Resistance Of Human Adult Oligodendrocytes To AMPA/Kainate Receptor-Mediated Glutamate Injury
Wosik K, Ruffini F, Almazan G, Olivier A, Nalbantoglu J, Antel JP
Brain 2004 Dec;127(Pt 12):2636-487
Montreal Neurological Institute, NeuroImmunology Unit, Montreal, Quebec, Canada
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.
CSF Nitric Oxide Metabolites Are Associated With Activity And Progression Of Multiple Sclerosis
Rejdak K, Eikelenboom MJ, Petzold A, Thompson EJ, Stelmasiak Z, Lazeron RH, Barkhof F, Polman CH, Uitdehaag BM, Giovannoni G
Neurology 2004 Oct 26;63(8):1439-45
Institute of Neurology, Department of NeuroInflammation, London, UK
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).
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.
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).
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.
Treatment Of Multiple Sclerosis With An Anti-InterLeukin-2 Receptor MonoClonal AntiBody
Rose JW, Watt HE, White AT, Carlson NG
Ann Neurol 2004 Oct 20
VA Salt Lake City Health Care System, NeuroVirology Research Laboratory
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.
Interferon-beta-1a For Brain Tissue Loss In Patients At Presentation With Syndromes Suggestive Of Multiple Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial
Filippi M, Rovaris M, Inglese M, Barkhof F, De Stefano N, Smith S, Comi G
Lancet 2004 Oct 23;364(9444):1489-96
Scientific Institute and University Ospedale San Raffaele, NeuroImaging Research Unit, Department of Neurology, Milan, Italy
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.
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.
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.
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.
Voxel-Based Analysis Of MTR Images: A Method To Locate Gray Matter Abnormalities At The Earliest Stage Of Multiple Sclerosis
Audoin B, Ranjeva JP, Duong MV, Ibarrola D, Malikova I, Confort-Gouny S, Soulier E, Viout P, Ali-Cherif A, Pelletier J, Cozzone PJ
J Magn Reson Imaging 2004 Nov;20(5):765-71
Centre de Resonance Magnetique Biologique et Medicale (CRMBM), UMR CNRS 6612, Faculte de Medecine, Marseille, France
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.
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.
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.
Evidence For Gray Matter MTR Abnormality In Minimally Disabled Patients With Early Relapsing/Remitting Multiple Sclerosis
Davies GR, Ramio-Torrenta L, Hadjiprocopis A, Chard DT, Griffin CM, Rashid W, Barker GJ, Kapoor R, Thompson AJ, Miller DH
J Neurol NeuroSurg Psychiatry 2004 Jul;75(7):998-1002
Institute of Neurology, University College London, NMR Research Unit, Queen Square, London, UK
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.
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.
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).
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.
Magnetization Transfer Ratio Histogram Analysis Of Normal-Appearing Gray Matter And Normal-Appearing White Matter In Multiple Sclerosis
Ge Y, Grossman RI, Udupa JK, Babb JS, Mannon LJ, McGowan JC
J Comput Assist Tomogr 2002 Jan-Feb;26(1):62-8
New York University School of Medicine, Department of Radiology, New York, NY 10016, USA
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.
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.
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.
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.