Kyushu University
Neurology

Author Of 2 Presentations

Biomarkers and Bioinformatics Late Breaking Abstracts

LB01.03 - Neutrophil granulocyte markers in cerebrospinal fluid differentiate NMOSD and anti-MOG antibody associated disease from MS in acute disease phase

Speakers
Presentation Number
LB01.03
Presentation Topic
Biomarkers and Bioinformatics
Lecture Time
09:24 - 09:36

Abstract

Background

Background
Neuromyelitis optica spectrum disorders (NMOSD), anti-MOG-antibody associated disease (MOGAD) and multiple sclerosis (MS) may be difficult to differentiate. Detection of antibodies (Ab) targeting AQP4 and MOG is the diagnostic gold standard for the former two diseases, but has limited sensitivity and long laboratory turnaround time. Neutrophil granulocyte (NG) invasion of brain tissue is a key differentiator of NMOSD from MS, and has also been described in MOGAD.

Objectives

Objectives
To examine the capability to differentiate NMOSD/MOGAD from MS by the profile of secreted primary (elastase (Ela); myeloperoxidase (MPO)) and secondary (matrix metalloproteinase-8 (MMP-8); neutrophil gelatinase-associated lipocalin (NGAL)) neutrophil granule products in CSF.

Methods

Methods
CSF from patients with NMOSD (n=42), MOGAD (n=6) and RRMS (n=41) were evaluated for Ela, MPO, MMP-8, NGAL, and compared with markers of neuronal (NfL) and astrocyte (GFAP, S100B) damage by conventional ELISA or single molecule array assay. CSFs from healthy controls (HC) (n=25) served as reference. The association between biomarkers and disease groups was assessed in linear models. The kinetic change of biomarkers in function of time since last relapse was modelled across disease groups. ROC curves and area under the curve (AUC) were calculated to estimate the potential to differentiate NMOSD/MOGAD from RRMS in acute disease phase (≤20 days after relapse), as well as between acute NMOSD and MOGAD. The association of biomarkers with EDSS in acute NMOSD and RRMS was assessed by linear models and Spearman correlation.

Results

Results
All disease groups had elevated NfL vs HC (p<0.01), while GFAP levels were increased only in NMOSD (p<0.01). In acute NMOSD, all 4 NG markers were increased vs HC and acute RRMS (all p<0.01). In MOGAD, Ela, MPO and MMP-8 were increased vs HC (p<0.025) and acute RRMS (p<0.04). AUC in ROC analyses comparing acute NMOSD/MOGAD vs acute RRMS was high (Ela and NGAL: 0.91; MPO: 0.82; MMP-8: 0.81). In acute NMOSD, S100B and GFAP levels were increased in 89% (AUC=0.82) and 83% (AUC=0.80) of patients, respectively, vs median values of MOGAD. In acute NMOSD, EDSS scores correlated with all 4 NG markers (all p<0.01), and GFAP (p<0.031), but not with NfL and S100B (both p=0.21).

Conclusions

Conclusion
NG-specific biomarkers correlate with current EDSS scores in NMOSD. They show high sensitivity and specificity for rapid differentiation of acute NMOSD and MOGAD vs RRMS, similar to those reported for Ab against AQP4 and MOG. As the 4 NG biomarkers can be measured within few hours, as compared to an up to 2-week turnaround time for gold-standard cell-based assays for AQP4 and MOG, they could support individual decision making for acute therapeutic intervention. Further, increased S100B and GFAP levels differentiate acute NMOSD from MOGAD. NG markers may have a role in the diagnosis of Ab-negative NMOSD.

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Biomarkers and Bioinformatics Oral Presentation

PS03.04 - Serum glial fibrillary acidic protein, but not S100B or neurofilament light chain predicts future relapses in neuromyelitis optica spectrum disorders

Speakers
Presentation Number
PS03.04
Presentation Topic
Biomarkers and Bioinformatics
Lecture Time
11:09 - 11:21

Abstract

Background

Neuromyelitis optica spectrum disorders (NMOSD) are autoimmune mediated astrocytopathies. Glial fibrillary acidic protein (GFAP) and S100B, two astrocyte specific, and neurofilament light chain (NfL), a neuron specific biomarker are reported to be elevated in CSF and serum or plasma in acute phases of NMOSD. Serum NfL is a predictor of relapse activity in multiple sclerosis (MS). However, whether serum levels of NfL (sNfL), GFAP (sGFAP) or S100B (sS100B) levels can be prognostic biomarkers for future acute disease activity in NMOSD has not been elucidated.

Objectives

To test the prognostic potential of sGFAP, sS100B and sNfL levels during remission phase as biomarker for future relapses in NMOSD with aquaporin-4-IgG.

Methods

Median values of sGFAP, sS100B and sNfL were calculated from 47 serum samples from 18 patients in remission (>180 days after last relapse), followed for up to 10 years, and marked cut-off levels for “high” and “low” sGFAP (141.6 pg/mL), sS100B (8.6 pg/mL), and sNfL (33.9 pg/mL), respectively. Kaplan-Meier analysis, univariable and a multivariable (adjusted for age, sex, time from recent relapse and treatment) Cox-hazard model were used to compare the time to and hazard risk of the next relapse between the high and low groups for all three markers.

Results

Twenty-five first post-relapse/remission phase samples from these 18 patients (11 had one relapse, 7 had two relapses) were selected for analyses. Patients in the high sGFAP group experienced future relapses earlier than those with low sGFAP levels (median 3710 versus 922 days, p = 0.0047) and had higher risk of future relapses (unadjusted hazard ratio (HR): 5.6 [95% CI 1.5–21.0], p = 0.010; adjusted hazard ratio: 9.5 [95% CI 1.9–47.0], p = 0.0061). In contrast, high sS100B and sNfL levels were unable to identify patients at increased risk for relapses.

Conclusions

We illustrate the prognostic capacity of an astrocyte specific marker, sGFAP, for future relapses in stable NMOSD. This further supports the value of this blood biomarker for potential future clinical application in guiding and monitoring treatment response of patients with NMOSD. The failure of sNfL as a neuronal marker in this capacity for NMOSD may reflect the pathogenetic differences between this disease and MS. The failure of sS100B may result from its pharmacokinetic profile as a short-lived marker in acute NMOSD, but not in stable disease.

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Presenter Of 1 Presentation

Biomarkers and Bioinformatics Oral Presentation

PS03.04 - Serum glial fibrillary acidic protein, but not S100B or neurofilament light chain predicts future relapses in neuromyelitis optica spectrum disorders

Speakers
Presentation Number
PS03.04
Presentation Topic
Biomarkers and Bioinformatics
Lecture Time
11:09 - 11:21

Abstract

Background

Neuromyelitis optica spectrum disorders (NMOSD) are autoimmune mediated astrocytopathies. Glial fibrillary acidic protein (GFAP) and S100B, two astrocyte specific, and neurofilament light chain (NfL), a neuron specific biomarker are reported to be elevated in CSF and serum or plasma in acute phases of NMOSD. Serum NfL is a predictor of relapse activity in multiple sclerosis (MS). However, whether serum levels of NfL (sNfL), GFAP (sGFAP) or S100B (sS100B) levels can be prognostic biomarkers for future acute disease activity in NMOSD has not been elucidated.

Objectives

To test the prognostic potential of sGFAP, sS100B and sNfL levels during remission phase as biomarker for future relapses in NMOSD with aquaporin-4-IgG.

Methods

Median values of sGFAP, sS100B and sNfL were calculated from 47 serum samples from 18 patients in remission (>180 days after last relapse), followed for up to 10 years, and marked cut-off levels for “high” and “low” sGFAP (141.6 pg/mL), sS100B (8.6 pg/mL), and sNfL (33.9 pg/mL), respectively. Kaplan-Meier analysis, univariable and a multivariable (adjusted for age, sex, time from recent relapse and treatment) Cox-hazard model were used to compare the time to and hazard risk of the next relapse between the high and low groups for all three markers.

Results

Twenty-five first post-relapse/remission phase samples from these 18 patients (11 had one relapse, 7 had two relapses) were selected for analyses. Patients in the high sGFAP group experienced future relapses earlier than those with low sGFAP levels (median 3710 versus 922 days, p = 0.0047) and had higher risk of future relapses (unadjusted hazard ratio (HR): 5.6 [95% CI 1.5–21.0], p = 0.010; adjusted hazard ratio: 9.5 [95% CI 1.9–47.0], p = 0.0061). In contrast, high sS100B and sNfL levels were unable to identify patients at increased risk for relapses.

Conclusions

We illustrate the prognostic capacity of an astrocyte specific marker, sGFAP, for future relapses in stable NMOSD. This further supports the value of this blood biomarker for potential future clinical application in guiding and monitoring treatment response of patients with NMOSD. The failure of sNfL as a neuronal marker in this capacity for NMOSD may reflect the pathogenetic differences between this disease and MS. The failure of sS100B may result from its pharmacokinetic profile as a short-lived marker in acute NMOSD, but not in stable disease.

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Author Of 1 Presentation

Epidemiology Poster Presentation

P0452 - Continued increase of multiple sclerosis and neuromyelitis optica and the north-south gradient in Japan; updates from the 5th nationwide survey (ID 775)

Abstract

Background

In Japan, nationwide survey for multiple sclerosis (MS) including neuromyelitis optica spectrum disorders (NMOSD) has regularly been conducted since 1972, and the past 4 surveys conducted before the discovery of anti-aquaporin 4 antibodies demonstrated the rapid increase of MS.

Objectives

To investigate the epidemiological characteristics of MS and NMOSD in Japan simultaneously through the 5th nationwide survey.

Methods

Preliminary survey was conducted to ascertain the approximate number of patients with either MS (pwMS) or NMOSD (pwNMOSD) who had seen at the selected facilities in 2017. Preliminary survey packages were sent to departments of neurology, internal medicine, ophthalmology, and pediatrics, at the facilities randomly selected using pre-determined sampling rates stratified based on the hospital bed counts. Secondary questionnaire was sent to the facilities with the cases to collect the detailed clinical information of each patient.

Results

Out of 3,799 departments where we sent preliminary survey, 2,284 (60.1%) replied and 645 departments reported the presence of the patients with the diseases. Second questionnaire form was sent to the 645 departments for 13,067 cases, and 6,990 (53.5%) forms were returned for further analysis. Estimated number of pwMS and pwNMOSD were 24,118 in total, which is more than 10-fold higher than that (2,280) of the 1st survey in 1972. The crude prevalence for both MS and NMOSD was 19.6/100,000 (14.3 for MS and 5.3 for NMOSD). Male: female ratios of MS and NMOSD were 1: 2.2 and 1: 4.1, respectively. The onset ages (mean ± standard deviation, year) of MS and NMOSD were 32.3 ± 11.6 and 44.2 ± 16.1, respectively. The Expanded Disability Status Scale scores and disease durations were 2.7 ± 2.4 in 12.9 ± 9.0 years for MS and 3.7 ± 2.4 in 10.9 ± 9.5 years for NMOSD. Disease-modifying therapy had been used for 77.2% in MS. The proportion of pwNMOSD against pwMS was 1: 0.37. Based on the prefectures at birth, the distribution of pwMS demonstrated north-south gradient (ρ = 0.39, p = 0.008), although no significant gradient was observed in pwNMOSD. Based on the registered sites, the proportion of pwMS among both pwMS and pwNMOSD showed north-south gradient (ρ = 0.4, p = 0.004).

Conclusions

As the combined prevalence of MS and NMOSD was 7.7/100,000 in the 4th survey (4.4 for conventional MS and 3.3 for others including opticospinal form), the prevalence of both MS and NMOSD appears to be still increasing. Disease severity may have become milder in MS and NMOSD compared with the 4th survey (3.5 ± 2.9 in conventional MS and 4.3 ± 2.7 in opticospinal form), though the disease durations in the two studies were comparable. Higher latitude is a risk for MS but not NMOSD in Japanese.

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