Validation of Serum Neurofilaments as Prognostic &amp; Potential Pharmacodynamic Biomarkers for ALS

Benatar, Michael; Zhang, Lanyu; Wang, Lily; Granit, Volkan; Statland, Jeffrey; Barohn, Richard J.; Swenson, Andrea; Ravits, John; Jackson, Carlayne E.; Burns, Ted M.; Trivedi, Jaya; Pioro, Erik P.; Caress, James B.; Katz, Jonathan; McCauley, Jacob L.; Rademakers, Rosa; Malaspina, Andrea; Ostrow, Lyle W.; Wuu, Joanne

doi:10.1101/19002998

Cited by 11 publications

(21 citation statements)

References 30 publications

(15 reference statements)

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“…243 of the 248 SIMOA samples were technically successful. A Cox proportional hazard analysis revealed that high plasma NfL predicts higher risk of death (from enrollment HR 2.09, 95% 1.49 – 2.94, p<0.001, C-index 0.59, Akaike’s information criteria (AIC) 2083, or from onset HR 2.26, 95% 1.73 – 2.96, p<0.001, C-index 0.62, AIC 2060 Figure 5A, B), as previously reported 28–30 . The performance of miR-181 in predicting risk of death is comparable with that of NfL (from enrollment HR 2.03, 95% CI: 1.45 – 2.85, p<0.001, C-index 0.56, AIC 2096, or from onset HR 2.07, 95% CI: 1.6 – 2.7, p<0.001, C-index 0.56, AIC 2081, Figure 5A, B).…”

Section: Resultssupporting

confidence: 85%

“…In such cases, the value of miR-181 may be even more pronounced. In addition, real-world patient profiles indicate that most ALS patients are in the middle tertile neurofilament level, 30 the enhanced sensitivity provided by miR-181 at this region of the spectrum will be particularly useful. Taken together, miR-181 emerges as a prognostic ALS biomarker that can be developed in combination with NfL to improve the accuracy of patient stratification in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

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Circulating miR-181 is a prognostic biomarker for amyotrophic lateral sclerosis

Magen

Coenen-Stass

Großkreutz

et al. 2019

Preprint

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word count: 203 Main text word count: 2738 words (excluding references and figure legends).No. of items (figures, tables): 4, 1 One Sentence Summary: higher plasma miR-181a-5p levels increase mortality risk in ALS patients. Abstract (210 words)Amyotrophic lateral sclerosis (ALS) is a ruthless neurodegenerative disease affecting the motor neuron system. Variability of disease progression has limited the effectiveness of ALS clinical trials, making novel tools for patient stratification at trial recruitment. Thus, better outcome measures are desperately needed in order to achieve therapeutic progress. Here, we investigate the potential of plasma cell-free microRNAs as biomarkers to predict ALS progression. We apply an unbiased high-throughput approach to define miRNA levels in a large cohort of ALS patients and controls. Crucially, we conduct our analysis also on longitudinal samples reflecting disease progression, and are able to integrate detailed clinical phenotyping in our analysis. We identify miR-181a-5p levels to be stable during disease course and demonstrate that high miR-181a-5p plasma levels predict shortened survival in ALS patients, with a 2.5 fold reduction in median survival for patients with high miR-181a-5p plasma levels. We replicated this finding in an independent validation cohort, where an eight-fold (×8) difference in miR-181a-5p levels between the two prognosis subgroups was robustly measurable by quantitative real time PCR. In conclusion, miR-181a-5p plasma levels can predict disease course in ALS suggesting it as a novel biomarker for patient stratification that might will greatly enhance the effectiveness of clinical trials.

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Section: Resultssupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Circulating miR-181 is a prognostic biomarker for amyotrophic lateral sclerosis

Magen

Coenen-Stass

Großkreutz

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…243 of the 248 SIMOA samples were technically successful. A Cox proportional hazard analysis revealed that high plasma NfL predicts higher risk of death (from enrollment HR 2.09, 95% 1.49 -2.94, p<0.001, concordance index (C-index) 0.59, Akaike's information criteria (AIC) 2083, or from onset HR 2.26, 95% 1.73 -2.96, p<0.001, Cindex 0.62, AIC 2060 Figure 5A, B), as previously reported [28][29][30] . The performance of miR-181 in predicting risk of death is comparable with that of NfL (from enrollment HR 2.03, 95% CI: 1.45 -2.85, p<0.001, C-index 0.56, AIC 2096, or from onset HR 2.07, 95% CI: 1.6 -2.7, p<0.001, Cindex 0.56, AIC 2081, Figure 5A, B).…”

Section: Mir-181 and Nfl Establish A Cooperative Mirna-protein Biomarker In Prediction Of Als Prognosissupporting

confidence: 84%

Circulating miR-181 is a prognostic biomarker for amyotrophic lateral sclerosis

Hornstein

Magen

Coenen-Stass

et al. 2021

Preprint

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Amyotrophic lateral sclerosis (ALS) is a relentless neurodegenerative syndrome of the human motor neuron system, for which no effective treatment exists. Variability in the rate of disease progression limits the efficacy of ALS clinical trials, suggesting that developing of better biomarkers for prognosis will facilitate therapeutic progress. Here, we applied unbiased next-generation sequencing to investigate the potential of plasma cell-free microRNAs as biomarkers of ALS prognosis, in 252 patients with detailed clinical-phenotyping. First, we identified miRNAs, whose plasma levels remain stable over the course of disease in a longitudinal cohort of 22 patients. Next, we demonstrated that high levels of miR-181, a miRNA enriched in neurons of the brain and spinal cord, predicts a >2 fold risk of death in discovery cohort (126 patients) and an independent replication cohort (additional 122 patients). miR-181 performance is comparable with the established neurofilament light chain (NfL) biomarker and when combined together, miR-181+NfL establish a novel RNA-protein biomarker pair with superior prediction capacity of ALS prognosis. Therefore, plasma miR-181 predicts ALS disease course, and a novel miRNA-protein biomarker approach, based on miR-181+NfL, boosts precision of patient stratification and may greatly enhance the power of clinical trials.

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“…In this study, the NFL level was detected using ultrasensitive Simoa technology in the serum, and this study showed elevated serum NFL levels in patients with ALS in China, which is consistent with the results of previous studies in Western countries. This result further proves the potential diagnostic value of serum NFL for the Chinese ALS population (11,14,18,(25)(26)(27). However, to evaluate the diagnostic performance and further establish a more accurate cut-off value of the serum NFL level for the diagnosis of ALS, the serum levels of NFL need to be investigated in a larger number of Chinese ALS patients and disease controls, including patients with other neurodegenerative diseases and non-neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 77%

Correlational Analysis of ALS Progression and Serum NfL Measured by Simoa Assay in Chinese Patients

et al. 2020

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Background: Neurofilament light chain (NFL) was believed to be a promising biomarker for the diagnosis of Amyotrophic lateral sclerosis (ALS) and disease burden evaluation.Objective: To determine the serum NFL level and its clinical relevance, including its association with disease severity [evaluated by the ALS Functional Rating Scale–revised (ALSFRS-r) score and King's College staging system] and progression (evaluated by the disease progression rate (DPR) and diagnostic delay), in ALS patients in China.Method: Serum NFL levels were detected using the Single Molecule Array (Simoa) technology in 30 ALS patients and 20 healthy controls (HCs).Results: There were significantly elevated levels of serum NFL in patients with ALS than in the HCs (P < 0.001). The serum NFL levels were significantly higher in rapidly progressive ALS and patients in Stage 3 than in slowly progressive ALS and patients in Stage 2 (PDPR < 0.001, PDiagnosticdelay = 0.019; Pstage= 0.033). Furthermore, the serum NFL levels negatively correlated with the diagnostic delay (R2 = 0.23, P = 0.016), the ALSFRS-r score (R2 = 0.15, P = 0.047) and disease duration (R2 = 0.15, P = 0.034), and positively correlated with the DPR (R2 = 0.42, P < 0.001).Conclusions: The present study preliminarily investigated the diagnostic value of serum NFL and its clinical relevance in the Chinese ALS population using the ultrasensitive Simoa technology. The results demonstrated that the level of serum NFL may become a potential biomarker for ALS diagnosis and indicate disease severity and progression.

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Validation of Serum Neurofilaments as Prognostic & Potential Pharmacodynamic Biomarkers for ALS

Cited by 11 publications

References 30 publications

Circulating miR-181 is a prognostic biomarker for amyotrophic lateral sclerosis

Circulating miR-181 is a prognostic biomarker for amyotrophic lateral sclerosis

Circulating miR-181 is a prognostic biomarker for amyotrophic lateral sclerosis

Correlational Analysis of ALS Progression and Serum NfL Measured by Simoa Assay in Chinese Patients

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