Factors associated with benign multiple sclerosis in the New York State MS Consortium (NYSMSC).

BACKGROUND: This retrospective analysis explored prognostic factors associated with a benign multiple sclerosis (BMS) disease course at baseline and over the 4-year follow-up. METHODS: Patients from the centralized New York State Multiple Sclerosis Consortium registry were classified as having BMS according to 3 different criteria centered on disease duration and disability. Additional analyses explored prognostic factors associated with BMS using the most conservative disability criteria (Expanded Disability Status Scale ≤2 and disease duration ≥10 years). RESULTS: Among 6258 patients who fulfilled eligibility criteria, 19.8 % to 33.3 % were characterized as having BMS, at baseline depending on classification criteria used. Positive prognostic factors for BMS at baseline included female sex (p < 0.0001) and younger age at onset (p < 0.0001); negative prognostic factors included progressive-onset type of MS and African-American race. Of the 1237 BMS patients (per most conservative criteria), 742 were followed for a median of 4 years to explore effect of disease-modifying treatment (DMT) on benign status. DMT (p = 0.009) and longer disease duration (p = 0.007) were the only significant positive predictors of maintaining BMS at follow-up. The protective effect was stronger for patients taking DMT at both enrollment and follow-up (OR = 0.71; p = 0.006). CONCLUSIONS: There is a need for development of more reliable prognostic indicators of BMS. Use of DMT was significantly associated with maintaining a benign disease state.

Relationship between Inflammation and Aspirin and Clopidogrel Antiplatelet Responses in Acute Ischemic Stroke.

OBJECTIVE: We measured serum levels of proinflammatory/prothrombotic markers P-selectin, CD40L, matrix metalloproteinase 9 (MMP-9), intracellular adhesion molecule 1 (ICAM-1), and interleukin (IL)-6 in ischemic stroke patients, correlating their levels with the results of aspirin (ASA) and clopidogrel antiplatelet responses, using 3 "point of care" platelet function instruments, thromboelastograph (TEG), Accumetrics (ACU), and impedance aggregometer (IMP). METHODS: Patients on chronic ASA regimen at the time of stroke were switched to 300 mg clopidogrel loading dose and 75 mg clopidogrel maintenance dose. Serum levels of the aforementioned inflammatory mediators were measured in 51 patients at baseline (on ASA regimen), and at 26 ± 5 hours and 64 ± 18 hours postclopidogrel administration by enzyme-linked immunosorbent assay. RESULTS: P-selectin, CD40L, and MMP-9 serum levels were reduced; ICAM-1 and IL-6 serum levels showed no difference postclopidogrel administration relative to baseline. Patients' stratification based on ASA dose showed more significant reductions in P-selectin, CD40L, and MMP-9 serum levels postclopidogrel administration in patients who were on baseline 81 mg ASA, as compared to patients on 325 mg ASA. Measurement with TEG was sensitive for correlating ASA antiplatelet responses to serum levels of inflammatory markers, whereas measurements with ACU and IMP were sensitive for correlating clopidogrel antiplatelet responses to serum levels of inflammatory markers. CONCLUSION: Clopidogrel exerts both platelet-dependent and platelet-independent anti-inflammatory effects. The association between platelet function and inflammation depends on the platelet function analyzer, the type of antiplatelet agent, the nature of the inflammatory marker, and the time of measurement relative to the time of drug administration.

Clopidogrel responsiveness in stroke patients on a chronic aspirin regimen.

This study evaluated the antiplatelet effects of clopidogrel (CPG) in patients sustaining acute ischemic stroke who were already receiving chronic outpatient aspirin therapy (81-325 mg/day). Platelet function was measured using 3 different "point-of-care" platelet function analyzers: the Thrombelastograph hemostasis system, the Accumetrics VerifyNow system, and the Chronolog 570VS impedance aggregometer. Platelet function was assessed before administration of a 300-mg CPG loading dose and again at 26 hours and 64 hours after this loading dose along with a 75-mg daily maintenance dose. All 3 instruments detected marked inhibition of platelet function at 26 hours and 64 hours after CPG administration. There were significant variations among the 3 instruments in monitoring antiplatelet responses to aspirin and CPG; however, these variations were eliminated when the platelet function results were corrected for baseline platelet variability. The percentage of patients who were poor responders to CPG after switching from aspirin depended on the measurement instrument used, but was higher at 26 hours after CPG administration than at 64 hours after CPG administration. Our findings indicate that poor response to antiplatelet agents in general, and to CPG in particular, is a function of the measuring instrument. The correction for baseline platelet variability results in similar levels of platelet inhibition measured by the 3 platelet function analyzers. Future studies are warranted to examine the association between ex vivo CPG-induced platelet inhibition and clinical outcomes in patients with ischemic stroke.

Lp-PLA2: inflammatory biomarker of vascular risk in multiple sclerosis.

A member of the A2 phospholipase superfamily, the enzyme lipoprotein-associated phospholipase A2 (Lp-PLA2), is involved in atherogenic processes. Lp-PLA2 mass and activity were measured by the enzyme-linked immunosorbent assay and by a colorimetric method, respectively, and compared among 63 multiple sclerosis (MS) patients and 47 age-matched healthy controls (HCs). Lp-PLA2 plasma levels were significantly higher in MS patients (236.7 ± 10 ng/ml) compared to HCs (197.0 ± 7 ng/ml) (p = 0.003), but LP-PLA2 activity did not differ between the two groups. Both Lp-PLA2 plasma mass and activity were higher in secondary progressive (mass 247.0 ±15.5 ng/ml, p = 0.05; activity 156.1 ±6 nmol/min/ml, p = 0.003) compared to relapsing-remitting MS patients (mass 227.0 ± 16 ng/ml; activity 128.8 ± 5 nmol/min/ml) and compared to HCs. Lp-PLA2 plasma activity was associated with measures of MS clinical disability. However, this association was attenuated after adjustment for the components of lipid profiles.

Plasma pentosidine: a potential biomarker in the management of multiple sclerosis.

BACKGROUND: The chronic inflammation associated with multiple sclerosis (MS) may lead to the upregulation of pentosidine. OBJECTIVES: This cross-sectional study compares plasma pentosidine levels among healthy controls (HCs) and patients with MS at different disease stages. The study also determines pentosidine's usefulness as a biomarker of MS disease activity and/or severity via its correlation with a number of indicators of MS disease. METHODS: Pentosidine levels were analyzed in 98 MS patients and 43 HCs using reverse-phase high-pressure liquid chromatography with fluorescence detection. RESULTS: Plasma pentosidine levels were significantly higher in MS patients when compared with HCs (p = 0.02). Patients on disease-modifying therapies (DMTs) had lower plasma pentosidine levels when compared with DMT-naïve patients (p = 0.01). Pentosidine plasma levels correlated with indicators of MS disease severity, including Extended Disability Status Scale (p = 0.03), MS Severity Scale (p = 0.01), and MS Functional Composite (p = 0.03). No correlation between pentosidine levels and age, rate of clinical relapse, and disease duration was observed. CONCLUSIONS: Our results suggest that pentosidine could be a novel, inflammatory biomarker in MS clinical practice. Longitudinal studies are warranted to determine any causal relationship between changes in plasma pentosidine levels and MS disease pathology. These studies may pave the way for use of advanced glycation end product (AGE) inhibitors and AGE-breaking agents as new therapeutic modalities in MS.

Sustained improvement in Expanded Disability Status Scale as a new efficacy measure of neurological change in multiple sclerosis: treatment effects with natalizumab in patients with relapsing multiple sclerosis.

BACKGROUND: Validated measures of sustained improvements in neurological function have not been established for multiple sclerosis (MS) clinical studies. OBJECTIVE: To evaluate sustained Expanded Disability Status Scale (EDSS) change as a potential indicator of neurological improvement and as an outcome measure in MS clinical studies. METHODS: Analyses were performed on patients (n = 620) from the pivotal natalizumab study AFFIRM with baseline EDSS scores ≥2.0. Cumulative probabilities of neurological improvement, defined as a 1.0-point decrease in EDSS score sustained for ≥12 weeks, were estimated by Kaplan-Meier analysis. A Cox proportional hazards model identified associated baseline factors and examined treatment effects. RESULTS: Sustained improvement (as well as sustained worsening) in neurological disability was seen in AFFIRM patients. Sustained EDSS changes correlated well with quality of life measurements (SF36 and VAS). Natalizumab increased the cumulative probability of improvement over 2 years by 69% versus placebo (HR = 1.69; 95% CI 1.16-2.45; p = 0.006). Sensitivity analyses showed consistent benefits of natalizumab with variations in improvement magnitude and duration, and baseline disease activity. CONCLUSION: These analyses demonstrate that sustained EDSS improvement is an additional measure that is sensitive to treatment effects over 2 years and correlates with quality of life. Further research is warranted to validate its use as an MS study clinical outcome.

AGE-RAGE in multiple sclerosis brain.

This pilot study used immunohistochemical techniques to investigate the advanced glycation end-product (AGE) Nepsilon-(carboxymethyl)lysine (CML) and its receptor (RAGE) in the brains of multiple sclerosis (MS) patients, comparing them with the brains of patients with Alzheimer's disease (AD) (positive controls) and with age-matched control subjects (negative controls). Postmortem slides derived from the hippocampi of MS patients, AD patients, and controls were stained with monoclonal antibodies for CML and human RAGE. Results showed increased AGE and RAGE immunostaining in the hippocampi of MS patients, similar to AD patients.

Diagnostic potential of plasma carboxymethyllysine and carboxyethyllysine in multiple sclerosis.

BACKGROUND: This study compared the level of advanced glycation end products (AGEs), N-(Carboxymethyl)lysine (CML) and N-(Carboxyethyl)lysine (CEL), in patients with multiple sclerosis (MS) and healthy controls (HCs), correlating these markers with clinical indicators of MS disease severity. METHODS: CML and CEL plasma levels were analyzed in 99 MS patients and 43 HCs by tandem mass spectrometry (LC/MS/MS). Patients were stratified based on drug modifying therapies (DMTs) including interferon beta, glatiramer acetate and natalizumab. RESULTS: The level of plasma CEL, but not CML, was significantly higher in DMT-naïve MS patients when compared to HCs (P < 0.001). Among MS patients, 91% had higher than mean plasma CEL observed in HCs. DMTs reduced CML and CEL plasma levels by approximately 13% and 40% respectively. CML and CEL plasma levels correlated with the rate of MS clinical relapse. CONCLUSION: Our results suggest that AGEs in general and CEL in particular could be useful biomarkers in MS clinical practice. Longitudinal studies are warranted to determine any causal relationship between changes in plasma level of AGEs and MS disease pathology. These studies will pave the way for use of AGE inhibitors and AGE-breaking agents as new therapeutic modalities in MS.

Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blind, placebo-controlled study found that MD1003 improved disability outcomes over 12 months in patients with progressive multiple sclerosis. The SPI2 study was designed to assess the safety and efficacy of MD1003 in progressive forms of multiple sclerosis in a larger, more representative patient cohort. METHODS: SPI2 was a randomised, double-blind, parallel-group, placebo-controlled trial done at 90 academic and community multiple sclerosis clinics across 13 countries. Patients were aged 18-65 years, had a diagnosis of primary or secondary progressive multiple sclerosis fulfilling the revised International Panel criteria and Lublin criteria, a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), an expanded disability status scale (EDSS) score of 3·5-6·5, a timed 25-foot walk (TW25) of less than 40 s, evidence of clinical disability progression, and no relapses in the 2 years before enrolment. Concomitant disease-modifying therapies were allowed. Patients were randomly assigned (1:1) by an independent statistician using an interactive web response system, with stratification by study site and disease history, to receive MD1003 (oral biotin 100 mg three times daily) or placebo. Participants, investigators, and assessors were masked to treatment assignment. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25 at month 12, confirmed at month 15, versus baseline. The primary endpoint was assessed in the intention-to-treat analysis set, after all participants completed the month 15 visit. Safety analyses included all participants who received at least one dose of MD1003. This trial is registered with ClinicalTrials.gov (NCT02936037) and the EudraCT database (2016-000700-29). FINDINGS: From Feb 22, 2017, to June 8, 2018, 642 participants were randomly assigned MD1003 (n=326) or placebo (n=316). The double-blind, placebo-controlled phase of the study ended when the primary endpoint for the last-entered participant was assessed on Nov 15, 2019. The mean time in the placebo-controlled phase was 20·1 months (SD 5·3; range 15-27). For the primary outcome, 39 (12%) of 326 patients in the MD1003 group compared with 29 (9%) of 316 in the placebo group improved at month 12, with confirmation at month 15 (odds ratio 1·35 [95% CI 0·81-2·26]). Treatment-emergent adverse events occurred in 277 (84%) of 331 participants in the MD1003 group and in 264 (85%) of 311 in the placebo group. 87 (26%) of 331 participants in the MD1003 group and 82 (26%) of 311 participants in the placebo group had at least one serious treatment-emergent adverse event. One (<1%) person died in the MD1003 group and there were no deaths in the placebo group. Despite use of mitigation strategies, MD1003 led to inaccurate laboratory results for tests using biotinylated antibodies. INTERPRETATION: This study showed that MD1003 did not significantly improve disability or walking speed in patients with progressive multiple sclerosis and thus, in addition to the potential of MD1003 for deleterious health consequences from interference of laboratory tests, MD1003 cannot be recommended for treatment of progressive multiple sclerosis. FUNDING: MedDay Pharmaceuticals.

Immunomodulatory responses of peripheral blood mononuclear cells from multiple sclerosis patients upon in vitro incubation with the flavonoid luteolin: additive effects of IFN-beta.

The study is aimed to determine the role of luteolin (3',4',5,7-tetrahydroxyflavone), alone and in combination with human interferon-beta (IFN-beta), in modulating the immune response(s) of peripheral blood mononuclear cells (PBMCs) isolated from multiple sclerosis (MS) patients. PBMC proliferation in the presence or absence of these drugs was determined and the production of pro-inflammatory cytokines (IL-1beta, TNF-alpha), and the ratio of cell migration mediator MMP-9, and its inhibitor, TIMP-1 was assessed in the culture supernatants. Luteolin reduced, in a dose-dependent manner, the proliferation of PBMCs, and modulated the levels of IL-1beta and TNF-alpha released by PBMCs in the culture supernatants. Luteolin reduced the MMP-9/TIMP-1 ratio via lowering MMP-9 production. In the majority of cases, luteolin, when combined with IFN-beta, had additive effects in modulating cell proliferation, IL-1beta, TNF-alpha, MMP-9 and TIMP-1.

Genomic effects of once-weekly, intramuscular interferon-beta1a treatment after the first dose and on chronic dosing: Relationships to 5-year clinical outcomes in multiple sclerosis patients.

PURPOSE: To characterize gene expression in multiple sclerosis (MS) patients after the first dose and chronic dosing of 30 microg, once weekly, intramuscular interferon-beta1a (IFN-beta) and to delineate the pharmacogenomic differences between Good Responders and Partial Responders to IFN-beta therapy. METHODS: The treatment responses after the first IFN-beta dose and chronic IFN-beta dosing were assessed in 22 relapsing MS patients (17 females, 5 males; average age: 41.5+/-SD 10.4 years). Gene expression profiles in peripheral blood mononuclear cells were obtained prior to treatment and at 1, 2, 4, 8, 24, 48, 120, 168 h after the first IFN-beta dose and at 1, 6 and 12 months after chronic dosing with once-weekly 30 microg IFN-beta-1a intramuscularly. Repeated measures statistics with false discovery rate control were used. The functional characteristics, biological pathways and transcription factor sites were analyzed. RESULTS: Of the 1000 genes modulated following the first dose and upon chronic dosing of IFN-beta in MS patients, approximately 35% were up-regulated and 65% were down- regulated; the percentage of modulated genes in common was approximately 50%. The expression of the pharmacodynamic mRNA markers of IFN-beta effect showed differences in time profiles for the Good Responder and Partial Responders to IFN-beta therapy and the Jak-STAT, TNFRSF10B, IL6, TGFbeta, retinoic acid and CDC42 pathways were differentially modulated. The patients with side effects to therapy showed differences in the TGFbeta1, IFNG/STAT3 and TNF pathways. CONCLUSIONS: Gene expression is a valuable tool for understanding the molecular mechanisms of IFN-beta action in MS patients.

Quercetin and interferon-beta modulate immune response(s) in peripheral blood mononuclear cells isolated from multiple sclerosis patients.

The study is aimed to determine the role of quercetin (3,3'4',5,7-pentahydroxy flavone), alone and in combination with human interferon-beta (IFN-beta), in modulating the immune response(s) of peripheral blood mononuclear cells (PBMC) isolated from multiple sclerosis (MS) patients and from normal healthy subjects. PBMC proliferation in the presence or absence of these drugs was determined and the production of proinflammatory cytokines (IL-1beta, TNF-alpha), and the ratio of cell migration mediator MMP-9, and its inhibitor, TIMP-1 were assessed in the culture supernatants. Quercetin reduced, in a dose-dependent manner, the proliferation of PBMC and modulated the level of IL-1beta and TNF-alpha released by PBMC in the culture supernatants. Quercetin reduced the MMP-9/TIMP-1 ratio via lowering MMP-9 production. Quercetin, when combined with IFN-beta, had additive effects in modulating TNF-alpha and MMP-9. These immunomodulatory responses to quercetin were similar between MS patients and healthy control (HC) subjects.

Cortical atrophy and personality in multiple sclerosis.

Although the cognitive disorder of multiple sclerosis (MS) is well characterized, little is known about personality changes that may occur in this disease. There are reliable personality tests available for research in neurological disease, based on the well-known Five Factor Model. Preliminary research suggests that cognitively impaired MS patients exhibit elevation in Neuroticism, and diminution in Extraversion, Agreeableness, and Conscientiousness, as do patients with Alzheimer's disease. We predicted that these characteristics would be associated with lower neocortical volume. We studied 44 patients using brain MRI and the NEO Five-Factor Inventory. Regression models controlling for T2 lesion volume, depression, and cognitive dysfunction revealed significant correlation between cortical atrophy and reduction in Extraversion and Conscientiousness. Discrepancies between patient- and informant-reports were found, and overreporting of high Openness and Conscientiousness among patients was associated with lower neocortical volume. A final regression model accounting for depression, cognitive function, and personality accounted for 38% of the variance in neocortical volume. These findings suggest that cortical atrophy in MS is associated with adverse impact on personality, although longitudinal research is needed to test this hypothesis.

Use of perfusion- and diffusion-weighted imaging in differential diagnosis of acute and chronic ischemic stroke and multiple sclerosis.

OBJECTIVE: To investigate differences in lesions and surrounding normal appearing white matter (NAWM) by perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) in patients with acute and chronic ischemic stroke and multiple sclerosis (MS). METHODS: Study subjects included 45 MS patients, 22 patients with acute ischemic stroke and 20 patients with chronic ischemic stroke. All subjects underwent T2-weighted imaging (WI), flair attenuated inversion recovery (FLAIR), DWI and dynamic contrast enhanced PWI. Apparent diffusion coefficient (ADC) and mean transit time (MTT) maps were generated and values were calculated in the acute and chronic ischemic and demyelinating lesions, and in NAWM for distances of 5, 10 and 15 mm. Fifty-three acute ischemic and 33 acute demyelinating lesions, and 775 chronic ischemic and 998 chronic demyelinating lesions, were examined. Univariate, multivariate and data mining analyses were used to examine the feasibility of a prediction model between different lesion types. Correctly and incorrectly classified lesions, true positive (TP), false positive (FP) and precision rates were calculated. RESULTS: Patients with acute ischemic lesions presented more prolonged mean MTT values in lesions (p=0.002) and surrounding NAWM for distances of 5, 10 and 15 mm (all p<0.0001) than those with acute demyelinating lesions. In multinomial logistic regression analysis, 65 of 86 acute lesions were correctly classified (75.6%). The TP rates were 81.1% for acute ischemic lesions and 66.7% for acute demyelinating lesions. The FP rates were 33.3% for acute ischemic and 18.9% for acute demyelinating lesions. The precision was 79.6% for classification of acute ischemic lesions and 68.8% for prediction of acute demyelinating lesions. The logistic model tree decision algorithm revealed that prolonged MTT of surrounding NAWM for a distance of 15 mm (> or =7459.2 ms) was the best classifier of acute ischemic versus acute demyelinating lesions. Patients with chronic ischemic lesions presented higher mean ADC (p<0.0001) and prolonged MTT (p=0.013) in lesions, and in surrounding NAWM for distances of 5, 10 and 15 mm (all p<0.0001), compared to the patients with chronic demyelinating lesions. Data mining analyses did not show reliable predictability for correctly discerning between chronic ischemic and chronic demyelinating lesions. The precision was 56.7% for classification of chronic ischemic and 58.9% for prediction of chronic demyelinating lesions. DISCUSSION: We found prolonged MTT values in lesions and surrounding NAWM of patients with acute and chronic ischemic stroke when compared to MS patients. The use of PWI is a promising tool for differential diagnosis between acute ischemic and acute demyelinating lesions. The results of this study contribute to a better understanding of the extent of hemodynamic abnormalities in lesions and surrounding NAWM in patients with MS.

Application of hidden Markov random field approach for quantification of perfusion/diffusion mismatch in acute ischemic stroke.

The perfusion/diffusion 'mismatch model' in acute ischemic stroke provides the potential to more accurately understand the consequences of thrombolytic therapy on an individual patient basis. Few methods exist to quantify mismatch extent (ischemic penumbra) and none have shown a robust ability to predict infarcted tissue outcome. Hidden Markov random field (HMRF) approaches have been used successfully in many other applications. The aim of the study was to develop a method for rapid and reliable identification and quantification of perfusion/diffusion mismatch using an HMRF approach. An HMRF model was used in combination with automated contralateral identification to segment normal tissue from non-infarcted tissue with perfusion abnormality. The infarct was used as a seed point to initialize segmentation, along with the contralateral mirror tissue. The two seeds were then allowed to compete for ownership of all unclassified tissue. In addition, a novel method was presented for quantifying tissue salvageability by weighting the volume with the degree of hypoperfusion, allowing the penumbra voxels to contribute unequal potential damage estimates. Simulated and in vivo datasets were processed and compared with results from a conventional thresholding approach. Both simulated and in vivo experiments demonstrated a dramatic improvement in accuracy with the proposed technique. For the simulated dataset, the mean absolute error decreased from 171.9% with conventional thresholding to 2.9% for the delay-weighted HMRF approach. For the in vivo dataset, the mean absolute error decreased from 564.6% for thresholding to 34.2% for the delay-weighted HMRF approach. The described method represents a significant improvement over thresholding techniques.

Clinical and MRI correlates of autoreactive antibodies in multiple sclerosis patients.

BACKGROUND: Autoreactive antibodies (ARAB) occur more frequently in patients with multiple sclerosis (MS) than in general population and the presence of these antibodies often causes uncertainty regarding the disease course, response to therapy and the diagnosis of MS. METHODS: Retrospective analyses of the ARAB, clinical and MRI data of a consecutive patient cohort of MS and clinically isolated syndrome (CIS) patients were conducted. The patients were evaluated for an extensive panel that included various subtypes of antiphospholipid antibody (APLA) including anti-phosphatidylethanolamine (APE), anti-phosphatidylserine (APS), anti-beta-2-glycoprotein-1 (ABGP), anti-cardiolipin (ACA), and several other ARAB such as antinuclear antibody (ANA), anti-neutrophilic cytoplasmic antibodies (ANCA), anti-thyroid peroxidase antibodies (ATA), anti-SS-A, and anti-SS-B antibodies. Quantitative MRI analysis was performed in a subgroup of MS patients measuring T2-lesion volume (LV), T1 black hole LV and brain parenchymal fraction (BPF). RESULTS: A total of 137 patients (mean age 44.7, 84% female) with either MS (n=111; age: mean 46.5+/-S.D. 10.3 years; disease duration: mean 13.0+/-S.D. 10.4 years; EDSS: mean 3.2+/-S.D. 1.9) or CIS (n=26; age: mean 37.7+/-S.D. 7.8 years; disease duration: mean 1.3+/-S.D. 1.1 years; EDSS: mean 1.0+/-S.D. 0.7) were enrolled. Among MS patients, 82 were RRMS, 26 SPMS, and 3 had PPMS. Seventy-seven (69%) of MS patients showed presence of one or more ARAB. The proportion of MS patients with APLA was 55% (61 patients); IgM subtype was most frequent. Co-occurrence of ACA and APE was more frequent in SPMS as compared to RRMS (15.4% vs. 1.2%, p=0.012). The proportion of CIS patients with ARAB was 75% with IgM subtype being the most frequent. However, the ARAB in majority of CIS patients (9 out of 14, 64%) were transient on repeated testing. In a subgroup of 62 MS patients, quantitative MRI analysis showed significantly higher T2-LV in patients with positive APLA (15.1 ml for APLA positive vs. 6.75 ml for APLA negative) after correcting for the disease duration (p=0.048). The patients with ATA also had significantly higher T2-LV after correction for disease duration (19.0 ml vs.8.5, p=0.044). CONCLUSIONS: ARAB were present in more than two thirds of MS and CIS patients although most of APLA in CIS were transient. The presence of APLA in MS patients was associated with higher T2-LV.

Hyperglycemia, insulin, and acute ischemic stroke: a mechanistic justification for a trial of insulin infusion therapy.

BACKGROUND AND PURPOSE: Hyperglycemia is associated with increased mortality and morbidity in acute ischemic stroke. SUMMARY OF REVIEW: Hyperglycemia induces a pro-oxidative and proinflammatory state that can cause direct neuronal toxicity. Hyperglycemia-mediated increase in matrix metalloproteinase-9 can cause neuronal damage by an increase in cerebral edema. Moreover, hyperglycemia may be responsible for a procoagulant state that can further compromise blood supply to the penumbral areas in acute ischemic stroke. Insulin infusion has an effect that is opposite to that of hyperglycemia. It not only lowers blood glucose levels but also exerts an antioxidant and anti-inflammatory effect. Insulin also improves NO production and results in improved blood circulation to the ischemic areas. This article focuses on the potential mechanisms underlying the injurious effects of glucose and the beneficial effects of insulin. CONCLUSIONS: In the absence of other potential beneficial therapies, there is an urgency to institute trials with insulin infusion in acute ischemic stroke.

Neocortical atrophy, third ventricular width, and cognitive dysfunction in multiple sclerosis.

BACKGROUND: Cognitive dysfunction is common in multiple sclerosis (MS). Correlations are reported between atrophy and neuropsychological test results. OBJECTIVE: To determine if neocortical volume would supplant or supplement third ventricular width and other magnetic resonance imaging measures when predicting neuropsychological impairment. DESIGN: Cross-sectional study. SETTING: University MS clinic. PARTICIPANTS: Seventy-seven patients with relapsing-remitting MS, 42 patients with secondary progressive MS, and 27 healthy control subjects. MAIN OUTCOME MEASURES: Brain atrophy and lesion burden measures were obtained in all patients. A subset of 82 patients and all controls underwent neuropsychological testing. RESULTS: Patients with secondary progressive MS had more atrophy than patients with relapsing-remitting MS and controls. Neocortical volume was significantly correlated with all neuropsychological measures, with r values ranging from 0.29 to 0.58. Third ventricular width was retained in most stepwise regression analyses predicting cognitive impairment in patients with MS and distinguishing secondary progressive from relapsing-remitting courses of MS. CONCLUSIONS: We confirm an association between neocortical volume and multiple cognitive domains in MS, although neocortical volume did not explain significantly more variance than other magnetic resonance imaging measures. Of the magnetic resonance imaging variables studied, third ventricular width was retained in most regression models.

Interferon inhibitory activity in patients with multiple sclerosis.

BACKGROUND: Interferon inhibitory activity (IIA) is a logical candidate for explaining neutralizing antibody-negative partial responsiveness to interferon beta in multiple sclerosis (MS), but its role has not been evaluated. OBJECTIVE: To investigate the role of IIA and soluble interferon-alpha/beta receptor (sIFNR) in determining response of patients with MS to interferon beta therapy. DESIGN: Parallel-group, open-label study. SETTING: Baird Multiple Sclerosis Center, Buffalo, NY. Patients Blood was obtained before and 24 hours after injection of interferon beta-1a from 38 anti-interferon beta neutralizing antibody-negative patients with relapsing-remitting MS and 16 untreated healthy controls. On the basis of clinical parameters of response to interferon beta therapy, the patients were divided into stable or good-responder (n = 20) and active or partial-responder (n = 18) groups. MAIN OUTCOME MEASURES: Quantitative analyses of magnetic resonance imaging were obtained; the IIA and sIFNR levels were measured using bioassay and enzyme-linked immunosorbent assay, respectively. RESULTS: The IIA and sIFNR levels were elevated in MS patients compared with controls (P<.001). The IIA levels were higher in active or partial responders compared with stable or good responders (P<.001); the sIFNR levels were not different between groups. The Extended Disability Status Score and T2 lesion volumes were higher in the active or partial-responder group compared with the stable or good-responder group. Interferon beta-1a did not have short-term effects on the IIA and sIFNR levels. In univariate general linear model and stepwise regression analyses, IIA levels were associated with T2 lesion volume. CONCLUSION: The levels of IIA are associated with increased MS disease activity and with responsiveness to interferon beta therapy in anti-interferon beta neutralizing antibody-negative MS patients.

Dynamics of interferon-beta modulated mRNA biomarkers in multiple sclerosis patients with anti-interferon-beta neutralizing antibodies.

The objective of this study was to evaluate multiple interferon (IFN) specific mRNA biomarkers in multiple sclerosis (MS) patients with anti-IFN-beta neutralizing antibodies (NAB) using a pharmacodynamic study design. Thirty patients were enrolled. Blood samples were drawn at pre-treatment, 4-, 8-h time points following the intramuscular dose of IFN-beta-1a. Total RNA was obtained from peripheral blood cells, processed to cDNA and analyzed using quantitative real-time polymerase chain reaction. Pre-treatment serum samples were analyzed for anti-IFN-beta binding and neutralizing antibodies: 22 patients were NAB negative; equal numbers of the eight remaining patients were either NAB positive or had borderline NAB status. The results showed that early assessment (at 4 h after IFN-beta injection) of mRNAs for Stat-1, MxA, MxB and TRAIL was more sensitive than the later measurements. Furthermore, the NAB positive patients had strongly attenuated gene expression responses on all the mRNAs. Patients with borderline NAB had average responses that appear to be lower than NAB negative patients on several genes, notably Stat-1, TRAIL and beta2 microglobulin.