Selective Decline In Information Processing In Subgroups Of Multiple Sclerosis: An 8-Year Longitudinal Study
Bergendal G, Fredrikson S, Almkvist O
Eur Neurol 2007;57(4):193-202
Karolinska Institute, Department of Clinical NeuroScience, Division of Neurology, Stockholm, Sweden
Multiple Sclerosis (MS) is an Inflammatory and Degenerative Disease of the Central Nervous System (CNS) that causes White Matter and Cortical lesions over many years.
The CNS is selectively affected by the disease with a great variety of symptoms between patients.
In this study, we describe the impact on various aspects of Cognition over an 8-year follow-up period in 31 consecutive MS patients subgrouped as Relapsing/Remitting (RRMS) , Secondary/Progressive (SPMS) , and Primary/Progressive (PPMS) .
Results showed a differential pattern of Cognitive decline already at baseline in Speed Of Information Processing.
During the follow-up, a pronounced decline occurred in Speed Of Information Processing, Finger-Motor Speed, Copying Geometrical Designs, Episodic Memory, and VisuoSpatial Short-Term Memory.
A striking difference was observed between a marked decline in Visual Reaction Time, whereas no significant change was seen in Auditory Reaction Time.
In contrast, there was no time-related decline in Verbal abilities.
However, an initial marked Cognitive Impairment predicted further Cognitive decline over the 8-year follow-up. Information-processing tests were found to be an especially strong predictor of long-term Cognitive decline.
In addition, high EDSS score at follow-up was associated with decline in information processes.
Results also showed that SP-MS patients deteriorated significantly more than the other two groups, particularly in Visual compared to Auditory information processing.
To conclude, Cognitive Decline appeared particularly in SP-MS patients and in Visual Information Processing.
2007 S. Karger AG, Basel
Combined Treatment With AtorvaStatin And Minocycline Suppresses Severity Of EAE
Luccarini I, Ballerini C, Biagioli T, Biamonte F, Bellucci A, Rosi MC, Grossi C, Massacesi L, Casamenti F
Exp Neurol 2008 Feb 14
University of Florence, Department of Pharmacology, Viale Pieraccini n. 6-50139 Florence, Italy
Multiple Sclerosis (MS) is the most common inflammatory DeMyelinating disorder of the Central Nervous System (CNS).
An approach to improve MS treatment is to identify a rational combination of new medications or existing therapies that impact different aspects of the disease process.
Statins are effective in the treatment of MS animal models and are promising candidates for future treatment.
Minocycline ameliorates clinical severity of Experimental Autoimmune Encephalomyelitis (EAE) and exhibits several anti-inflammatory and NeuroProtective activities.
In this study, we tested whether the combination of these two drugs could produce beneficial effects in EAE mice immunized with Myelin Oligodendrocyte Protein (MOG).
Our findings show that combined treatment, compared to using the medications alone, resulted in a significant reduction in disease severity, in both the acute and chronic phases of the disease, along with attenuation of inflammation, DeMyelination and Axonal Loss.
Stereological analysis revealed that the combined treatment significantly guarded against NeuroInflammation and NeuroDegeneration. Moreover, a significant suppression of Anti-MOG AntiBody production in animals treated with the two medications was found.
In conclusion, our findings prove that this combination of drugs is NeuroProtective and suppresses the severity of EAE. Furthermore, this pharmacological approach appears to be promising as a future therapeutic strategy to control MS.
Outcome Measures For Trials Of ReMyelinating Agents In Multiple Sclerosis: Retrospective Longitudinal Analysis Of Visual Evoked Potential Latency
Niklas A, Sebraoui H, Heß E, Wagner A, Then Bergh F
Mult Scler 2008 Nov 21
Universität Leipzig, Klinik und Poliklinik für Neurologie, Leipzig, Germany; Translational Centre for Regenerative Medicine (TRM-Leipzig), Universität Leipzig, Leipzig, Germany
Visual Evoked Potentials (VEPs) may be suitable surrogate outcome measures in Multiple Sclerosis (MS) ReMyelination trials.
The extent of spontaneous changes of SubClinically delayed VEP is unknown, whereas VEP improve after acute Optic Neuritis (ON).
In all, 124 patients with three VEP recordings at least 3 months apart: 71 patients with MS who had never suffered clinical ON; 53 patients with ON (isolated ON or ON as an attack of MS at first recording).
Latencies of P100 were analyzed by multivariate analysis of variance.
Eyes of patients with MS had a mean P100 latency of 110.2 ms, worsening mildly over time (n = 104 eyes, P = 0.022).
MS patients' eyes with SubClinical DeMyelination (delayed P100 latency at first recording > 116 ms) showed no significant evidence of ReMyelination (n = 24 eyes, P = 0.27).
By contrast, in ON patients' affected eyes, mean P100 latency decreased (P = 0.001), whereas unaffected eyes remained stable (P = 0.26).
Clinically non-affected eyes from both diagnostic groups with SubClinically prolonged latencies remained stable (n = 32: mean P100 at 124.8 +/- 10.7, 123.5 +/- 13.6, and 122.8 +/- 13.1 ms; P = 0.57).
Whereas non-affected eyes with normal latency at baseline deteriorated slightly (P = 0.001).
A subgroup with more homogeneously defined follow-up periods confirmed this observation.
Non-affected eyes selected for stability (difference < 5 ms) between first and second recording deteriorated (normal baseline, n = 66 eyes, P = 0.013) or remained stable (prolonged baseline, n = 18 eyes, 95% confidence interval of change -5.42 to +6.89 ms, P = 0.805).
Prolonged P100 latencies in eyes never affected by clinical ON remain stable and thus can be used as surrogate outcome measure for ReMyelination trials.
Constraint-Induced Movement Therapy Can Improve HemiParetic Progressive Multiple Sclerosis. Preliminary Findings
Mark VW, Taub E, Bashir K, Uswatte G, Delgado A, Bowman MH, Bryson CC, McKay S, Cutter GR
Mult Scler 2008 Jun 23
University of Alabama at Birmingham, Department of Physical Medicine and Rehabilitation, Birmingham, Alabama, USA
To evaluate whether Constraint-Induced Movement therapy (CI therapy) may benefit chronic upper extremity HemiParesis in Progressive Multiple Sclerosis (MS).
Five patients with Progressive MS, who had chronic upper extremity HemiParesis.
And evidence for learned non-use of the paretic limb in the life situation, underwent 30 hours of repetitive task training and shaping for the paretic limb over 2-10 consecutive weeks.
Along with physical restraint of the less-affected arm and a "transfer package" of behavioral techniques to reinforce treatment adherence.
The patients showed significantly improved spontaneous, real-world limb use at post-treatment and 4 weeks post-treatment, along with improved Fatigue ratings and maximal movement ability displayed in a laboratory motor test.
The findings suggest for the first time that slowly Progressive MS may benefit from CI therapy. Further studies are needed to determine the retention of treatment responses.
Gender-Specific Influence Of The Chromosome 16 Chemokine Gene Cluster On The Susceptibility To Multiple Sclerosis
Galimberti D, Scalabrini D, Fenoglio C, De Riz M, Comi C, Venturelli E, Cortini F, Piola M, Leone M, Dianzani U, D'Alfonso S, Monaco F, Bresolin N, Scarpini E
J Neurol Sci 2008 Apr 15;267(1-2):86-90
"Dino Ferrari" Center, University of Milan, IRCCS Ospedale Maggiore Policlinico, Department of Neurological Sciences, Via F. Sforza, 35, 20122, Milan, Italy
Macrophage-Derived Chemokine (MDC/CCL22) plays a role in Experimental Autoimmune Encephalomyelitis (EAE), the animal model of Multiple Sclerosis (MS).
MDC/CCL22 gene is part of a Chemokine cluster, which includes also Thymus and Activation-Regulated Chemokine (TARC/CCL17).
The frequency of the C/T and C/A Single Nucleotide Polymorphisms (SNPs) in the promoter and coding sequence of CCL22.
As well as the C/T SNP in the promoter of CCL17 were determined in 370 patients with Multiple Sclerosis (MS) compared with 380 controls.
A trend towards a decreased allelic frequency of the A allele of the CCL22 C/A SNP as well as of the T allele of the CCL17 C/T SNP was found in patients compared with controls.
The frequency of the AT haplotype was significantly decreased in MS patients (P=0.017, OR: 0.49, CI: 0.28-0.87).
Stratifying patients according to gender, the observed association was even more pronounced in male patients compared with male controls (P=0.004, OR=0.18, 95% CI: 0.06-0.50), whereas no significant differences were observed in females.
Therefore, the presence of the AT haplotype in Chromosome 16 Chemokine cluster is likely to confer a decreased risk of developing MS, particularly in males.
Effect Of Statins On Clinical And Molecular Responses To Intramuscular Interferon-beta-1a
Rudick RA, Pace A, Rani MR, Hyde R, Panzara M, Appachi S, Shrock J, Maurer SL, Calabresi PA, Confavreux C, Galetta SL, Lublin FD, Radue EW, Ransohoff RM
Neurology 2009 Jun 9;72(23):1989-93
Mellen Center for Treatment and Research in Multiple Sclerosis, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
Findings from a small clinical study suggested that Statins may counteract the therapeutic effects of Interferon-beta (IFN-ß) in patients with Relapsing/Remitting Multiple Sclerosis (RRMS).
We conducted a post hoc analysis of data from the Safety and Efficacy of Natalizumab in Combination With IFN-ß-1a in Patients With Relapsing/Remitting Multiple Sclerosis (SENTINEL) study to determine the effects of Statins on efficacy of IFN-ß.
SENTINEL was a prospective trial of patients with RRMS treated with Natalizumab (Tysabri, Biogen Idec, Inc., Cambridge, MA) plus IM IFN-ß-1a (Avonex, Biogen Idec, Inc.) 30 microg compared with placebo plus IM IFN-ß-1a 30 microg.
Clinical and MRI outcomes in patients treated with IM IFN-ß-1a only (No-Statins group, n = 542) were compared with those of patients taking IM IFN-ß-1a and Statins at doses used to treat HyperLipidemia (Statins group, n = 40).
No significant differences were observed between treatment groups in adjusted annualized relapse rate (p = 0.937), disability progression (p = 0.438), number of Gadolinium-enhancing lesions (p = 0.604), or number of new or enlarging T2-HyperIntense lesions (p = 0.802) at 2 years.
More patients in the Statins group reported fatigue, extremity pain, muscle aches, and increases in hepatic transaminases compared with patients in the No-Statins group.
Statin treatment had no ex vivo or in vitro effect on induction of IFN-stimulated genes.
Statin therapy does not appear to affect clinical effects of IM Interferon-ß-1a in patients with Relapsing/Remitting Multiple Sclerosis or the primary molecular response to Interferon-beta treatment.
Reversal Of Axonal Loss And Disability In A Mouse Model Of Progressive Multiple Sclerosis
Basso AS, Frenkel D, Quintana FJ, Costa-Pinto FA, Petrovic-Stojkovic S, Puckett L, Monsonego A, Shir AB, Engel Y, Gozin M, Weiner HL
J Clin Invest 2008 Mar 13
Harvard Medical School, Brigham and Women’s Hospital, Center for Neurologic Diseases, Boston, Massachusetts, USA. Tel Aviv University, George S. Wise Faculty of Life Sciences, Department of NeuroBioChemistry, Tel Aviv, Israel. University of São Paulo, Faculty of Veterinary Medicine and Animal Science, Department of Pathology, São Paulo, Brazil. Ben-Gurion University of the Negev, Faculty of Health Sciences, National Institute of Biotechnology and Department of MicroBiology and Immunology, Beersheba, Israel. Tel Aviv University, School of Chemistry, Faculty of Exact Sciences, Tel Aviv, Israel
Axonal degeneration is an important determinant of progressive Neurological disability in Multiple Sclerosis (MS). Thus, therapeutic approaches promoting NeuroProtection could aid the treatment of Progressive MS.
Here, we used what we believe is a novel water-soluble Fullerene derivative (ABS-75) attached to an NMDA receptor antagonist.
Which combines AntiOxidant and Anti-ExcitoToxic properties, to block Axonal Damage and reduce disease progression in a Chronic Progressive EAE model.
Fullerene ABS-75 treatment initiated after disease onset reduced the clinical progression of chronic EAE in NOD mice immunized with Myelin-Oligodendrocyte Glycoprotein (MOG).
Reduced disease progression in ABS-75-treated mice was associated with reduced Axonal Loss and DeMyelination in the Spinal Cord.
Fullerene ABS-75 halted Oxidative Injury, CD11b+ infiltration, and CCL2 expression in the Spinal Cord of mice without interfering with Antigen-specific T-Cell responses.
In vitro, Fullerene ABS-75 protected Neurons from Oxidative and Glutamate-induced injury and restored Glutamine synthetase and Glutamate transporter expression in Astrocytes under inflammatory insult.
Glutamine synthetase expression was also increased in the White Matter of Fullerene ABS-75-treated animals.
Our data demonstrate the NeuroProtective effect of treatment with a Fullerene compound combined with a NMDA receptor antagonist, which may be useful in the treatment of Progressive MS and other NeuroDegenerative Diseases.