).
Therefore, the GGTT haplotype of the CXCL10 gene is not a susceptibility factor for the development of MS, but is probably to influence the course of MS, possibly contributing to slow down the progression of the disease.
Clinical And MRI Correlates Of AutoReactive AntiBodies In Multiple Sclerosis Patients
Garg N, Zivadinov R, Ramanathan M, Vasiliu I, Locke J, Watts K, Lema J, Rajeswary J, Munschauer FE, Ambrus J Jr, Weinstock-Guttman B
J NeuroImmunol 2007 May 17
Multiple Sclerosis Center, UMass Memorial Medical Center, Worcester, MA 01605, United States; Baird Multiple Sclerosis Center, Jacobs Neurological Institute, Buffalo General Hospital, Buffalo, NY 14203, United States
AutoReactive AntiBodies (ARAB) occur more frequently in patients with Multiple Sclerosis (MS) than in general population and the presence of these AntiBodies often causes uncertainty regarding the disease course, response to therapy and the diagnosis of MS.
Retrospective analyses of the ARAB, clinical and MRI data of a consecutive patient cohort of MS and Clinically Isolated Syndrome (CIS) patients were conducted.
The patients were evaluated for an extensive panel that included various subtypes of AntiPhosphoLipid AntiBody (APLA) including Anti-PhosphatidylEthanolamine (APE), Anti-PhosphatidylSerine (APS), Anti-ß-2-GlycoProtein-1 (ABGP), Anti-Cardiolipin (ACA), and several other ARAB such as AntiNuclear AntiBody (ANA), Anti-Neutrophilic Cytoplasmic AntiBodies (ANCA), Anti-Thyroid Peroxidase AntiBodies (ATA), anti-SS-A, and anti-SS-B AntiBodies.
Quantitative MRI analysis was performed in a subgroup of MS patients measuring T2-lesion volume (LV), T1 black hole LV and Brain Parenchymal Fraction (BPF).
A total of 137 patients (mean age 44.7, 84% female) with either MS (n=111; age: mean 46.5+/-S.D. 10.3 years; disease duration: mean 13.0+/-S.D. 10.4 years; EDSS: mean 3.2+/-S.D. 1.9) or CIS (n=26; age: mean 37.7+/-S.D. 7.8 years; disease duration: mean 1.3+/-S.D. 1.1 years; EDSS: mean 1.0+/-S.D. 0.7) were enrolled.
Among MS patients, 82 were RRMS, 26 SPMS, and 3 had PPMS.
Seventy-seven (69%) of MS patients showed presence of one or more ARAB. The proportion of MS patients with APLA was 55% (61 patients); IgM subtype was most frequent. Co-occurrence of ACA and APE was more frequent in SPMS as compared to RRMS (15.4% vs. 1.2%, p=0.012).
The proportion of CIS patients with ARAB was 75% with IgM subtype being the most frequent.
However, the ARAB in majority of CIS patients (9 out of 14, 64%) were transient on repeated testing.
In a subgroup of 62 MS patients, quantitative MRI analysis showed significantly higher T2-LV in patients with positive APLA (15.1 ml for APLA positive vs. 6.75 ml for APLA negative) after correcting for the disease duration (p=0.048).
The patients with ATA also had significantly higher T2-LV after correction for disease duration (19.0 ml vs.8.5, p=0.044).
ARAB were present in more than two thirds of MS and CIS patients although most of APLA in CIS were transient. The presence of APLA in MS patients was associated with higher T2-LV.
Brass SD, Benedict RH, Weinstock-Guttman B, Munschauer F, Bakshi R
Mult Scler 2006 Aug;12(4):437-44
Brigham & Women's Hospital, Harvard Medical School, Department of Neurology, Center for Neurological Imaging, Partners Multiple Sclerosis Center, Boston, MA 02115, USA
Gray Matter hypointensity on T2-weighted Magnetic Resonance Imaging (MRI) scans, suggesting Iron deposition, has been described in Multiple Sclerosis (MS) and is related to physical disability, disease course and Brain Atrophy.
We tested the hypothesis that SubCortical Gray Matter T2 HypoIntensity is related to Cognitive Impairment after adjusting for the effect of MRI lesion and Atrophy measures. We studied 33 patients with MS and 14 healthy controls.
Normalized T2 signal intensity in the Caudate, Putamen, Globus Pallidus and Thalamus, total Brain T1-HypoIntense lesion volume (T1LV), Fluid-Attenuated Inversion-Recovery-HyperIntense Lesion Volume (FLLV) and Brain Parenchymal Fraction (BPF) were obtained quantitatively.
A NeuroPsychological Composite Score (NCS) encompassed New Learning, Attention, Working Memory, Spatial Processing and Executive Function.
In each of the regions of interest, the normalized T2 intensity was lower in the MS versus control group (all P < 0.001). Regression modelling tested the relative association between all MRI variables and NCS.
Globus Pallidus T2 HypoIntensity was the only variable selected in the final model (R2 = 0.301, P = 0.007).
Pearson correlations between MRI and NCS were T1LV: r = -0.319; FLLV: r = -0.347; BPF: r = 0.374; T2 HypoIntensity of the Caudate: r = 0.305; Globus Pallidus: r = 0.395; Putamen: r = 0.321; and Thalamus: r = 0.265.
Basal Ganglia T2 HypoIntensity and BPF demonstrated the strongest associations with Cognitive Impairment on individual Cognitive subtests.
SubCortical Gray Matter T2 HypoIntensity is related to Cognitive Impairment in MS, supporting the clinical relevance of T2 HypoIntensity as a biological marker of MS tissue damage.
These data implicate a role for Basal Ganglia Iron deposition in NeuroPsychological Dysfunction.
Garg N, Weinstock-Guttman B, Bhasi K, Locke J, Ramanathan M
Mult Scler 2007 Aug;13(7):895-9
Jacobs Neurological Institute, Buffalo General Hospital, Buffalo, NY, USA
Approximately 5-25% of Interferon-beta (IFN-ß) treated Multiple Sclerosis (MS) patients develop anti-IFN-ß Neutralizing AntiBodies (NAb) but the patient-specific variables associated with the risk of developing Anti-IFN-ß AntiBodies are poorly understood.
Anti-IFN-ß NAb are a subset of anti-IFN-ß binding AntiBodies (BAb) and all patients with NAb generally have high levels of associated BAb.
The purpose of this research was to assess the association between AutoReactive AntiBodies (ARAB) and the risk of developing Anti-IFN-ß BAb in MS patients.
This was a retrospective study that included consecutive patients diagnosed with clinically definite MS evaluated at our center and considered appropriate for IFN-ß therapy.
The patients were tested for various subtypes of AntiPhosphoLipid AntiBodies (APLA) including Anti-PhosphatidylEthanolamine (APE), Anti-PhosphatidylSerine (APS), and Anti-Cardiolipin (ACA) AntiBodies, and other ARAB, AntiNuclear and Anti-Neutrophilic Cytoplasmic AntiBodies, Anti-Thyroid Peroxidase AntiBodies (ATA), anti-SS-A and anti-SS-B AntiBodies.
BAb levels were assessed using a commercial binding ELISA assay. A total of 33 patients (mean age: 45.4 years, 85% female) were enrolled; 15 patients were negative and 18 patients were positive for BAb.
APLA or ATA were present in 95% (17 of 18 patients) of patients positive for BAb.
In comparison, APLA or ATA occurred in only 27% (four of 15 patients) of patients in the BAb negative group.
The associations between the occurrence of BAb and the occurrence of high APLA or ATA were significant (chi(2)=13.4, P < 0.001 in Fisher exact test).
The odds ratio for the association was 46.8 (with a 95% confidence interval range of 4.6-475). No significant correlations were found for other ARAB.
The presence of AutoReactive AntiBodies, particularly APLA and ATA is associated with increased risk of occurrence of IFN-ß BAb in MS patients on long-term IFN-ß therapy.