Secondary Progressive Patients Research Articles

CD40 expression on CD4+ T cells (Th40 cells) as a biomarker for multiple sclerosis (HUM3P.265)

Abstract Multiple Sclerosis is a neurodegenerative disease with autoimmune components. Diagnosis is invasive and time consuming. The etiology is unclear as are clues for disease progression. The autoimmune components have largely been defined in the EAE mouse model. The problem has been defining a reliable biomarker for pathogenic cells. We described a unique T cell subset, Th40 cells that is highly auto-aggressive. We compared Th40 levels in clinically isolated syndrome (CIS), relapsing/remitting (RRMS), secondary progressive (SPMS) and primary progressive (PPMS) patients to non-autoimmune controls. MS subjects have significantly increased percentages of Th40 cells compared to controls. In CIS and RRMS Th40 cell levels cover a broad range while in SPMS and PPMS the range is centralized. Longitudinal studies show that Th40 cell levels remain elevated. Th40 cells produce IFNg, TNFa and IL-17. HLA haplotypes were diverse with only 50% of patients expressing the DR2 (DR15) haplotype or DR3 and DR4. Th40 cells are significantly elevated in MS regardless of HLA haplotype and responded to CNS antigens creating antigen signatures. The ratio of Th40 to or to Tr1 cells is 7 to 1. Th40 cells have a memory phenotype. The chemokine receptors CCR5 and CXCR3 were detected. Samples from patients on disease-modifying-therapy (DMT) demonstrated lymphopenia, but the Th40 percentage was not altered. Th40 cells provide a unique diagnostic tool for MS with significant improvement over current options.

DIR-visible grey matter lesions and atrophy in multiple sclerosis: partners in crime?

BackgroundThe extent and clinical relevance of grey matter (GM) pathology in multiple sclerosis (MS) are increasingly recognised. GM pathology may present as focal lesions, which can be visualised using double...

Investigating the phenomenon of “cognitive-motor interference” in multiple sclerosis by means of dual-task posturography

BackgroundTwo simultaneously performed tasks may compete for common brain network resources in patients with multiple sclerosis (MS), suggesting the occurrence of a cognitive-motor interference. While this phenomenon has been well described for walking and gait, data on static balance are scarce. MethodsIn this cross-sectional study, 92 patients and 46 sex/age-matched healthy controls (HCs) were tested by means of static posturography under eyes opened (single-task condition) and while performing the Stroop word-colour task (dual-task condition), to estimate the dual-task cost (DTC) of standing balance. The patient group also underwent the Expanded Disability Status Scale, 25-foot walking test, 12-item MS walking scale, Modified Fatigue Impact Scale, and Symbol Digit Modalities Test. ResultsPatients had larger postural sway under both single-task and dual-task conditions (p<0.001), as well as greater DTC of standing balance (p=0.021) than HCs. Although secondary progressive (SP) patients had larger sway in both conditions than relapsing-remitting (RR) patients (p<0.05), these latter ones exhibited a greater DTC of postural balance (p=0.045). Deficits in sustained attention and information processing speed, as assessed by the SDMT, were also independently associated with the magnitude of DTC of standing balance (p=0.005). ConclusionsThe phenomenon of cognitive-motor interference might be unmasked by a dual-task posturography and was associated with impaired sustained attention and information processing speed, especially in RR patients. The smaller DTC of standing balance observed in SP patients may be due to the ceiling effect of postural sway, or alternatively to the lack of postural reserve which constrained the more disabled patients to prioritize the balance over the cognitive task.

First evidence of in vivo pro-angiogenic activity of cerebrospinal fluid samples from multiple sclerosis patients.

Increased vascular density and endothelial cell proliferation have been demonstrated in multiple sclerosis (MS) white matter, as well as an elevated vascular endothelial growth factor expression was detected in reactive astrocytes of both active and inactive chronic demyelinated lesions and in sera of MS patients during clinical relapses. In this study, we have investigated the angiogenic activity of cerebrospinal fluid (CSF) samples from MS patients with different stages of disease by means of the chick embryo chorioallantoic membrane (CAM), a well-known assay to study angiogenesis in vivo. Results have shown that CSF samples from MS patients induced a significant (p < 0.05) angiogenic response in CAM in comparison with CSF from neurological controls. The vessel density was higher (p < 0.0001) in secondary (23.60 ± 1.14) and primary (23.50 ± 1.87) progressive patients in comparison with relapsing MS (17.25 ± 1.75) and clinically isolated syndrome suggestive of MS (13.00 ± 1.79), and a significant correlation (r = 0.611, p = 0.005) was found between the angiogenic response and disability level. The results of this preliminary report demonstrate for the first time an angiogenic activity in vivo of CSF samples from MS patients and confirm the importance of angiogenesis as a key event in MS pathogenesis and progression.

Relations between mood characteristics, circadian preferences, and functionality in multiple sclerosis

Objective. Multiple sclerosis (MS) is a progressive disorder that results in demyelinization of the nerve fibers of the central nervous system. We aimed to determine chronobiological and mood features in patients with MS. Methods. The sample comprised 75 patients with MS (54 women and 21 men) and 50 healthy individuals (38 women and 12 men). Sixty-three patients were relapsing–remitting MS and twelve patients had secondary progressive-type MS. Mood characteristics were assessed using subscales of the Profile of Mood States (POMS). Chronotypical characteristics were determined by the Morningness–Eveningness Questionnaire (MEQ). Univariate and structural equation modeling was applied to untangle the possible connections between variables. Results. Both relapsing–remitting and secondary progressive patients scored higher on the depression–dejection and fatigue–inertia scales of the POMS than healthy individuals. Circadian preferences did not differ significantly between these groups. Patients using glatiramer acetate and other types of drugs had greater severity of functional impairment measured relative to interferon-beta treatment group. Glatiramer acetate had more negative effects on mood than interferon-beta therapy. This finding may be the result of significantly higher duration of disease and higher symptom severity scores in glatiramer acetate group. Conclusions. In the structural equation model, gender was found to be predictive for characteristics of mood.

Circulating microparticles reflect treatment effects and clinical status in multiple sclerosis.

To evaluate whether circulating microparticles (MPs) derived from three cell subtypes (platelets, total leukocytes or monocytes) obtained from multiple sclerosis (MS) patients were modulated depending on the clinical status and to investigate the effect of treatments on MP levels. The MP counts were assessed with flow cytometry. The platelet-derived MP level was higher in untreated MS patients than controls. Relapsing-remitting patients showed the highest levels in the three subtypes of MP while secondary progressive patients presented similar levels to those of healthy controls. Treatments had significant effects increasing the three subtypes of MP counts. We suggest that MPs play a role in MS pathogenesis, reflecting disease status with an increment of their shedding during inflammatory periods and turning to baseline during chronic progressive degeneration.

High frequency of antiphospholipid antibodies in relapse of multiple sclerosis: a possible indicator of inflammatory-thrombotic processes.

The exact prevalence and pathogenic role of antiphospholipid antibodies (aPL) in multiple sclerosis (MS) remain unclear. This observational laboratory-blinded study evaluated the rate of aPL positivity in healthy controls and MS patients in different disease phases to recognize their frequency and possible pathogenic meaning. Reactivity for anti-cardiolipin, anti-β2 glycoprotein I, anti-prothrombin, anti-annexin V (IgG and IgM) was studied by enzyme immunoassays in 60 healthy controls and 100 consecutive MS patients [58 relapsing-remitting (RR) patients in remission, 26 RR patients in relapse, and 16 secondary progressive patients]. The overall rate of positivity for at least one aPL was significantly higher in MS patients compared to controls (32 % vs. 7 %, respectively, p < 0.0001), and in relapsing phase compared to those remitting or secondary progressive (53.8, 20.7 and 37.5 %, respectively, p = 0.002). In the single aPL analysis, the rate of positivity was significantly higher in MS patients compared to controls for anti-prothrombin IgM (7 % vs. 0, p = 0.05), and in relapsing phase compared to remitting and secondary progressive phases for anti-β2 glycoprotein I IgM (26.9, 1.7, 6.3 %, respectively, p < 0.0001), anti-prothrombin IgM (15.4, 3.4, 6.3 %, respectively, p = 0.05) and IgG (19.2, 5.2, 0 %, respectively, p = 0.05). We showed a significant aPL increase in MS patients compared to healthy controls, particularly during disease relapse which was also associated with significantly higher values of anti-β2 glycoprotein I and anti-prothrombin. These data suggest that antiphospholipid antibody occurrence in multiple sclerosis could be related to modification of structure and function of proteins involved in the inflammatory-thrombotic processes during disease re-activation.

Defining pathogenic T cells in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) (HUM1P.318)

Abstract The etiology of MS is unclear, but autoimmunity plays a significant role. The autoimmune components are defined in the EAE model yet defining a biomarker remains problematic. We described a cell subset, Th40 cells, which proved highly auto-aggressive in diabetes. We compared Th40 levels in 90 MS subjects including clinically isolated syndrome (CIS), relapsing/remitting (RRMS) and secondary progressive (SPMS) patients to non-autoimmune controls. Diagnosed MS subjects have significantly increased percentages of Th40 cells in PBL compared to controls. Th40 cells produce pro-inflammatory cytokines. HLA haplotypes of MS patients were diverse although many carry DR2 (DR15). Th40 cells were elevated in MS patients regardless of HLA haplotype. Th40 cells responded to CNS antigens in an HLA dependent fashion. TRAV 8.1.3+ cells were expanded within the Th40 population in MS subjects. We used the EAE model to better define Th40 cells. EAE induction drastically expanded Th40 cell levels prior to symptoms. Th40 cells produce IFNg and IL-17 and infiltrate both brain and spinal cord. Th40 cells transfer EAE but surprisingly CD4+CD40- T cells also did but significantly (p &amp;lt; 0.001) more slowly and with less severity. CD4+CD40- cells became CD40+; suggesting the disease process induces CD40 on T cells. CD40flox.CD4.Cre mice did not develop EAE even after multiple disease induction attempts. These data suggest an important role for CD40 in T cell pathogenesis of MS and EAE.

Surface-based analysis reveals regions of reduced cortical magnetization transfer ratio in patients with multiple sclerosis: a proposed method for imaging subpial demyelination.

The in vivo detection of subpial cortical gray matter lesions in multiple sclerosis is challenging. We quantified the spatial extent of subpial decreases in the magnetization transfer ratio (MTR) of cortical gray matter in subjects with multiple sclerosis, as such reductions may indicate regions of cortical demyelination. We exploited the unique geometry of cortical lesions by using two-dimensional parametric surface models of the cortex instead of traditional three-dimensional voxel-wise analyses. MTR images were mapped onto intermediate surfaces between the pial and white matter surfaces and were used to compute differences between secondary-progressive MS (n = 12), relapsing-remitting MS (n = 12), and normal control (n = 12) groups as well as between each individual patient and the normal controls. We identified large regions of significantly reduced cortical MTR in secondary-progressive patients when compared with normal controls. We also identified large regions of reduced cortical MTR in 11 individual patients (8 secondary-progressive, 3 relapsing-remitting). The secondary-progressive patients showed larger areas of abnormally low MTR compared with relapsing-remitting patients both at the group level and on an individual basis. The spatial distributions of abnormal MTR preferentially involved cingulate cortex, insula, and the depths of sulci, in agreement with pathological descriptions of subpial gray matter lesion distribution. These findings suggest that our method is a plausible in vivo imaging technique for quantifying subpial cortical demyelinating lesions in patients with multiple sclerosis and, furthermore, can be applied at the typical clinical field strength of 1.5 T.

What We Know About Creativity

<b>Objective:</b> We sought to establish the reliability and validity of a novel composite cognitive endpoint for monitoring improvement in memory and processing speed in future drug trials. <b>Background</b> Approximately 50% of all patients with Multiple Sclerosis have clinically significant symptoms of cognitive impairment that impact their ability to work and interfere with the quality of their home life and leisure activities. FDA officials have approved composite cognitive endpoints for the study of drug interventions for Alzheimer9s (ADAS-COG) and Schizophrenia (MATRICS), but not MS. <b>Design/Methods:</b> We administered the Selective Reminding Test (SRT), Brief Visuospatial Memory Test, Revised, PASAT, and SDMT to 60 MS patients at 4 centers twice over a 45 day timespan. These measures were chosen based on their known sensitivity to MS cognitive symptoms, the availability of alternate forms and known cross-cultural utility. Norm-referenced data was used to study the test-retest reliability of each measure. A composite measure for use as an endpoint in a drug trial was constructed based on factor structure. <b>Results:</b> Test-retest reliability for individual subtests ranged from r = .62 for the SRT delayed recall trial to .88 for the SDMT. A general composite representative of performance across measures had reliability of .91. Processing Speed and Memory composite indices were r =.89 and r =.86, respectively with modest practice effects. Secondary Progressive patients performed approximately .8 standard deviations below Relapsing-Remitting patients, with the two populations demonstrating cognitive impairment with frequencies 77% and 39%, respectively. Cognitive impairment correlated reasonably well (r = .40) with Informant reports on the Multiple Sclerosis Neuropsychological Questionnaire. <b>Conclusions:</b> The novel composite endpoint is a reliable, repeatable measure of general cognitive functioning that is sensitive to cognitive impairment in both Secondary Progressive and Relapsing –Remitting MS patients. Supported by: Biogen-Idec. <b>Disclosure:</b> Dr. DeLuca has received personal compensation for activities with Kessler Foundation Research Center and Biogen Idec.Dr. DeLuca has received research support from Biogen Idec. Dr. Foley has received personal compensation for activities with Biogen Idec. Dr. Foley has received research support from Bayer Pharmaceuticals. Dr. Benedict has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Serono, Inc., Novartis, Merck &amp; Co., Inc. and Pfizer Inc as speaker, consultant and/or member on advisory panel. Dr. Benedict has received research support from Memen Pharmaceuticals, Shire Pharmaceuticals and Biogen Idec. Dr. Caruso has received personal compensation for activities with Biogen Idec as a consultant. Dr. Caruso has received research support from Biogen Idec. Dr. Erlanger has received personal compensation for activities with Biogen Idec as a consultant. Dr. Erlanger has received research support from Biogen Idec. Dr. Kaushik has received personal compensation for activities with Panmedix as a research coordinator. Dr. Kaushik has received research support from Biogen-Idec.

Chronic cerebrospinal venous insufficiency in multiple sclerosis: a highly prevalent age-dependent phenomenon

BackgroundThis study aimed to investigate the prevalence and clinical relevance of chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis (MS) patients and healthy controls using extra- and intracranial colour Doppler sonography.MethodsWe examined 146 MS patients, presenting with a clinically isolated syndrome, relapsing-remitting, secondary progressive, or primary progressive MS, and 38 healthy controls. Sonographic examination was performed according to Zamboni’s protocol and was performed by three independent sonographers. The results of sonographic examination were compared with clinical and demographic characteristics of the patients.ResultsCCSVI, defined as the presence of at least two positive Zamboni’s criteria, was found in 76% of MS patients and 16% of control subjects. B-mode anomalies of internal jugular veins, such as stenosis, malformed valves, annuli, and septa were the most common lesions detected in MS patients (80.8%) and controls (47.4%). We observed a positive correlation between sonographic diagnosis of CCSVI and the patients’ age (p = 0.003). However, such a correlation was not found in controls (p = 0.635). Notably, no significant correlations were found between sonographic signs of CCSVI and clinical characteristics of MS, except for absent flow in the jugular veins, which was found more often in primary (p<0.005) and secondary (p<0.05) progressive patients compared with non-progressive patients. Absent flow in jugular veins was significantly correlated with patients’ age (p < 0.0001).ConclusionsSonographically defined CCSVI is common in MS patients. However, CCSVI appears to be primarily associated with the patient’s age, and poorly correlated with the clinical course of the disease.

Microstructural magnetic resonance imaging of cortical lesions in multiple sclerosis

Background: Pathologic and magnetic resonance imaging (MRI) studies have shown that cortical lesions (CLs) are a frequent finding in multiple sclerosis (MS). Objective: To quantify microstructural damage in CLs and normal appearing (NA) cortex in relapse-onset MS patients at different stages of the disease. Methods: Brain double inversion recovery (DIR), diffusion tensor (DT) MRI and 3D T 1-weighted scans were acquired from 35 relapsing–remitting (RR) patients, 23 secondary progressive (SP) patients, 12 benign (B) MS patients and 41 healthy controls (HC). Diffusivity values in CLs, cortex, white matter (WM) lesions and normal-appearing white matter (NAWM) were assessed. Results: Compared to HC, MS patients had a significantly lower fractional anisotropy (FA) and higher mean diffusivity (MD) in the cortex and NAWM. CLs had higher FA vs HC cortex and vs patients’ cortex. Compared to RRMS patients, SPMS patients had higher WM lesion volume, higher MD in the cortex, and more severe damage to the NAWM and WM lesions. Compared to SPMS patients, BMS patients had lower MD and FA of CLs. Damage in other compartments was similar between SPMS and BMS patients. Damage in CLs had a high power to discriminate BMS from SPMS (area under the curve: 79–91%), with high specificity (85%), sensitivity (100%) and accuracy (90%). Conclusions: Microstructural imaging features of CLs differ from those of WM lesions and are likely to reflect neuronal damage and microglial activation. The nature and extent of CL damage can be used to help distinguish the different MS clinical phenotypes.

Reliability and Sensitivity to Cognitive Impairment of a Novel Endpoint for Use in Pharmaceutical Trials in Multiple Sclerosis (P04.114)

Objective: We sought to establish the reliability and validity of a novel composite cognitive endpoint for monitoring improvement in memory and processing speed in future drug trials. Background Approximately 50% of all patients with Multiple Sclerosis have clinically significant symptoms of cognitive impairment that impact their ability to work and interfere with the quality of their home life and leisure activities. FDA officials have approved composite cognitive endpoints for the study of drug interventions for Alzheimer9s (ADAS-COG) and Schizophrenia (MATRICS), but not MS. Design/Methods: We administered the Selective Reminding Test (SRT), Brief Visuospatial Memory Test, Revised, PASAT, and SDMT to 60 MS patients at 4 centers twice over a 45 day timespan. These measures were chosen based on their known sensitivity to MS cognitive symptoms, the availability of alternate forms and known cross-cultural utility. Norm-referenced data was used to study the test-retest reliability of each measure. A composite measure for use as an endpoint in a drug trial was constructed based on factor structure. Results: Test-retest reliability for individual subtests ranged from r = .62 for the SRT delayed recall trial to .88 for the SDMT. A general composite representative of performance across measures had reliability of .91. Processing Speed and Memory composite indices were r =.89 and r =.86, respectively with modest practice effects. Secondary Progressive patients performed approximately .8 standard deviations below Relapsing-Remitting patients, with the two populations demonstrating cognitive impairment with frequencies 77% and 39%, respectively. Cognitive impairment correlated reasonably well (r = .40) with Informant reports on the Multiple Sclerosis Neuropsychological Questionnaire. Conclusions: The novel composite endpoint is a reliable, repeatable measure of general cognitive functioning that is sensitive to cognitive impairment in both Secondary Progressive and Relapsing –Remitting MS patients. Supported by: Biogen-Idec. Disclosure: Dr. DeLuca has received personal compensation for activities with Kessler Foundation Research Center and Biogen Idec.Dr. DeLuca has received research support from Biogen Idec. Dr. Foley has received personal compensation for activities with Biogen Idec. Dr. Foley has received research support from Bayer Pharmaceuticals. Dr. Benedict has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Serono, Inc., Novartis, Merck & Co., Inc. and Pfizer Inc as speaker, consultant and/or member on advisory panel. Dr. Benedict has received research support from Memen Pharmaceuticals, Shire Pharmaceuticals and Biogen Idec. Dr. Caruso has received personal compensation for activities with Biogen Idec as a consultant. Dr. Caruso has received research support from Biogen Idec. Dr. Erlanger has received personal compensation for activities with Biogen Idec as a consultant. Dr. Erlanger has received research support from Biogen Idec. Dr. Kaushik has received personal compensation for activities with Panmedix as a research coordinator. Dr. Kaushik has received research support from Biogen-Idec.

Spotlight on the December 13 Issue

While hospitalization is advocated following TIA, whether it is cost-effective compared to urgent clinic referral is uncertain. In patients with TIA aged 65–74, hospitalization yielded additional 0.00026 quality-adjusted life-years at 1 year, but at an additional cost of $5,573 per patient compared to urgent clinic evaluation. See p. 2082; Editorial, p. 2078 The authors analyzed 167 patients who failed to meet their primary outcome: one group consisted of primarily relapsing-remitting patients, while the other consisted solely of secondary progressive patients. …

Deficient MWF mapping in multiple sclerosis using 3D whole-brain multi-component relaxation MRI

Recent multiple sclerosis (MS) MRI research has highlighted the need to move beyond the lesion-centric view and to develop and validate new MR imaging strategies that quantify the invisible burden of disease in the brain and establish much more sensitive and specific surrogate markers of clinical disability. One of the most promising of such measures is myelin-selective MRI that allows the acquisition of myelin water fraction (MWF) maps, a parameter that is correlated to brain white matter (WM) myelination. The aim of our study was to apply the newest myelin-selective MRI method, multi-component Driven Equilibrium Single Pulse Observation of T1 and T2 (mcDESPOT) in a controlled clinical MS pilot trial. This study was designed to assess the capabilities of this new method to explain differences in disease course and degree of disability in subjects spanning a broad spectrum of MS disease severity. The whole-brain isotropically-resolved 3D acquisition capability of mcDESPOT allowed for the first time the registration of 3D MWF maps to standard space, and consequently a formalized voxel-based analysis of the data. This approach combined with image segmentation further allowed the derivation of new measures of MWF deficiency: total deficient MWF volume (DV) in WM, in WM lesions, in diffusely abnormal white matter and in normal appearing white matter (NAWM). Deficient MWF volume fraction (DVF) was derived from each of these by dividing by the corresponding region volume. Our results confirm that lesion burden does not correlate well with clinical disease activity measured with the extended disability status scale (EDSS) in MS patients. In contrast, our measurements of DVF in NAWM correlated significantly with the EDSS score (R2=0.37; p<0.001). The same quantity discriminated clinically isolated syndrome patients from a normal control population (p<0.001) and discriminated relapsing-remitting from secondary-progressive patients (p<0.05); hence this new technique may sense early disease-related myelin loss and transitions to progressive disease. Multivariate analysis revealed that global atrophy, mean whole-brain myelin water fraction and white matter atrophy were the three most important image-derived parameters for predicting clinical disability (EDSS). Overall, our results demonstrate that mcDESPOT-defined measurements in NAWM show great promise as imaging markers of global clinical disease activity in MS. Further investigation will determine if this measure can serve as a risk factor for the conversion into definite MS and for the secondary transition into irreversible disease progression.

Grey matter volume in a large cohort of MS patients: relation to MRI parameters and disability

Background: Although grey matter damage in multiple sclerosis is currently recognized, determinants of grey matter volume and its relationship with disability are not yet clear. Objectives: The objectives of the study were to measure grey and white matter volumes across different disease phenotypes; identify MRI parameters associated with grey matter volume; and study grey and white matter volume as explanatory variables for clinical impairment. Methods: This is a cross-sectional study in which MRI data of 95 clinically isolated syndrome, 657 relapsing–remitting, 125 secondary-progressive and 50 primary-progressive multiple sclerosis patients from three centres were acquired. Grey and white matter volumes were determined, together with T2 and T1 lesion volumes. Physical disability was assessed with the Expanded Disability Status Scale, cognitive impairment with the Paced Auditory Serial Addition Task. Data were analysed using multiple regression. Results: Grey matter volume was lower in relapsing–remitting patients (mean [SD]: 0.80 [0.05] L) than in clinically isolated syndrome patients (0.82 [0.05] L), and even greater relative atrophy was found in secondary-progressive patients (0.77 [0.05] L). In contrast, white matter volume in secondary-progressive patients was comparable to that in relapsing–remitting patients. Grey matter volume was the strongest independent predictor of physical disability and cognitive impairment, and was associated with both T2 and T1 lesion volume. Conclusions: Our findings show that grey matter volume is lower in secondary-progressive than in relapsing–remitting disease. Grey matter volume explained physical and cognitive impairment better than white matter volume, and is itself associated with T2 and T1 lesion volume.

POI08 Serum C4a levels in multiple sclerosis correlate with disease activity

Complement is known to play a key role in MS and recent work utilising proteomic analysis identified raised serum levels of C4a in patients compared to controls which decreased following...

Impaired information processing speed and attention allocation in multiple sclerosis patients versus controls: A high-density EEG study

BackgroundThe no-go P3a is a variant of the P300 event-related potential (ERP) that indexes speed of information processing and attention allocation. The aim of this study was to compare ERP findings with results from the paced auditory serial addition test (PASAT) and to quantify latency, amplitude and topographical differences in P3a ERP components between multiple sclerosis (MS) patients and controls. Patients and methodsSeventy-four subjects (20 relapsing remitting (RRMS) patients, 20 secondary progressive (SPMS) patients and 34 controls) completed a three-stimulus oddball paradigm (target, standard, and non-target). Subjects participated in separate visual and auditory tasks while data were recorded from 134 EEG channels. Latency differences were tested using an ANCOVA. Topographical differences were tested using statistical parametric mapping. ResultsVisual P3a amplitude correlated with PASAT score in all MS patients over frontal and parietal areas. There were significant differences in latency, amplitude, and topography between MS patients and controls in the visual condition. RRMS and SPMS patients differed in visual P3a latency and amplitude at frontal and parietal scalp regions. In the auditory condition, there were latency differences between MS patients and controls only over the parietal region. ConclusionThe present results demonstrate that information processing speed and attention allocation are impaired in MS.

A high-density ERP study reveals latency, amplitude, and topographical differences in multiple sclerosis patients versus controls

To quantify latency, amplitude and topographical differences in event-related potential (ERP) components between multiple sclerosis (MS) patients and controls and to compare ERP findings with results from the paced auditory serial addition test (PASAT). Fifty-four subjects (17 relapsing remitting (RRMS) patients, 16 secondary progressive (SPMS) patients, and 21 controls) completed visual and auditory oddball tasks while data were recorded from 134 EEG channels. Latency and amplitude differences, calculated using composite mean amplitude measures, were tested using an ANOVA. Topographical differences were tested using statistical parametric mapping (SPM). In the visual modality, P2, P3 amplitudes and N2 latency were significantly different across groups. In the auditory modality, P2, N2, and P3 latencies and N1 amplitude were significantly different across groups. There were no significant differences between RRMS and SPMS patients on any ERP component. There were topographical differences between MS patients and controls for both early and late components for the visual modality, but only in the early components for the auditory modality. PASAT score correlated significantly with auditory P3 latency for MS patients. There were significant ERP differences between MS patients and controls. The present study indicated that both early sensory and later cognitive ERP components are impaired in MS patients relative to controls.

CSF oligoclonal band patterns reveal disease heterogeneity in multiple sclerosis

Oligoclonal IgG bands (OCGB) are characteristic of multiple sclerosis (MS). Most patients show OCGB exclusively in cerebrospinal fluid (CSF). Others have serum bands with additional ones in CSF. Moreover, IgM bands against myelin lipids (LS-OCMB) associate with aggressive relapsing–remitting MS (RRMS). We studied oligoclonal bands in 424 MS patients. Most primary progressive (PPMS) patients showed serum OCGB with additional bands in CSF. Conversely, most RRMS and secondary progressive (SPMS) patients showed OCGB exclusively in CSF ( p < 0.0001). Moreover, no PPMS patient presented LS-OCMB, while 31% of RRMS and 60% of SPMS groups showed these antibodies ( p < 0.0001). This suggests heterogeneous autoimmune mechanisms in MS.