Proteomic Biomarker Discovery in Cerebrospinal Fluid for Cerebral Vasospasm Following Subarachnoid Hemorrhage

doi:10.1016/j.jstrokecerebrovasdis.2010.04.004

Journal of Stroke and Cerebrovascular Diseases

Volume 21, Issue 1, January 2012, Pages 30-41

https://doi.org/10.1016/j.jstrokecerebrovasdis.2010.04.004 Get rights and content

Currently, there are no established biomarkers for diagnosing preclinical vasospasm or monitoring its progression. Two areas of extensive biomarker research are neuroimaging and biochemical markers in body fluids, such as cerebrospinal fluid (CSF). We performed a review of studies conducted over the past 2 decades summarizing the science to date and the evolution of CSF biomarkers in subarachnoid hemorrhage (SAH). A Medline search performed using the search terms “subarachnoid hemorrhage marker AND cerebrospinal fluid,” limited to the period January 1, 1990 to June 1, 2009, returned 62 references. Abstracts that did not deal primarily with SAH and potential markers in the CSF of humans were excluded, resulting in 27 abstracts. Only articles providing sufficient information for a substantiated analysis were selected. In addition, articles identified in reference lists of individual articles were selected if considered appropriate. Evidence was classified as class I-IV and recommendations were classified as category A-C according to European Federation of Neurological Societies guidelines. We evaluated CSF markers in SAH patients and divided them into 3 categories: A, markers with auspicious value; B, candidate markers; and C, noncandidate markers. Category A markers included tumor necrosis factor (TNF)-α, soluble tumor necrosis factor receptor I (sTNFR-I), and interleukin (IL)-1 receptor antagonist (IL-1ra), as well as the neurofilament proteins NFL and NfH. Category B markers included apolipoprotein E (ApoE), F2-isoprostane (F2-IsoP), NOx, and the indicators for thrombin activity membrane-bound tissue factor (mTF) and thrombin–antithrombin III complex (TAT) for neurologic outcome prediction, as well as E-selectin, lactate, alpha-II spectrin breakdown products (SBDPs), asymmetric dimethyl-L-arginine (ADMA), and monocyte chemoattractant protein-1 (MCP-1) for vasospasm prognostication. Category C markers included S100B, platelet-derived growth factor (PDGF), YKL-40, chitotriosidase, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and IL-8. Cytokines and their receptors, as well as neuronal intracellular proteins, seem to be potential markers for outcome determination in patients after SAH.

Section snippets

Search Strategy

A Medline search performed using the search terms “subarachnoid hemorrhage marker AND cerebrospinal fluid,” limited to the period January 1990 to June 1, 2009, returned 62 references. This time frame was selected because it correlated with the advent of molecular diagnostic technologies needed to assess biomarker concentrations. Abstracts that did not deal primarily with SAH and potential markers in the CSF of humans (eg, cerebral damage, ischemic cerebrovascular disease, head injury,

Endothelin-1

Endothelin-1 (ET-1) is an important mediator involved in the development of vasospasm. ET-1 concentrations in the CSF of patients after SAH were significantly elevated compared with control groups, consisting mainly of healthy volunteers and patients with another neurologic nonhemorrhagic disease, such as hydrocephalus or degenerative spinal disease.2, 3, 4, 5, 6, 7, 8 In patients who did not develop CV, ET-1 concentrations decreased gradually with time,6, 8 whereas CV patients exhibited a

Conclusion

A considerable amount of literature suggests possible roles for various CSF markers in the pathogenesis and prediction of CV, as well as in the prediction of neurologic outcome after SAH. Those CSF markers that show the most promise, including class I evidence implying prognostic significance, have been discussed individually. In addition to CSF, brain interstitial fluid (ISF) may be an important future source of markers for the study of CV occurring after SAH. Studies using microdialysis

References (45)

M. Brainin et al.
Guidance for the preparation of neurological management guidelines by EFNS scientific task forces: Revised recommendations, 2004
Eur J Neurol
(2004)
K. Fassbender et al.
Endothelin-1 in subarachnoid hemorrhage: An acute-phase reactant produced by cerebrospinal fluid leukocytes
Stroke
(2000)
S. Kastner et al.
Endothelin-1 in plasma, cisternal CSF and microdialysate following aneurysmal SAH
Acta Neurochir (Wien)
(2005)
I.M. Kessler et al.
Endothelin-1 levels in plasma and cerebrospinal fluid of patients with cerebral vasospasm after aneurysmal subarachnoid hemorrhage
Surg Neurol
(2005)
H. Kobayashi et al.
Endothelin-1 levels in plasma and cerebrospinal fluid following subarachnoid hemorrhage
J Clin Neurosci
(1995)
V. Seifert et al.
Endothelin concentrations in patients with aneurysmal subarachnoid hemorrhage: Correlation with cerebral vasospasm, delayed ischemic neurological deficits, and volume of hematoma
J Neurosurg
(1995)
G. Shirakami et al.
Changes of endothelin concentration in cerebrospinal fluid and plasma of patients with aneurysmal subarachnoid hemorrhage
Acta Anaesthesiol Scand
(1994)
K. Suzuki et al.
Endothelin-1 concentration increases in the cerebrospinal fluid in cerebral vasospasm caused by subarachnoid hemorrhage
Surg Neurol
(2000)
R. Suzuki et al.
The role of endothelin-1 in the origin of cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage
J Neurosurg
(1992)
H. Ehrenreich et al.
Long-term monitoring of immunoreactive endothelin-1 and endothelin-3 in ventricular cerebrospinal fluid, plasma, and 24-h urine of patients with subarachnoid hemorrhage
Res Exp Med (Berl)
(1992)

L. Mascia et al.

Temporal relationship between endothelin-1 concentrations and cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage

Stroke

(2001)

M. Zimmermann

Endothelin in cerebral vasospasm: Clinical and experimental results

J Neurosurg Sci

(1997)

P. Gaetani et al.

Endothelin and aneurysmal subarachnoid hemorrhage: A study of subarachnoid cisternal cerebrospinal fluid

J Neurol Neurosurg Psychiatry

(1994)

A. Gruber et al.

Evaluation of big endothelin-1 concentrations in serum and ventricular cerebrospinal fluid after early surgical compared with nonsurgical management of ruptured intracranial aneurysms

Neurosurg Focus

(2000)

T. Mathiesen et al.

Cerebrospinal fluid interleukin-1 receptor antagonist and tumor necrosis factor-alpha following subarachnoid hemorrhage

J Neurosurg

(1997)

A. Gruber et al.

Ventricular cerebrospinal fluid and serum concentrations of sTNFR-I, IL-1ra, and IL-6 after aneurysmal subarachnoid hemorrhage

J Neurosurg Anesthesiol

(2000)

P. Gaetani et al.

Cisternal CSF levels of cytokines after subarachnoid hemorrhage

Neurol Res

(1998)

B. Schoch et al.

Analysis of intrathecal interleukin-6 as a potential predictive factor for vasospasm in subarachnoid hemorrhage

Neurosurgery

(2007)

M.Y. Kaynar et al.

Detection of soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in both cerebrospinal fluid and serum of patients after aneurysmal subarachnoid hemorrhage

J Neurosurg

(2004)

R.S. Polin et al.

Detection of soluble E-selectin, ICAM-1, VCAM-1, and L-selectin in the cerebrospinal fluid of patients after subarachnoid hemorrhage

J Neurosurg

(1998)

R.D. Rothoerl et al.

ICAM-1 and VCAM-1 expression following aneurysmal subarachnoid hemorrhage and their possible role in the pathophysiology of subsequent ischemic deficits

Cerebrovasc Dis

(2006)

T. Tanriverdi et al.

Serum and cerebrospinal fluid concentrations of E-selectin in patients with aneurysmal subarachnoid hemorrhage

Braz J Med Biol Res

(2005)

Cited by (73)

Advances in biomarkers for vasospasm – Towards a future blood-based diagnostic test
2024, World Neurosurgery: X
Cerebral vasospasm and the resultant delayed cerebral infarction is a significant source of mortality following aneurysmal SAH. Vasospasm is currently detected using invasive or expensive imaging at regular intervals in patients following SAH, thus posing a risk of complications following the procedure and financial burden on these patients. Currently, there is no blood-based test to detect vasospasm.
PubMed, Web of Science, and Embase databases were systematically searched to retrieve studies related to cerebral vasospasm, aneurysm rupture, and biomarkers. The study search dated from 1997 to 2022. Data from eligible studies was extracted and then summarized.
Out of the 632 citations screened, only 217 abstracts were selected for further review. Out of those, only 59 full text articles met eligibility and another 13 were excluded.
We summarize the current literature on the mechanism of cerebral vasospasm and delayed cerebral ischemia, specifically studies relating to inflammation, and provide a rationale and commentary on a hypothetical future bloodbased test to detect vasospasm. Efforts should be focused on clinical-translational approaches to create such a test to improve treatment timing and prediction of vasospasm to reduce the incidence of delayed cerebral infarction.
Effect of cerebrospinal fluid drainage on clinical outcomes following aneurysmal subarachnoid hemorrhage
2022, Journal of Clinical Neuroscience
We study the relationship between external ventricular drainage (EVD) of cerebrospinal fluid output and functional outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH).
A retrospective chart review of patients presenting to a single center with aSAH was performed. The primary outcome was good functional outcomes assessed by a composite of the modified Rankin scale (mRS 0–2) at last follow-up. Secondary outcomes were clinical and radiographic vasospasm. For data analysis, multivariable generalized estimating equations adjusting for potential confounders were used.
A total of 119 patients were included; 91 (75.6%) presented with a modified Fisher grade 4 and 76 (63.9%) had hydrocephalus. The median EVD duration was 13 days. On average, most EVDs were set at 15 cmH₂O (50, 42%). Follow-up was available in 109 patients; median time was 10.7 months; 69 (63.3%) had good outcomes. Multivariable analysis showed that EVDs set at 10 cmH₂O had increased odds of good outcomes for every ml increase in the EVD output (OR = 1.02; 95% CI 1.01–1.03; p = 0.001). Post estimation analyses show that EVDs at 10 cmH₂O with output close to 200 ml predicted a 50% probability of good outcomes.
Increased EVD outputs were associated with favorable outcomes at the last follow-up.
Neurovascular disease, diagnosis, and therapy: Subarachnoid hemorrhage and cerebral vasospasm
2021, Handbook of Clinical Neurology
The worldwide incidence of spontaneous subarachnoid hemorrhage is about 6.1 per 100,000 cases per year (Etminan et al., 2019). Eighty-five percent of cases are due to intracranial aneurysms. The mean age of those affected is 55 years, and two-thirds of the patients are female. The prognosis is related mainly to the neurologic condition after the subarachnoid hemorrhage and the age of the patient. Overall, 15% of patients die before reaching the hospital, another 20% die within 30 days, and overall 75% are dead or remain disabled. Case fatality has declined by 17% over the last 3 decades. Despite the improvement in outcome probably due to improved diagnosis, early aneurysm repair, administration of nimodipine, and advanced intensive care support, the outcome is not very good. Even among survivors, 75% have permanent cognitive deficits, mood disorders, fatigue, inability to return to work, and executive dysfunction and are often unable to return to their premorbid level of functioning. The key diagnostic test is computed tomography, and the treatments that are most strongly supported by scientific evidence are to undertake aneurysm repair in a timely fashion by endovascular coiling rather than neurosurgical clipping when feasible and to administer enteral nimodipine. The most common complications are aneurysm rebleeding, hydrocephalus, delayed cerebral ischemia, and medical complications (fever, anemia, and hyperglycemia). Management also probably is optimized by neurologic intensive care units and multidisciplinary teams.
Fingolimod administration improves neurological functions of mice with subarachnoid hemorrhage
2020, Neuroscience Letters
To investigate the brain protective effects of fingolimod on inflammatory response of SAH mice.
We utilized an endovascular mouse perforation model of SAH. Mice were divided into three groups: sham group, SAH group and SAH + Fingolimod group. Mice received either saline or fingolimod (1 mg/kg) intraperitoneally 2 h after sham surgery or SAH. The modified neurological severity score (mNSS) and Morris water maze were respectively used to evaluate the influence of nerve function. Evens blue (EB) extravasation was used to detect the permeability of blood-brain barrier, and water content in brain tissue was also detected. Flow cytometry, ELISA kits and western blotting were used to detect inflammatory factors in brain tissue.
The results showed that compared with SAH group, after treatment, the delay time of locating the hidden platform was shorter. The mNSS results showed that fingolimod improved the behavior of SAH mice. In addition, fingolimod could reduce the water content in brain. Flow cytometry results showed that after 3 d of treatment, fingolimod significantly increased Treg cells and down-regulated NK cells. Western blotting results showed fingolimod inhibited the expression of inflammatory cytokines in brain tissue. ELISA kit results showed that fingolimod could down-regulate IL-6 and TNF-α and up-regulate IL-10 and TGF-β1 in serum.
Fingolimod could regulate the inflammatory response to alleviate SAH-induced brain damage and promote neurological recovery, which provides a new therapeutic strategy for SAH treatment.
Lactate and Lactate Dehydrogenase in Cistern as Biomarkers of Early Brain Injury and Delayed Cerebral Ischemia of Subarachnoid Hemorrhage
2020, Journal of Stroke and Cerebrovascular Diseases
Citation Excerpt :
Delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) involves the combination of early brain injury (EBI), cerebral vasospasm, and cortical spreading depolarization. Several reports have suggested that certain cellular and molecular biomarkers might offer useful predictors of DCI, but no biomarker has yet been validated as a core recommendation.1-8 Lactate is overproduced under anaerobic and aerobic conditions.9,10
Objective: The pathophysiology of delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) has not been fully evaluated. The aim of this study was to evaluate the dynamics of lactate and lactate dehydrogenase (LDH) in carotid cisternal cerebrospinal fluid (CSF), and to discuss their effectiveness as markers of early brain injury (EBI) and DCI following aSAH. Patients and Methods: Among 91 consecutive aSAH patients treated between January 2012 and March 2019 at National Hospital Organization Beppu Medical Center, 19 patients (20.9%) were eligible for this retrospective study. Concentrations of lactate and LDH in carotid cisternal CSF within 14 days after onset of aSAH were evaluated. Results: Six of the 19 patients (31.6%) had a history of DCI. Both lactate and LDH levels in carotid cisternal CSF were significantly higher in the DCI group than in the non-DCI group on postbleeding day (PBD) 1-2, 3-4, and 5-6. Interestingly, neither lactate nor LDH levels in blood differed significantly between DCI and non-DCI groups on PBD 1-2. Conclusions: Lactate and LDH concentrations in carotid cisternal CSF may vividly reflect the EBI and may thus represent predictive biomarkers of DCI following aSAH.
Progressive Shrinkage of Involved Arteries in Parallel with Disease Progression in Moyamoya Disease
2019, World Neurosurgery
Citation Excerpt :
Past studies have reported that platelet-derived growth factor (PDGF)-β associates with cerebral vasospasm; furthermore, the degree of vessel stenosis directly correlates with the temporal expression dynamics of PDGF-β, as shown in a rabbit model of SAH.20 In human patients with SAH, higher PDGF levels predict greater probability of developing cerebral vasospasm.21-23 Considering that arterial shrinkage is a specific finding in MMD and a similar phenomenon has been recognized in cerebral vasospasm, such genetic variants or polymorphisms may play a key role in clarifying the cause of shrinkage in the involved arteries in MMD.
Recent three-dimensional constructive interference in steady state (3D-CISS) studies have shown that the involved arteries decrease not only their own luminal caliber but also outer diameter in moyamoya disease (MMD). This study was aimed to clarify how the outer diameter of the involved arteries serially change during disease progression in MMD using qunatitaive 3D-CISS imaging.
This study included 8 hemispheres of 7 patients with MMD whose Suzuki angiographic stage spontaneously progressed during follow-up. Using 3D-CISS, the outer diameter was quantified serially in supraclinoid portion of internal carotid artery (C1), the horizontal portion of middle and anterior cerebral arteries (M1 and A1, respectively) before and after the spontaneous disease progression, and also 3–12 months later.
In 7 hemispheres with early disease stage (stage 1–3) at initial presentation, the involved arteries decreased in their outer dimater in parallel with luminal stenosis during spontaneous disease progression in the C1 (P = 0.005), M1 (P < 0.0001), and A1 portions (P = 0.0048). In the remaining 1 hemisphere with stage 4 at initial presentation, 3D-CISS imaging showed no significant change in the outer diameter of C1, M1, and A1 segments during disease progression.
Using quantitative 3D-CISS imaging, this study clearly shows that the involved arteries serially decrease in their own outer diameter in parallel with luminal stenosis during spontaneous disease progression in early stages of MMD (stage 1–3). This phenomenon has not been reported previously and may result from the pathognomic mechanisms underlying the development of MMD.

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Original ArticleProteomic Biomarker Discovery in Cerebrospinal Fluid for Cerebral Vasospasm Following Subarachnoid Hemorrhage

Section snippets

Search Strategy

Endothelin-1

Conclusion

Guidance for the preparation of neurological management guidelines by EFNS scientific task forces: Revised recommendations, 2004

Eur J Neurol

Endothelin-1 in subarachnoid hemorrhage: An acute-phase reactant produced by cerebrospinal fluid leukocytes

Stroke

Endothelin-1 in plasma, cisternal CSF and microdialysate following aneurysmal SAH

Acta Neurochir (Wien)

Endothelin-1 levels in plasma and cerebrospinal fluid of patients with cerebral vasospasm after aneurysmal subarachnoid hemorrhage

Surg Neurol

Endothelin-1 levels in plasma and cerebrospinal fluid following subarachnoid hemorrhage

J Clin Neurosci

Endothelin concentrations in patients with aneurysmal subarachnoid hemorrhage: Correlation with cerebral vasospasm, delayed ischemic neurological deficits, and volume of hematoma

J Neurosurg

Changes of endothelin concentration in cerebrospinal fluid and plasma of patients with aneurysmal subarachnoid hemorrhage

Acta Anaesthesiol Scand

Endothelin-1 concentration increases in the cerebrospinal fluid in cerebral vasospasm caused by subarachnoid hemorrhage

Surg Neurol

The role of endothelin-1 in the origin of cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage

J Neurosurg

Long-term monitoring of immunoreactive endothelin-1 and endothelin-3 in ventricular cerebrospinal fluid, plasma, and 24-h urine of patients with subarachnoid hemorrhage

Res Exp Med (Berl)

Temporal relationship between endothelin-1 concentrations and cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage

Stroke

Endothelin in cerebral vasospasm: Clinical and experimental results

J Neurosurg Sci

Endothelin and aneurysmal subarachnoid hemorrhage: A study of subarachnoid cisternal cerebrospinal fluid

J Neurol Neurosurg Psychiatry

Evaluation of big endothelin-1 concentrations in serum and ventricular cerebrospinal fluid after early surgical compared with nonsurgical management of ruptured intracranial aneurysms

Neurosurg Focus

Cerebrospinal fluid interleukin-1 receptor antagonist and tumor necrosis factor-alpha following subarachnoid hemorrhage

J Neurosurg

Ventricular cerebrospinal fluid and serum concentrations of sTNFR-I, IL-1ra, and IL-6 after aneurysmal subarachnoid hemorrhage

J Neurosurg Anesthesiol

Cisternal CSF levels of cytokines after subarachnoid hemorrhage

Neurol Res

Analysis of intrathecal interleukin-6 as a potential predictive factor for vasospasm in subarachnoid hemorrhage

Neurosurgery

Detection of soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in both cerebrospinal fluid and serum of patients after aneurysmal subarachnoid hemorrhage

J Neurosurg

Detection of soluble E-selectin, ICAM-1, VCAM-1, and L-selectin in the cerebrospinal fluid of patients after subarachnoid hemorrhage

J Neurosurg

ICAM-1 and VCAM-1 expression following aneurysmal subarachnoid hemorrhage and their possible role in the pathophysiology of subsequent ischemic deficits

Cerebrovasc Dis

Serum and cerebrospinal fluid concentrations of E-selectin in patients with aneurysmal subarachnoid hemorrhage

Braz J Med Biol Res

Original Article
Proteomic Biomarker Discovery in Cerebrospinal Fluid for Cerebral Vasospasm Following Subarachnoid Hemorrhage