Table 4.

Biomarkers for acute ischemic stroke

Authors/year/Ref	Study design	Population	N	Bio-marker	Sample source	Findings
Molecules of CNS origin
Kazmierski/2012/[123]	Pro	AIS	458	s100β, OCLN, CLDN5, ZO1	Serum	Patients with clinical deterioration due to hemorrhagic transformation had higher s100β, OCLN, and CLDN/ZO1 ratio
Foerch/2004/[93]	Pro	AIS within 6 h of onset with proximal MCA occlusion	51	s100β	Serum	Mean s100β were higher in patients with malignant cerebral edema defined. s100β >1.03 μg/L at 24 h post AIS predicted malignant infarction (94 % sensitivity; 83 % specificity)
Missler/1997/[89]	Pro	AIS diagnosed by CT	44	s100β, NSE	Serum	s100β correlated with infarct volume and with 6 month outcome NSE correlated with infarct volume but not with clinical outcome Did not adjust for stroke subtype or tPA treatment
Foerch/2005/[91]	Pro	AIS within 6 h of onset	39	s100β	Serum	s100β at 48–72 h post AIS correlated with 6-month outcome and with infarct volume s100β ≤0.37 μg/L at 48 h post stroke predicted functional independence at 6 months (87 % sensitivity; 78 % specificity)
Herrmann/2000/[90]	Pro	Anterior circulation AIS	32	s100β, GFAP	Serum	s100β and GFAP correlated with total infarct volume and neurologic status at hospital discharge Did not adjust for stroke subtype or tPA treatment
Foerch/2003/[92]	Pro	AIS ≤5 h of onset with Ml occlusion	23	s100β	Serum	s100β <0.4 μg/L at 48–96 h post AIS predicted MCA recanalization within 6 h (86 % sensitivity; 100 % specificity)
Biomarkers of inflammation and blood brain barrier
Den Hertog/2009/[100]	RCT	AIS ≤12 h onset, no liver disease, prior mRS <2	561	CRP	Serum	From RCT for paracetamol for ischemic stroke. CRP measured within 12 h of stroke onset CRP >7 mg/L is associated with poor outcome (OR = 1.6 [1.1–2.4]) and death (OR = 1.7 [1.0–2.9])
Idicula/2009/[101]	Nested Pro	AIS ≤24 h onset	498	CRP	Serum	CRP >10 mg/L is independently associated with high NIHSS and high long-term mortality at 2.5 years
Montaner/2006/[99]	Pro	AIS in MCA territory treated with IV tPA within 3 h; exclude inflammatory disease or infection	143	CRP	Serum	CRP measured before tPA administration. CRP was higher in those who died after thrombolysis compared with survivors (0.85 vs. 0.53 mg/dL) CRP is independently associated with mortality at 3 months (OR = 8.51 [2.16–33.5]).
Winbeck/2002/[102]	Pro	AIS ≤12 h onset, NOT treated with IV tPA	127	CRP	Serum	CRP >0.86 mg/dL 24 h and at 48 h post-stroke are associated with death and lower likelihood of event-free survival at 1 year
Topakian/2008/[103]	Pro	AIS in MCA territory treated with IV tPA ≤6 h of onset, exclude CRP >6 mg/dL	111	CRP	Serum	CRP measured before tPA administration CRP level was not associated with NIHSS within 24 h or outcome at 3 months
Shantikumar/2009/[98]	Pro	AIS surviving >30 days	394	CRP	Serum	CRP higher in subject who died compared to survivors CRP is independently predictive of mortality after adjusting for conventional risk factors
Elkind/2006/[96]	Retro	Age >40, reside in northern Manhattan >3 months	467	hs-CRP	Serum	Highest quartile of hs-CRP is associated with increased risk of stroke recurrence (HR 2.08 [1.04–4.18]) and with combined outcome of stroke, MI, or vascular death (HR = 1.86 [1.01–3.42])
Huang/2012/[97]	Retro	Age >40, reside in northern Manhattan >3 months	741	hs-CRP	Serum	hs-CRP >3 mg/L was associated with higher mortality at 3 months and all-cause mortality (HR = 6.48 [1.41–29.8])
Castellanos/2003/[116]	Pro	Hemispheric AIS within 7.8 ± 4.5 h of onset	250	MMP-9	Plasma	MMP-9 ≥140 μg/L predicted hemorrhagic transformation (61 % PPV; 97 % NPV)
Castellanos/2007/[113]	Pro	AIS ≤3 h treated with IV tPA	134	c-Fn, MMP-9	Serum	MMP-9 ≥140 μg/L predicted hemorrhagic transformation (92 % sensitivity; 74 % specificity; 26 % PPV; 99 % NPV) c-Fn ≥3.6 μg/mL predicted hemorrhagic transformation (100 % sensitivity; 60 % specificity; 20 % PPV; 100 % NPV)
Moldes/2008/[119]	Pro	AIS treated with IV tPA	134	ET-1, MMP-9, c-Fn	Serum	ET-1, MMP-9, and c-Fn measured upon admission before tPA bolus ET-1 and c-Fn significantly higher in those with severe cerebral edema ET-1 >5.5 fmol/mL before tPA was independently associated with severe brain edema in multivariate analysis
Serena/2005/[118]	Case control	Malignant MCA infarction, <70 years	40 AIS, 35 CTRL	c-Fn, MMP-9	Plasma	c-Fn and MMP-9 were significantly higher in patients with malignant MCA infarcts c-Fn >16.6 μg/mL predicted malignant infarction (90 % sensitivity; 100 % specificity; 89 % NPV; 100 % PPV)
Montaner/2003/[114]	Pro	AIS in MCA territory treated with IV tPA within 3 h	41	MMP-9	Plasma	Higher baseline (pre-tPA) MMP-9 was associated with hemorrhagic transformation in dose-dependent fashion MMP-9 was predictive of hemorrhagic transformation in multivariate model (OR = 9.62)
Montaner/2001/[115]	Pro	Cardioembolic AIS in MCA territory	39	MMP-9	Plasma	Elevated baseline MMP-9 was associated with late-hemorrhagic transformation in multivariate regression (OR = 9)
Castellanos/2004/[93]	Pro	AIS treated with IV tPA by ECASS II criteria	87	c-Fn	Plasma	c-Fn was independently associated with hemorrhagic transformation in multivariate analysis (OR = 2.1) 71 of the patients were treated within 3 h of AIS onset. Similar results were found in these patients
Guo/2011/[57]	Pro	First onset AIS	172 AIS, 50 CTRL	pGSN	Plasma	Samples from first 24 h of stroke onset obtained pGSN decreased in AIS compared to controls pGSN was independent predictor for 1-year mortality pGSN >52 mg/L predicted 1-year mortality (73 % sensitivity; 65.2 % specificity)
Yin/2013/[106]	Pro	AIS	186 AIS, 100 CTRL	Visfastin	Plasma	Visfatin was higher in AIS than in controls. Visfatin was independent predictor of 6-month clinical outcome Adding visfatin did not improve predictive performance of NIHSS
Other biomarkers
Haapaniemi/2000/[122]	Case control	AIS	101 AIS, 101 CTRL	ET-1	Plasma	No difference in ET-1 levels between stroke and controls
Lampl/1997/[126]	Pro	AIS within 18 h from onset	26	ET-1	CSF, Plasma	CSF ET-1 correlated with volume of the lesion and higher in cortical infarcts compared to subcortical infarcts Plasma ET-1 was not elevated
Chiquete/2013/[124]	Pro	AIS	463	Uric acid	Serum	Uric acid ≤4.5 mg/dL at hospital admission was associated with very good 30 day outcome (OR = 1.76 [1.05–2.95]; 81.1 % NPV)
Matsumoto/2013/[125]	Retro	AIS from non-valvular AF within 48 h of onset	124	d-dimer	Plasma	d-dimer level at hospital admission is independently associated with infarct volume Highest d-dimer tertile group had worse outcome compared to middle and lowest tertiles

AF atrial fibrillation, NPV negative predictive value, PPV positive predictive value, Pro prospective observational, RCT randomized controlled trial, Retro retrospective, CTRL control subjects, NIHSS NIH stroke scale, OR odds ratio