Serum biomarkers of neuroinflammation and blood-brain barrier leakage in amyotrophic lateral sclerosis
Abstract 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 identif...
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| Format: | Article |
| Language: | English |
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BMC
2022-06-01
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| Series: | BMC Neurology |
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| Online Access: | https://doi.org/10.1186/s12883-022-02730-1 |
| _version_ | 1811258101561556992 |
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| author | Maize C. Cao Erin E. Cawston Grace Chen Collin Brooks Jeroen Douwes Dave McLean E. Scott Graham Mike Dragunow Emma L. Scotter |
| author_facet | Maize C. Cao Erin E. Cawston Grace Chen Collin Brooks Jeroen Douwes Dave McLean E. Scott Graham Mike Dragunow Emma L. Scotter |
| author_sort | Maize C. Cao |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-12T18:07:58Z |
| format | Article |
| id | doaj.art-43fcd70d92914590b6a31c00e5751e33 |
| institution | Directory Open Access Journal |
| issn | 1471-2377 |
| language | English |
| last_indexed | 2024-04-12T18:07:58Z |
| publishDate | 2022-06-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Neurology |
| spelling | doaj.art-43fcd70d92914590b6a31c00e5751e332022-12-22T03:21:55ZengBMCBMC Neurology1471-23772022-06-0122111210.1186/s12883-022-02730-1Serum biomarkers of neuroinflammation and blood-brain barrier leakage in amyotrophic lateral sclerosisMaize C. Cao0Erin E. Cawston1Grace Chen2Collin Brooks3Jeroen Douwes4Dave McLean5E. Scott Graham6Mike Dragunow7Emma L. Scotter8Department of Pharmacology and Clinical Pharmacology, University of AucklandDepartment of Pharmacology and Clinical Pharmacology, University of AucklandCentre for Public Health Research, Massey UniversityCentre for Public Health Research, Massey UniversityCentre for Public Health Research, Massey UniversityCentre for Public Health Research, Massey UniversityCentre for Brain Research, University of AucklandDepartment of Pharmacology and Clinical Pharmacology, University of AucklandDepartment of Pharmacology and Clinical Pharmacology, University of AucklandAbstract 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.https://doi.org/10.1186/s12883-022-02730-1Amyotrophic lateral sclerosisSerumCytokineBlood-brain barrierNeuroinflammation |
| spellingShingle | Maize C. Cao Erin E. Cawston Grace Chen Collin Brooks Jeroen Douwes Dave McLean E. Scott Graham Mike Dragunow Emma L. Scotter Serum biomarkers of neuroinflammation and blood-brain barrier leakage in amyotrophic lateral sclerosis BMC Neurology Amyotrophic lateral sclerosis Serum Cytokine Blood-brain barrier Neuroinflammation |
| title | Serum biomarkers of neuroinflammation and blood-brain barrier leakage in amyotrophic lateral sclerosis |
| title_full | Serum biomarkers of neuroinflammation and blood-brain barrier leakage in amyotrophic lateral sclerosis |
| title_fullStr | Serum biomarkers of neuroinflammation and blood-brain barrier leakage in amyotrophic lateral sclerosis |
| title_full_unstemmed | Serum biomarkers of neuroinflammation and blood-brain barrier leakage in amyotrophic lateral sclerosis |
| title_short | Serum biomarkers of neuroinflammation and blood-brain barrier leakage in amyotrophic lateral sclerosis |
| title_sort | serum biomarkers of neuroinflammation and blood brain barrier leakage in amyotrophic lateral sclerosis |
| topic | Amyotrophic lateral sclerosis Serum Cytokine Blood-brain barrier Neuroinflammation |
| url | https://doi.org/10.1186/s12883-022-02730-1 |
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