Machine Learning Reveals Protein Signatures in CSF and Plasma Fluids of Clinical Value for ALS

Abstract

We use shotgun proteomics to identify biomarkers of diagnostic and prognostic value in individuals diagnosed with amyotrophic lateral sclerosis. Matched cerebrospinal and plasma fluids were subjected to abundant protein depletion and analyzed by nano-flow liquid chromatography high resolution tandem mass spectrometry. Label free quantitation was used to identify differential proteins between individuals with ALS (n = 33) and healthy controls (n = 30) in both fluids. In CSF, 118 (p-value < 0.05) and 27 proteins (q-value < 0.05) were identified as significantly altered between ALS and controls. In plasma, 20 (p-value < 0.05) and 0 (q-value < 0.05) proteins were identified as significantly altered between ALS and controls. Proteins involved in complement activation, acute phase response and retinoid signaling pathways were significantly enriched in the CSF from ALS patients. Subsequently various machine learning methods were evaluated for disease classification using a repeated Monte Carlo cross-validation approach. A linear discriminant analysis model achieved a median area under the receiver operating characteristic curve of 0.94 with an interquartile range of 0.88–1.0. Three proteins composed a prognostic model (p = 5e-4) that explained 49% of the variation in the ALS-FRS scores. Finally we investigated the specificity of two promising proteins from our discovery data set, chitinase-3 like 1 protein and alpha-1-antichymotrypsin, using targeted proteomics in a separate set of CSF samples derived from individuals diagnosed with ALS (n = 11) and other neurological diseases (n = 15). These results demonstrate the potential of a panel of targeted proteins for objective measurements of clinical value in ALS.

Altered serum protein levels in frontotemporal dementia and amyotrophic lateral sclerosis indicate calcium and immunity dysregulation

“…Proteomics analysis of FTD and ALS has been conducted primarily in CSF with limited reproducibility across studies 16,[28][29][30][31] . To date, no studies have been reported for FTD using serum or plasma.…”

“…Proteomics technology has been recently applied to a number of neurodegenerative diseases for the purpose of biomarker development 14 . Only few proteomics studies have been carried out on ALS plasma [15][16][17] . However, to date no work has been reported on the proteomics of FTD serum/plasma nor any side-by-side comparisons of FTD and ALS proteins in serum/plasma.…”

Development of robust targeted proteomics assays for cerebrospinal fluid biomarkers in multiple sclerosis

“…Chitinase-3-like protein 1 (CH3L1) has been linked to several neurological diseases [23,26,[35][36][37][38][39], including MS [22,24,25,27,28]. However, it seems that this protein is not ideal for an absolute targeted assay, due to the unstable peptide measurements across runs.…”

Cerebrospinal fluid proteomic profiling in nusinersen‐treated patients with spinal muscular atrophy

“…In this non‐targeted proof‐of‐concept and feasibility study, we used high accuracy mass spectrometry (MS)‐based CSF proteomic analysis (Bereman, Beri, Enders, & Nash, ; Coscia et al, ; Zhang et al, ) in a restricted number of adult patients with later‐onset SMA (SMA 2 and 3). We (i) evaluated SMA‐specific CSF proteomes in comparison with healthy controls, (ii) screened for candidate proteins specifically deregulated in response to the first 10 months of nusinersen treatment in correlation with changes in motor function, and iii) analyzed basic CSF parameters before and during therapy in comparison with healthy controls.…”