Table 1.
Human studies investigating cerebrospinal fluid biomarkers for ischemic stroke.
| Author, Year | Study Location | No. of Subjects | Time CSF Collected for Stroke Patients | Study Design | Biomarker Tested | Associated Characteristic | NOS | Study Outcomes |
|---|---|---|---|---|---|---|---|---|
| Vila et al., 2000 [36] | Spain | 81 stroke | At admission | Prospective clinical trial | Inflammatory markers (IL-6 and TNF-α) | Progression | 6 | Elevated IL-6 (>6.3 pg/mL) was an independent risk factor of progression/worsening 48 h after admission. TNF-α was elevated in stroke but not independently significant. |
| Beridze and Shakarishvili, 2006 [23] | Georgia | 58 stroke, 15 control | N/A | Prospective | Proinflammatory cytokines IL-1b, IL-6, TNF-α and anti-inflammatory cytokine IL-10 | Severity, progression | 8 | IL-6 levels were considered a stable prognostic indicator of clinical course of disease; only marker statistically significant after 1 wk. |
| Brouns et al., 2008 [25] | Belgium | 85 stroke, 51 control | Within 24 h of stroke onset | Prospective clinical trial | Lactate | Diagnosis, progression | 9 | Lactate in CSF correlated with stroke evolution in 72 h and patient outcomes at 3 months (mortality, poor outcome (mRS >3)), validated by multivariate models. |
| Petzold et al., 2008 [27] | UK | 33 stroke, 20 control | Early hospitalization | Prospective clinical trial | S100B, ferritin, and NfH SMI35 | Diagnosis | 9 | Elevated S100B and ferritin in patients with ischemic stroke compared to controls. NfH levels were not elevated. |
| Brouns et al., 2010 [22] | Belgium | 89 stroke, 35 control | Mean of 8.7 h after onset | Prospective study | MBP, GFAP, S100B, and NSE | Severity | 7 | MBP was a marker for infarct location. GFAP and S100B correlated with stroke severity and outcome. |
| Beridze et al., 2011 [18] | Israel | 95 stroke, 25 age-matched controls | Early hospitalization | Prospective clinical trial | Acute phase reactants (IL-1, IL-6, IL-10, TNF-α, NO2, NO, LOO) | Severity of stroke | 9 | All acute phase reactants were generally elevated. NO2 and IL-6 were independently predictive of severe stroke symptoms. LOO and TNF-α were also elevated in univariate analysis but not significant in multivariate analysis. |
| Kaerst et al., 2013 [31] | Germany | 18 stroke | Varied from day of ischemic event to several weeks after | Retrospective study | s t-tau, p-tau and Aβ42 | Diagnosis | 5 | Increase in CSF biomarkers depended on size and duration after event; however, even small infarct area led to increased CSF tau levels. |
| Ke and Zhang, 2013 [28] | China | 50 stroke, 30 control | Prior to medication | Prospective clinical trial | HIF-1α, VEGF, NGF, and BDNF | Diagnosis | 7 | HIF-1a and NGF levels were significantly reduced in stroke patients compared to controls. VEGF and BDNF were unchanged. |
| Hjalmarsson et al., 2014 [32] | UK | 20 stroke | 5–10 days after stroke | Prospective study | NfL, T-tau, MBP, YKL-40, and GFAP | Severity | 5 | T-tau, MBP, YKL-40, and GFAP increased in stroke, and they correlated to clinical stroke severity. However, only NFL was found to be a marker of degree of white-matter lesion. |
| Sørensen et al., 2014 [19] | Denmark | 10 stroke, 10 control | At admission | Prospective study | miRNAs | Diagnosis | 8 | Two miRNAs (let-7c and miR-221-3p) were upregulated in relation to stroke. Some miRNAs occurred exclusively in the CSF, including miR-523-3p, which was detected in 50% of stroke patients but was completely absent in controls. |
| Li et al., 2015 [29] | China | 37 stroke, 21 control | Early hospitalization | Prospective clinical trial | Autophagy markers (BECLIN1, LC3B) | Progression | 9 | Demonstrated that BECLIN1 and LC3B were highly correlated with infarct volume and NIHSS scores and moderately correlated with functional outcome (mRS). |
| Peng et al., 2015 [26] | China | 28 stroke, 12 control | Acute stage (11), subacute stage (9), recovery (8) | Prospective clinical trial | MicroRNA markers via PCR (let-7e and miR-338) | Diagnosis, progression | 7 | Elevated miR-338 was observed in the subacute phase of AIS patients (vs. control) but returned to normal levels in recovery. Elevated let-7e levels were found in all levels of stroke (acute, subacute, and recovery). Let-7e had an AUC of 0.86 for diagnosis of stroke, whereas miR-338 had an AUC of 0.63. |
| Sun et al., 2015 [24] | China | 41 stroke, 78 control | At admission and 12, 24, 48 h postadmission | Prospective clinical trial | FFA levels | Diagnosis, progression | 8 | Good diagnostic value for cardioembolic vs. non-cardioembolic stroke, correlated for infarction volume and NIHSS scores. A two-fold increase of FFAs compared with the baseline values began 12 h after admission, reaching peak values at 24 h and returning to admission values by 48 h. |
| De Vos et al., 2017 [30] | Belgium | 50 stroke | Mean of 8.7 h after onset | Prospective study | Neurogranin and tau | Diagnosis, severity | 5 | Tau was a more promising predictor in CSF. Levels of neurogranin were significantly associated with infarct volume but not stroke severity or long-term outcome. |
| Duan et al., 2017 [33] | China | 252 stroke | Within 24 h | Prospective study | FFA levels | Severity, progression | 6 | Patients with unfavorable outcomes had significantly elevated FFA levels versus patients with favorable outcomes. |
| Niu et al., 2017 [34] | China | 272 stroke | Within 24 h of stroke onset | Prospective clinical trial | FFA levels | Progression | 5 | Elevated FFA levels correlated to greater stroke volume and NIHSS score for patients. |
| Sørensen et al., 2017 [20] | Denmark | 21 stroke, 21 control | Upon admission | Prospective study | miRNAs | Progression | 9 | miR-9-5p and miR-128-3p were significantly higher in CSF of stroke patients compared to controls. miRNAs (miR-9-5p, miR-9-3p, miR-124-3p, and miR-128-3p) were elevated in patients with larger infarcts. |
| Sandelius et al., 2018 [17] | Sweden | 28 stroke, 19 control | Day 0–1, day 2–4, day 7–9, 3 wk, 3–5 mo | Prospective study | GAP-43 | Severity, progression | 8 | In the first 2 weeks, a transient increase was noted. |
| Pujol-Calderón et al., 2019 [15] | Sweden | 30 stroke, 30 control | Day 0–1, day 2–3, day 7–9, 3 wk, 3–5 mo | Prospective study | Serum and CSF NfL and NfH proteins | Severity, progression | 9 | Both serum and CSF NfL and NfH concentrations reflected neuronal injury after acute stroke. The highest levels were around week 3, and levels decreased after 3–5 months. |
| Gaber et al., 2020 [21] | Egypt | 80 stroke, 28 control | Within 24 h | Prospective trial | FFA levels | Severity, progression | 7 | Positive correlation with larger infarction volume and significant predictor of all-cause mortality. |
| Hagberg et al., 2020 [35] | Norway | 13 stroke | 1 y after stroke | Prospective clinical trial | Amyloid-beta 12 | Progression | 5 | CSF markers 1-year post-AIS were not predictive of neurodegeneration or cognitive decline after 7-year follow-up. |
| Xiong et al., 2021 [16] | China | 105 stroke, 80 control | Day 1 after diagnosis | Prospective study | a2d-1 | Severity | 8 | Level of a2d-1 in large infarct volume was significantly higher than in the medium and small infarct volume groups. Levels were also higher in patients with greater severity. |
Abbreviations: AIS, acute ischemic stroke; AUC, area under the curve; BDNF, brain-derived neurotrophic factor; CSF, cerebrospinal fluid; FFA, free fatty acid; GAP-43, growth-associated protein 43; GFAP, glial fibrillary astrocytic protein; HIF, hypoxia-inducible factor; IL, interleukin; LOO, lipoperoxide radical; MBP, myelin basic protein; miRNA, microRNA; mRS, modified Rankin Scale; N/A, not available; NfH, neurofilament heavy chain; NfL, neurofilament light chain; NGF, nerve growth factor; NIHSS, National Institutes of Health Stroke Scale; NO, nitric oxide; NO2, nitrogen dioxide; NOS, Newcastle Ottawa Scale; NSE, neuron-specific enolase; TNF, tumor necrosis factor; T-tau, total tau; VEGF, vascular endothelial growth factor.