Identification of brain-enriched proteins in CSF as biomarkers of relapsing remitting multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a clinically and biologically heterogenous disease with currently unpredictable progression and relapse. After the development and success of neurofilament as a cerebrospinal fluid (CSF) biomarker, there is reinvigorated interest in identifying other markers of or contributors to disease. The objective of this study is to probe the predictive potential of a panel of brain-enriched proteins on MS disease progression and subtype. METHODS: This study includes 40 individuals with MS and 14 headache controls. The MS cohort consists of 20 relapsing remitting (RR) and 20 primary progressive (PP) patients. The CSF of all individuals was analyzed for 63 brain enriched proteins using a method of liquid-chromatography tandem mass spectrometry. Wilcoxon rank sum test, Kruskal-Wallis one-way ANOVA, logistic regression, and Pearson correlation were used to refine the list of candidates by comparing relative protein concentrations as well as relation to known imaging and molecular biomarkers. RESULTS: We report 30 proteins with some relevance to disease, clinical subtype, or severity. Strikingly, we observed widespread protein depletion in the disease CSF as compared to control. We identified numerous markers of relapsing disease, including KLK6 (kallikrein 6, OR = 0.367, p < 0.05), which may be driven by active disease as defined by MRI enhancing lesions. Other oligodendrocyte-enriched proteins also appeared at reduced levels in relapsing disease, namely CNDP1 (carnosine dipeptidase 1), LINGO1 (leucine rich repeat and Immunoglobin-like domain-containing protein 1), MAG (myelin associated glycoprotein), and MOG (myelin oligodendrocyte glycoprotein). Finally, we identified three proteins-CNDP1, APLP1 (amyloid beta precursor like protein 1), and OLFM1 (olfactomedin 1)-that were statistically different in relapsing vs. progressive disease raising the potential for use as an early biomarker to discriminate clinical subtype. CONCLUSIONS: We illustrate the utility of targeted mass spectrometry in generating potential targets for future biomarker studies and highlight reductions in brain-enriched proteins as markers of the relapsing remitting disease stage.

Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Intrathecal immunoglobulin-G synthesis is a hallmark of multiple sclerosis (MS), which can be detected by oligoclonal IgG bands (OCB) or by κ-free light chains (κ-FLC) in cerebrospinal fluid. OBJECTIVE: To perform a systematic review and meta-analysis to evaluate whether κ-FLC index has similar diagnostic value to identify patients with clinically isolated syndrome (CIS) or MS compared to OCB, and to determine κ-FLC index cut-off. METHODS: PubMed was searched for studies that assessed diagnostic sensitivity and specificity of κ-FLC index and OCB to discriminate CIS/MS patients from control subjects. Two reviewers following preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines performed study eligibility assessment and data extraction. Findings from studies were analyzed with bivariate mixed models. RESULTS: A total of 32 studies were included in the meta-analysis to evaluate diagnostic value of κ-FLC index. Sensitivity and specificity ranged from 52% to 100% (weighted average: 88%) and 69% to 100% (89%) for κ-FLC index and from 37% to 100% (85%) and 74% to 100% (92%) for OCB. Mean difference of sensitivity and specificity between κ-FLC index and OCB was 2 and -4 percentage points. Diagnostic accuracy determined by mixed models revealed no significant difference between κ-FLC index and OCB. A discriminatory cut-off for κ-FLC index was determined at 6.1. CONCLUSION: The findings indicate that κ-FLC index has similar diagnostic accuracy in MS as OCB.

Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A consensus statement.

Cerebrospinal fluid (CSF) analysis is of utmost importance for diagnosis and differential diagnosis of patients with suspected multiple sclerosis (MS). Evidence of intrathecal immunoglobulin G (IgG) synthesis proves the inflammatory nature of the disease, increases diagnostic certainty and substitutes for dissemination in time according to current diagnostic criteria. The gold standard to determine intrathecal IgG synthesis is the detection of CSF-restricted oligoclonal bands (OCBs). However, advances in laboratory methods brought up κ-free light chains (FLCs) as a new biomarker, which are produced in excess over intact immunoglobulins and accumulate in CSF in the case of central nervous system-derived inflammation. Overwhelming evidence showed a high diagnostic accuracy of intrathecal κ-FLC synthesis in MS with sensitivity and specificity of approximately 90% similar to OCB. κ-FLCs have advantages as its detection is fast, easy, cost-effective, reliable, rater-independent and returning quantitative results which might also improve the value of predicting MS disease activity. An international panel of experts in MS and CSF diagnostics developed a consensus of all participants. Six recommendations are given for establishing standard CSF evaluation in patients suspected of having MS. The panel recommended to include intrathecal κ-FLC synthesis in the next revision of MS diagnostic criteria as an additional tool to measure intrathecal immunoglobulin synthesis.

An Update on Laboratory-Based Diagnostic Biomarkers for Multiple Sclerosis and Beyond.

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated central nervous system (CNS) inflammatory demyelinating disease in which analysis of clinical presentation, imaging studies, and laboratory tests aid in diagnosis. CONTENT: This review discusses laboratory tests ordered to rule out and rule in MS, such as the traditional measurement of cerebrospinal fluid (CSF) IgG index and oligoclonal bands. Biomarkers discovered in the past 2 decades, such as aquaporin-4 (AQP4) antibodies and myelin oligodendrocyte glycoprotein (MOG) antibodies, have been incorporated into clinical practice in the diagnosis of disorders referred to as MS mimics. The importance of test selection, assay methodology, optimal sample for testing, and diagnostic utility of these biomarkers is reviewed. Other laboratory testing that can aid in the differentiation between MS and these biomarker-defined CNS demyelinating diseases is described. There is a focus on emerging biomarkers such as the use of kappa immunoglobulin free light chain concentration in CSF and kappa CSF index measurement as an alternative to oligoclonal bands which has a potential for an improvement in laboratory workflows. Finally, the role of biomarkers of disease activity and prognosis are discussed, including neurofilament light chain, glial fibrillary acidic protein, and myelin basic protein. Future perspectives with improved laboratory testing tools and discovery of additional biomarkers are provided. SUMMARY: Laboratory testing for demyelinating disorders using CSF and serum are routine practices that can benefit from an update, as novel biomarker-defined entities have reduced the potential for MS misdiagnosis, and CSF/serum biomarkers reinstated in the diagnostic criteria of MS.

CSF Kappa Free Light Chains: Cutoff Validation for Diagnosing Multiple Sclerosis.

OBJECTIVE: To determine and validate a cerebrospinal fluid (CSF) κ (KCSF) value statistically comparable to detection of CSF-specific oligoclonal bands (OCB) to support the diagnosis of multiple sclerosis (MS). PATIENTS AND METHODS: A total of 702 retrospective and 657 prospective paired CSF/serum samples from residual waste samples of physician-ordered OCB tests were obtained and tested for KCSF at Mayo Clinic. Charts were reviewed by a neurologist blinded to KCSF results. Specificity and sensitivity for MS diagnosis were evaluated to establish a diagnostic cutoff value for KCSF in the retrospective cohort and then validated in the prospective cohort. RESULTS: Retrospective and prospective subgroups, respectively, included MS (n=85, 70), non-MS (n=615, 585), and undetermined diagnosis (excluded, n=2, 2). The retrospective data established a KCSF cutoff value of 0.1 mg/dL to be comparable to OCB testing. In the retrospective subgroup, KCSF vs OCB sensitivities for diagnosis of MS were 68.2% vs 75.0% (P=.08) and specificities were 86.1% vs 87.6% (P=.27). The KCSF area under the receiver operating characteristic curve was 0.772 (95% CI, 0.720 to 0.824), and for OCB was 0.813 (95% CI, 0.764 to 0.861). The prospective cohort was then used to validate the diagnostic KCSF value of 0.1 mg/dL; KCSF vs OCB sensitivities were 78.6% for both (P>.99) and specificities were 87.1% vs 89.4% (P=.09). CONCLUSION: The KCSF value of 0.1 mg/dL is a valid alternative to OCB testing, offering a standardized quantitative measure, eliminating human error, reducing cost and turnaround time, with no significant difference in sensitivity and specificity. This study provides class I evidence that a KCSF value of 0.1 mg/dL can be used in place of OCB testing to support the diagnosis of MS.

Coexisting systemic and organ-specific autoimmunity in MOG-IgG1-associated disorders versus AQP4-IgG+ NMOSD.

Aquaporin-4 (AQP4) neuromyelitis optica spectrum disorder (NMOSD) has been demonstrated to be associated with non-organ and organ-specific autoantibodies (antinuclear antibody, extractable nuclear antibody, double-stranded DNA, muscle acetylcholine receptor antibody) and systemic autoimmune diseases. In this study, we evaluated whether a similar association with non-organ and organ-specifc autoantibodies occurs in patients with MOG-IgG1-associated disorders. We determined that MOG-IgG1 was not strongly associated with these organ and non-organ-specific autoantibodies. Systemic lupus erythematous (SLE) was significantly associated with AQP4-IgG+ NMOSD and not with MOGAD (p = 0.037). These findings suggest differences in co-existing systemic and organ-specific autoimmunity between MOGAD and AQP4-IgG+ NMOSD.

Prevalence and risk factors of muscle complications secondary to statins.

INTRODUCTION: The aim of the study was to investigate the prevalence and risk factors of muscle complications among patients using statins. METHODS: We conducted a prospective comparative study on 345 patients receiving statins and compared the findings with an age- and gender-matched control group of 85 subjects. Univariate and multivariate analyses with logistic regression models were used to study the association of different patient and disease characteristics with muscle complications. RESULTS: Adverse reactions were reported by 21% of patients and 5.9% of controls (P = 0.0013). Objective weakness was found in 15% of the patients who reported muscle symptoms (3.2% of the total cohort), but not in controls. Older age, longer duration of statin use, diabetes, stroke, and lower body mass index were associated with increased risk of developing these symptoms. CONCLUSIONS: Adverse reactions to statins may be more common than previously reported, and they may be affected by specific patient and disease characteristics.

A case report of cranial polyneuropathy in Behcet's disease.

Behcet's disease (BD) is a multisystem relapsing inflammatory disorder. Nervous system involvement is the most serious manifestation of BD. Neuro-Behcet's disease (n-BD) is classified into parenchymal meningoencephalitis pattern and non-parenchymal vascular patterns. Isolated meningitis is rarely the sole presenting feature of n-BD. We report a 19-year-old man with BD who presented with cranial polyneuropathy secondary to aseptic meningitis. He made a gradual though incomplete recovery with steroid therapy. Cranial polyneuropathy secondary to meningeal involvement can be a presentation of n-BD, and Behcet's disease should be a consideration in patients with idiopathic cranial polyneuropathy.