Author Of 3 Presentations
P0051 - Comparison of serum and CSF fluid biomarkers for predicting long term disease progression in MS
(ID 1448)
Abstract
Background
With the availability of more powerful treatments for multiple sclerosis (MS), prognostic biomarkers are badly needed.
Objectives
Our objective was to evaluate the long-term prognostic value of 4 protiens in paired serum and CSF samples obtained early-on following MS diagnosis.
Methods
In this prospective cohort study, we identified patients with serum collected within 5 years of first MS symptom onset (baseline) and more than 15 years of routine clinical follow-up. Neurofilament light Chain (NfL), Glial Fibrillary Acidic Protein (GFAP), Tau and UCHL-1 were quantified in paired serum (s) and CSF (c) samples from patients and matched controls using digital immunoassay (SiMoA HD-1 Analyzer, Quanterix). Outcomes of biomarker performance included conversion to progressive MS phenotype and reaching an EDSS ≥4.
Results
67 patients had a median follow-up of 17.4 years (range:15.1-26.1), by which time 10/67 had been classified as PPMS, 16 SPMS and 41 RRMS. 29 had developed EDSS ≥4. Baseline CSF levels 3 of the candidate markers were higher than MS patients compared to controls: cNfL (Mann Whitney p=0.0001, median 624 vs. 277pg/mL), cGFAP (p<0.0001, 6900 vs. 694pg/mL) and cTau (p=0.0001, 15.4 vs. 8.12pg/mL) but not UCH-L1. Patient-control differences were less marked in serum: sNfL (p= 0.0037, 10.1 vs. 7.3pg/mL), sGFAP (p=0.0011, 68 vs 51pg/mL), no difference in sTau and sUCH-L1. Positive correlations existed between paired serum and CSF samples only for NfL (Spearman r=0.71, p<0.0001) and GFAP (r=0,4, p=0.003). ROC curve analysis showed cUCH-L1 was most predictive of developing EDSS ≥4 after 15 years of follow-up (AUC 0.72, p=0.003) followed by sNfL (AUC 0.70, p=0.012) and cGFAP (AUC 0.66, p=0.03). Similarly, cUCH-L1 was most predictive of developing a progressive phenotype (PP/SPMS, AUC 0.69, p=0.0097), followed by cGFAP (AUC 0.66, p=0.024) and barely by sNfL (AUC 0.64,p=0.057). cNfL (AUC 0.60,p=0.17), sGFAP, sTau, cTau and sUCH-L1 were not predictive of either reaching EDSS ≥4 or converting to a progressive phenotype (PP/SPMS).
Conclusions
This is the first study to report and association of baseline CSF UCH-L1 levels with long term clinical outcomes in MS. This marker was more predictive of EDSS worsening and conversion to a progressive phenotype than well-established markers NfL and GFAP. More generally, CSF biomarker levels better segregating MS patients from controls at baseline compaired to levels in paired serum samples.
P0088 - Identification of putative multiple sclerosis biomarkers in CSF by targeted-mass spectrometry (ID 913)
Abstract
Background
The individual expression of Multiple Sclerosis (MS) is highly heterogeneous. One of the greatest potential benefits of biomarkers is to predict disease severity and guide therapeutic choices.
Objectives
Our objective is to evaluate the predictive value of soluble brain-specific proteins of 10-year MS clinical outcomes.
Methods
This retrospective study analyzed cerebrospinal fluid (CSF) from 35 MS patients (mean age: 42; 79% female) and 23 non-MS controls (mean age: 35.5; 68% female) collected within 5 years of disease onset. We quantified 63 brain-specific proteins in the CSF of these patients using a targeted liquid-chromatography tandem mass spectrometry assay. This assay was previously developed in-house by mining of the Human Protein Atlas database and experimental search of CSF to establish brain-enriched proteins.
Results
Our parallel reaction monitoring assay (PRM) used in this study had high assay reproducibility (median across peptides CV = 5.7%). Twelve proteins significantly differentiated MS from controls (p<0.05). The levels of 6 proteins at baseline were significantly associated with CIS, RRMS or PPMS. We also observed a trend with a number of proteins negatively predicting evolution of CIS to RRMS or SPMS. Finally, we observed an association between 3 proteins and the rate of EDSS progression rate over 10 years (Spearman rank correlation: r=-0.59, r=-0.36, r=-0.44; p=0.0006, p=0.046, p=0.0151 respectively).
Conclusions
We identified 12 CSF brain-specific proteins that are unique to MS patients and 3 proteins that seem to predict disease course over the next decade. These proteins also highlight putative pathways implicated in MS pathogenesis and can be targets for future therapeutic regimes.
P0105 - Longitudinal proteomic analysis of MS patients before and after autologous hematopoietic stem cell transplantation (ID 1549)
Abstract
Background
Serum markers which reflect MS disease activity could help personalize MS therapeutics. Longitudinal samples from patients undergoing autologous haematopoetic stem cell transplantation (HSCT) for aggressive MS represent a valuable cohort to search for such biomarkers, as these patients had very active disease prior to treatment followed by durable supression of inflammatory disease activity after treatment.
Objectives
To investigate changes in candidate serum proteins in patients with active MS compared to controls as well as before and after HSCT in relation to clinical and MRI outcomes.
Methods
97 proteins of interest were identified including established markers of inflammation and neurodegeneration. Levels were quantified using an in-house antibody colocalization microarray in 24 MS patients with aggressive relapsing MS at baseline compared to 10 controls. Pre-post HSCT changes were analyzed over 10 timepoints pre and up to 36 months post HSCT. We used principal componant analysis for data reduction prior to correlation as well as mixed effects models of individual proteins to compare changes in levels to clinical and MRI covariates of interest (age, EDSS score, relapses, sustained progression, lesional and volumetric MRI measures).
Results
Levels of 19 proteins differed between MS patients at baseline and controls and 17 proteins differed comparing baseline and 12-months post HSCT (simple t tests, p<0.1); we focused on the levels of these proteins for subsequent analyses. 7 proteins were identified in both comparisons including amphiregulin, cathepsin, CRP, GRO, HAI-1 and leptin, which may indicate normalization post HSCT. 8/24 patients developed sustained EDSS progression in the absence of ongoing relapses post HSCT; using mixed effects models, of the 17 candidate proteins, the longitudinal trajectory of CRP levels differed in patients who developed sustained progression compared to those who did not (B=-0.003, p=0.045). Component analysis was used to summarize clusters of proteins into a single value based on internal correlation/discordance. At baseline, one cluster of proteins (CRP, KLK14, PAI-1, IGFBP-7, PDGF) correlated with preceding rapid progression from diagnosis to EDSS 6 (p=0.011, r=0.80) and EDSS worsening in the preceding 24 months (p=0.047, r=0.46). A different cluster of proteins (HAI-1, amhiregulin, FAS, capthespsin B, e-cadherin, GFAP) correlated with the pretreatment rate of brain atrophy. Comparing pre-post changes, one cluster correlated with rate of brain atrophy in the first year post HSCT (p=0.024, r=0.059).
Conclusions
This exploratory analysis of longitudinal serum biomarkers changes pre and post HSCT provides hypothesis generating observations worthy of future investigation.
Presenter Of 2 Presentations
P0051 - Comparison of serum and CSF fluid biomarkers for predicting long term disease progression in MS
(ID 1448)
Abstract
Background
With the availability of more powerful treatments for multiple sclerosis (MS), prognostic biomarkers are badly needed.
Objectives
Our objective was to evaluate the long-term prognostic value of 4 protiens in paired serum and CSF samples obtained early-on following MS diagnosis.
Methods
In this prospective cohort study, we identified patients with serum collected within 5 years of first MS symptom onset (baseline) and more than 15 years of routine clinical follow-up. Neurofilament light Chain (NfL), Glial Fibrillary Acidic Protein (GFAP), Tau and UCHL-1 were quantified in paired serum (s) and CSF (c) samples from patients and matched controls using digital immunoassay (SiMoA HD-1 Analyzer, Quanterix). Outcomes of biomarker performance included conversion to progressive MS phenotype and reaching an EDSS ≥4.
Results
67 patients had a median follow-up of 17.4 years (range:15.1-26.1), by which time 10/67 had been classified as PPMS, 16 SPMS and 41 RRMS. 29 had developed EDSS ≥4. Baseline CSF levels 3 of the candidate markers were higher than MS patients compared to controls: cNfL (Mann Whitney p=0.0001, median 624 vs. 277pg/mL), cGFAP (p<0.0001, 6900 vs. 694pg/mL) and cTau (p=0.0001, 15.4 vs. 8.12pg/mL) but not UCH-L1. Patient-control differences were less marked in serum: sNfL (p= 0.0037, 10.1 vs. 7.3pg/mL), sGFAP (p=0.0011, 68 vs 51pg/mL), no difference in sTau and sUCH-L1. Positive correlations existed between paired serum and CSF samples only for NfL (Spearman r=0.71, p<0.0001) and GFAP (r=0,4, p=0.003). ROC curve analysis showed cUCH-L1 was most predictive of developing EDSS ≥4 after 15 years of follow-up (AUC 0.72, p=0.003) followed by sNfL (AUC 0.70, p=0.012) and cGFAP (AUC 0.66, p=0.03). Similarly, cUCH-L1 was most predictive of developing a progressive phenotype (PP/SPMS, AUC 0.69, p=0.0097), followed by cGFAP (AUC 0.66, p=0.024) and barely by sNfL (AUC 0.64,p=0.057). cNfL (AUC 0.60,p=0.17), sGFAP, sTau, cTau and sUCH-L1 were not predictive of either reaching EDSS ≥4 or converting to a progressive phenotype (PP/SPMS).
Conclusions
This is the first study to report and association of baseline CSF UCH-L1 levels with long term clinical outcomes in MS. This marker was more predictive of EDSS worsening and conversion to a progressive phenotype than well-established markers NfL and GFAP. More generally, CSF biomarker levels better segregating MS patients from controls at baseline compaired to levels in paired serum samples.
P0105 - Longitudinal proteomic analysis of MS patients before and after autologous hematopoietic stem cell transplantation (ID 1549)
Abstract
Background
Serum markers which reflect MS disease activity could help personalize MS therapeutics. Longitudinal samples from patients undergoing autologous haematopoetic stem cell transplantation (HSCT) for aggressive MS represent a valuable cohort to search for such biomarkers, as these patients had very active disease prior to treatment followed by durable supression of inflammatory disease activity after treatment.
Objectives
To investigate changes in candidate serum proteins in patients with active MS compared to controls as well as before and after HSCT in relation to clinical and MRI outcomes.
Methods
97 proteins of interest were identified including established markers of inflammation and neurodegeneration. Levels were quantified using an in-house antibody colocalization microarray in 24 MS patients with aggressive relapsing MS at baseline compared to 10 controls. Pre-post HSCT changes were analyzed over 10 timepoints pre and up to 36 months post HSCT. We used principal componant analysis for data reduction prior to correlation as well as mixed effects models of individual proteins to compare changes in levels to clinical and MRI covariates of interest (age, EDSS score, relapses, sustained progression, lesional and volumetric MRI measures).
Results
Levels of 19 proteins differed between MS patients at baseline and controls and 17 proteins differed comparing baseline and 12-months post HSCT (simple t tests, p<0.1); we focused on the levels of these proteins for subsequent analyses. 7 proteins were identified in both comparisons including amphiregulin, cathepsin, CRP, GRO, HAI-1 and leptin, which may indicate normalization post HSCT. 8/24 patients developed sustained EDSS progression in the absence of ongoing relapses post HSCT; using mixed effects models, of the 17 candidate proteins, the longitudinal trajectory of CRP levels differed in patients who developed sustained progression compared to those who did not (B=-0.003, p=0.045). Component analysis was used to summarize clusters of proteins into a single value based on internal correlation/discordance. At baseline, one cluster of proteins (CRP, KLK14, PAI-1, IGFBP-7, PDGF) correlated with preceding rapid progression from diagnosis to EDSS 6 (p=0.011, r=0.80) and EDSS worsening in the preceding 24 months (p=0.047, r=0.46). A different cluster of proteins (HAI-1, amhiregulin, FAS, capthespsin B, e-cadherin, GFAP) correlated with the pretreatment rate of brain atrophy. Comparing pre-post changes, one cluster correlated with rate of brain atrophy in the first year post HSCT (p=0.024, r=0.059).
Conclusions
This exploratory analysis of longitudinal serum biomarkers changes pre and post HSCT provides hypothesis generating observations worthy of future investigation.