Objectives To use a proteomic approach to study amyotrophic lateral sclerosis (ALS), to search for plasma biomarkers of ALS patients and healthy controls by using SWATH quantification mass spectrometry and to compare ALS patients with and without cognitive impairment (CI) based on proteomic analysis. Ingenuity Pathway Analysis (IPA) was used to investigate biological pathways that differ between groups.

Methods Forty-two patients with ALS and 18 healthy controls were recruited from the motor neuron disease clinic at Royal Brisbane and Women’s Hospital. Addenbrooke’s cognitive examination-III (ACE-III) was used to test cognitive function of all the ALS patients. SWATH proteomic analysis was utilised to look for differences between ALS patients and controls, and between ALS subjects with and without CI. Surrogate variable analysis was performed to remove the batch effect of the samples. IPA was applied to the final proteomic data.

Results Between ALS patients and healthy controls, there was significant difference in the expression of 30 proteins, including complement proteins and inflammatory markers. Of these, plasma Gelsolin concentration was 1.5 fold higher in healthy control in comparison with ALS patients (p=0.001). There were significant differences in 22 proteins between healthy controls and ALS patients with CI. Clusterin level was 1.2 fold upregulated in heathy people compared with patients with CI (p=0.03). Between ALS with and without CI, there was significant difference in expression of 25 proteins. CD5L concentration was significantly raised in patients without CI (p=0.013). The IPA shows that the complement pathway and coagulation pathway plays an important role in the ALS pathogenesis.

Conclusions Gelsolin, Clusterin and CD5L are potential plasma biomarkers to differentiate the healthy controls, ALS patients with and without CI.