Correlation between early neurological deterioration and serum neurite guidance factor-1 level after acute ischemic stroke_West China Medical Journal

Authors：

CHEN Zhuo ¹ , YI Xin ¹ , FU Wei ¹ , YOU Zhike ¹ , ZHOU Qi ¹ , ZENG Yang ¹ , ZHONG Xingju ¹ , WU Yong ¹ , FAN Chaoli ¹ , JIANG Yu ¹ , PENG Jie ¹ , LIAO Jieyu ¹ ,  XIANG Bin ²

1. Department of Neurology, Mianzhu People’s Hospital, Mianzhu, Sichuan 618200, P. R. China;
2. Department of Orthopedics, Mianzhu People’s Hospital, Mianzhu, Sichuan 618200, P. R. China;

Corresponding?author：

XIANG Bin, Email: 271601846@163.com

Keywords：

Acute ischemic stroke; early neurological deterioration; biomarker; neurite guidance factor-1

DOI：

10.7507/1002-0179.202508241

Video：

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Objective To clarify whether neurite guidance factor-1 (Netrin-1) can serve as a potential biomarker for early neurofunctional deterioration (END) risk assessment after acute ischemic stroke (AIS), providing a basis for early identification of high-risk patients in clinical practice. Methods AIS patients admitted to the Neurology Department of Mianzhu People’s Hospital between July 2022 and June 2024 with symptoms occurring within 24 hours of admission were included. At admission, the patient’s serum Netrin-1 level was measured and NIHSS scoring was performed. Within 3 days after admission, NIHSS scoring was performed 1-3 times a day to determine whether the patient had END based on the increase in NIHSS score compared to baseline, patients were categorized into END2 and END4 groups. Results A total of 384 patients were included, including 212 males, 172 females, with an average age of (63.10±9.39) years. The median level of serum Netrin-1 was 466.35 (342.85, 589.23) pg/mL. Within 72 hours after admission, 122 cases (31.8%) developed END2 and 75 cases (19.5%) developed END4. Multivariate logistic regression analysis showed that a decrease in Netrin-1 levels was an independent risk factor for END2 and END4 (P＜0.05). Conclusion The decrease in serum Netrin-1 levels is significantly correlated with an increased risk of END within 72 hours after ischemic stroke, suggesting that Netrin-1 may serve as a biological indicator for assessing END risk in patients with ischemic stroke.

Citation： CHEN Zhuo, YI Xin, FU Wei, YOU Zhike, ZHOU Qi, ZENG Yang, ZHONG Xingju, WU Yong, FAN Chaoli, JIANG Yu, PENG Jie, LIAO Jieyu, XIANG Bin. Correlation between early neurological deterioration and serum neurite guidance factor-1 level after acute ischemic stroke. West China Medical Journal, 2026, 41(4): 593-598. doi: 10.7507/1002-0179.202508241 Copy

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2.	Siegler JE, Martin-Schild S. Early neurological deterioration (END) after stroke: the END depends on the definitions. Int J Stroke, 2011, 6(3): 211-212.
3.	Thanvi B, Treadwell S, Robinson T. Early neurological deterioration in acute ischaemic stroke: predictors, mechanisms and management. Postgrad Med J, 2008, 84(994): 412-417.
4.	Zhang X, Sun Z, Ding C, et al. Metabolic syndrome augments the risk of early neurological deterioration in acute ischemic stroke patients independent of inlammatory mediators: a hospital-based prospective study. Oxid Med Cell Longev, 2016: 8346301.
5.	Dávalos A, Toni D, Iweins F, et al. Neurological deterioration in acute ischemic stroke: potential predictors and associated factors in the European cooperative acute stroke study (ECASS) I. Stroke, 1999, 30(12): 2631-2636.
6.	Yang P, Zhang Y, Zhang L, et al. Endovascular thrombectomy with or without intravenous alteplase in acute stroke. N Engl J Med, 2020, 382(21): 1981-1993.
7.	Helbok R, Kurtz P, Vibbert M, et al. Early neurological deterioration after subarachnoid haemorrhage: risk factors and impact on outcome. J Neurol Neurosurg Psychiatry, 2013, 84(3): 266-270.
8.	Rajasekharan S, Kennedy TE. The netrin protein family. Genome Biol, 2009, 10(9): 239.
9.	Moore SW, Tessier-Lavigne M, Kennedy TE. Netrins and their receptors. Adv Exp Med Biol, 2007, 621: 17-31.
10.	Huber AB, Kolodkin AL, Ginty DD, et al. Signaling at the growth cone: ligand-receptor complexes and the control of axon growth and guidance. Annu Rev Neurosci, 2003, 26: 509-563.
11.	Podjaski C, Alvarez JI, Bourbonniere L, et al. Netrin 1 regulates blood-brain barrier function and neuroinlammation. Brain, 2015, 138 (Pt 6): 1598-1612.
12.	Liao SJ, Gong Q, Chen XR, et al. Netrin-1 rescues neuron loss by attenuating secondary apoptosis in ipsilateral thalamic nucleus following focal cerebral infarction in hypertensive rats. Neuroscience, 2013, 231: 225-232.
13.	Yu J, Li C, Ding Q, et al. Netrin-1 Ameliorates blood- brain barrier impairment secondary to ischemic stroke via the activation of PI3K pathway. Front Neurosci, 2017, 11: 700.
14.	Sun H, Le T, Chang TT, et al. AAV-mediated netrin-1 overexpression increases peri-infarct blood vessel density and improves motor function recovery after experimental stroke. Neurobiol Dis, 2011, 44(1): 73-83.
15.	Guo D, Zhu Z, Zhong C, et al. Increased serum netrin-1 is associated with improved prognosis of ischemic stroke. Stroke, 2019, 50(4): 845-852.
16.	Chen Z, Cao T, Zhong X, et al. Decreased serum netrin-1 as a predictor for post-stroke depression in Chinese patients with acute ischemic stroke. J Stroke Cerebrovasc Dis, 2020, 29(10): 105149.
17.	Stroke--1989. Recommendations on stroke prevention, diagnosis, and therapy. Report of the WHO task force on stroke and other cerebrovascular disorders. Stroke, 1989, 20 (10): 1407-1431.
18.	Brott T, Adams HP Jr, Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke, 1989, 20(7): 864-870.
19.	Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classiication of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke, 1993, 24(1): 35-41.
20.	Sun W, Liu W, Zhang Z, et al. Asymmetrical cortical vessel sign on susceptibility-weighted imaging: a novel imaging marker for early neurological deterioration and unfavorable prognosis. EurJ Neurol, 2014, 21(11): 1411-1418.
21.	Alawneh JA, Moustafa RR, Baron JC. Hemodynamic factors and perfusion abnormalities in early neurological deterioration. Stroke, 2009, 40(6): e443-e450.
22.	Kim JM, Bae JH, Park KY, et al. Incidence and mechanism of early neurological deterioration after endovascular thrombectomy.J Neurol, 2019, 266(3): 609-615.
23.	Chen JL, Yuan DH, Yang SJ, et al. Serum netrin-1 serves as a prognostic biomarker of aneurysmal subarachnoid hemorrhage. Clin Chim Acta, 2019, 495: 294-300.
24.	Lou XH, Cai YY, Yang XQ, et al. Serum netrin-1 concentrations are associated with clinical outcome in acute intracerebral hemorrhage. Clin Chim Acta, 2020, 508: 154-160.
25.	Mu?oz JC, Martín R, Alonso C, et al. Relation between serum levels of chemotaxis-related factors and the presence of coronary artery calciication as expression of subclinical atherosclerosis. Clin Biochem, 2017, 50(18): 1048-1055.
26.	Liu C, Ke X, Wang Y, et al. The level of netrin-1 is decreased in newly diagnosed type 2 diabetes mellitus patients. BMC Endocr Disord, 2016, 16(1): 33.
27.	Lu H, Wang Y, He X, et al. Netrin-1 hyperexpression in mouse brain promotes angiogenesis and long-term neurological recovery after transient focal ischemia. Stroke, 2012, 43(3): 838-843.
28.	Khan JA, Cao M, Kang BY, et al. Systemic human Netrin-1 gene delivery by adeno-associated virus type 8 alters leukocyte accumulation and atherogenesis in vivo. Gene Ther, 2011, 18:437-444.

1. GBD 2016 Stroke Collaborators. Global, regional, and national burden of stroke, 1990-2016: a systematic analysis for the global burden of disease study 2016. Lancet Neurol, 2019, 18(5): 439-458.
2. Siegler JE, Martin-Schild S. Early neurological deterioration (END) after stroke: the END depends on the definitions. Int J Stroke, 2011, 6(3): 211-212.
3. Thanvi B, Treadwell S, Robinson T. Early neurological deterioration in acute ischaemic stroke: predictors, mechanisms and management. Postgrad Med J, 2008, 84(994): 412-417.
4. Zhang X, Sun Z, Ding C, et al. Metabolic syndrome augments the risk of early neurological deterioration in acute ischemic stroke patients independent of inlammatory mediators: a hospital-based prospective study. Oxid Med Cell Longev, 2016: 8346301.
5. Dávalos A, Toni D, Iweins F, et al. Neurological deterioration in acute ischemic stroke: potential predictors and associated factors in the European cooperative acute stroke study (ECASS) I. Stroke, 1999, 30(12): 2631-2636.
6. Yang P, Zhang Y, Zhang L, et al. Endovascular thrombectomy with or without intravenous alteplase in acute stroke. N Engl J Med, 2020, 382(21): 1981-1993.
7. Helbok R, Kurtz P, Vibbert M, et al. Early neurological deterioration after subarachnoid haemorrhage: risk factors and impact on outcome. J Neurol Neurosurg Psychiatry, 2013, 84(3): 266-270.
8. Rajasekharan S, Kennedy TE. The netrin protein family. Genome Biol, 2009, 10(9): 239.
9. Moore SW, Tessier-Lavigne M, Kennedy TE. Netrins and their receptors. Adv Exp Med Biol, 2007, 621: 17-31.
10. Huber AB, Kolodkin AL, Ginty DD, et al. Signaling at the growth cone: ligand-receptor complexes and the control of axon growth and guidance. Annu Rev Neurosci, 2003, 26: 509-563.
11. Podjaski C, Alvarez JI, Bourbonniere L, et al. Netrin 1 regulates blood-brain barrier function and neuroinlammation. Brain, 2015, 138 (Pt 6): 1598-1612.
12. Liao SJ, Gong Q, Chen XR, et al. Netrin-1 rescues neuron loss by attenuating secondary apoptosis in ipsilateral thalamic nucleus following focal cerebral infarction in hypertensive rats. Neuroscience, 2013, 231: 225-232.
13. Yu J, Li C, Ding Q, et al. Netrin-1 Ameliorates blood- brain barrier impairment secondary to ischemic stroke via the activation of PI3K pathway. Front Neurosci, 2017, 11: 700.
14. Sun H, Le T, Chang TT, et al. AAV-mediated netrin-1 overexpression increases peri-infarct blood vessel density and improves motor function recovery after experimental stroke. Neurobiol Dis, 2011, 44(1): 73-83.
15. Guo D, Zhu Z, Zhong C, et al. Increased serum netrin-1 is associated with improved prognosis of ischemic stroke. Stroke, 2019, 50(4): 845-852.
16. Chen Z, Cao T, Zhong X, et al. Decreased serum netrin-1 as a predictor for post-stroke depression in Chinese patients with acute ischemic stroke. J Stroke Cerebrovasc Dis, 2020, 29(10): 105149.
17. Stroke--1989. Recommendations on stroke prevention, diagnosis, and therapy. Report of the WHO task force on stroke and other cerebrovascular disorders. Stroke, 1989, 20 (10): 1407-1431.
18. Brott T, Adams HP Jr, Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke, 1989, 20(7): 864-870.
19. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classiication of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke, 1993, 24(1): 35-41.
20. Sun W, Liu W, Zhang Z, et al. Asymmetrical cortical vessel sign on susceptibility-weighted imaging: a novel imaging marker for early neurological deterioration and unfavorable prognosis. EurJ Neurol, 2014, 21(11): 1411-1418.
21. Alawneh JA, Moustafa RR, Baron JC. Hemodynamic factors and perfusion abnormalities in early neurological deterioration. Stroke, 2009, 40(6): e443-e450.
22. Kim JM, Bae JH, Park KY, et al. Incidence and mechanism of early neurological deterioration after endovascular thrombectomy.J Neurol, 2019, 266(3): 609-615.
23. Chen JL, Yuan DH, Yang SJ, et al. Serum netrin-1 serves as a prognostic biomarker of aneurysmal subarachnoid hemorrhage. Clin Chim Acta, 2019, 495: 294-300.
24. Lou XH, Cai YY, Yang XQ, et al. Serum netrin-1 concentrations are associated with clinical outcome in acute intracerebral hemorrhage. Clin Chim Acta, 2020, 508: 154-160.
25. Mu?oz JC, Martín R, Alonso C, et al. Relation between serum levels of chemotaxis-related factors and the presence of coronary artery calciication as expression of subclinical atherosclerosis. Clin Biochem, 2017, 50(18): 1048-1055.
26. Liu C, Ke X, Wang Y, et al. The level of netrin-1 is decreased in newly diagnosed type 2 diabetes mellitus patients. BMC Endocr Disord, 2016, 16(1): 33.
27. Lu H, Wang Y, He X, et al. Netrin-1 hyperexpression in mouse brain promotes angiogenesis and long-term neurological recovery after transient focal ischemia. Stroke, 2012, 43(3): 838-843.
28. Khan JA, Cao M, Kang BY, et al. Systemic human Netrin-1 gene delivery by adeno-associated virus type 8 alters leukocyte accumulation and atherogenesis in vivo. Gene Ther, 2011, 18:437-444.

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Correlation between early neurological deterioration and serum neurite guidance factor-1 level after acute ischemic stroke

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