A Multiplex Protein Panel Applied to Cerebrospinal Fluid Reveals Three New Biomarker Candidates in ALS but None in Neuropathic Pain Patients

Anne-Li Lind, Di Wu, Eva Freyhult, Constantin Bodolea, Titti Ekegren, Anders Larsson, Mats G Gustafsson, Lenka Katila, Jonas Bergquist, Torsten Gordh, Ulf Landegren, Masood Kamali-Moghaddam, Anne-Li Lind, Di Wu, Eva Freyhult, Constantin Bodolea, Titti Ekegren, Anders Larsson, Mats G Gustafsson, Lenka Katila, Jonas Bergquist, Torsten Gordh, Ulf Landegren, Masood Kamali-Moghaddam

Abstract

The objective of this study was to develop and apply a novel multiplex panel of solid-phase proximity ligation assays (SP-PLA) requiring only 20 μL of samples, as a tool for discovering protein biomarkers for neurological disease and treatment thereof in cerebrospinal fluid (CSF). We applied the SP-PLA to samples from two sets of patients with poorly understood nervous system pathologies amyotrophic lateral sclerosis (ALS) and neuropathic pain, where patients were treated with spinal cord stimulation (SCS). Forty-seven inflammatory and neurotrophic proteins were measured in samples from 20 ALS patients and 15 neuropathic pain patients, and compared to normal concentrations in CSF from control individuals. Nineteen of the 47 proteins were detectable in more than 95% of the 72 controls. None of the 21 proteins detectable in CSF from neuropathic pain patients were significantly altered by SCS. The levels of the three proteins, follistatin, interleukin-1 alpha, and kallikrein-5 were all significantly reduced in the ALS group compared to age-matched controls. These results demonstrate the utility of purpose designed multiplex SP-PLA panels in CSF biomarker research for understanding neuropathological and neurotherapeutic mechanisms. The protein changes found in the CSF of ALS patients may be of diagnostic interest.

Conflict of interest statement

Competing Interests: U. Landegren is a co-founder and stockholder of the Olink Bioscience that commercializes the PLA technology. The other authors have declared that no competing interests exist.

Figures

Fig 1. Protein variation among the investigated…
Fig 1. Protein variation among the investigated individuals.
A) Boxplots showing protein concentrations ranges in CSF from 72 individuals without neurological disorders. The concentration ranges between the upper and lower limits of detection for each marker are shown in grey. The numbers below and above the boxplots show the number of patient samples (out of the total 72) that are outside the detection limits. B) Performance measures for each protein assay. The 1st, 2nd (median) and 3rd quartile values of the robust % CV. The numbers of detectable samples out of a total of 72 samples are found at the bottom line for each marker.
Fig 2
Fig 2
Protein level comparisons for ALS patients and matched controls (a) and neuropathic pain patients with SCS on and off (b). The y-axes represent Ct-values. The detectable concentration ranges between the upper and lower limits of detection for each marker are shown in grey. The numbers above and below the boxplots show the number of samples that are outside the detection limits.
Fig 3. ALS Biomarker candidates.
Fig 3. ALS Biomarker candidates.
Boxplots showing the CSF levels for follistatin, IL1-alpha and KLK5 for ALS patients and matched controls. The protein levels are compared using the Mann-Whitney U-test and p-values are displayed in the Figures. The limits of detection are indicated by dashed horizontal lines. The y-axes represent Ct-values.

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Source: PubMed

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