Involvement Of Neuropsin In The Pathogenesis Of Experimental Autoimmune Encephalomyelitis
Terayama R, Bando Y, Yamada M, Yoshida S
Glia 2005 Nov 1;52(2):108-18
Asahikawa Medical College, Department of Anatomy, Asahikawa, Japan
Inflammation, DeMyelination, and Axonal damage of the Central Nervous System (CNS) are major pathological features of Multiple Sclerosis (MS).
ProteoLytic digestion of the Blood-Brain Barrier and Myelin protein by Serine Proteases is known to contribute to the development and progression of MS.
Neuropsin, a Serine protease, has a role in Neuronal plasticity, and its expression has been shown to be upregulated in response to injury to the CNS.
To determine the possible involvement of Neuropsin in DeMyelinating Diseases of the CNS, we examined its expression in Myelin Oligodendrocyte Glycoprotein (MOG)-induced Experimental Autoimmune Encephalomyelitis (EAE), a recognized animal model for MS.
Neuropsin mRNA expression was induced in the Spinal Cord White Matter of mice with EAE.
Combined in situ hybridization and ImmunoHistoChemistry demonstrated that most of the cells expressing Neuropsin mRNA showed ImmunoReactivity for CNPase, a cell-specific marker for Oligodendrocytes.
Mice lacking Neuropsin (Neuropsin(-/-)) exhibited an altered EAE progression characterized by delayed onset and progression of clinical symptoms as compared to wild-type mice.
Neuropsin(-/-) mice also showed attenuated DeMyelination and delayed Oligodendroglial death early during the course of EAE.
These observations suggest that Neuropsin is involved in the pathogenesis of EAE mediated by DeMyelination and Oligodendroglial death.
(c) 2005 Wiley-Liss, Inc.
Changes In The Ascertainment Of Multiple Sclerosis
Marrie RA, Cutter G, Tyry T, Hadjimichael O, Campagnolo D, Vollmer T
Neurology 2005 Oct 11;65(7):1066-70
Cleveland Clinic Foundation, Department of Neurology, Cleveland, OH 44195, USA
With diagnostic criteria alterations, increased MRI availability, and awareness of therapies, temporal changes in incidence and prevalence rates may occur, with an increase in the proportion of mildly affected persons diagnosed with Multiple Sclerosis (MS).
The authors assessed temporal trends in the delay from symptom onset to diagnosis (DONDX), and determined whether the degree of disability at diagnosis differs by year of symptom onset (YONSET), using the NARCOMS Registry.
The authors selected US participants with an age at symptom onset of 10 to 60 years, and YONSET > or = 1980 (n = 16,581).
The authors divided YONSET into 5-year groups and compared DONDX between groups using multivariate Cox regression.
The authors classified participants enrolled within 2 years of diagnosis (n = 5,548) as having mild, moderate, or severe disability using Patient Determined Disease Steps, and assessed the association of disability with YONSET using polytomous logistic regression.
DONDX decreased with later YONSET (r = -0.43, p < 0.0001). This association remained after adjustment for demographic factors in a multivariate Cox model.
Later YONSET was associated with increased odds of having mild disability at diagnosis as compared to severe disability (OR = 1.10 per year; 1.09 to 1.11).
The delay from symptom onset to diagnosis is steadily decreasing in MS. An increasing proportion of patients with MS have mild disability at diagnosis after accounting for confounders.
As the effectiveness of therapies is influenced by disease duration, this has implications for comparison of treatment effects in modern clinical trials to earlier study results.
A Randomized Crossover Study Of Bee Sting Therapy For Multiple Sclerosis
Wesselius T, Heersema DJ, Mostert JP, Heerings M, Admiraal-Behloul F, Talebian A, van Buchem MA, De Keyser J
Neurology 2005 Oct 12
University Medical Center Groningen, Department of Neurology, Groningen; Leiden University Medical Center, Gemini Hospital, Department of Radiology, Department of Radiology, Leiden, The Netherlands
Bee Sting Therapy is increasingly used to treat patients with Multiple Sclerosis (MS) in the belief that it can stabilize or ameliorate the disease. However, there are no clinical studies to justify its use.
In a randomized, crossover study, we assigned 26 patients with Relapsing/Remitting or Relapsing Secondary/Progressive MS to 24 weeks of medically supervised Bee Sting Therapy or 24 weeks of no treatment.
Live bees (up to a maximum of 20) were used to administer Bee Venom three times per week. The primary outcome was the cumulative number of new Gadolinium-enhancing lesions on T1-weighted MRI of the Brain.
Secondary outcomes were lesion load on T2-weighted MRI, relapse rate, disability (Expanded Disability Status Scale, Multiple Sclerosis Functional Composite, Guy's Neurologic Disability Scale), Fatigue (Abbreviated Fatigue Questionnaire, Fatigue Impact Scale), and health-related quality of life (Medical Outcomes Study 36-Item Short Form General Health Survey).
During Bee Sting Therapy, there was no significant reduction in the cumulative number of new Gadolinium-enhancing lesions.
The T2-weighted lesion load further progressed, and there was no significant reduction in relapse rate.
There was no improvement of disability, Fatigue, and quality of life. Bee Sting Therapy was well tolerated, and there were no serious adverse events.
In this trial, treatment with Bee Venom in patients with Relapsing Multiple Sclerosis did not reduce disease activity, disability, or Fatigue and did not improve quality of life.
Magnetization Transfer Histograms In Clinically Isolated Syndromes Suggestive Of Multiple Sclerosis
Fernando KT, Tozer DJ, Miszkiel KA, Gordon RM, Swanton JK, Dalton CM, Barker GJ, Plant GT, Thompson AJ, Miller DH
Brain 2005 Oct 11
Institute of Neurology, NMR Research Unit, London, UK; Moorfields Eye Hospital, London, UK
In established Multiple Sclerosis, Magnetization Transfer Ratio (MTR) Histograms reveal abnormalities of Normal-Appearing White Matter (NAWM) and Gray Matter (NAGM).
The aim of this study was to investigate for such abnormalities in a large cohort of patients presenting with Clinically Isolated Syndromes suggestive of Multiple Sclerosis.
Magnetization Transfer Imaging was performed on 100 patients (67 women, 33 men, median age 32 years) a mean of 19 weeks (SD 3.8, range 12-33 weeks) after symptom onset with a Clinically Isolated Syndrome.
And, in 50 healthy controls (34 women, 16 men, median age 32.5 years). SPM99 software was used to generate segmented NAWM and NAGM MTR maps.
The volumes of T2 lesions, White Matter and Gray Matter were calculated. Eighty-one patients were followed up clinically and with conventional MRI after 3 years (n = 61) or until they developed Multiple Sclerosis if this occurred sooner (n = 20).
Multiple regression analysis was used to investigate differences between patients and controls with age, gender and volume measures as covariates to control for potential confounding effects.
The MTR Histograms for both NAWM and NAGM showed a reduction in the mean (NAWM, 38.14 versus 38.33, P = 0.001; NAGM 32.29 versus 32.50, P = 0.009; units in pu) and peak location, with a left shift in the histogram.
Mean NAWM and NAGM MTR were also reduced in the patients who developed Clinically Definite Multiple Sclerosis and Multiple Sclerosis according to the McDonald Criteria but not in the 24 patients with normal T2-weighted Brain Magnetic Resonance Imaging.
MTR abnormalities occur in the NAWM and NAGM at the earliest clinical stages of Multiple Sclerosis
Bone Marrow Transplantation Combined With Gene Therapy To Induce Antigen-Specific Tolerance And Ameliorate EAE
Xu B, Haviernik P, Wolfraim LA, Bunting KD, Scott DW
Mol Ther 2005 Oct 7
University of Maryland, Department of Surgery and Department of MicroBiology and Immunology, Baltimore, MD 21201, USA
Hematopoietic Stem Cell (HSC) transplantation is a potential therapy that can offer Multiple Sclerosis patients a radical, potentially curative treatment.
Using Experimental Autoimmune Encephalomyelitis (EAE) as a model, we previously reported that retrovirally transduced B-Cells expressing Myelin Basic Protein (MBP), MBP Ac1-11, or Myelin Oligodendrocyte Glycoprotein p35-55 induced tolerance and reduced symptoms.
Here, we extend our tolerance approach using Bone Marrow (BM) cells expressing full-length PhosphoLipid Protein (PLP) in a model for Relapsing/Remitting EAE.
Using GFP expression as a marker, we found that up to 50% of cells were positive for transgene expression in peripheral blood after 900 rad irradiation and transduced BM transplantation, and expression was stable in hematopoietic lineages for over 10 weeks.
Upon challenge, T-Cell proliferation in response to PLP p139-151 was reduced and EAE was completely abolished in a pretreatment protocol. In addition, protection from EAE could be achieved with PLP-transduced BM cells given on day 12 after immunization, a potential therapeutic protocol.
Finally, the protective effect of PLP-expressing BM could also be observed using a NonMyeloAblative protocol, albeit with lower efficacy. Our results suggest that HSC may be useful to achieve long-lasting tolerance to protect mice from EAE and possibly to promote CNS repair in ongoing EAE.
Zhang X, Haaf M, Todorich B, Grosstephan E, Schieremberg H, Surguladze N, Connor JR
Glia 2005 Nov 15;52(3):199-208
Pennsylvania State University, College of Medicine Hershey, Department of NeuroSurgery, Pennsylvania
Inflammatory processes play a key role in the pathogenesis of a number of common NeuroDegenerative Disorders such as Alzheimer's Disease (AD), Parkinson's Disease (PD), and Multiple Sclerosis (MS).
Abnormal Iron accumulation is frequently noted in these diseases and compelling evidence exists that Iron is involved in inflammatory reactions.
HistoChemical stains for Iron repeatedly demonstrate that Oligodendrocytes, under normal conditions, stain more prominently than any other cell type in the Brain.
Therefore, we examined the hypothesis that Cytokine toxicity to Oligodendrocytes is Iron mediated.
Oligodendrocytes in culture were exposed to Interferon-gamma (IFN-γ), InterLeukin-1beta (IL-1ß), and Tumor Necrosis Factor-alpha (TNF-).
Toxicity was observed in a dose-dependent manner for IFN-γ and TNF-.
IL-1ß was not toxic in the concentrations used in this study. The toxic concentration of IFN-γ, and TNF- was lower if the cells were Iron loaded, but Iron loading had no effect on the toxicity of IL-1ß.
These data provide insight into the controversy regarding the toxicity of Cytokines to Oligodendrocytes by revealing that Iron status of these cells will significantly impact the outcome of Cytokine treatment.
The exposure of Oligodendrocytes to Cytokines plus Iron decreased Mitochondrial membrane potential but activation of Caspase 3 is limited.
The antioxidant, TPPB, which targets Mitochondria, protected the Oligodendrocytes from the Iron-mediated CytoToxicity, providing further support that Mitochondrial dysfunction may underlie the Iron-mediated Cytokine toxicity.
Therapeutic strategies involving AntiInflammatory agents have met with limited success in the treatment of DeMyelinating Disorders.
A better understanding of these agents and the contribution of cellular Iron status to Cytokine toxicity may help develop a more consistent intervention strategy.
(c) 2005 Wiley-Liss, Inc.
Evidence For Progressive Gray Matter Loss In Patients With Relapsing/Remitting MS
Valsasina P, Benedetti B, Rovaris M, Sormani MP, Comi G, Filippi M
Neurology 2005 Oct 11;65(7):1126-8
Scientific Institute and University H San Raffaele, NeuroImaging Research Unit, Via Olgettina 60, 20132 Milan, Italy
Little is known about the temporal evolution of Gray Matter damage occurring early in the course of Multiple Sclerosis (MS). The authors investigated the evolution of Gray Matter volume loss in 117 patients with Relapsing/Remitting MS, scanned monthly for a 9-month period.
Time-trend analysis revealed a decrease of Gray Matter volumes over the study period (p < 0.001). This study shows that Gray Matter damage in Relapsing/Remitting MS evolves markedly over a short period of observation.