Serum Neurofilament Light and Multiple Sclerosis Progression Independent of Acute Inflammation

Gafson, Arie; Jiang, Xiaotong; Shen, Changyu; Kapoor, Raj; Zetterberg, Henrik; Fox, Robert J.; Belachew, Shibeshih

doi:10.1001/jamanetworkopen.2021.47588

Cited by 26 publications

(26 citation statements)

References 5 publications

(11 reference statements)

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“…9 Similar findings have been recently reported from the ASCEND cohort of secondary progressive MS patients treated with natalizumab. 10 While sNfL is known to be a powerful tool to detect axonal loss related to acute inflammation, its prognostic value for MRI-derived neurodegeneration during highly effective therapy remains unclear. 11 Contactin-1 (CNTN1) is a cellular adhesion molecule involved in axo-glial interaction, is thought to be released into the cerebrospinal fluid (CSF) and blood after axonal injury, and could therefore be an alternative marker for disease progression in MS.…”

Section: Neurofilament-light and Contactin-1 Association With Long-te...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neurofilament-light and contactin-1 association with long-term brain atrophy in natalizumab-treated relapsing-remitting multiple sclerosis

et al. 2022

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Background: Despite highly effective treatment strategies for patients with relapsing-remitting multiple sclerosis (RRMS), long-term neurodegeneration and disease progression are often considerable. Accurate blood-based biomarkers that predict long-term neurodegeneration are lacking. Objective: To assess the predictive value of serum neurofilament-light (sNfL) and serum contactin-1 (sCNTN1) for long-term magnetic resonance imaging (MRI)–derived neurodegeneration in natalizumab-treated patients with RRMS. Methods: sNfL and sCNTN1 were measured in an observational cohort of natalizumab-treated patients with RRMS at baseline (first dose) and at 3 months, Year 1, Year 2, and last follow-up (median = 5.2 years) of treatment. Disability progression was quantified using “EDSS-plus” criteria. Neurodegeneration was measured by calculating annualized percentage brain, ventricular, and thalamic volume change (PBVC, VVC, and TVC, respectively). Linear regression analysis was performed to identify longitudinal predictors of neurodegeneration. Results: In total, 88 patients (age = 37 ± 9 years, 75% female) were included, of whom 48% progressed. Year 1 sNfL level (not baseline or 3 months) was associated with PBVC (standardized (std.) β = −0.26, p = 0.013), VVC (standardized β = 0.36, p < 0.001), and TVC (standardized β = −0.24, p = 0.02). For sCNTN1, only 3-month level was associated with VVC (standardized β = −0.31, p = 0.002). Conclusion: Year 1 (but not baseline) sNfL level was predictive for long-term brain atrophy in patients treated with natalizumab. sCNTN1 level did not show a clear predictive value.

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Section: Neurofilament-light and Contactin-1 Association With Long-te...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neurofilament-light and contactin-1 association with long-term brain atrophy in natalizumab-treated relapsing-remitting multiple sclerosis

et al. 2022

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“…Blood biomarkers could potentially aid MS monitoring. [8][9][10][11] Serum neurofilament light chain (sNEFL) and glial fibrillary acidic protein (sGFAP) are well-studied blood biomarkers of MS. [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] NEFL and GFAP are neuron-specific and astrocyte-derived intermediate filament cytoskeletal proteins, respectively. 12,18 Blood NEFL (e.g., sNEFL) has potential clinical applications in monitoring neuroaxonal damage associated with inflammatory disease activity (i.e., clinical and/or neuroimaging relapse), short-term disability worsening, and treatment response, though its utility to inform long-term disability remains unsettled.…”

Section: Introductionmentioning

confidence: 99%

“…Blood biomarkers could potentially aid MS monitoring. 8–11 Serum neurofilament light chain (sNEFL) and glial fibrillary acidic protein (sGFAP) are well-studied blood biomarkers of MS. 12–27 NEFL and GFAP are neuron-specific and astrocyte-derived intermediate filament cytoskeletal proteins, respectively. 12,18 Blood NEFL ( e .…”

Section: Introductionmentioning

confidence: 99%

Association between Serum Biomarker Profile and Real-World Evidence of Disability in Multiple Sclerosis

Zhu

Chen

Zhang

et al. 2022

Preprint

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ObjectiveBiomarkers could inform disease worsening and severity in people with MS (pwMS). Few studies have examined blood biomarkers informative of patient-reported outcome (PRO) of disability in pwMS. In this study we examine the associations between serum protein biomarker profiles and patient-reported disability in pwMS.MethodsThis cross-sectional study included adults with a neurologist-confirmed diagnosis of MS from the University of Pittsburgh Medical Center (Pittsburgh, PA) and the Rocky Mountain MS Clinic (Salt Lake City, Utah) between 2017 and 2020. For exposure, we included 19 serum protein biomarkers potentially associated with MS inflammatory disease activity and 7 key clinical factors (age at sample collection, sex, race/ethnicity, disease subtype, disease duration, disease-modifying treatment, and time interval between sample collection and closest PRO assessment). Using 6 machine learning approaches (Least Absolute Shrinkage and Selection Operator [LASSO] regression, Random Forest [RF], XGBoost, Support-Vector Machines [SVM], stacking ensemble learning, and stacking classification algorithm), we examined model performance in predicting Patient Determined Disease Steps (PDDS) as the primary outcome. We assessed model prediction of Patient-Reported Outcomes Measurement Information System (PROMIS) physical function in a subgroup. We reported model performance using the held-out testing set.ResultsWe included 431 unique participants (mean age 49 years, 81% women, 94% non-Hispanic White). Using binary outcomes, models comprising both routine clinical factors and the 19 proteins as features consistently outperformed base models (containing clinical features alone or clinical features plus single protein) in predicting severe (PDDS≥4, PROMIS<35) versus mild/moderate (PDDS<4, PROMIS≥35) disability for all machine learning approaches, with LASSO achieving the best area under the curve (AUCPDDS=0.91, AUCPROMIS=0.90). Using ordinal/continuous outcomes, LASSO models with combined clinical factors and 19 proteins as features (R2PDDS=0.31, R2PROMIS=0.35) again outperformed base models. The four LASSO models (PDDS, PROMIS; both binary and ordinal/continuous) with combined clinical and protein features shared 2 clinical features (disease subtype, disease duration) and 4 protein biomarkers (CDCP1, IL-12B, NEFL, PRTG).ConclusionsSerum protein biomarker profiles improve the prediction of real-world MS disability status beyond clinical profile alone or clinical profile plus individual protein biomarker, reaching clinically actionable performance.

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“…There is growing evidence showing that serum NfL correlates with inflammatory disease activity in RRMS [7,8,19], but the association of serum NfL with the slow, diffuse neurodegeneration that characterizes PPMS is less clear [19,20]. participants with no inflammatory disease activity (at baseline or during the trial) in the ASCEND trial of natalizumab in SPMS [22].…”

Section: Discussionmentioning

confidence: 99%

Serum neurofilament‐light and glial fibrillary acidic protein levels in hydroxychloroquine‐treated primary progressive multiple sclerosis

Cámara-Lemarroy

Gohill

Yong

et al. 2022

Euro J of Neurology

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Background In a recent trial, hydroxychloroquine (HCQ) treatment reduced the expected rate of disability worsening at 18 months in primary progressive multiple sclerosis (PPMS). Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are emerging biomarkers in multiple sclerosis. Methods We measured NfL and GFAP levels in serum samples from 39 patients with inactive PPMS included in a phase II clinical trial of HCQ treatment in PPMS at multiple time points over 18 months, and investigated the association of these biomarkers with clinical disability at screening and during follow‐up. Screening and 12‐month retinal nerve fiber layer (RNFL) thickness was also recorded and analyzed. Results NfL and GFAP levels increased over time, but only significantly from screening to month 6. NfL and GFAP levels did not significantly increase from month 6 up to month 18. At screening, NfL and GFAP levels did not correlate with the Expanded Disability Status Scale (EDSS), and GFAP but not NfL modestly correlated with Timed 25‐Foot Walk test (T25FW). Screening NfL and GFAP levels did not predict disability worsening (≥20% worsening on the T25FW) at month 18. RNFL thickness decreased significantly from screening to month 12 and independently predicted disability worsening. Conclusions In this cohort of people with inactive PPMS, HCQ treatment attenuated the increase of NfL and GFAP after 6 months of treatment and up to 18 months of follow‐up, suggesting a treatment effect of HCQ over these biomarkers. RNFL thickness, a marker of neuroaxonal atrophy, was associated with disability worsening, and should be explored further as a prognostic marker in this population.

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Serum Neurofilament Light and Multiple Sclerosis Progression Independent of Acute Inflammation

Abstract: Open Access. This is an open access article distributed under the terms of the CC-BY-NC-ND License.

Cited by 26 publications

References 5 publications

Neurofilament-light and contactin-1 association with long-term brain atrophy in natalizumab-treated relapsing-remitting multiple sclerosis

Neurofilament-light and contactin-1 association with long-term brain atrophy in natalizumab-treated relapsing-remitting multiple sclerosis

Association between Serum Biomarker Profile and Real-World Evidence of Disability in Multiple Sclerosis

Serum neurofilament‐light and glial fibrillary acidic protein levels in hydroxychloroquine‐treated primary progressive multiple sclerosis

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