Statins In The Treatment Of Central Nervous System Autoimmune Disease
Weber MS, Youssef S, Dunn SE, Prod'homme T, Neuhaus O, Stuve O, Greenwood J, Steinman L, Zamvil SS
J NeuroImmunol 2006 Sep;178(1-2):140-8
University of California, Department of Neurology and Program in Immunology, San Francisco, USA
Statins, inhibitors of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase, are widely prescribed for their Cholesterol-lowering properties to reduce Atherogenesis and CardioVascular morbidity.
Over recent years, Statins have also been shown to exert pleiotropic ImmunoModulatory effects that might be of therapeutic benefit in Autoimmune Disorders.
The primary mechanism by which Statins alter Immune function appears to be mediated through the inhibition of post-translational protein prenylation of small GTP-binding proteins and is largely independent of lipid-lowering.
In Experimental Autoimmune Encephalomyelitis (EAE), the mouse model for Multiple Sclerosis (MS), Statins prevent or reverse paralysis and were recently shown to exert synergistic benefit when combined with agents approved for MS therapy.
Based primarily upon the beneficial effects in EAE, Statins are now being tested in patients in MS clinical trials.
Kolln J, Ren HM, Da RR, Zhang Y, Spillner E, Olek M, Hermanowicz N, Hilgenberg LG, Smith MA, van den Noort S, Qin Y
J Immunol 2006 Oct 15;177(8):5652-8
University of California, Department of Neurology, Irvine, CA 92697, USA
Our previous results revealed that Igs in lesions and single chain variable fragment Abs (scFv-Abs) generated from clonal B-Cells in the CerebroSpinal Fluid (CSF) from patients with Multiple Sclerosis (MS) bind to Axons in MS Brains.
To study the Axonal Ags involved in MS, we identified the GlycoLytic Enzymes, TriosePhosphate Isomerase (TPI) and GAPDH, using Igs from the CSF and scFv-Abs generated from clonal B-Cells in the CSF and in lesions from MS patients.
Elevated levels of CSF-Abs to TPI were observed in patients with MS (46%), Clinically Isolated Syndrome (CIS) suggestive of MS (40%), Other Inflammatory Neurological Diseases (OIND; 29%), and Other Noninflammatory Neurological Diseases (ONIND; 31%).
Levels of GAPDH-reactive Abs were elevated in MS patients (60%), in patients with CIS (10%), OIND (14%), and ONIND (8%).
The coexistence of both AutoAntiBodies was detected in 10 MS patients (29%), and 1 CIS patient (3%), but not in patients with OIND/ONIND.
Two scFv-Abs generated from the CSF and from lesions of a MS Brain showed ImmunoReactivity to TPI and GAPDH, respectively. The findings suggest that TPI and GAPDH may be candidate Ags for an Autoimmune response to Neurons and Axons in MS.
Fainardi E, Castellazzi M, Bellini T, Manfrinato MC, Baldi E, Casetta I, Paolino E, Granieri E, Dallocchio F
Mult Scler 2006 Jun;12(3):294-301
Multiple Sclerosis Center, Section of Neurology, University of Ferrara, Arcispedale S. Anna, Corso della Giovecca 203, Ferrara 1-44100, Italy
In this study, we employed a sensitive activity assay system to measure CerebroSpinal Fluid (CSF) and Serum levels of active Matrix MetalloProteinase-9 (MMP-9).
In 37 Relapsing/Remitting (RR), 15 Secondary/Progressive (SP) and nine Primary/Progressive (PP) Multiple Sclerosis (MS) patients, grouped according to clinical and Magnetic Resonance Imaging (MRI) evidence of disease activity.
We also studied, as Neurological controls, 48 patients with Other Inflammatory Neurological Disorders (OIND) and 48 with Non-Inflammatory Neurological Disorders (NIND).
To assess active MMP-9/TIMP-1 circuit, CSF and Serum levels of MMP-9 Tissue Inhibitor TIMP-1 were quantified by ELISA in the same patient population.
CSF mean levels of active MMP-9, CSF active MMP-9/TIMP-1 ratios and Intrathecal active MMP-9 synthesis, as indicated by specific index, were more elevated in MS than in NIND (P < 0.05, < 0.02 and < 0.02, respectively).
Serum active MMP-9/TIMP-1 ratio was higher in MS (P < 0.01) and OIND (P < 0.02) than in NIND, and serum TIMP-1 concentrations were lower in MS than in NIND (P< 0.05).
More importantly, Serum active MMP-9 mean levels, Serum active MMP-9/TIMP-1 ratio and Intrathecal production of active MMP-9 were increased in MS patients with clinical (P < 0.001, < 0.001 and < 0.05, respectively) and MRI (P < 0.001, < 0.001 and < 0.02, respectively) disease activity.
Whereas, CSF mean concentrations of active MMP-9 and CSF active MMP-9/TIMP-1 ratio were enhanced only in MS patients with MRI evidence of disease activity (P < 0.02 and < 0.01, respectively).
Altogether, these findings suggest that a shift in MMP-9/TIMP-1 balance towards proteolytic activity of MMP-9 could be relevant in MS Immune dysregulation.
In addition, our results indicate that CSF and Serum levels of active MMP-9 may represent a potential surrogate biomarker for monitoring MS disease activity.
In particular, Serum active MMP-9/TIMP-1 ratio seems to be a very appropriate indicator of ongoing MS inflammation, since it is easily measurable.
Simon JH, Zhang S, Laidlaw DH, Miller DE, Brown M, Corboy J, Bennett J
J Magn Reson Imaging 2006 Nov;24(5):983-8
University of Colorado, Department of Radiology, Denver, Colorado, USA
Focal inflammatory/DeMyelinating lesions are thought to be the source of Wallerian Degeneration or other injury to local, transiting fiber tracts in the Brain or Spinal Cord in Multiple Sclerosis (MS).
A methodology is established to isolate connections between focal DeMyelinating lesions and intersecting fibers to permit explicit analyzes of the pathology of secondary fiber injury distant from the focal lesion.
Materials And Methods
A strategy is described and feasibility demonstrated in three patients with a Clinically Isolated Syndrome and positive MRI (at high risk for MS).
The strategy utilizes streamtube Diffusion Tractography to identify Neuronal fibers that intersect a focal lesion and pass through a region of interest, in this case the Corpus Callosum, where distal (to focal lesion) interrogation can be accomplished.
A sizeable fraction of the Normal-Appearing White Matter (NAWM) in the early stages of disease can be defined in the Corpus Callosum, which is distinctive in that this tissue connects to distant DeMyelinating lesions.
The new class of tissue called Fibers-At-Risk for degeneration (FAR) can be identified and interrogated by a variety of quantitative MRI methodologies to better understand Neuronal Degeneration in MS.
J. Magn. Reson. Imaging 2006. Published 2006 Wiley-Liss, Inc.
Howell OW, Palser A, Polito A, Melrose S, Zonta B, Scheiermann C, Vora AJ, Brophy PJ, Reynolds R
Brain 2006 Dec;129(Pt 12):3173-85
Imperial College Faculty of Medicine, Charing Cross Hospital Campus, Division of NeuroScience and Mental Health, Department of Cellular and Molecular NeuroScience, London
Saltatory Conduction in the Nervous System is enabled through the intimate association between the leading edge of the Myelin sheath and the Axonal membrane to demarcate the Node of Ranvier.
The 186 kDa Neuron specific isoform of the Adhesion Molecule Neurofascin (Nfasc186) is required for the clustering of Voltage gated Na+ channels at the Node, whilst the 155 kDa Glial specific isoform (Nfasc155) is required for the assembly of correct ParaNodal Junctions.
In order to understand the relationship between these vital structures and how they are affected in Multiple Sclerosis we have examined the expression of Nfasc155 and Nfasc186 in areas of Inflammation, DeMyelination and ReMyelination from post-mortem Brains.
Fourteen cases of NeuroPathologically confirmed Multiple Sclerosis (8 female and 6 male; post-mortem delay 7-24 h; age 37-77 years; and disease duration 15-40 years), comprising 20 tissue blocks with 32 DeMyelinating or ReMyelinating lesions, were used in this study.
A significant early alteration in Nfasc155+ ParaNodal structures occurs within and adjacent to actively DeMyelinating White Matter lesions that are associated with damaged Axons.
Shaker-type Kv1.2 channels, normally located distally to the ParaNode, overlapped with the disrupted Nfasc155+ structures.
In the absence of Nfasc155, Kv1.2 channels abutted normally clustered Nfasc186+ Nodes, indicating that complete disruption of the ParaNodal structure and movement of Kv1.2 channels precede alterations at the Node itself.
Within areas of partial ReMyelination, a number of atypical triple-Nfasc155+ structures were noted that may represent transient Oligodendrocyte-Axonal contacts during the process of Myelin repair or aberrant interactions.
Within shadow plaques discretely clustered Nav+, Nfasc186+ and Nfasc155+ domains indicated the restoration of normal Nodal architecture.
The alterations in Oligodendrocyte Nfasc155 expression that accompany inflammation and DeMyelination suggest an ongoing disruption to the Axonal-Oligodendrocyte complex.
Within newly forming as well as established lesions in Multiple Sclerosis, resulting in destruction of the Nfasc186+/Nav+ Nodal complex vital to successful fast NeuroTransmission in the CNS.
Vrenken H, Geurts JJ, Knol DL, Polman CH, Castelijns JA, Pouwels PJ, Barkhof F
AJNR Am J NeuroRadiol 2006 Oct;27(9):2005-11
MR Center for MS Research, VU University Medical Center, Department of Radiology, Amsterdam, the Netherlands
Background And Purpose
Multiple Sclerosis (MS) disease processes in Normal-Appearing White Matter (NAWM) may be different close to MR-visible lesions than farther from these lesions.
We aimed to investigate the relationship of NAWM changes to the distance to the lesions.
We measured B(1)-corrected T1 and Magnetization Transfer Ratio (MTR) maps in 63 patients with MS (11 Primary/Progressive, 34 Relapsing/Remitting, 18 Secondary/Progressive).
We used Histogram analyses to assess the global properties of lesions, of 4 consecutive 1-mm pixel layers of NAWM around the lesions, and of distant NAWM located at least 4-mm from lesions in all directions.
In 22 healthy controls, we measured White Matter MTR and T1 Histograms. Histogram parameters were statistically analyzed by using a linear mixed model.
The first and second NAWM pixel layers around the lesions had a significantly lower MTR Histogram peak position than distant NAWM.
Whereas T1 Histogram peak position was similar between all types of NAWM.
Furthermore, MTR Histograms of distant NAWM were statistically indistinguishable from those of control White Matter.
Whereas T1 Histograms of distant NAWM had significantly decreased peak height for Relapsing/Remitting MS and Secondary/Progressive MS and significantly increased peak position for Secondary/Progressive MS.
Our results may suggest that Axonal damage and DeMyelination in NAWM mainly arise as a secondary result of visible lesions, with the largest effect close to these lesions.
NAWM disease farther from the lesions may be mainly characterized by subtle Blood-Brain Barrier damage, with leakage of Fibrinogen into the Parenchyma and microplaque formation, processes that are detected with T1 but not with MTR.
Charil A, Yousry TA, Rovaris M, Barkhof F, De Stefano N, Fazekas F, Miller DH, Montalban X, Simon JH, Polman C, Filippi M
Lancet Neurol 2006 Oct;5(10):841-52
Scientific Institute and University Ospedale San Raffaele, NeuroImaging Research Unit, Department of Neurology, Milan, Italy
Although the diagnosis of Multiple Sclerosis relies on the demonstration of disease dissemination in space and time, the exclusion of other Neurological Disorders is also essential.
The limited specificity of abnormalities disclosed by MRI may increase the likelihood of diagnosis of Multiple Sclerosis in patients affected by other disorders.
The available criteria for diagnosis of Multiple Sclerosis have not taken advantage of the potential of MRI to detect features "not suggestive" of Multiple Sclerosis.
Recognition of such features in the work-up of patients suspected of having Multiple Sclerosis may reduce the likelihood of a false positive diagnosis of the disorder in some, while suggesting the correct alternative diagnosis in other patients.
On the basis of this, a workshop of the European MAGNIMS (Magnetic Resonance Network in Multiple Sclerosis) was held to define a series of MRI red flags in the setting of clinically suspected Multiple Sclerosis that is derived from evidence-based findings and educated guesses.
The presence of such red flags should alert clinicians to reconsider the differential diagnosis more extensively.
In this review we will report on the conclusions of this international consensus, which should represent a first step beyond the concept of "no better explanation", and inform future diagnostic criteria for Multiple Sclerosis.