De Stefano N, Battaglini M, Stromillo ML, Zipoli V, Bartolozzi ML, Guidi L, Siracusa G, Portaccio E, Giorgio A, Sorbi S, Federico A, Amato MP
Brain 2006 Aug;129(Pt 8):2008-16
Neurology and NeuroMetabolic Unit, Department of Neurological and Behavioral Sciences, University of Siena, Italy
The trend to start disease-modifying therapy early in the course of Multiple Sclerosis makes it important to establish whether the Benign form is a real entity.
In previous studies, measures of Magnetization Transfer (MT) ratio (MTr) have been shown to provide good estimates of the amount of tissue damage occurring in Multiple Sclerosis Brains.
Thus, with the hypothesis that if Benign Multiple Sclerosis patients were really Benign, sensitive measures of subtle tissue damage would be less pronounced in these patients than in very early Relapsing-/Remitting (RR) Multiple Sclerosis patients.
We carried out conventional MRI and MT imaging in 50 patients with Benign Multiple Sclerosis [defined as having Kurtzke Expanded Disability Status Score (EDSS) < 3 and disease duration > 15 years].
And in 50 early RR patients selected to have similar disability (EDSS < 3) and short disease duration ( < 3 years).
Data were compared with those of 32 demographically-matched normal controls.
We used a fully automated procedure to measure lesional-MTr, PeriLesional-MTr, Normal-Appearing White Matter (NAWM) MTr and Cortical-MTr.
We found that, after correction for common effects of age, Lesional-MTr and PeriLesional-MTr of Benign patients were significantly (P < 0.0001) lower than WM of normal controls.
But significantly (P < 0.0001) higher than corresponding tissues of RR patients.
In NAWM and Cortex, MTr values of Benign patients were similar to those of normal controls (P > 0.5) and significantly higher than those of the RR patients (P < 0.0001 and P < 0.01, respectively).
Similar differences in MTr measures between Benign and RR patients were found when patient groups were selected to have no disability (EDSS < or = 2) and, for Benign Multiple Sclerosis, very long disease duration ( > 20 years).
Or when both groups were matched for high lesion load (T2-weighted lesion volume > 10 cm3).
We conclude that lesional and non-lesional MTr values can be significantly less pronounced in Benign Multiple Sclerosis than in a cohort of RR patients at their earliest disease stages.
Suggesting that Brain tissue damage is milder in Benign Multiple Sclerosis than in early RR disease.
This can be due to an extraordinary beneficial response to DeMyelination of Benign patients.
And, may represent the evidence that Benign Multiple Sclerosis truly exists and might be differentiated from other forms of this illness.
The Impact Of Interferon-ß Treatment On The Blood-Brain Barrier
Kraus J, Oschmann P
Drug Discov Today 2006 Aug;11(15-16):755-762
Paracelsus Private Medical University and Salzburger Landesklinken, Christian-Doppler-Klinik, Department of Neurology, Ignaz-Harrer-Strasse 79, 5020 Salzburg, Austria
Changes in the Blood-Brain Barrier (BBB) are crucial to the pathogenesis of Multiple Sclerosis (MS).
There are currently few established treatments for MS, and Interferon-beta (IFN-ß) therapy is one of the most promising - proposed to act as an ImmunoModulator of the Cytokine network reducing inflammatory damage.
However, there is increasing evidence that direct effects on the BBB could also be relevant. This review surveys the evidence that IFN-ß stabilizes the BBB, and that this process itself might be the key target.
Understanding IFN-ß-derived changes at the BBB will not only provide new insights in the pathogenesis of MS but will also be helpful to develop new, more-specific drugs for MS treatment.
Cytokine Responses To Resistance Training In People With Multiple Sclerosis
White LJ, Castellano V, Mc Coy SC
J Sports Sci 2006 Aug;24(8):911-4
University of Florida, Center for Exercise Science, Applied Human Physiology Laboratory,
Department of Applied Physiology and Kinesiology, Gainesville, FL, USA
Exercise for individuals with Multiple Sclerosis (MS) has been shown to improve CardioVascular function, increase strength and endurance, and reduce fatigue.
The impact of exercise on Immune function in the disease, however, remains mostly unexplored.
Ten female MS patients participated in an 8 week programme of twice-weekly progressive resistance training, with pre- and post-training assessment of serum concentrations of Cytokines IL-2, IL-4, IL-6 IL-10, CRP, TNF- and IFN-γ.
After training, IL-4, IL-10, CRP and IFN-γ showed statistically reduced resting concentrations in blood.
While TNF- showed non-significant reductions and IL-2 and IL-6 remained unchanged.
These results suggest that progressive resistance training may have an impact on Cytokine concentrations in individuals with MS and should be confirmed in studies with stronger statistical power.
The impact of these changes on overall Immune function in MS and on disease status and prognosis remains to be determined.
Intravenous Synthetic Peptide MBP8298 Delayed Disease Progression In An HLA Class II-Defined Cohort Of Patients With Progressive Multiple Sclerosis: Results Of A 24-Month Double-Blind Placebo-Controlled Clinical Trial And 5 Years Of Follow-Up Treatment
Warren KG, Catz I, Ferenczi LZ, Krantz MJ
Eur J Neurol 2006 Aug;13(8):887-95
Multiple Sclerosis Patient Care and Research Clinic, Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
MBP8298 is a synthetic Peptide with a sequence corresponding to Amino Acid residues 82-98 of human Myelin Basic Protein (DENPVVHFFKNIVTPRT).
It represents the ImmunoDominant target for both B-Cells and T-Cells in Multiple Sclerosis (MS) patients with HLA haplotype DR2.
Its administration in accordance with the principle of high dose Tolerance:
Results in long-term suppression of Anti-Myelin Basic Protein (MBP) AutoAntiBody levels in the CerebroSpinal Fluid (CSF) of a large fraction of Progressive MS patients.
MBP8298 was evaluated in a 24-month placebo-controlled double-blinded Phase II clinical trial in 32 patients with Progressive MS.
The objective was to assess the clinical efficacy of 500 mg of MBP8298 administered intravenously every 6 months, as measured by changes in Expanded Disability Status Scale (EDSS) scores.
Contingency analysis for all patients at 24 months showed no significant difference between MBP8298 and placebo-treatments (n = 32, P = 0.29).
Contingency analysis in an HLA Class II defined subgroup showed a statistically significant benefit of MBP8298 treatment compared with placebo in patients with HLA haplotypes HLA-DR2 and/or DR4 (n = 20, P = 0.01).
Long-term follow-up treatment and assessment of patients in this responder group showed a median time to progression of 78 months for MBP8298 treated patients.
Compared with 18 months for placebo-treatment (Kaplan-Meier analysis, P = 0.004; relative rate of progression = 0.23).
Anti-MBP AutoAntiBody levels in the CSF of most MBP8298 treated patients were suppressed, but AntiBody suppression was not predictive of clinical benefit.
Anti-MBP AutoAntibodies that reappeared in the CSF of one patient at 36 months, while under treatment with MBP8298, were not reactive with the MBP8298 peptide in vitro.
The identification of a responder subgroup (62.5% of the patients in this study) enables a more efficient design of a large confirmatory clinical trial of MBP8298.
The probability that patients with other less common HLA-DR haplotypes will respond to this treatment should not be ignored.
Microglia, Major Player In The Brain Inflammation: Their Roles In The Pathogenesis Of Parkinson's Disease
Kim YS, Joh TH
Exp Mol Med 2006 Aug 31;38(4):333-47
Weill Medical College of Cornell University, Department of Neurology and NeuroScience, New York, NY 10021, USA
Inflammation, a self-defensive reaction against various pathogenic stimuli, may become harmful self-damaging process.
Increasing evidence has linked chronic inflammation to a number of NeuroDegenerative disorders including Alzheimer's Disease (AD), Parkinson's Disease (PD), and Multiple Sclerosis.
In the Central Nervous System, Microglia, the resident Innate Immune cells play major role in the inflammatory process.
Although they form the first line of defense for the Neural Parenchyma, uncontrolled activation of Microglia may be directly toxic to Neurons.
By releasing various substances such as inflammatory Cytokines (IL-1beta, TNF-, IL-6), NO, PGE(2), and SuperOxide.
Moreover, our recent study demonstrated that activated Microglia phagocytose not only damaged cell debris but also neighboring intact cells.
It further supports their active participation in self-perpetuating Neuronal damaging cycles.
In the following review, we discuss Microglial responses to damaging Neurons, known activators released from injured Neurons and how Microglia cause Neuronal Degeneration.
In the last part, Microglial activation and their role in PD are discussed in depth.
Effect Of The Treatment With MethylPrednisolone On The CerebroSpinal Fluid And Serum Levels Of CCL2 And CXCL10 Chemokines In Patients With Active Multiple Sclerosis
Moreira MA, Tilbery CP, Monteiro LP, Teixeira MM, Teixeira AL
Acta Neurol Scand 2006 Aug;114(2):109-13
Federal University of Minas Gerais, CIEM MS Research Center, Belo Horizonte, Brazil
Several experimental and human studies suggest that the Chemokines CCL2 and CXCL10 may play a role in the pathogenesis of Multiple Sclerosis (MS).
Here, we evaluated the effect of IntraVenous MethylPrednisolone (IVMP) therapy on the levels of CCL2 and CXCL10 in the CerebroSpinal Fluid (CSF) and Serum of patients with active MS.
Serum and CSF samples were obtained from 14 patients with active Relapsing/Remitting MS (age +/- SD years, 37.0 +/- 8.1; M/F, 6/8) and age- and gender-matched control subjects.
All patients were submitted to IVMP treatment (500 mg daily for 5 days).
Blood and CSF sampling were performed at admission, i.e. before treatment (day 0), at the end of the treatment (day 6) and 30 days after treatment (day 30).
The clinical status of MS patients was also assessed. CCL2 and CXCL10 were measured by Enzyme-Linked Immunosorbent Assay.
Multiple Sclerosis patients had lower CCL2 and higher CXCL10 in CSF when compared with control subjetcs.
After treatment with MethylPrednisolone, MS patients showed clinical improvement and the CSF concentrations of CCL2 and CXCL10 modified toward normal values.
The clinical improvement of active MS following the treatment with MethylPrednisolone was associated with the modification of CSF levels of CCL2 and CXCL10.
Suggesting that these Chemokines may be useful markers of response to treatment and relapses in MS patients.
Chemokine Expression By Astrocytes Plays A Role In Microglia/Macrophage Activation And subsequent NeuroDegeneration In Secondary/Progressive Multiple Sclerosis
Tanuma N, Sakuma H, Sasaki A, Matsumoto Y
Acta NeuroPathol (Berl) 2006 Aug;112(2):195-204
Tokyo Metropolitan Institute for NeuroScience, Department of Molecular NeuroPathology, 2-6, Musashidai, Fuchu, Tokyo, 183-8526, Japan
The pathological hallmarks of Secondary/Progressive (SP) Multiple Sclerosis (MS) include slowly expanding DeMyelination and Axonal Damage with less inflammation.
To elucidate the pathomechanisms of Secondary/Progressive (SP) Multiple Sclerosis (MS), we have investigated the expression of Chemokines, Chemokine Receptors, Matrix MetalloProteinase-9 (MMP-9) and ImmunoGlobulins in the DeMyelinating plaques.
ImmunoHistoChemical analysis revealed that numerous hypertrophic Astrocytes were observed at the rim, but not in the center, of the chronic active lesions.
Microglia/Macrophages Phagocytosing Myelin debris were also found at the lesion border. In contrast, T-Cell infiltration was minimal in these plaques.
Characteristically, at the rim of the lesions, there were abundant ImmunoReactivities for Monocyte ChemoAttractant Protein-1 (MCP-1)/CCL2.
And Interferon-gamma inducible protein-10 (IP-10)/CXCL10 and their Receptors, CCR2 and CXCR3, while these ImmunoReactivities were weak in the center, thus forming a Chemokine gradient.
Double immunofluorescense staining demonstrated that cellular sources of MCP-1/CCL2 and IP-10/CXCL10 were hypertrophic Astrocytes.
And, that both Astrocytes and Microglia/Macrophages expressed CCR2 and CXCR3. MMP-9 was also present at the rim of the lesions.
These results suggest that MCP-1/CCL2 and IP-10/CXCL10 produced by Astrocytes may activate Astrocytes in an Autocrine or Paracrine manner.
And, direct reactive Gliosis followed by migration and activation of Microglia/Macrophages as effector cells in DeMyelinating lesions.
Targeting Chemokines in SPMS may therefore be a powerful therapeutic approach to inhibit lesional expansion.