Evidence Of Wallerian Degeneration In Normal-Appearing White Matter In The Early Stages Of Relapsing/Remitting Multiple Sclerosis: A HMRS Study
Casanova B, Martinez-Bisbal MC, Valero C, Celda B, Marti-Bonmati L, Pascual A, Landente L, Coret F
J Neurol 2003 Jan;250(1):22-8
Neurology Service, Hospital La Fe, Avd Campanar 21, Valencia 46009, Spain
Wallerian Degeneration in Normal-Appearing White Matter in early Relapsing/Remitting Multiple Sclerosis (RRMS), and its correlation with the number of relapses and disease duration.
Recent pathological studies have demonstrated Wallerian Degeneration in Normal-Appearing White Matter (NAWM) in Multiple Sclerosis (MS), in established RRMS, and in chronic MS.
However, the presence of Wallerian Degeneration early in the disease and its correlation with relapse and with disease duration has not been studied.
We performed Proton Magnetic Resonance Spectroscopic Imaging in 21 MS patients, and 4 healthy controls, age and gender matched, aged under 45 years, with a maximum of 4 years since first bout.
And, an EDSS score of less than 3.0. N-AcetylAspartate (NAA) (an index of Axonal integrity) was measured in the NAWM from the Pons and the Cerebellar Peduncles.
We observed that the NAA levels were abnormally low in the NAWM in the early RRMS patients (p = 0.04, Student's t-test).
The decrease in the NAA concentration correlated with disease duration in the two areas studied (p = 0.03 for Pons and p = 0.04 for Cerebellar Peduncle); and with the number of previous relapses (Pearson's correlation = -0.582, p < 0.002).
Wallerian Degeneration measured by the NAA concentration at Pons and Cerebellar Peduncles is present early in the disease and correlates with the number of relapses and disease duration.
Diffusely Elevated Cerebral Choline And Creatine In Relapsing/Remitting Multiple Sclerosis
Inglese M, Li BS, Rusinek H, Babb JS, Grossman RI, Gonen O
Magn Reson Med 2003 Jul;50(1):190-5
New York University School of Medicine, Department of Radiology, New York, New York 10016, USA
It is well known that Multiple Sclerosis (MS) pathogenesis continues even during periods of clinical silence.
To quantify the metabolic characteristics of this activity we compared the absolute levels of N-AcetylAspartate (NAA), Creatine (Cr), and Choline (Cho) in the Normal-Appearing White Matter (NAWM) between Relapsing/Remitting (RR) MS patients and controls.
Metabolite concentrations were obtained with 3D proton MR Spectroscopy at 1.5 T in a 480 cm(3) Volume-Of-Interest (VOI), centered on the Corpus Callosum of 11 MS patients and 9 matched controls.
Gray/White-Matter/Cerebral-Spinal-Fluid (CSF) volumes were obtained from MRI segmentation.
Patients' average VOI tissue volume (V(T)), 410.8 +/- 24.0 cm(3), and metabolite levels, NAA = 6.33 +/- 0.70, Cr = 4.67 +/- 0.52, Cho = 1.40 +/- 0.17 mM, were different from the controls by -8%, -9%, +22% and +32%.
The Cho level was the only single metric differentiating patients from controls at 100% specificity and > 90% sensitivity.
Diffusely elevated Cho and Cr probably reflect widespread microscopic inflammation, Gliosis, or De- and ReMyelination in the NAWM.
Both metabolites are potential prognostic indicators of current disease activity, preceding NAA decline and Atrophy.
Copyright 2003 Wiley-Liss, Inc.
From Inflammation To Degeneration: The Lessons Of Clinical Trials
Neurol Sci 2003 Dec;24 Suppl 5:S295-7
Universita Vita Salute IRCCS S. Raffaele, Department of Neurology, Milan, Italy
About two-third of patients with Multiple Sclerosis (MS) accumulate severe disabilities before the age of 50. Disability depends mostly on Axonal Loss even if persistent Conduction Block also may be a contributing factor.
Axonal Loss is predominant in the early phase of the disease and is strictly related to the inflammatory activity.
In this phase the Axonal damage is mostly, if not exclusively, determined by Axonal transection inside the lesions, so that reduction of the lesion rate results in a proportional effect of the irreversible tissue damage.
With disease evolution, the redundancy of the Central Nervous System (CNS) starts to be insufficient to compensate the Axonal Loss resulting from reactivation (or persistence at a low degree) of inflammatory activity inside the lesions.
Secondary Axonal Degeneration of Axons damaged by previous attacks and (possibly) by a primitive Axonal Degeneration. In this phase of the disease, most of the irreversible damage does not depend on new lesions.
As a consequence, the reduction of disease activity produces only marginal efforts on Nervous Tissue degeneration.
Clinical trials demonstrate that the positive effect of ImmunoModulatory and AntiInflammatory therapies is maximal in patients with Clinically Isolated Syndromes.
And, it starts to decrease in Relapsing/Remitting phases and is almost lost in Secondary/Progressive phases. From the practical point of view, early treatment is mandatory.
CD83+ Dendritic Cells Are Present In Occasional Perivascular Cuffs In Multiple Sclerosis Lesions
Plumb J, Armstrong MA, Duddy M, Mirakhur M, McQuaid S
Mult Scler 2003 Mar;9(2):142-7
Royal Group of Hospitals Trust, NeuroPathology Laboratory, Belfast, Northern Ireland, UK
Multiple Sclerosis (MS) has a wide spectrum of clinical courses, characterized by multifocal Central Nervous System (CNS) damage, postulated to be mediated by CNS Antigen-specific T-Cells.
Dendritic Cells (DC), the most potent Antigen-Presenting Cell, play a pivotal role in the decision between T-Cell activation or Anergy.
MonoClonal AntiBodies to CD1a+ (immature DC) and CD83+ (mature DC) were used to screen lesions with evidence of recent DeMyelinating activity.
And chronic plaque and Normal-Appearing White Matter (NAWM) tissue sections from 12 MS cases by ImmunoCytoChemistry. No CD1a+ Cells were detected in the MS or control CNS tissue blocks investigated.
CD83+ Cells were not detected in tissues from any of the control cases or in the majority of PeriVascular Cuffs in the MS tissue sections.
However; in eight of the MS tissue blocks with evidence of recent DeMyelination, and in one block each from chronic plaque and NAWM, small numbers of distinct CD83+ Cells were present within occasional PeriVascular Cuffs.
In one area only of MS NAWM were CD83+ Cells detected in the tissue Parenchyma, in an area of intense Immunological activity.
DC in MS tissue may originate in the peripheral circulation as Monocytes or immature DC and migrate to areas of plaque in response to signals received from CNS-produced Chemokines.
Nippon Rinsho 2003 Aug;61(8):1402-8
Tokyo Medical and Dental University Graduate School, Department of Neurology and Neurological Science
The Blood-Brain Barrier(BBB) restricts exchanges of soluble factors and cells between the blood and Brain, thus playing a crucial role in maintenance of Cerebral homeostasis.
In Multiple Sclerosis (MS), disruption of the BBB is the initial key step in the development of inflammatory lesions. BBB impairment may occur before the formation of DeMyelinative foci or T-Cell infiltration around small vessels.
However, once the BBB breaks, massive infiltration of T-Cells, augmented expression of Adhesion Molecules on Endothelial Cell surface, and leakage of inflammatory Cytokines and AntiBodies will aggravate the MS lesions.
Although GlucoCorticoids and Type 1 Interferons are now widely used and are known to decrease BBB permeability additively, the development of novel therapeutic strategy focusing on the repairment of BBB integrity should be awaited.
Inflammation And Degeneration In Multiple Sclerosis
Bruck W, Stadelmann C
Multiple Sclerosis (MS) is a chronic Inflammatory DeMyelinating Disease of the Central Nervous System with the pathological hallmarks of Inflammation, DeMyelination, Axon Loss and Gliosis.
Neurol Sci 2003 Dec;24 Suppl 5:S265-7
Georg-August-Universitat Gottingen, Department of NeuroPathology, Robert-Koch-Strasse 40, D-37075, Gottingen, Germany
In the initial Relapsing/Remitting phase of the disease, the Inflammatory-DeMyelinating component seems to predominate, whereas the Progressive disease appears to be characterized by a NeuroDegenerative component leading to extensive NeuroAxonal Damage in the MS Brain.
Axon Loss most likely determines the persistent Neurological deficit in Progressive MS. Recent studies pointed out that Axon Damage occurs early in the disease and during lesion development.
Two different phases of Axon degeneration were characterized, the first occurring during active Myelin breakdown and the second in chronic DeMyelinated plaques in which the naked Axon seems more susceptible to further damage.
The exact mechanisms and effector molecules of Axonal degeneration, however, are not yet defined, and an Axon-protective therapy has not yet been established.
Differential Expression Of CoStimulatory Molecules B7-1 And B7-2 On Microglial Cells Induced By Th1 And Th2 Cells In OrganoTypic Brain Tissue
Wolf SA, Gimsa U, Bechmann I, Nitsch R
Glia 2001 Dec; 36(3): 414-20
Humboldt University Hospital Charite, Institute of Anatomy, Department of Cell and NeuroBiology, Berlin, Germany
PMID# 11746777; UI# 21610737
AutoReactive T-Cells are involved in DeMyelination, NeuroDegeneration, and the recruitment of Peripheral Macrophages and nonspecific activated T-Cells in AutoImmune Diseases such as Multiple Sclerosis (MS).
The Ligation of CoStimulatory B7 molecules on Microglia with CD28+/CTLA-4+ on T-Cells is thought to be crucial to the onset and course of MS and its rodent model Experimental AutoImmune Encephalomyelitis (EAE).
It is currently unclear as to how far the nature of infiltrating T-Cells has an impact on the expression of the B7 molecules on Microglia, the resident Antigen-Presenting Cells (APCs) of the Brain.
We studied the expression of B7-1 and B7-2 on Microglia after encounter with preactivated Th1 and Th2 Cells from transgenic mice.
Whose T-Cells express a Receptor (TCR) either specific to Myelin Basic Protein (MBP) or Ovalbumin (OVA) using murine Organotypic Entorhinal-Hippocampal Slice Cultures (OEHSC).
Our main finding was that Th1 Cells downregulate the constitutive expression of B7-2 and induce B7-1 expression while Th2 Cells do not induce this B7-1 upregulation.
The main difference between MBP- and OVA-specific cells was seen in experiments were Th1 Cells had direct contact to APCs but not to Brain tissue.
In contrast to MBP-specific Th1 Cells, OVA-specific Th1 Cells required the addition of Antigen to upregulate B7-1 and downregulate B7-2.
When the cells were allowed to have contact to Brain tissue, no difference was seen in the pattern of B7 regulation between OVA- and MBP-specific T-Cells.
Our data suggest that T-Cells are able to modulate B7 expression on MicroGlial Cells in the Brain independent of Antigen presentation through TCR/MHC-II Ligation but presumably by soluble mediators.
Copyright 2001 Wiley-Liss, Inc.