Cader S, Cifelli A, Abu-Omar Y, Palace J, Matthews PM
Brain 2006 Feb;129(Pt 2):527-37
Centre for Functional Magnetic Resonance Imaging of the Brain, The John Radcliffe Hospital, Headington, Oxford, UK
Cognitive Dysfunction (affecting particularly Attention and Working Memory) occurs early in patients with Multiple Sclerosis.
Previous studies have focused on identifying potentially adaptive functional reorganization through recruitment of new Brain regions that could limit expression of these deficits.
However, lesion studies remind us that functional specializations in the Brain make certain Brain regions necessary for a given task.
We therefore have asked whether altered functional interactions between regions normally recruited provide an alternative adaptive mechanism with Multiple Sclerosis pathology.
We used a version of the n-back task to probe Working Memory in patients with early Multiple Sclerosis.
We applied a functional connectivity analysis to test whether relationships between relative activations in different Brain regions change in potentially adaptive ways with Multiple Sclerosis.
We studied 21 patients with Relapsing/Remitting Multiple Sclerosis and 16 age- and sex-matched healthy controls with 3T functional MRI.
The two groups performed equally well on the task. Task-related activations were found in similar regions for patients and controls.
However, patients showed relatively reduced activation in the Superior Frontal and Anterior Cingulate Gyri (P > 0.01).
Patients also showed a variable, but generally substantially smaller increase in activation than healthy controls with greater task complexity, depending on the specific Brain region assessed (P < 0.001).
Functional connectivity analysis defined further differences not apparent from the univariate contrast of the task-associated activation patterns.
Control subjects showed significantly greater correlations between Right DorsoLateral PreFrontal and Superior Frontal/Anterior Cingulate activations (P < 0.05).
Patients showed correlations between activations in the Right and Left PreFrontal Cortices, although this relationship was not significant in healthy controls (P < 0.05).
We interpret these results as showing that, while Cognitive processing in the task appears to be performed using similar Brain regions in patients and controls, the patients have reduced functional reserve for Cognition relevant to Memory.
Functional connectivity analysis suggests that altered InterHemispheric interactions between Dorsal and Lateral PreFrontal regions may provide an adaptive mechanism that could limit clinical expression of the disease distinct from recruitment of novel processing regions.
Together, these results suggest that therapeutic enhancement of the coherence of interactions between Brain regions normally recruited (functional enhancement).
As well as recruitment of alternative areas or use of complementary Cognitive strategies (both forms of adaptive functional change), may limit expression of Cognitive Impairments in Multiple Sclerosis.
Confavreux C, Vukusic S
Brain 2006 Mar;129(Pt 3):606-16
Service de Neurologie A, the European Database for Multiple Sclerosis (EDMUS) Coordinating Center and INSERM U 433, Hopital Neurologique, Lyon, France
Multiple Sclerosis can follow very different patterns of evolution and variable rates of disability accumulation. This raises the issue whether it represents one or several distinct diseases.
We assessed demographic and clinical characteristics in 1844 patients with Multiple Sclerosis that we categorized according to the classification of Lublin and Reingold (1996) into 1066 (58%) Relapsing/Remitting, 496 (27%) Secondary/Progressive, 109 (6%) Progressive/Relapsing and 173 (9%) Primary/Progressive cases of Multiple Sclerosis.
Relapsing/Remitting and Secondary/Progressive cases shared similar age at disease onset (median = 28.7 versus 29.5 years; P = 0.21), initial symptoms of the Relapsing/Remitting phase, degree of recovery from the first Neurological episode, and time from the first to the second episode.
By contrast, disease duration was twice as long in Secondary/Progressive than in Relapsing/Remitting cases (mean +/- SD = 17.6 +/- 9.6 versus 8.7 +/- 8.6 years; P < 0.001).
Relapsing/Progressive and Primary/Progressive cases were essentially similar in their clinical characteristics.
In patients experiencing a Progressive course, median age at onset of progressive phase was similar in Secondary/Progressive cases and in cases who were Progressive from onset (39.1 versus 40.1 years; P = 0.47).
The proportion of cases with superimposed relapses during progression was approximately 40% in both categories.
Finally, the 1562 patients with an Exacerbating/Remitting initial course and the 282 patients with a Progressive initial course of the disease were essentially similar with respect to the time course of disability accumulation from assignment to a given disability score, and the age at assignment of disability landmarks.
These observational data suggest that the clinical phenotype and course of Multiple Sclerosis are age dependent.
Relapsing/Remitting disease can be regarded as Multiple Sclerosis in which insufficient time has elapsed for the conversion to Secondary/Progressive.
Secondary/Progressive forms as Relapsing/Remitting Multiple Sclerosis that has 'grown older'; and Progressive from onset cases as Multiple Sclerosis 'amputated' from the usual preceding Relapsing/Remitting phase.
Times to reach disability milestones, and ages at which these landmarks are reached, follow a predefined schedule not obviously influenced by relapses, whenever they may occur, or by the initial course of the disease, whatever its phenotype.
This leads to a unifying concept of the disease in which Progressive and Secondary/Progressive might be regarded as essentially similar.
From the clinical and statistical positions, Multiple Sclerosis might be considered as one disease with different clinical phenotypes rather than an entity encompassing several distinct diseases--the position of complexity rather than true heterogeneity.
Sanna A, Fois ML, Arru G, Huang YM, Link H, Pugliatti M, Rosati G, Sotgiu S
Clin Exp Immunol 2006 Feb;143(2):357-62
Institute of Clinical Neurology, University of Sassari, Italy
Dendritic Cells (DC), as the most effective Antigen-Presenting Cells, are protagonists of the complex Immune Network involved in Multiple Sclerosis (MS) lesion formation.
Glatiramer Acetate (GA), a synthetic random copolymer, is thought to exert its therapeutical effect in MS by favoring both Th2 cell development and IL-10 production from peripheral Lymphocytes as well as by systemically affecting the Antigen-Presenting Cells.
In the present study we further analyzed the mechanisms of action of GA by using an autologous DC-Lymphocytes (Ly) coculture system from 11 MS patients and 12 matched healthy controls (HC).
We found that, in MS patients, pretreatment with GA significantly decreases the in vitro proliferative effect of DC on Lymphocytes as compared to HC and to unpulsed or Myelin Basic Protein (MBP)-pulsed DC from MS patients (P < 0.05).
In addition, GA-treated DC from both MS patients and HC significantly increase the Lymphocyte production of IL-5 and IL-13 as compared to MBP-treated DC (P < 0.05).
In conclusion our in vitro study may provide new therapeutical mechanisms of GA on Lymphocytes, antiproliferative and Th2-favouring effects, which are mediated by Monocyte-derived DC.
IL-15 Is Elevated In Serum And CerebroSpinal Fluid Of Patients With Multiple Sclerosis
Rentzos M, Cambouri C, Rombos A, Nikolaou C, Anagnostouli M, Tsoutsou A, Dimitrakopoulos A, Triantafyllou N, Vassilopoulos D
J Neurol Sci 2006 Feb 15;241(1-2):25-9
Aeginition Hospital-Athens Medical School, Department of Neurology, 72-74 Vas.So phias Av, Greece
InterLeukin-15 (IL-15) is a novel proinflammatory Cytokine having similar biological activities to IL-2 which is implicated in the pathogenesis of Multiple Sclerosis.
It is produced by activated blood Monocytes, Macrophages and Glial Cells. There is little information about the involvement of IL-15 in the development of Multiple Sclerosis (MS).
The objective of our study was to measure IL-15 Serum and CerebroSpinal Fluid (CSF) levels in MS patients and to correlate serum and CSF IL-15 concentrations with clinical parameters of the disease.
CSF IL-15/Serum IL-15 ratio (c/s IL-15 ratio) was introduced to assess the origin of elevated IL-15 levels.
Materials And Methods
We measured Serum and CSF IL-15 levels in 52 patients with MS and 36 age and gender matched patients with Inflammatory (IND) and Non-Inflammatory Neurological Diseases (NIND) studied as control groups.
IL-15 levels were correlated with clinical parameters as duration, disability, MRI activity and clinical subtypes of the disease.
MS patients were found to have significantly higher Serum IL-15 levels compared with IND (p=0.00016) and NIND patients (p=0.00045).
Elevated levels of IL-15 were also found in CSF samples from MS patients compared with patients with IND (p=0.00034) and NIND (p=0.0003).
Among MS subgroups there were no statistically different IL-15 Serum and CSF concentrations. No significant correlation of serum and CSF IL-15 concentrations with MRI activity, disability assessed by EDSS score and duration of the disease were also found.
C/S IL-15 ratio was found lower in MS patients compared with IND (p=0.01) and not significantly different compared with NIND patients (p=0.14) suggesting that systemic activation might be the source of high CSF IL-15 levels in MS patients.
Our findings suggest a possible role of IL-15 in the immunopathogenetic mechanisms of MS.
AutoAntibodies Against HSP70 Family Proteins Were Detected In The CerebroSpinal Fluid From Patients With Multiple Sclerosis
Chiba S, Yokota S, Yonekura K, Tanaka S, Furuyama H, Kubota H, Fujii N, Matsumoto H
J Neurol Sci 2006 Feb 15;241(1-2):39-43
Sapporo Medical University School of Medicine, Department of Neurology, Minami 1-Jo Nishi 16 chome, Chuo-ku, Sapporo 060-8543, Japan
We evaluated the specific IgG AntiBodies against Heat Shock Proteins (HSPs) in CerebroSpinal Fluids (CSF) from patients with Multiple Sclerosis (MS).
ELISA was employed to examine IgG AntiBodies against ten HSPs (HSP27, alphaA and alphaB Crystallins, HSP60, CCT, Mycobacterium bovis HSP65, Escherichia coli GroEL, HSP70, HSC70 and HSP90) in CSF from 30 patients with MS, and 25 patients with Motor Neuron Diseases (MND).
Significantly higher AntiBody Titers against HSP70 and HSC70 proteins were found in CSF obtained from patients with MS as compared with MND independent of CSF total protein, IgG concentrations and IgG indices, respectively.
The AntiBody Titers against HSP70 were indicated to be significantly higher in the progressive cases than in cases of remission.
The results suggest that IgG AntiBodies against specific types of HSPs especially HSP70 family proteins (HSP70 and HSC70) in CSF may play an important role in the pathophysiology of MS through the modification of Immune Response and cytoprotective functions of molecular chaperons.
MRI T2 HypoIntensity Of The Dentate Nucleus Is Related To Ambulatory Impairment In Multiple Sclerosis
Tjoa CW, Benedict RH, Weinstock-Guttman B, Fabiano AJ, Bakshi R
J Neurol Sci 2005 Jul 15;234(1-2):17-24
University at Buffalo, State University of New York, Department of Neurology, Buffalo, NY, USA
MRI T2 HypoIntensity in Multiple Sclerosis (MS) Gray Matter, suggesting Iron deposition, is associated with physical disability, disease course, lesion load, and Brain Atrophy.
Ambulatory dysfunction limits quality of life; however correlation with conventional MRI remains poor.
Normalized intensity on T2-weighted images was obtained in the Basal Ganglia, Thalamus, Red Nucleus, and Dentate Nucleus in 47 MS patients and 15 healthy controls.
Brain T1-HypoIntense and FLAIR-HyperIntense lesion volume, Third Ventricle width, Brain Parenchymal Fraction and timed 25 foot walk (T25FW) were measured in the MS group.
T2 HypoIntensity was present throughout Gray Matter in MS vs. controls (all p< 0.01).
Dentate T2 HypoIntensity was the only MRI variable significantly correlated with T25FW (Pearson r=-0.355, p=0.007) and was also the best MRI correlate of physical disability (EDSS) score in regression modeling (r=-0.463, R(2)=0.223, p=0.004).
T2 HypoIntensity is present in SubCortical Gray Matter Nuclei in patients with MS vs. normal controls.
Dentate Nucleus T2 HypoIntensity is independently related to ambulatory impairment and disability, accounting for more variance than conventional lesion and Atrophy measures.
This study adds more weight to the notion that T2 HypoIntensity is a clinically relevant marker of tissue damage in MS.
Absence Of CerebroSpinal Fluid OligoClonal Bands Is Associated With Delayed Disability Progression In Relapsing/Remitting MS Patients Treated With Interferon-ß
Annunziata P, Giorgio A, De Santi L, Zipoli V, Portaccio E, Amato MP, Clerici R, Scarpini E, Moscato G, Iudice A, Vacca G, Orefice G, Morra VB, Maimone D
J Neurol Sci 2006 May 15;244(1-2):97-102
University of Siena, Department of Neurological Sciences and Behaviour, Italy
To assess the role of CSF OligoClonal Bands (OB) in determining the clinical outcome in patients with Relapsing/Remitting Multiple Sclerosis (RRMS) treated with IFN-ß.
We carried out a retrospective, multicenter, observational study recruiting 209 RRMS patients from six MS centres from northern, central and southern areas of Italy under treatment with IFN-ß-1a i.m., IFN-ß-1a s.c. and IFN-ß-1b s.c.
Twenty-two of 209 patients (10.6%) showed no OB in CSF. The patients without had, at disease onset, significantly higher frequency of visual disturbances (p=0.02) and less sensory involvement (p=0.04) than those with OB.
A statistical trend (p=0.056) towards a longer time to reach sustained disability progression during treatment was found in patients without compared to those with OB.
Thirty-six of 187 (19%) patients with OB worsened by at least 1 EDSS point compared to none of 22 (0%) OB-negative patients (p=0.017).
The delaying of disability progression in OB-negative patients during treatment was significantly dependent only on the number of baseline MRI T2-weighted lesions (p=0.012) that was found to be significantly lower in OB-negative than in OB-positive patients (p=0.04).
The absence of OB and low number of baseline T2-weighted lesions in this cohort of MS patients are favorable prognostic factors influencing the clinical response to IFN-ß treatment in RRMS patients.