OBJECTIVES: This study aimed to investigate relationships between cholesterol profile, brain volumetric MRI, and clinical measures in a large observational cohort of multiple sclerosis (MS) patients. MATERIALS AND METHODS: We included 1.505 patients with 4.966 time points including complete lipid, clinical, and imaging data. The time among lipid, brain MRI and clinical measures was under 90 days. Cross-sectional statistical analysis at baseline was performed using an adjusted linear regression and analysis of longitudinal lipid and MRI measures data was performed using adjusted linear mixed models. RESULTS: We found associations between higher high-density lipoprotein cholesterol (HDL-C) and lower brain parenchymal fraction (BPF) at cross-sectional analysis at baseline (B = -0.43, CI 95%: -0.73, -0.12, p = 0.005), as well as in longitudinal analysis over follow-up (B = -0.32 ± 0.072, χ2 = 36.6; p = < 0.001). Higher HDL-C was also associated with higher T2-lesion volume in longitudinal analysis (B = 0.11 ± 0.023; χ2 = 23.04; p = < 0.001). We observed a weak negative association between low-density lipoprotein cholesterol (LDL-C) levels and BPF at baseline (B = -0.26, CI 95%: -0.4, -0.11, p = < 0.001) as well as in longitudinal analysis (B = -0.06 ± 0.03, χ2 = 4.46; p = 0.03). T2-LV did not show an association with LDL-C. We did not find any association between lipid measures and disability. The effect of lipid levels on MRI measures and disability was minimal (Cohen f2 < 0.02). CONCLUSIONS: Our results contradict the previously described exclusively positive effect of HDL-C on brain atrophy in patients with MS. Higher LDL-C was weakly associated with higher brain atrophy but not with higher lesion burden.

• Keywords
• Brain atrophy, Cholesterol, HDL, LDL, Lesion volume, Lipid, MRI, Multiple sclerosis,
• MeSH
• Cholesterol blood   MeSH
• Adult MeSH
• Cholesterol, HDL * blood   MeSH
• Cohort Studies MeSH
• Cholesterol, LDL blood   MeSH
• Middle Aged MeSH
• Humans MeSH
• Longitudinal Studies MeSH
• Magnetic Resonance Imaging * MeSH
• Brain * diagnostic imaging   pathology   MeSH
• Cross-Sectional Studies MeSH
• Multiple Sclerosis * diagnostic imaging   blood   pathology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Observational Study MeSH
• Names of Substances
• Cholesterol MeSH
• Cholesterol, HDL * MeSH
• Cholesterol, LDL MeSH

Background: Neutralizing anti-drug antibodies (ADA) can greatly reduce the efficacy of biopharmaceuticals used to treat patients with multiple sclerosis (MS). However, the biological factors pre-disposing an individual to develop ADA are poorly characterized. Thus, there is an unmet clinical need for biomarkers to predict the development of immunogenicity, and subsequent treatment failure. Up to 35% of MS patients treated with beta interferons (IFNβ) develop ADA. Here we use machine learning to predict immunogenicity against IFNβ utilizing serum metabolomics data. Methods: Serum samples were collected from 89 MS patients as part of the ABIRISK consortium-a multi-center prospective study of ADA development. Metabolites and ADA were quantified prior to and after IFNβ treatment. Thirty patients became ADA positive during the first year of treatment (ADA+). We tested the efficacy of six binary classification models using 10-fold cross validation; k-nearest neighbors, decision tree, random forest, support vector machine and lasso (Least Absolute Shrinkage and Selection Operator) logistic regression with and without interactions. Results: We were able to predict future immunogenicity from baseline metabolomics data. Lasso logistic regression with/without interactions and support vector machines were the most successful at identifying ADA+ or ADA- cases, respectively. Furthermore, patients who become ADA+ had a distinct metabolic response to IFNβ in the first 3 months, with 29 differentially regulated metabolites. Machine learning algorithms could also predict ADA status based on metabolite concentrations at 3 months. Lasso logistic regressions had the greatest proportion of correct classifications [F1 score (accuracy measure) = 0.808, specificity = 0.913]. Finally, we hypothesized that serum lipids could contribute to ADA development by altering immune-cell lipid rafts. This was supported by experimental evidence demonstrating that, prior to IFNβ exposure, lipid raft-associated lipids were differentially expressed between MS patients who became ADA+ or remained ADA-. Conclusion: Serum metabolites are a promising biomarker for prediction of ADA development in MS patients treated with IFNβ, and could provide novel insight into mechanisms of immunogenicity.

• Keywords
• anti-drug antibodies, cholesterol, immunogenicity, machine learning, metabolomics, multiple sclerosis,
• MeSH
• Biomarkers blood   MeSH
• Interferon-beta adverse effects   therapeutic use   MeSH
• Leukocytes, Mononuclear immunology   metabolism   MeSH
• Humans MeSH
• Membrane Lipids metabolism   MeSH
• Membrane Microdomains MeSH
• Metabolome * MeSH
• Metabolomics * methods   MeSH
• Antibodies, Neutralizing blood   immunology   MeSH
• Prognosis MeSH
• Antibodies blood   immunology   MeSH
• Multiple Sclerosis blood   diagnosis   drug therapy   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Biomarkers MeSH
• Interferon-beta MeSH
• Membrane Lipids MeSH
• Antibodies, Neutralizing MeSH
• Antibodies MeSH

The purpose of this work was to determine whether changes in cholesterol profiles after interferon-β (IFN-β)1a treatment initiation following the first demyelinating event suggestive of multiple sclerosis are associated with clinical and MRI outcomes over 4 years. A group of 131 patients (age: 27.9 ± 7.8 years, 63% female) with serial 3-monthly clinical and 12-monthly MRI follow-ups over 4 years were investigated. Serum cholesterol profiles, including total cholesterol (TC), HDL cholesterol (HDL-C), and LDL cholesterol (LDL-C) were obtained at baseline, 1 month, 3 months, and every 6 months thereafter. IFN-β1a initiation caused rapid decreases in serum HDL-C, LDL-C, and TC within 1 month of IFN-β1a initiation (all P < 0.001) that returned slowly toward baseline. In predictive mixed model analyses, greater percent decreases in HDL-C after 3 months of IFN-β1a treatment initiation were associated with less brain atrophy over the 4 year time course, as assessed by percent brain volume change (P < 0.001), percent gray matter volume change (P < 0.001), and percent lateral ventricle volume change (P = 0.005). Decreases in cholesterol biomarkers following IFN-β1a treatment are associated with brain atrophy outcomes over 4 years. Pharmacological interventions targeting lipid homeostasis may be clinically beneficial for disrupting neurodegenerative processes.

• Keywords
• brain atrophy, cholesterol, magnetic resonance imaging,
• MeSH
• Cholesterol blood   MeSH
• Nerve Degeneration blood   diagnostic imaging   drug therapy   pathology   MeSH
• Demyelinating Diseases blood   diagnostic imaging   drug therapy   pathology   MeSH
• Adult MeSH
• Cholesterol, HDL blood   MeSH
• Interferon beta-1a administration & dosage   MeSH
• Cholesterol, LDL blood   MeSH
• Humans MeSH
• Lipids blood   MeSH
• Magnetic Resonance Imaging MeSH
• Brain diagnostic imaging   drug effects   physiopathology   MeSH
• Multiple Sclerosis blood   diagnostic imaging   drug therapy   pathology   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Cholesterol MeSH
• Cholesterol, HDL MeSH
• Interferon beta-1a MeSH
• Cholesterol, LDL MeSH
• Lipids MeSH

The purpose of this work was to investigate the associations of serum cholesterol and apolipoproteins with measures of blood-brain barrier (BBB) permeability and CNS inflammation following the first clinical demyelinating event. This study included 154 patients [67% female; age, 29.5 ± 8.2 years (mean ± SD)] enrolled in a multi-center study of interferon β1-a treatment following the first demyelinating event. Blood and cerebrospinal fluid (CSF) were obtained at screening prior to treatment. A comprehensive serum lipid profile and multiple surrogate markers of BBB breakdown and CNS immune activity were obtained. Higher levels of serum HDL cholesterol (HDL-C) and ApoA-I were associated with lower CSF total protein level, CSF albumin level, albumin quotient, and CSF IgG level (all P ≤ 0.001 for HDL-C and all P < 0.01 for ApoA-I). HDL-C was also associated with CSF CD80+ (P < 0.001) and with CSF CD80+CD19+ (P = 0.007) cell frequencies. Higher serum HDL is associated with lower levels of BBB injury and decreased CD80+ and CD80+CD19+ cell extravasation into the CSF. HDL may potentially inhibit the initiation and/or maintenance of pathogenic BBB injury following the first demyelinating event.

• Keywords
• apolipoproteins, cholesterol, clinically isolated syndrome, high density lipoprotein,
• MeSH
• Apolipoproteins blood   cerebrospinal fluid   MeSH
• Biomarkers blood   cerebrospinal fluid   MeSH
• Demyelinating Diseases MeSH
• Adult MeSH
• Cholesterol, HDL blood   MeSH
• Blood-Brain Barrier drug effects   metabolism   pathology   MeSH
• Interferon-beta therapeutic use   MeSH
• Humans MeSH
• Longitudinal Studies MeSH
• Nervous System Diseases blood   cerebrospinal fluid   MeSH
• Multiple Sclerosis blood   cerebrospinal fluid   drug therapy   pathology   MeSH
• Inflammation blood   cerebrospinal fluid   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Observational Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Apolipoproteins MeSH
• Biomarkers MeSH
• Cholesterol, HDL MeSH
• Interferon-beta MeSH

BACKGROUND: Gray matter (GM) and white matter (WM) pathology has an important role in disease progression of multiple sclerosis (MS). OBJECTIVES: To investigate the association between the development of GM and WM pathology and clinical disease progression in patients with clinically isolated syndrome (CIS). METHODS: This prospective, observational, 48-month follow-up study examined 210 CIS patients treated with 30 µg of intramuscular interferon beta-1a once a week. MRI and clinical assessments were performed at baseline, 6, 12, 24, 36 and 48 months. Associations between clinical worsening [24-weeks sustained disability progression (SDP) and occurrence of a second clinical attack] and longitudinal changes in lesion accumulation and brain atrophy progression were investigated by a mixed-effect model analysis after correction for multiple comparisons. RESULTS: SDP was observed in 32 (15.2%) CIS patients, while 146 (69.5%) were stable and 32 (15.2%) showed sustained disability improvement. 112 CIS patients (53.3%) developed clinically definite MS (CDMS). CIS patients who developed SDP showed increased lateral ventricle volume (p < .001), and decreased GM (p = .011) and cortical (p = .001) volumes compared to patients who remained stable or improved in disability. Converters to CDMS showed an increased rate of accumulation of number of new/enlarging T2 lesions (p < .001), decreased whole brain (p = .007) and increased lateral ventricle (p = .025) volumes. CONCLUSIONS: Development of GM pathology and LVV enlargement are associated with SDP. Conversion to CDMS in patients with CIS over 48 months is dependent on the accumulation of new lesions, LVV enlargement and whole brain atrophy progression.

• Keywords
• Atrophy, Clinically isolated syndrome, Gray matter, Lesions, Longitudinal, MRI, Multiple sclerosis,
• MeSH
• White Matter pathology   MeSH
• Demyelinating Diseases drug therapy   pathology   MeSH
• Adult MeSH
• Interferon beta-1a MeSH
• Interferon-beta therapeutic use   MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Young Adult MeSH
• Follow-Up Studies MeSH
• Disease Progression * MeSH
• Prospective Studies MeSH
• Gray Matter pathology   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Observational Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Interferon beta-1a MeSH
• Interferon-beta MeSH