AbstractObjectiveAmyotrophic lateral sclerosis (ALS) is an adult‐onset fatal neurodegenerative disease which lacks identified biological markers. A label‐free plasma surface‐enhanced Raman spectroscopy (SERS) method was developed to explore a simple and noninvasive test for ALS.MethodsALS patients were enrolled serially and plasma samples were collected at the time of diagnosis prior to the start of ALS treatment. SERS spectra were recorded using a Renishaw micro‐Raman system.ResultsTo exclude the interference by varying disease severity, we enrolled three groups of ALS patients, including ALS‐1 (n = 60; ALSFRS‐R ≥ 42 and time interval ≤ 12 months), ALS‐2 (n = 61; ALSFRS‐R < 42 and time interval ≤ 12 months), and ALS‐3 (n = 61; ALSFRS‐R ≥ 38 and time interval> 12 months). The SERS spectra were analyzed using principal component analysis (PCA), which showed that ALS‐1, ALS‐2, ALS‐3, and control groups were separated significantly. Then, decision tree (DT) models and receiver operating characteristic curves were employed and identified that bands at 722 and 739 cm−1, and ratios of 635–722 cm−1 and 635–739 cm−1 were able to distinguish ALS from controls significantly. Finally, we highlighted six metabolism pathways correlated with ALS, including phenylalanine‐tyrosine‐tryptophan biosynthesis, aminoacyl‐tRNA biosynthesis, phenylalanine metabolism, pantothenate and CoA biosynthesis, porphyrin and chlorophyll metabolism, and pyrimidine metabolism.Interpretation:Plasma SERS could be a promising tool for the detection of ALS. The bands at 722 and 739 cm−1, and the ratios of 635–722 cm−1 and 635–739 cm−1 could serve as potential indicator for ALS.
