TABLE 3.
Proposed Candidate Biomarkers (Panel 1)
| Biomarkers to be assessed by ELISA assays | Mechanistic justification or preliminary validation | Differential transcriptomes (P value, FDR corrected) |
|---|---|---|
| C-Reactive Protein (CRP) | Increased CRP plasma levels in CA patients after SH; belongs to the weighted combined diagnostic biomarker.41 | .001a (FCGR2B) |
| Interleukin-1β (IL-1β) | Higher plasma levels of IL-1β in CA subjects who experienced a SH within the year following the initial blood sample; belongs to the weighted combined prognostic biomarker.40 | .048a |
| Lower plasma levels of IL-1β in CA patients after SH.41 | ||
| Interleukin-10 (IL-10) | Lower plasma levels of IL-10 in CA patients after SH; belongs to the weighted combined diagnostic biomarker.41 | .013a |
| Roundabout4 (ROBO4) | Greater plasma levels of ROBO4 in CA subjects who experienced SH within the year following the initial blood sample; belongs to the weighted combined prognostic biomarker.40 | .187a |
| Soluble cluster of differentiation 14 (sCD14) | Lower plasma levels of sCD14 in CA patients after SH; belongs to the weighted combined diagnostic biomarker.41 | .025a |
| Lower plasma levels of sCD14 in CA subjects who experienced SH within the year following the initial blood sample; belongs to the weighted combined prognostic biomarker.40 | ||
| Vascular endothelial growth factor (VEGF) | Lower plasma levels of VEGF in CA patients after SH; belongs to the weighted combined diagnostic biomarker.41 | .009a (VEGFA) |
| Lower plasma levels of VEGF in CA subjects who experienced SH within the year following the initial blood sample; belongs to the weighted combined prognostic biomarker.40 | .007a (FLT1) | |
| ADAM metallopeptidase with thrombospondin type 1 motif 4 (ADAMTS4) | Endothelial TLR4 and the microbiome drive CAs | 2.3 × 10−4a |
| ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS5) | CAs arise from endothelial gain of MEKK3-KLF2/4 signaling.56,57 | 2.1 × 10−3a |
| Angiopoietin-1 | Endothelial exocytosis of angiopoietin-2 resulting from CCM3 deficiency contributes to CAs.54 | 1.09 × 10−17a |
| Angiopoietin-2 | ||
| Lipopolysaccharide binding protein (LBP) | LBP inhibits LPS bio-activity in-vivo and in-vitro; increased LBP plasma levels in healthy non-CA subjects vs CA cases.67 | N.A. |
| Interleukins (IL-) | IL-4, -7, -16, - 21 and -33 were strong contenders in differential transcriptome of laser capture microdissected human CA neurovascular units.52 | .02a |
| IL-7 | 2.9 × 10−4a | |
| IL-16 | 0.02a | |
| IL-21 | 4.9 × 10−3a | |
| IL-33 | 0.01a | |
| Thrombomodulin | Thrombomodulin increased in human CA lesions and higher plasma levels in CA patients.60 | 9.64 × 10−14b |
| Thrombospondin-1 | Thrombospondin1 replacement prevents CAs.58 | 3.19 × 10−3b |
| Thrombospondin-2 | 5.1 × 10−4a | |
| Tissue plasminogen activator (tPA) | Central nervous system hemorrhage in CAs associated with greater expression of endothelial protein C receptor.60 | N.A. |
Cerebral angioma (CA); enzyme-linked immunosorbent assay (ELISA); lipopolysaccharide (LPS); Not Applicable (N.A.).
aData from laser capture microdissected neurovascular units from human resected CA lesions in comparison to human normal brain.
bData from mouse brain microvascular ECs with and without induced Ccm gene loss.