Bot JC, Barkhof F, Polman CH, Lycklama a Nijeholt GJ, de Groot V, Bergers E, Ader HJ, Castelijns JA
Neurology 2004 Jan 27;62(2):226-33
MR Center for MS Research, Departments of Radiology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands
The most recent diagnostic criteria for Multiple Sclerosis (MS) ascertain that findings from Spinal Cord MRI can be used to demonstrate dissemination in space.
Because little is known about the prevalence and characteristics of Cord lesions early in the disease, the authors studied the prevalence of Spinal Cord abnormalities in patients with early-stage MS and assessed their impact on diagnostic classification.
The Brains and Spinal Cords of 104 recently diagnosed patients with MS were examined. Median interval between first symptom and diagnosis was 18.4 months.
The Brain MRI protocol included before and after Gadolinium Axial T1-weighted conventional Spin-Echo sequences and Dual-Echo Spin-Echo images.
For Spinal Cord MRI, Sagittal cardiac-triggered Dual-Echo T2-weighted and Sagittal T1-weighted Spin-Echo images were included.
Clinical assessment for each patient included age, sex, clinical signs for Spinal Cord involvement, and Expanded Disability Status Scale.
Abnormal Cord MRIs were found in 83% of patients, usually with only focal lesions. Diffuse Cord Abnormalities were found in 13% of patients, although in isolation they were found in only three patients.
Focal Cord lesions were often multiple (median number, 3.0), small (median, 0.8 Vertebral Segments), and primarily (56.4%) situated in the Cervical Spinal Cord. In 68 of 104 patients (65.4%), two or more focal lesions were visible on Spinal Cord images.
The criteria for dissemination in space, as defined in the McDonald Criteria for the Brain, were met in only 66.3% of the patients. This percentage increased to 84.6% when Spinal Cord MRI abnormalities were also included.
Spinal Cord abnormalities are prevalent in patients with early-stage MS, have distinct morphologic characteristics, and help to determine dissemination in space at time of diagnosis.
Multiple Sclerosis As A Generalized CNS Disease - Comparative Microarray Analysis Of Normal-Appearing White Matter And Lesions In Secondary/Progressive MS
Lindberg RL, De Groot CJ, Certa U, Ravid R, Hoffmann F, Kappos L, Leppert D
J NeuroImmunol 2004 Jul;152(1-2):154-67
University Hospitals Basel, Clinical NeuroImmunology Laboratory, Departments of Research and Neurology, Pharmazentrum, Klingelbergstrasse 50, CH-4056 Basel, Switzerland
We used microarrays to compare the gene expression profile in active lesions and donor-matched Normal-Appearing White Matter (NAWM) from Brain autopsy samples of patients with Secondary/Progressive Multiple Sclerosis (MS).
With that from controls who died from Non-Neurological Diseases. The 123 Genes in lesions, and 47 genes in NAWM were differentially expressed.
Lesions distinguished from NAWM by a higher expression of Genes related to ImmunoGlobulin synthesis and Neuroglial differentiation, while Cellular Immune Response elements were equally dysregulated in both tissue compartments.
Current results provide molecular evidence of a continuum of dysfunctional homeostasis and inflammatory changes between lesions and NAWM, and support the concept of MS pathogenesis being a generalized process that involves the entire CNS.
A Method For The Analysis Of The Geometrical Relationship Between White Matter Pathology And The Vascular Architecture Of The Brain
Kozinska D, Holland CM, Krissian K, Westin CF, Guttmann CR
NeuroImage 2004 Aug;22(4):1671-8
Center for Neurological Imaging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
A novel method for the visual and quantitative analysis of the geometrical relationship between the Vascular architecture of the Brain and White Matter Pathology is presented.
The Cerebro Vascular System is implicated in the pathogenesis of many diseases of the Cerebral White Matter, for example, Stroke, MicroCerebroVascular Disease, and Multiple Sclerosis (MS).
In our work, White Matter lesions and Vessels are depicted using Magnetic Resonance Imaging (MRI) and extracted using image analysis techniques. We focus on measuring distance relationships between White Matter lesions and Vessels, and distribution of lesions with respect to Vessel Caliber.
Vascular distance maps are generated by computing for each voxel the Euclidean distance to the closest vessel. Analogously, radius maps assign the radius of the closest vessel to each Voxel in the image volume.
The distance and radius maps are used to analyze the distribution of lesions with respect to the vessels' locations and their calibers. The method was applied to three MS patients to demonstrate its functionality and feasibility.
Preliminary findings indicate that larger MS lesions tend to be farther from detected vessels and that the caliber of the vessels nearest to larger lesions tends to be smaller, suggesting a possible role of relative HypoPerfusion or Hypoxia in lesion formation.
Kealey SM, Kim Y, Provenzale JM
AJR Am J RoentGenol 2004 Aug;183(2):497-503
Duke University Medical Center, Department of NeuroRadiology, Box 3808, Erwin Rd., Durham, NC 27710, USA
We used Diffusion Tensor MRI to redefine the size of Multiple Sclerosis (MS) plaques on Fractional Anisotropy (FA) maps.
Materials And Methods
Thirty-six White Matter (WM) plaques were identified in 20 patients with MS. Plaque FA was measured by placing Regions Of Interest (ROIs) on plaques on Diffusion Tensor images.
We compared FA values in identical mirror-image ROIs placed on Normal-Appearing WM in the ContraLateral Hemisphere.
This comparison showed a mean decrease in FA of 41% in plaques, serving as the threshold for outlining abnormal regions in Normal-Appearing WM surrounding plaques. ROIs were placed around each plaque and FA values were compared with those in the mirror-image ROIs.
Combined areas of PeriLesional Normal-Appearing WM with 40% or more FA reduction plus plaque were compared with the areas of abnormality on T2-weighted images using a paired Student's t test. A p value of 0.05 or less was considered significant.
Mean plaque area was 60 mm(2) (range, 15-103 mm(2)), mean plaque FA was 0.251 (range, 0.133-0.436), and mean FA of ContraLateral Normal-Appearing WM was 0.429 (range, 0.204-0.712).
Applying a threshold of 40% FA reduction, mean combined area of abnormal WM (including plaque seen on T2-weighted sequences) was 87 mm(2) (range, 30-251 mm(2)) or 145% of the mean Plaque area that was seen on T2-weighted images (p < 0.001).
Using an operator-defined threshold of abnormal FA values based on plaque Anisotropy characteristics, we saw a statistically significant increase in plaque size.
J Clin NeuroSci 2004 Sep;11(7):689-92
The University of Queensland, School of Medicine, NeuroImmunology Research Centre, Australia; Royal Brisbane and Women's Hospital, Department of Neurology, Herston, Qld., Australia
Primary/Progressive Multiple Sclerosis (MS) differs from the more common form of MS which has an initial Relapsing/Remitting course in a number of ways, including pathological features, clinical course, differential diagnosis and response to treatment.
The lesions in Primary/Progressive MS tend to be more diffuse, less inflammatory and less likely to ReMyelinate than those occurring in Relapsing/Remitting MS and Secondary/Progressive MS; there are also fewer focal lesions in the Brain in Primary/Progressive MS.
Recent evidence suggests that AntiBodies to Central Nervous System (CNS) Antigens have an important role in disease progression. Such AntiBodies could cause DeMyelination, inhibit ReMyelination and cause Axonal destruction.
Ongoing Immune attack by AutoAntiBody and lack of CNS repair could be responsible for the gradually increasing disability in Primary/Progressive MS.
Further research on the B-Cell and AutoAntiBody response in Primary/Progressive MS might lead to advances in diagnosis and treatment. Inhibition of AutoAntiBody production by inducing B-Cell Apoptotic with Rituximab is a potential new therapy for Primary/Progressive MS.
Thyroid Hormone Administration Enhances ReMyelination In Chronic DeMyelinating Inflammatory Disease
Fernandez M, Giuliani A, Pirondi S, D'Intino G, Giardino L, Aloe L, Levi-Montalcini R, Calza L
Proc Natl Acad Sci USA 2004 Nov 8
University of Bologna, Department of Veterinary MorphoPhysiology and Animal Production, 40064 Ozzano Emilia, Bologna, Italy; PathoPhysiology Center for the Nervous System, Hesperia Hospital, 41100 Modena, Italy
Chronic disabilities in Multiple Sclerosis are believed to be due to Neuron damage and degeneration, which follow ReMyelination failure.
Due to the presence of numerous Oligodendrocyte Precursors inside DeMyelination plaques, one reason for DeMyelination failure could be the inability of Oligodendrocyte Precursor Cells to turn into Myelinating Oligodendrocytes.
In this study, we show that Thyroid Hormone enhances and accelerates ReMyelination in an experimental model of chronic DeMyelination, i.e., Experimental Allergic Encephalomyelitis in congenic female Dark Agouti rats immunized with complete guinea pig Spinal Cord.
Thyroid Hormone, when administered during the acute phase of the disease, increases expression of platelet-derived Growth Factor alpha Receptor, restores normal levels of Myelin Basic Protein mRNA and protein
And, allows an early and Morphologically competent reassembly of Myelin Sheaths. Moreover, Thyroid Hormone exerts a NeuroProtective effect with respect to Axonal pathology.
Kim HJ, Ifergan I, Antel JP, Seguin R, Duddy M, Lapierre Y, Jalili F, Bar-Or A
J Immunol 2004 Jun 1;172(11):7144-53
McGill University, Montreal Neurological Institute, NeuroImmunology Unit, Montreal, Quebec, Canada
Glatiramer Acetate (GA) therapy of patients with Multiple Sclerosis (MS) represents a unique setting in which in vivo Th2 deviation of T-Cells is consistently observed and associated with clinical benefit in a human AutoImmune Disease.
We postulated that APCs are important targets of GA therapy and demonstrate that treatment of MS patients with GA reciprocally regulates the IL-10/IL-12 Cytokine Network of Monocytes in vivo.
We further show that Th1- or Th2-polarized GA-reactive T-Cells isolated from untreated or treated MS patients mediate Type 1 and 2 APC differentiation of human Monocytes, based on their ability to efficiently induce subsequent Th1 and Th2 deviation of naive T-Cells, respectively.
These observations are extended to human Microglia, providing the first demonstration of Type 2 differentiation of CNS-derived APCs.
Finally, we confirm that the fundamental capacity of polarized T-Cells to reciprocally modulate APC function is not restricted to GA-reactive T-Cells, thereby defining a novel and dynamic positive feedback loop between human T-Cell and APC responses.
In the context of MS, we propose that GA therapy results in the generation of Type 2 APCs, contributing to Th2 deviation both in the periphery and in the CNS of MS patients.
In addition to extending insights into the therapeutic mode of action of GA, our findings revisit the concept of bystander suppression and underscore the potential of APCs as attractive targets for therapeutic Immune modulation.