Diffusion Tensor Imaging In Multiple Sclerosis: Assessment Of Regional Differences In The Axial Plane Within Normal-Appearing Cervical Spinal Cord
Hesseltine SM, Law M, Babb J, Rad M, Lopez S, Ge Y, Johnson G, Grossman RI
AJNR Am J NeuroRadiol 2006 Jun-Jul;27(6):1189-93
New York University Medical Center, Department of Radiology, 530 First Avenue, New York, NY 10016, USA
Background And Purpose
Evaluation of the Spinal Cord is important in the diagnosis and follow-up of patients with Multiple Sclerosis.
Our purpose was to investigate Diffusion Tensor Imaging (DTI) changes in different regions of Normal-Appearing Spinal Cord (NASC) in Relapsing/Remitting Multiple Sclerosis (RRMS).
Axial DTI of the Cervical Spinal Cord was performed in 24 patients with RRMS and 24 age- and sex-matched control subjects.
Fractional Anisotropy (FA) and Mean Diffusivity (MD) were calculated in separate Regions Of Interest (ROIs) in the Anterior, Lateral, and Posterior Spinal Cord, bilaterally, and the Central Spinal Cord, at the C2-C3 level.
Patients and control subjects were compared with respect to FA and MD with the use of an exact Mann-Whitney test. Logistic regression and receiver operating characteristic (ROC) curve analysis assessed the utility of each measure for the diagnosis of RRMS.
DTI metrics in areas of NASC in MS were significantly different in patients compared with control subjects:
FA was lower in the Lateral (mean +/- SD of 0.56 +/- 0.10 versus 0.69 +/- 0.09 in control subjects, P < .0001), Posterior (0.52 +/- 0.11 versus 0.63 +/- 0.10, P < .0001), and Central (0.53 +/- 0.10 versus 0.58 +/- 0.10, P = .049) NASC ROIs.
Assessing DTI metrics in the diagnosis of MS, a sensitivity of 87.0% (95% confidence interval [CI], 66.4 to 97.1) and a specificity of 91.7% (95% CI, 73.0 to 98.7) were demonstrated.
The NASC in RRMS demonstrates DTI changes. This may prove useful in detecting occult Spinal Cord pathology, predicting clinical course, and monitoring disease progression and therapeutic effect in MS.
Nodal, ParaNodal And JuxtaParaNodal Axonal Proteins During DeMyelination And ReMyelination In Multiple Sclerosis
Coman I, Aigrot MS, Seilhean D, Reynolds R, Girault JA, Zalc B, Lubetzki C
Brain 2006 Jun 9
INSERM U711, Hopital de la Salpetriere, Federation des maladies du systeme nerveux, Paris, France; Universite Pierre & Marie Curie (UPMC Paris 6), Hopital de la Salpetriere, Federation des maladies du systeme nerveux, Paris, France; AP-HP, Hopital de la Salpetriere, Federation des maladies du systeme nerveux, Paris, France
Saltatory Conduction in Myelinated fibers depends on the specific molecular organization of highly specialized Axonal domains at the Nodes of Ranvier, the ParaNodal and the JuxtaParaNodal regions.
Voltage-gated Sodium Channels (Nav) have been shown to be deployed along the naked DemMyelinated Axon in experimental models of CNS DeMyelination and in Multiple Sclerosis lesions.
Little is known about aggregation of Nodal, ParaNodal and JuxtaParaNodal constituents during the repair process.
We analyzed by ImmunoHistoChemistry on free-floating sections from Multiple Sclerosis Brains the expression and distribution of Nodal (Nav channels), ParaNodal (ParaNodin/Caspr) and JuxtaParaNodal (Kv channels and Caspr2) molecules in DeMyelinated and ReMyelinated lesions.
Whereas in DeMyelinated lesions, ParaNodal and JuxtaParaNodal proteins are diffusely distributed on denuded Axons, the distribution of Nav channels is heterogeneous, with a diffuse ImmunoReactivity but also few broad Nav channel aggregates in all DeMyelinated lesions.
In contrast to the DeMyelinated plaques, all ReMyelinated lesions are characterized by the detection of aggregates of Nav channels, ParaNodin/Caspr, Kv channels and Caspr2.
Our data suggest that these aggregates precede ReMyelination, and that Nav channel aggregation is the initial event, followed by aggregation of ParaNodal and then JuxtaParaNodal Axonal proteins.
ReMyelination takes place in Multiple Sclerosis tissue but Myelin repair is often incomplete, and the reasons for this ReMyelination deficit are many.
We suggest that a defect of Nav channel aggregation might be involved in the ReMyelination failure in DeMyelinated lesions with spared Axons and Oligodendroglial Cells.
A Subtype Of Multiple Sclerosis Defined By An Activated Immune Defense Program
van Baarsen LG, van der Pouw Kraan TC, Kragt JJ, Baggen JM, Rustenburg F, Hooper T, Meilof JF, Fero MJ, Dijkstra CD, Polman CH, Verweij CL
Genes Immun 2006 Jul 13
VU Medical Center, Department of Molecular Cell Biology & Immunology, Amsterdam, The Netherlands
Given the heterogeneous nature of Multiple Sclerosis (MS), we applied DNA microarray technology to determine whether variability is reflected in Peripheral Blood (PB) Cells.
In this study, we studied whole-blood gene expression profiles of 29 patients with Relapsing/Remitting MS (RRMS) and 25 age- and sex-matched healthy controls. We used microarrays with a complexity of 43K cDNAs.
The data were analyzed using sophisticated pathway-level analysis in order to provide insight into the deregulated peripheral Immune Response programs in MS.
We found a remarkable elevated expression of a spectrum of genes known to be involved in Immune defense in the PB of MS patients compared to healthy individuals.
Cluster analysis revealed that the increased expression of these genes was characteristic for approximately half of the patients.
In addition, the gene signature in this group of patients was comparable with a Virus response program.
We conclude that the transcriptional signature of the PB Cells reflects the heterogeneity of MS.
And defines a sub-population of RRMS patients, who exhibit an activated Immune defense program that resembles a Virus response program, which is supportive for a link between Viruses and MS.
Genes and Immunity 13 July 2006; doi:10.1038/sj.gene.6364324.
Ann Pharmacother 2006 Jun;40(6):1158-61
The University of Montana, College of Health Professions and Biomedical Sciences, Skaggs School of Pharmacy, Drug Information Service, Missoula, 59812-1522, USA
To evaluate the literature about the role of Vitamin D in the prevention and treatment of Multiple Sclerosis (MS).
MEDLINE (1966-April 2006) and International Pharmaceutical Abstracts (1970-April 2006) searches were performed. In addition, pertinent references from identified articles were obtained.
Vitamin D supplementation prevented the development and progression of Experimental Autoimmune Encephalitis, an animal model of MS, in mice.
A large, prospective, cohort study found that Vitamin D supplementation was associated with a 40% reduction in the risk of developing MS.
Four small, noncontrolled studies suggested that Vitamin D supplementation may decrease exacerbation of MS symptoms.
Vitamin D supplementation may help prevent the development of MS and may be a useful addition to therapy.
However, current studies are in small populations and are confounded by other variables, such as additional Vitamin and Mineral supplementation.
Bieniek M, Altmann DR, Davies GR, Ingle GT, Rashid W, Sastre-Garriga J, Thompson AJ, Miller DH
J Neurol NeuroSurg Psychiatry 2006 Jul 10
Institute of Neurology, United Kingdom
The onset of Multiple Sclerosis (MS) is Relapsing/Remitting (RR) or Primary/Progressive (PP).
An improved understanding of the causes of early progressive disability (PPMS) could provide mechanistic targets for therapeutic intervention.
Five MRI parameters were investigated that could potentially cause progressive disability in 43 patients with early PPMS and 37 with early RRMS:
Atrophy in Brain Gray Matter and White Matter; intrinsic abnormality in Brain Gray Matter and White Matter (measured by the Magnetization Transfer Ratio [MTR]}; and Atrophy of the Upper Cervical Spinal Cord. Both groups were also compared with healthy controls.
PPMS patients were older and more likely to be male. Both patient groups had Atrophy of Brain Gray Matter and White Matterr and intrinsic abnormality of Normal-Appearing Gray Matter and White Matter MTR.
Cord Atrophy was present only in the PPMS (mean Cord area:
- controls 73.4mm2, p=0.007)
This was confirmed by multivariate analysis of all 5 MRI parameters plus age and gender.
Brain Gray Matter and White Matter is abnormal in both early RR and PPMS, but Cord Atrophy is present only in PPMS.
This is concordant with Myelopathy being the usual clinical presentation of PPMS. Measurement of Cord Atrophy appears clinically relevant in PPMS treatment trials.
Intrathecal IgM Production At Clinical Onset Correlates With A More Severe Disease Course In Multiple Sclerosis
Perini P, Ranzato F, Calabrese M, Battistin L, Gallo P
J Neurol NeuroSurg Psychiatry 2006 Aug;77(8):953-5
University of Padova, Multiple Sclerosis Centre of the Veneto Region, Department of NeuroSciences, via Giustiniani 1 Padova 35128, Italy
The Intrathecal synthesis of IgM, determined at clinical onset in patients with Multiple Sclerosis, was found to correlate with the degree of disability (as evaluated by means of the Expanded Disability Status Scale) reached 15 years later (p < 0.001).
Moreover, a significant inverse correlation was observed between the value of the IgM index and time to the first relapse (p < 0.001) and the initiation of the Progressive phase of the disease (p = 0.01).
The prognostic value of IgM in the CSF is confirmed in previous reports as well as by our study.
If these findings are confirmed in patients with Multiple Sclerosis in a larger series, a helpful biological marker for selecting patients for ImmunoModulatory treatments will be available to Neurologists.
Long-Term Favorable Response To Interferon-ß-1b Is Linked To Cytokine Deviation Toward The Th2 And Tc2 Sides In Japanese Patients With Multiple Sclerosis
Mei FJ, Osoegawa M, Ochi H, Minohara M, Nan S, Murai H, Ishizu T, Taniwaki T, Kira J
J Neurol Sci 2006 Jul 15;246(1-2):71-7
Kyushu University, Graduate School of Medical Sciences, Department of Neurology, Neurological Institute, Fukuoka 812-8582, Japan
To address the Immune mechanism of the long-term beneficial effects of Interferon-beta (IFN-ß), we measured the IntraCellular Cytokine production patterns of IFN-γ, IL-4 and IL-13 in peripheral blood CD4+ and CD8+ T-Cells.
Which, previously displayed alterations during the early course of IFN-ß treatment, in 15 Japanese patients after long-term IFN-ß administration.
The patients were treated with IFN-ß-1b 8 x 10(6) units given subcutaneously every other day for a mean period of 34.5 +/- 5.5 months (range: 26-43 months).
During the follow-up period, 6 patients experienced 33 relapses, while the other 9 were relapse-free.
The results revealed the following Cytokine alterations:
(1) type 2 Cytokine, such as IL-4 and IL-13, were significantly increased in producing cell percentages in both CD4+ (p = 0.0356 and p = 0.0007, respectively) and CD8+ (p = 0.0231 and p = 0.0170, respectively). T-Cells
While IFN-γ, a representative type 1 Cytokine, was significantly decreased in the absolute producing cell numbers (p = 0.0125 in CD4+ T-Cells and p = 0.0022 in CD8+ T-Cells).
Even after approximately 3 years of IFN-ß administration;
(2) the IntraCellular IFN-γ / IL-4 ratio tended to decrease in both CD4+ and CD8+ T-Cells (p = 0.0535 and p = 0.0783, respectively), reflecting a strong downmodulation of type 1 Cytokine producing cells.
And importantly, (3) alterations such as the decreased IntraCellular IFN-γ / IL-4 ratio in CD4+ T-Cells and increased percentage of CD8+ IL-13+ T-Cells compared with the pretreatment levels were only statistically significant in MS patients without relapse during IFN-ß therapy (p = 0.0152 and p = 0.0078, respectively).
Therefore, we consider that Cytokine deviation toward the Th2 and Tc2 sides is linked to a long-term favorable response to IFN-ß.
While a higher IntraCellular IFN-γ / IL-4 ratio is associated with treatment failure.