Amyotrophic lateral sclerosis (ALS) is an incurable and rapidly progressive
neurological disorder.
Biomarkers are critical to understanding disease causation, monitoring
disease progression and assessing the efficacy of treatments. However, robust peripheral
biomarkers are yet to be identified.
Neuroinflammation and breakdown of the blood-brain barrier (BBB) are common to familial and sporadic ALS and may produce a unique
biomarker signature in peripheral blood. Using cytometric bead array (n = 15 participants per group (ALS or control)) and
proteome profiling (n = 6 participants per group (ALS or control)), we assessed a total of 106 serum
cytokines,
growth factors, and BBB breakdown markers in the serum of control and ALS participants. Further, primary human brain pericytes, which maintain the BBB, were used as a biosensor of
inflammation following pre-treatment with ALS serum. Principal components analysis of all
proteome profile data showed no clustering of control or ALS sera, and no individual
serum proteins met the threshold for statistical difference between ALS and controls (adjusted P values). However, the 20 most changed
proteins between control and ALS sera showed a medium effect size (Cohen's d = 0.67) and cluster analysis of their levels together identified three sample subsets; control-only, mixed control-ALS, and ALS-only. These 20
proteins were predominantly pro-angiogenic and
growth factors, including
fractalkine,
BDNF,
EGF, PDGF, Dkk-1, MIF and
angiopoietin-2. S100β, a
protein highly concentrated in glial cells and therefore a marker of BBB leakage when found in blood, was unchanged in ALS serum, suggesting that
serum protein profiles were reflective of peripheral rather than CNS biofluids. Finally, primary human brain pericytes remained proliferative and their secretome was unchanged by chronic exposure to ALS serum. Our exploratory study suggests that individual serum
cytokine levels may not be robust
biomarkers in small studies of ALS, but that larger studies using multiplexed analysis of pro-angiogenic and
growth factors may identify a peripheral signature of ALS pathogenesis.