Table 2.

Studies indicating the biomarker potential of HMGB1 after SAH.

S.N.	Study Type	Study Design	HMGB1 Levels	Observations	References
1	Clinical investigation with aneurysmal SAH patients (n = 53)	Retrospective observational study	Serum	Serum HMGB1 levels were elevated in SAH patients from day 1 and remained elevated until day 13 in patients developing cerebral vasospasm reflecting a biomarker potential.	[90]
2	A human study with aneurysmal SAH and controls (n = 40)	CSF was collected 7 days post-SAH and functional outcome was assessed using GOS.	CSF	Elevated CSF HMGB1 levels were independently correlated with the unfavorable outcome at three months after SAH.	[91]
3	Clinical study with aneurysmal SAH patients (n = 149) and healthy controls (n = 50)	Prospective, 2-center study evaluating C/G HMGB1 SNP rs2249825.	Protein	The presence of minor allele G of rs2249825 was correlated with a higher risk of DCI, or cerebral infarction after aneurysmal SAH reflecting an up-regulated expression of HMGB1 protein.	[92]
4	Clinical investigation with aneurysmal SAH patients (n = 47)	Prospective population-based study	Plasma	Plasma concentration of HMGB1 detected during the early 24 h was not correlated with the neurological outcome. In addition, as suggested by the linear regression analysis no correlation between HMGB1 levels and neurological outcome was observed during the follow up (first 5 days).	[89]
5	A clinical study with aneurysmal SAH patients (n = 10) and healthy controls (n = 8)	The subjects were followed until death (endpoint) or 3 months post-SAH. The primary outcome was the functional state as determined by the GOS score and secondary outcome was mortality (in-hospital).	CSF	HMGB1 (CSF) levels were up-regulated in the SAH patients when compared to normal controls where initial levels and gradual changes in HMGB1 levels (CSF) were associated with neurological outcomes.	[93]
6	A clinical study with aneurysmal SAH patients (n = 347) and healthy controls (n = 150)	The study endpoints were mortality after 1 year, mortality in-hospital, cerebrovasospasm and poor functional outcome following 1 year.	Plasma	Plasma levels of HMGB1 were elevated in SAH patients as compared to healthy controls. HMGB1 levels (plasma) were correlated with the poor functional outcome and mortality after 1 year, in-hospital mortality and cerebrovasospasm as determined by multivariate analysis.	[88]
7	A clinical study with SAH patients (n = 9) and healthy controls (n = 7)		CSF	Compared to SAH patients, HMGB1 expression was below the level of detection in the CSF of control subjects reflecting that HMGB1 release might be specific to brain injury. HMGB1 levels (CSF) were retrospectively associated with the neurological outcome, as determined by the Hunt and Hess grading scale.	[94]
8	Human studies with SAH populations (n = 39) and controls (13)	Samples (CSF) were taken on days 3, 7, and 14 after admission.	CSF	HMGB1 (CSF) levels were elevated in patients with unfavorable outcomes after SAH, reflecting a role in brain damage post-SAH.	[95]

SAH, Subarachnoid hemorrhage; HMGB1, High mobility group box-1; CSF, Cerebrospinal fluid; GOS, Glasgow outcome scale; SNP, Single-nucleotide-polymorphism.