Proteomic signatures of physical, cognitive, and imaging outcomes in multiple sclerosis.

BACKGROUND: A quantitative measurement of serum proteome biomarkers that would associate with disease progression endpoints can provide risk stratification for persons with multiple sclerosis (PwMS) and supplement the clinical decision-making process. MATERIALS AND METHODS: In total, 202 PwMS were enrolled in a longitudinal study with measurements at two time points with an average follow-up time of 5.4 years. Clinical measures included the Expanded Disability Status Scale, Timed 25-foot Walk, 9-Hole Peg, and Symbol Digit Modalities Tests. Subjects underwent magnetic resonance imaging to determine the volumetric measures of the whole brain, gray matter, deep gray matter, and lateral ventricles. Serum samples were analyzed using a custom immunoassay panel on the Olink™ platform, and concentrations of 18 protein biomarkers were measured. Linear mixed-effects models and adjustment for multiple comparisons were performed. RESULTS: Subjects had a significant 55.6% increase in chemokine ligand 20 (9.7 pg/mL vs. 15.1 pg/mL, p < 0.001) and neurofilament light polypeptide (10.5 pg/mL vs. 11.5 pg/mL, p = 0.003) at the follow-up time point. Additional changes in CUB domain-containing protein 1, Contactin 2, Glial fibrillary acidic protein, Myelin oligodendrocyte glycoprotein, and Osteopontin were noted but did not survive multiple comparison correction. Worse clinical performance in the 9-HPT was associated with neurofilament light polypeptide (p = 0.001). Increases in several biomarker candidates were correlated with greater neurodegenerative changes as measured by different brain volumes. CONCLUSION: Multiple proteins, selected from a disease activity test that represent diverse biological pathways, are associated with physical, cognitive, and radiographic outcomes. Future studies should determine the utility of multiple protein assays in routine clinical care.

Generative models for age, race/ethnicity, and disease state dependence of physiological determinants of drug dosing.

Dosing requires consideration of diverse patient-specific factors affecting drug pharmacokinetics and pharmacodynamics. The available pharmacometric methods have limited capacity for modeling the inter-relationships and patterns of variability among physiological determinants of drug dosing (PDODD). To investigate whether generative adversarial networks (GANs) can learn a generative model from real-world data that recapitulates PDODD distributions. A GAN architecture was developed for modeling a PDODD panel comprised of: age, sex, race/ethnicity, body weight, body surface area, total body fat, lean body weight, albumin concentration, glomerular filtration rate (EGFR), urine flow rate, urinary albumin-to-creatinine ratio, alanine aminotransferase to alkaline phosphatase R-value, total bilirubin, active hepatitis B infection status, active hepatitis C infection status, red blood cell, white blood cell, and platelet counts. The panel variables were derived from National Health and Nutrition Examination Survey (NHANES) data sets. The dependence of GAN-generated PDODD on age, race, and active hepatitis infections was assessed. The continuous PDODD biomarkers had diverse non-normal univariate distributions and bivariate trend patterns. The univariate distributions of PDODD biomarkers from GAN simulations satisfactorily approximated those in test data. The joint distribution of the continuous variables was visualized using three 2-dimensional projection methods; for all three methods, the points from the GAN simulation random variate vectors were well dispersed amongst the test data. The age dependence trend patterns in GAN data were similar to those in test data. The histograms for R-values and EGFR from GAN simulations overlapped extensively with test data histograms for the Hispanic, White, African American, and Other race/ethnicity groups. The GAN-simulated data also mirrored the R-values and EGFR changes in active hepatitis C and hepatitis B infection. GANs are a promising approach for simulating the age, race/ethnicity and disease state dependencies of PDODD.

Dysregulated Sulfide Metabolism in Multiple Sclerosis: Serum and Vascular Endothelial Inflammatory Responses.

Multiple sclerosis (MS) is a leading cause of neurodegenerative disability in younger individuals. When diagnosed early, MS can be managed more effectively, stabilizing clinical symptoms and delaying disease progression. The identification of specific serum biomarkers for early-stage MS could facilitate more successful treatment of this condition. Because MS is an inflammatory disease, we assessed changes in enzymes of the endothelial hydrogen sulfide (H2S) pathway in response to inflammatory cytokines. Blotting analysis was conducted to detect Cystathionine γ-lyase (CSE), Cystathionine beta synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (MST) in human brain microvascular endothelial apical and basolateral microparticles (MPs) and cells following exposure to tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). CSE was increased in MPs and cells by exposure to TNF-α/IFN-γ; CBS was elevated in apical MPs but not in cells or basolateral MPs; MST was not significantly affected by cytokine exposure. To test how our findings relate to MS patients, we evaluated levels of CSE, CBS, and MST in serum samples from healthy control and MS patients. We found significantly decreased levels of CBS and MST (p = 0.0004, 0.009) in MS serum samples, whereas serum levels of CSE were marginally increased (p = 0.06). These observations support increased CSE and lower CBS and MST expression being associated with the vascular inflammation in MS. These changes in endothelial-derived sulfide enzymes at sites of inflammation in the brain may help to explain sulfide-dependent changes in vascular dysfunction/neuroinflammation underlying MS. These findings further support the use of serum samples to assess enzymatic biomarkers derived from circulating MPs. For example, "liquid biopsy" can be an important tool for allowing early diagnosis of MS, prior to the advanced progression of neurodegeneration associated with this disease.

Effect of ocrelizumab on leptomeningeal inflammation and humoral response to Epstein-Barr virus in multiple sclerosis. A pilot study.

BACKGROUND: Ocrelizumab is an effective treatment for relapsing and primary-progressive multiple sclerosis (MS). However, the effect of ocrelizumab on leptomeningeal (LM) inflammation is unknown. OBJECTIVE: To investigate whether ocrelizumab reduces LM inflammation by reducing the exposure to Epstein-Barr virus (EBV)-infected B cells in relapsing-remitting (RR) MS. METHODS: This was a Phase IV, prospective, open-label, single-center, observational, longitudinal pilot study of RRMS patients who started treatment with ocrelizumab (NCT03025269). Clinical, MRI and EBV-antibodies outcomes at baseline, 12- and 24-month of the study were evaluated. The MRI outcomes included T2, T1 and T1-contrast enhancing (CE) lesion counts and volumes, LM CE count, and percentage brain volume changes. RESULTS: 27 RRMS patients started ocrelizumab and 24 remained on the treatment for whole duration of the study. Most patients remained stable (74.1%) or improved (18.5%) in their disability status. At baseline, 42.3% of patients showed LM CE lesions. The majority of patients remained stable in their LM CE status over the follow-up (72.7%). A significant decrease in percentage volume loss of cortex (p=0.009), GM (p=0.01) and thalamus (p=0.038) was detected, while T1-LV increased (p=0.02). A significant decrease of EBNA-1 IgG (p=0.013) was evidenced. An infusion-related allergic reaction led to discontinuation of the medication in one patient at first dose. CONCLUSIONS: Treatment with ocrelizumab was safe and clinically effective. Brain volume loss and accumulation of T1-LV occurred. While ocrelizumab decreased humoral response to EBV possibly by reducing B cells, it did not reduce LM inflammation.

Lower cerebral arterial blood flow is associated with greater serum neurofilament light chain levels in multiple sclerosis patients.

BACKGROUND AND PURPOSE: Hypoperfusion, vascular pathology, and cardiovascular risk factors are associated with disease severity in multiple sclerosis (MS). We aimed to assess relationships between cerebral arterial blood flow (CABF) and serum neurofilament light chain (sNfL) as neuronal damage biomarkers. METHODS AND MATERIALS: Total CABF was measured in 137 patients (86 with clinically isolated syndrome/relapsing-remitting (RR) MS and 51 with progressive MS [PMS]) and 48 healthy controls using Doppler ultrasonography. sNfL was quantitated using a single-molecule assay (Simoa). Examination using 3.0-T magnetic resonance imaging (MRI) allowed quantification of T2 lesions and whole-brain volume (WBV). Multiple linear regression models determined the sNfL association with CABF after correction for demographic and MRI-derived variables. RESULTS: After adjustment for age, sex and body mass index (BMI), total CABF remained statistically significant and model comparisons showed that CABF explained an additional 2.6% of the sNfL variance (ß = -0.167, p = 0.044). CABF also remained significant in a stepwise regression model (ß = 0.18, p = 0.034) upon the inclusion of T2 lesion burden and WBV effects. Patients in the lowest CABF quartile (CABF ≤ 761 ml/min) had significantly higher sNfL levels (34.6 vs. 23.9 pg/ml, age and BMI-adjusted-p = 0.042) when compared to the highest quartile (CABF ≥ 1130 ml/min). CONCLUSION: Lower CABF is associated with increased sNfL in MS patients, highlighting the relationship between cerebral hypoperfusion and axonal pathology.

Hypertension and hypertension severity in Hispanics/Latinx with MS.

BACKGROUND: Vascular comorbidities (VCs) including hypertension (HTN) are associated with worse multiple sclerosis (MS) outcomes. HTN is common in Latinx, but the prevalence and relationship with disability are unknown in Latinx with MS. METHODS: Latinx (n = 451) from the Alliance for Research in Hispanic MS (ARHMS) seen between 2007 and 2019 were included. HTN, diabetes (DM), hyperlipidemia (HLD), ischemic events, and smoking were considered VC. Blood pressures (BPs) were classified using the American Heart Association (AHA) criteria. Logistic regression determined associations between VC and ambulatory disability accounting for age, sex, and disease duration. RESULTS: Medical comorbidities were found in 41.9% and VC in 24.2%. Smoking (13.6%) and HTN (7.3%) were the most common. HTN was the most common over the age of 40 (12.6%). The odds of having severe disability were three times higher for those with HTN (odds ratio [OR], 3.12; 95% confidence interval (CI), 1.37-7.12). Stage II HTN according to AHA also tripled the odds (OR, 2.89; 95%CI, 1.11-7.55). AHA BP confirmed HTN in 27.5% (compared to 7.3% with established diagnosis). CONCLUSION: HTN diagnosis and stage II HTN defined by AHA were independently associated with severe ambulatory disability in Latinx with MS. HTN was underdiagnosed. Future studies should assess whether HTN treatment control would prevent disability in MS.

Application of Brunauer-Emmett-Teller (BET) theory and the Guggenheim-Anderson-de Boer (GAB) equation for concentration-dependent, non-saturable cell-cell interaction dose-responses.

To systematically assess the characteristics and potential utility of the Guggenheim-Anderson-de Boer (GAB) formulation of the Brunauer-Emmett-Teller (BET) equation from physical chemistry for modeling dose-responses in pharmaceutical applications. The GAB-BET equation was derived using pharmacodynamic first principles to underscore the assumptions involved and the functional characteristics of the equation were investigated. The properties of the GAB-BET equation were compared to the familiar Michaelis-Menten and Hill equations and its utility for pharmacokinetic-pharmacodynamic modeling was assessed by fitting the model equations to four diverse data sets from the literature. The results enabled the salient characteristics of the unconstrained GAB-BET equation and the corresponding GAB-BET equation with finite layers for modeling pharmacodynamic effects to be critically assessed. The GAB-BET approach allows for the accumulation of heterogeneous stacks containing multiple cells or molecules at the target site. The unconstrained GAB-BET equation is capable of describing concentration-dependent dose-response curves that do not exhibit saturation. The GAB-BET equation for finite layers exhibits saturation but increases more slowly than the comparable Michaelis-Menten and Hill equations. The fitting results of the model equations to literature data sets provided support for key aspects of the GAB-BET model. The GAB-BET equation may be a useful method for mechanistic modeling of diverse immune processes and drugs that recruit immune cell activity at the site of action.

Infections, Vaccines and Autoimmunity: A Multiple Sclerosis Perspective.

Background: Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease that is associated with multiple environmental factors. Among suspected susceptibility events, studies have questioned the potential role of overt viral and bacterial infections, including the Epstein Bar virus (EBV) and human endogenous retroviruses (HERV). Furthermore, the fast development of immunomodulatory therapies further questions the efficacy of the standard immunization policies in MS patients. Topics reviewed: This narrative review will discuss the potential interplay between viral and bacterial infections and their treatment on MS susceptibility and disease progression. In addition, the review specifically discusses the interactions between MS pathophysiology and vaccination for hepatitis B, influenza, human papillomavirus, diphtheria, pertussis, and tetanus (DTP), and Bacillus Calmette-Guerin (BCG). Data regarding potential interaction between MS disease modifying treatment (DMT) and vaccine effectiveness is also reviewed. Moreover, HERV-targeted therapies such as GNbAC1 (temelimab), EBV-based vaccines for treatment of MS, and the current state regarding the development of T-cell and DNA vaccination are discussed. Lastly, a reviewing commentary on the recent 2019 American Academy of Neurology (AAN) practice recommendations regarding immunization and vaccine-preventable infections in the settings of MS is provided. Conclusion: There is currently no sufficient evidence to support associations between standard vaccination policies and increased risk of MS. MS patients treated with immunomodulatory therapies may have a lower benefit from viral and bacterial vaccination. Despite their historical underperformance, new efforts in creating MS-based vaccines are currently ongoing. MS vaccination programs follow the set back and slow recovery which is widely seen in other fields of medicine.

Lifestyle-based modifiable risk factors in multiple sclerosis: review of experimental and clinical findings.

Multiple sclerosis (MS) is a lifelong inflammatory and neurodegenerative disease influenced by multiple lifestyle-based factors. We provide a narrative review of the effects of modifiable risk factors that are identified as being associated with risk to develop MS and/or influencing the future clinical disease outcomes. The emerging data regarding the beneficial effects of diet modifications and exercise are further reviewed. In contrast, obesity and comorbid cardiovascular diseases are associated with increased MS susceptibility and worse disease progression. In addition, the potential influence of smoking, coffee and alcohol consumption on MS onset and disability development are discussed. Successful management of the modifiable risk factors may lead to better long-term outcomes and improve patients' quality of life. MS specialists should participate in educating and facilitating lifestyle-based modifications as part of their neurological consults.

Marijuana Use by Patients with Multiple Sclerosis.

BACKGROUND: With social attitudes about marijuana changing and patients sometimes seeking nonmainstream treatment options, the main goal of this study was to investigate the prevalence of, and factors associated with, marijuana use by patients with multiple sclerosis (MS). METHODS: Adult patients with MS (n = 521) and controls (n = 279) from a study of clinical, neuroimaging, genetic, and environmental factors in MS progression were included. Patients with MS stated whether they had ever used marijuana before MS diagnosis, after MS diagnosis, and in the preceding 3 months as part of an in-person questionnaire. The control group stated whether they had ever used marijuana and in the preceding 3 months. RESULTS: The percentage of patients with MS reporting ever use of marijuana was 39.9%, compared with 32.7% of controls. Marijuana use in the preceding 3 months was significantly more prevalent among patients with MS (9.4%) compared with controls (0.4%) (P < .001). Marijuana use was most prevalent in male patients with MS (P = .004) and in patients with MS who used complementary and alternative medicine (P = .045). Cigarette smoking was associated with marijuana use in patients with MS (P < .001) and controls (P = .001). Increasing age was associated with decreasing prevalence of marijuana use in the patients with MS (P < 0.001). CONCLUSIONS: Patients with MS are more likely to report recent marijuana use than are people without MS. Owing to potential adverse effects, marijuana use by patients with MS may warrant vigilance by MS caregivers, given shifting social attitudes and the trend towards legalization of marijuana in the United States.

Dietary and lifestyle factors in multiple sclerosis progression: results from a 5-year longitudinal MRI study.

BACKGROUND: Evidence regarding the role, if any, of dietary and lifestyle factors in the pathogenesis of multiple sclerosis (MS) is poorly understood. OBJECTIVE: To assess the effect of lifestyle-based risk factors linked to cardiovascular disease (CVD) on clinical and MRI-derived MS outcomes. METHODS: The study enrolled 175 MS or clinically isolated syndrome (CIS) patients and 42 age- and sex-matched healthy controls (HCs) who were longitudinally followed for 5.5 years. The 20-year CVD risk was calculated by Healthy Heart Score (HHS) prediction model which includes age, smoking, body mass index, dietary intake, exercise, and alcohol consumption. Baseline and follow-up MRI scans were obtained and cross-sectional and longitudinal changes of T2-lesion volume (LV), whole brain volume (WBV), white matter volume (WMV), gray matter volume (GMV), and lateral ventricular volume (LVV) were calculated. RESULTS: After correcting for disease duration, the baseline HHS values of the MS group were associated with baseline GMV (rs = - 0.20, p = 0.01), and longitudinal LVV change (rs = 0.19, p = 0.01). The association with LVV remained significant after adjusting for baseline LVV volumes (rs = 0.2, p = 0.008) in MS patients. The diet component of the HHS was associated with the 5-year T2-LV accrual (rs = - 0.191, p = 0.04) in MS. In the HC group, the HHS was associated with LVV (rs = 0.58, p < 0.001), GMV (rs = - 0.57, p < 0.001), WBV (rs = - 0.55, p = 0.001), T2-LV (rs = 0.41, p = 0.027), and WMV (rs = - 0.38, p = 0.042). Additionally, the HC HHS was associated with the 5-year change in LVV (rs = 0.54, p = 0.001) and in WBV (rs = - 0.45, p = 0.011). CONCLUSION: Lifestyle risk factors contribute to accelerated central brain atrophy in MS patients, whereas unhealthier diet is associated with MS lesion accrual. Despite the lower overall effect when compared to HCs, lifestyle-based modifications may still provide a beneficial effect on reducing brain atrophy in MS patients.

The role of Epstein-Barr virus in multiple sclerosis: from molecular pathophysiology to in vivo imaging.

Multiple sclerosis (MS) is a disease of the central nervous system characterized by inflammation, demyelination, and neuronal damage. Environmental and genetic factors are associated with the risk of developing MS, but the exact cause still remains unidentified. Epstein-Barr virus (EBV), vitamin D, and smoking are among the most well-established environmental risk factors in MS. Infectious mononucleosis, which is caused by delayed primary EBV infection, increases the risk of developing MS. EBV may also contribute to MS pathogenesis indirectly by activating silent human endogenous retrovirus-W. The emerging B-cell depleting therapies, particularly anti-CD20 agents such as rituximab, ocrelizumab, as well as the fully human ofatumumab, have shown promising clinical and magnetic resonance imaging benefit. One potential effect of these therapies is the depletion of memory B-cells, the primary reservoir site where EBV latency occurs. In addition, EBV potentially interacts with both genetic and other environmental factors to increase susceptibility and disease severity of MS. This review examines the role of EBV in MS pathophysiology and summarizes the recent clinical and radiological findings, with a focus on B-cells and in vivo imaging. Addressing the potential link between EBV and MS allows the better understanding of MS pathogenesis and helps to identify additional disease biomarkers that may be responsive to B-cell depleting intervention.

Iron-related gene variants and brain iron in multiple sclerosis and healthy individuals.

Brain iron homeostasis is known to be disturbed in multiple sclerosis (MS), yet little is known about the association of common gene variants linked to iron regulation and pathological tissue changes in the brain. In this study, we investigated the association of genetic determinants linked to iron regulation with deep gray matter (GM) magnetic susceptibility in both healthy controls (HC) and MS patients. Four hundred (400) patients with MS and 150 age- and sex-matched HCs were enrolled and obtained 3 T MRI examination. Three (3) single nucleotide polymorphisms (SNPs) associated with iron regulation were genotyped: two SNPs in the human hereditary hemochromatosis protein gene HFE: rs1800562 (C282Y mutation) and rs1799945 (H63D mutation), as well as the rs1049296 SNP in the transferrin gene (C2 mutation). The effects of disease and genetic status were studied using quantitative susceptibility mapping (QSM) voxel-based analysis (VBA) and region-of-interest (ROI) analysis of the deep GM. The general linear model framework was used to compare groups. Analyses were corrected for age and sex, and adjusted for false discovery rate. We found moderate increases in susceptibility in the right putamen of participants with the C282Y (+ 6.1 ppb) and H63D (+ 6.9 ppb) gene variants vs. non-carriers, as well as a decrease in thalamic susceptibility of progressive MS patients with the C282Y mutation (left: - 5.3 ppb, right: - 6.7 ppb, p < 0.05). Female MS patients had lower susceptibility in the caudate (- 6.0 ppb) and putamen (left: - 3.9 ppb, right: - 4.6 ppb) than men, but only when they had a wild-type allele (p < 0.05). Iron-gene linked increases in putamen susceptibility (in HC and relapsing remitting MS) and decreases in thalamus susceptibility (in progressive MS), coupled with apparent sex interactions, indicate that brain iron in healthy and disease states may be influenced by genetic factors.

Dicer and microRNA expression in multiple sclerosis and response to interferon therapy.

Dysregulation of microRNA expression has been shown in multiple sclerosis (MS); however, the mechanisms underlying these changes, their response to therapy and the impact of microRNA changes in MS are not completely understood. Dicer mediates the cleavage of precursor microRNAs to mature microRNAs and is dysregulated in multiple pathologies. Having shown that interferons regulate Dicer in vitro, we hypothesized that MS patient IFNß1a treatment could potentially alter Dicer expression. Dicer mRNA and protein levels, as well as microRNA expression, were determined in MS patient and healthy control PBL. Acute responses to IFNß1a were assessed in 50 patients. We found that Dicer protein but not mRNA levels decreases in MS patients while both are selectively induced in patients responding well to IFNß1a. Potential microRNA biomarkers for relapsing remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) and IFNß1a response are described. Contrasts in Dicer and microRNA expression levels between patient populations may offer insight into mechanisms underlying disease courses and responses to IFNß1a therapy. This work identifies Dicer regulation as both a potential mediator of MS pathology and a therapeutic target.

Cardiovascular risk factors are associated with increased lesion burden and brain atrophy in multiple sclerosis.

BACKGROUND: Cardiovascular (CV) risk factors have been associated with changes in clinical outcomes in patients with multiple sclerosis (MS). OBJECTIVES: To investigate the frequency of CV risks in patients with MS and their association with MRI outcomes. METHODS: In a prospective study, 326 patients with relapsing-remitting MS and 163 patients with progressive MS, 61 patients with clinically isolated syndrome (CIS) and 175 healthy controls (HCs) were screened for CV risks and scanned on a 3T MRI scanner. Examined CV risks included hypertension, heart disease, smoking, overweight/obesity and type 1 diabetes. MRI measures assessed lesion volumes (LVs) and brain atrophy. Association between individual or multiple CV risks and MRI outcomes was examined adjusting for age, sex, race, disease duration and treatment status. RESULTS: Patients with MS showed increased frequency of smoking (51.7% vs 36.5%, p = 0.001) and hypertension (33.9% vs 24.7%, p=0.035) compared with HCs. In total, 49.9% of patients with MS and 36% of HCs showed ≥ 2 CV risks (p = 0.003), while the frequency of ≥ 3 CV risks was 18.8% in the MS group and 8.6% in the HCs group (p = 0.002). In patients with MS, hypertension and heart disease were associated with decreased grey matter (GM) and cortical volumes (p < 0.05), while overweight/obesity was associated with increased T1-LV (p < 0.39) and smoking with decreased whole brain volume (p = 0.049). Increased lateral ventricle volume was associated with heart disease (p = 0.029) in CIS. CONCLUSIONS: Patients with MS with one or more CV risks showed increased lesion burden and more advanced brain atrophy.

Humoral Responses to Diverse Autoimmune Disease-Associated Antigens in Multiple Sclerosis.

UNLABELLED: To compare frequencies of autoreactive antibody responses to endogenous disease-associated antigens in healthy controls (HC), relapsing and progressive MS and to assess their associations with clinical and MRI measures of MS disease progression. METHODS: The study analyzed 969 serum samples from 315 HC, 411 relapsing remitting MS (RR-MS), 128 secondary progressive MS (SP-MS), 33 primary progressive MS (PP-MS) and 82 patients with other neurological diseases for autoantibodies against two putative MS antigens CSF114(Glc) and KIR4.1a and KIR4.1b and against 24 key endogenous antigens linked to diseases such as vasculitis, systemic sclerosis, rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, polymyositis, scleroderma, polymyositis, dermatomyositis, mixed connective tissue disease and primary biliary cirrhosis. Associations with disability and MRI measures of lesional injury and neurodegeneration were assessed. RESULTS: The frequencies of anti-KIR4.1a and anti-KIR4.1b peptide IgG positivity were 9.8% and 11.4% in HC compared to 4.9% and 7.5% in RR-MS, 8.6% for both peptides in SP-MS and 6.1% for both peptides in PP-MS (p = 0.13 for KIR4.1a and p = 0.34 for KIR4.1b), respectively. Antibodies against CSF114(Glc), KIR4.1a and KIR4.1b peptides were not associated with MS compared to HC, or with MS disease progression. HLA DRB1*15:01 positivity and anti-Epstein Barr virus antibodies, which are MS risk factors, were not associated with these putative MS antibodies. CONCLUSIONS: Antibody responses to KIR4.1a and KIR4.1b peptides are not increased in MS compared to HC nor associated with MS disease progression. The frequencies of the diverse autoreactive antibodies investigated are similar in MS and HC.

Effects of diet on brain iron levels among healthy individuals: an MRI pilot study.

Increased brain iron levels may be a risk factor for age-related neurologic disorders. Little is known about factors other than age and sex potentially affecting brain iron concentration. We investigated dietary habits (iron and calcium supplements, dairy products, vegetables, and red meat) as a potential modifiable predictor of brain iron levels using 3-T susceptibility-weighted magnetic resonance imaging. One hundred ninety volunteers were scanned, and mean phase and mean phase of low-phase voxels were determined for deep gray-matter (DGM) structures, including the caudate, putamen, thalamus, pulvinar, hippocampus, amygdala, red nucleus, and substantia nigra. There was a trend for lower mean phase (suggestive of high iron levels) in individuals taking iron supplements (p = 0.075). Among men, both increased dairy and vegetable intakes were significantly associated with lower DGM mean phase (p < 0.05) and mean phase of low-phase voxels (p < 0.05) in the thalamus, pulvinar, and red nucleus. In contrast, among women, iron levels were not associated with dairy consumption (p > 0.05) in the DGM but were inversely associated with vegetable intake in the thalamus (p = 0.006). Brain iron levels appear to be modulated by diet, with effects being highly dependent on gender.

Genetic factors associated with gemcitabine pharmacokinetics, disposition, and toxicity.

AIM: The goal of this work was to investigate the associations of genetic and environmental factors with gemcitabine disposition and toxicity from genomewide data using a novel information theoretic approach. METHODS: We utilized the information theoretic K-way interaction information (KWII) metric to detect gene-gene and gene-environment interactions associated with gemcitabine disposition and gemcitabine-induced neutropenia in genomic and clinical data from Japanese cancer patients. RESULTS: The information theoretic KWII analyses identified age and four genes - DMD, HEXDC, CNTN4, and ALOX5AP - to be associated with gemcitabine pharmacokinetics (PK). The rs4769060 single-nucleotide polymorphism in the ALOX5AP gene was associated with all PK parameters studied. For gemcitabine-induced neutropenia, multiple associations with long intergenic noncoding RNA regions were detected. Pathway analysis identified leukotriene and eoxin synthesis, platelet homeostasis, and L1CAM interactions as potential pathways associated with gemcitabine disposition. CONCLUSION: The KWII analyses detected novel associations with gemcitabine PK and toxicity. These results could be used to inform future investigations involving gemcitabine efficacy in clinical settings.

Interactions of serum cholesterol with anti-herpesvirus responses affect disease progression in clinically isolated syndromes.

OBJECTIVES: To investigate whether anti-herpesvirus antibodies are associated with serum cholesterol profiles in clinically isolated syndromes (CIS). METHODS: Pre-treatment serum samples from 118 high-risk CIS patients were analyzed for IgG antibodies against cytomegalovirus (anti-CMV), Epstein Barr virus (EBV) viral capsid antigen (VCA) and EBV nuclear antigen-1 (EBNA-1). A lipid profile consisting of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) was obtained. Clinical and MRI assessments were obtained at baseline, 6, 12, and 24 months after start of interferon-beta treatment. RESULTS: The study included 118 CIS patients (77 females, 41 males, 65.3% female; mean age: 28.1±SD 8.1 years). Anti-EBV EBNA-1 antibody levels were associated with LDL-C (p=0.009) and TC (p=0.008) levels. Anti-CMV positivity status was associated with reduced time to relapse (p=0.006) and the greater number of relapses (p=0.009) in patients with high HDL-C. Anti-EBV VCA antibody levels were associated with greater number of new T2 lesions (p=0.002) and with increased brain atrophy (p<0.001) in patients with high LDL-C. CONCLUSIONS: Our results indicate that higher levels of anti-EBV EBNA-1 antibodies are associated with higher LDL-C and TC levels. Anti-CMV positive individuals have greater disease progression in the presence of higher HDL-C levels. Individuals with higher levels of anti-EBV VCA antibodies have greater progression on MRI measures in the presence of higher LDL-C.