Timely and Blood-Based Multiplex Molecular Profiling of Acute Stroke
Abstract
:1. Introduction
2. Circulating Protein Biomarkers for Ischemic Stroke Differential Diagnosis
3. Circulating Protein Biomarkers to Differentiate Acute IS from HS
4. Conventional and Point-of-Care Technologies
5. Future Perspectives
- The recognition of stroke mimics would become more efficient. The frequency of these can vary between 15% and 42% and entail an inappropriate use of the available stroke facilities leading to additional costs and a delayed diagnosis of the actual disease [19,23,24]. Even more, the administration of thrombolytic medication in wrongly diagnosed patients may lead to undesirable side effects such as intracranial hemorrhage [111];
- Stroke chameleons’ recognition at patient admission to the hospital would be more sensitive and specific. The frequency of these can vary between 2% and 26% [18]. The problem of chameleons resides in the lack of proper treatment of stroke patients during the hyper-acute settings due to the fact of missing diagnosis, lowering the chance to administer thrombolytic medication or to undergo mechanical thrombectomy as well as to receive suitable secondary prevention. Consequently, stroke chameleon patients have the worst outcomes at 12 months [10];
- The reperfusion treatments would be hastened. Thrombolytic iv treatment would start right after the first encounter of the paramedic team with the patient, saving over 15 min, depending on the time and distance from the scene to hospital [70], at a significantly lower cost than specialized stroke ambulances with portable imaging devices [112];
- Biomarkers able to anticipate successful recanalization (e.g., reduced levels of inflammation-associated α2-antiplasmin and thrombin-activatable fibrinolysis inhibitor (TAFI) or C-Reactive Protein) [113,114,115], could guide adjuvant therapies (e.g., growth factors administration) [116] to improve the efficacy of thrombolytic iv treatment in centers where mechanical thrombectomy is not readily available or when thrombectomy is not recommended (distal clots with low NIHSS at presentation and high pretreatment modified Rankin scale) [117]. In addition, biomarkers that predict the risk of hemorrhagic transformation after iv thrombolysis or mechanical recanalization (e.g., cellular Fibronectin (c-Fn)) could be measured with POC diagnostic platforms preventing damaging interventions [79];
- The identification of the stroke subtype in the pre-hospital setting would be more sensitive. For instance, the earlier recognition of patients with large vessel occlusions would be possible, and the transport for a comprehensive stroke center would be ensured (Figure 3), reducing the need for secondary transfers (saving up to 100 min) and reducing the time from symptoms onset to mechanical thrombectomy in a timely fashion [32]. The inverse is also applicable to the identification of cases in which mechanical thrombectomy would not be a valuable strategy and would save time and avoid the inappropriate use of comprehensive stroke facilities [118].
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Biomarker Origin | Protein | Biomarker Level in IS | Biomarker Level in Control | Cut-Off Point | Sensitivity | Specificity | AUC | Study Sample | Reference |
---|---|---|---|---|---|---|---|---|---|
Brain Cells | NR2 | 5.4 (0.1–62.7) ng/mL | 0.3 (0.02–1.1) ng/mL | 1 ng/mL | 92.1% | 96.5% | 0.92 | Combined stroke mimics and healthy controls | [41] |
S100B | N/A | N/A | 39.9 pg/mL | 76.5% | 82.7% | 0.87 | Non-stroke controls | [42] | |
GPBB | 46.3 (±38.6) ng/mL | 4.1 (±7.6) ng/mL | 7.0 ng/mL | 93.0% | 93.0% | 0.96 | Non-stroke controls | [43] | |
BNP | 90.8 (±156.4) pg/mL | 11.3 (±6.1) pg/mL | N/A | N/A | N/A | 0.69 | Healthy and stroke mimics | [34] | |
Anti-NMDA (NR2A/2B ab) | 5.0 (3.2–7.2) ng/mL | 1.5 (1.0–1.9) ng/mL | 2.0 ng/mL | 97.0% | 98.0% | 0.99 | Healthy controls | [44] | |
Brain Cells, Endothelium/Matrix, Blood | MMP-9 | 242.1 (±242.6) ng/mL | 211.2 (±184.8) ng/mL | N/A | N/A | N/A | 0.55 | Healthy and stroke mimics | [34] |
PARK 7 | N/A | N/A | 14.2 ng/mL | 58.0% | 90.0% | 0.88 | Healthy controls | [45] | |
NDKA | N/A | N/A | 22.5 ng/mL | 67.0% | 89.9% | 0.94 | Healthy controls | [45] | |
Blood | APOA1-UP/LRP | 1.3 (IQR 0.4) | 2.1 (IQR 0.4) | <1.8 | 90.6% | 97.1% | 0.98 | Non-stroke controls | [46] |
Biomarker Origin | Proteins | Biomarker Level in IS | Biomarker Level in Control | Cut-Off Point | Sensitivity | Specificity | AUC | Study Sample | Reference |
---|---|---|---|---|---|---|---|---|---|
Brain Cells, Endothelium/Matrix, Blood | MMP9 | N/A | N/A | N/A | 91.7% | 93.0% | 0.99 | Healthy controls | [36] |
BNGF | |||||||||
vWF | |||||||||
MCP-1 | |||||||||
S-100B | |||||||||
Brain Cells, Endothelium/Matrix | Eotaxin | N/A | N/A | N/A | N/A | 0.92 | Stroke mimics | [22] | |
EGFR | |||||||||
S100A12 | |||||||||
TIMP-4 | |||||||||
Prolactin | |||||||||
Brain Cells, Endothelium/Matrix, Blood | BNP | 90.8 (±156.4) pg/mL | 11.3 (±6.1) pg/mL | N/A | 91.0% | 21.5% | N/A | Healthy controls and stroke mimics | [34] |
D-dimer | 888.1 (±1289) ng/mL | 188.6 (±113.8) ng/mL | |||||||
MMP9 | 242.1 (±242.6) ng/mL | 211.2 (±184.8) ng/mL | |||||||
S100B | 103.1 (±13.6) pg/mL | 188.6 (±147.1) pg/mL | |||||||
Brain Cells, Endothelium/Matrix, Blood | IL-6 | 4.0 (0.8–12.3) pg/mL | 1.2 (0.0–2.4) pg/mL | - | N/A | N/A | 0.75 | Stroke mimics | [48] |
S100B | 63.3 (29.7–122.8) ng/mL | 33.8 (15.4–60.8) ng/mL | |||||||
MMP-9 | 30.4 (0–115.2) pg/mL | 2.3 (0.0–20.6) pg/mL |
Biomarker Origin | Protein | Biomarker Level in IS | Biomarker Level in HS | Cut-Off Point | Sensitivity | Specificity | AUC | Reference |
---|---|---|---|---|---|---|---|---|
Brain Cells | GFAP | 0.08 (0.02–0.14) ng/mL | 1.91 (0.41–17.7) ng/mL | 0.30 ng/mL | 84.2% | 96.3% | 0.91 | [56] |
S100B | 61.7 (±37.3) pg/mL | 161.2 (±79.7) pg/mL | 67.0 pg/mL | 95.7% | 70.4% | 0.90 | [60] | |
UCH-L1 | 338.0 pg/mL | 401.0 pg/mL | 291.0 pg/mL | 73% | 45.0% | 0.59 | [61] | |
Endothelium/Matrix | sRAGE | 1.0 ng/mL | 0.8 ng/mL | <0.97 ng/mL | NA | NA | NA | [62] |
Blood | RBP4 | 59.8 (±12.3) µg/mL | 36.9 (±14.7) µg/mL | 61.0 µg/mL | 68.4% | 84.0% | NA | [55] |
Biomarkers Origin | Proteins | Biomarker Level in Ischemic Stroke | Biomarker Level in Hemorrhagic Stroke | Cut-Off Point | Sensitivity | Specificity | AUC | Reference |
---|---|---|---|---|---|---|---|---|
Brain Cells, Endothelium/Matrix, Blood | RBP-4 | 29.2 (25.1–35.7) μg/mL | 34.4 (26.0–40.0) μg/mL | 38.0 μg/mL | 51.5% | 100% | N/A | [27] |
NT-proBNP | 0.8 (0.2–2.4) ng/mL | 0.4 (0.2–0.7) ng/mL | 1.3 ng/mL | |||||
GFAP | 186.3 (132.8–280.2) pg/mL | 1699.6 (411.1–10,145.4) pg/mL | 325 pg/mL | |||||
sRAGE | 1.0 ng/mL | 0.8 ng/mL | <0.9 ng/mL | 22.7% | 80.2% | 0.76 | [62] | |
S100B | 58.7 pg/mL | 107.7 pg/mL | 96.0 pg/mL |
POC Device | Analytical Platform | Blood Biomarkers | Application | Reference |
---|---|---|---|---|
Hemochron® Junior | Optical | ACT-LR, ACT, PT, Citrate PT, APTT, and Citrate APTT | Pre- and In-hospital | [94] |
PocH-100i Hematology Analyzer | Hydrodynamics/Impedance | Full blood cell count | Pre- and In-hospital | [95] |
i-STAT | Electrochemical | Blood gases, electrolytes, metabolites, and coagulation | Pre- and In-hospital | [96] |
Reflotron® plus analyzer | Optical | c-glutamyltransferase, p-amylase, glucose | Pre- and In-hospital | [97] |
AxSYM® BNP | Optical | BNP | In/Post-hospital | [98] |
Triage® BNP | Optical | BNP | In/Post-hospital | [99] |
iSTAT BNP | Electrochemical | BNP | In/Post-hospital | [100] |
TBI Check® | N/A * | H-FABP and GFAP | Pre- and In-hospital | [101] |
Prediction Sciences LLC | Optical | c-Fn | In-hospital | [102,103] |
ReSTTM | N/A * | Immune response | In-hospital | [104,105] |
SMARTChip | Electrochemical | Purines | In-hospital | [106] |
POC | Modality | Analytical Platform | Multiplex Capacity * | On-Site Analysis | Reference |
---|---|---|---|---|---|
µPADs | Paper-based system | Optical | ≥2 biomarkers | Yes | [73] |
Stack Pad | Paper-based system | Optical | >2 biomarkers | Yes | [88,89,90,106] |
ELFI | Paper-based system | Electrochemical | >2 biomarkers | Yes | [85,86,87] |
EIS-SERS | Paper-based system | Electrochemical and surface-enhanced Raman spectroscopy | ≥2 biomarkers | Yes | [107] |
EIS | Array-based system | Electrochemical | ≥5 biomarkers | Yes | [108,109] |
MuitiLab | Microfluidic-based system | Electrochemical | ≥8 biomarkers | Yes | [73] |
mChip | Microfluidic-based system | Optical | ≥5 biomarkers | Yes | [73] |
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Dias, A.; Silva, I.; Pinto, I.M.; Maia, L.F. Timely and Blood-Based Multiplex Molecular Profiling of Acute Stroke. Life 2021, 11, 816. https://doi.org/10.3390/life11080816
Dias A, Silva I, Pinto IM, Maia LF. Timely and Blood-Based Multiplex Molecular Profiling of Acute Stroke. Life. 2021; 11(8):816. https://doi.org/10.3390/life11080816
Chicago/Turabian StyleDias, Alexandre, Isabel Silva, Inês Mendes Pinto, and Luís F. Maia. 2021. "Timely and Blood-Based Multiplex Molecular Profiling of Acute Stroke" Life 11, no. 8: 816. https://doi.org/10.3390/life11080816