Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Plasma Endostatin Levels at Acute Phase of Ischemic Stroke Are Associated with Post-Stroke Cognitive Impairment

  • 25 Accesses

Abstract

The effect of plasma endostatin on cognitive impairment after ischemic stroke remains unclear. We conducted this study to explore the association between plasma endostatin in the acute phase of ischemic stroke and post-stroke cognitive impairment (PSCI). Baseline plasma endostatin levels were measured, and cognitive function status was assessed by Montreal cognitive assessment at 3 months among 613 ischemic stroke patients. PSCI was defined as Montreal cognitive assessment score less than 26. The association of endostatin with PSCI was analyzed by logistic regression model. The receiver operating characteristic curve was applied to explore the optimal cutoff value of plasma endostatin levels in predicting PSCI. In a multivariable-adjusted model, the odds ratio for the highest vs lowest quartile of endostatin was 2.01 (95% CI, 1.15–3.53) for PSCI. Restricted cubic spline regression model showed a linear dose-response association between endostatin and PSCI (p for linearity = 0.01). The optimal cut point of endostatin was 84.22 ng/mL; higher endostatin levels (≥ 84.22 ng/mL) were associated with increased risk of 2.17-fold for PSCI (adjusted odds ratio, 2.17; 95% CI, 1.44–3.26; p = 0.0002). Furthermore, adding endostatin to a model containing conventional factors led to significant reclassification for PSCI (net reclassification improvement, 0.20; p = 0.025; integrated discrimination improvement, 0.016; p = 0.002). Our findings showed that elevated plasma endostatin levels were associated with cognitive impairment at 3 months after acute ischemic stroke, independently of established conventional risk factors, suggesting that endostatin may be an important biomarker of cognitive impairment after ischemic stroke.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3

References

  1. Almeida OP, Ford AH, Flicker L, Hankey GJ, Yeap BB, Clancy P, Golledge J (2014) Angiogenesis inhibition and depression in older men. J Psychiatry Neurosci 39:200–205

  2. Arenillas JF, Alvarez-Sabin J, Montaner J, Rosell A, Molina CA, Rovira A, Ribo M, Sanchez E, Quintana M (2005) Angiogenesis in symptomatic intracranial atherosclerosis: predominance of the inhibitor endostatin is related to a greater extent and risk of recurrence. Stroke 36:92–97. https://doi.org/10.1161/01.STR.0000149617.65372.5d

  3. Arnlov J, Ruge T, Ingelsson E, Larsson A, Sundstrom J, Lind L (2013) Serum endostatin and risk of mortality in the elderly: findings from 2 community-based cohorts. Arterioscler Thromb Vasc Biol 33:2689–2695. https://doi.org/10.1161/ATVBAHA.113.301704

  4. Bustamante A, Lopez-Cancio E, Pich S, Penalba A, Giralt D, Garcia-Berrocoso T, Ferrer-Costa C, Gasull T, Hernandez-Perez M, Millan M, Rubiera M, Cardona P, Cano L, Quesada H, Terceno M, Silva Y, Castellanos M, Garces M, Reverte S, Ustrell X, Mares R, Baiges JJ, Serena J, Rubio F, Salas E, Davalos A, Montaner J (2017) Blood biomarkers for the early diagnosis of stroke: the stroke-chip study. Stroke 48:2419–2425. https://doi.org/10.1161/strokeaha.117.017076

  5. Carlsson AC, Ruge T, Sundstrom J, Ingelsson E, Larsson A, Lind L, Arnlov J (2013) Association between circulating endostatin, hypertension duration, and hypertensive target-organ damage. Hypertension 62:1146–1151. https://doi.org/10.1161/HYPERTENSIONAHA.113.02250

  6. Deininger MH, Fimmen BA, Thal DR, Schluesener HJ, Meyermann R (2002) Aberrant neuronal and paracellular deposition of endostatin in brains of patients with Alzheimer's disease. J Neurosci 22:10621–10626

  7. Faye C, Chautard E, Olsen BR, Ricard-Blum S (2009) The first draft of the endostatin interaction network. J Biol Chem 284:22041–22047. https://doi.org/10.1074/jbc.M109.002964

  8. Fujiyoshi K, Yamaoka-Tojo M, Minami Y, Kutsuna T, Obara S, Kakizaki R, Nemoto T, Hashimoto T, Namba S, Shimohama T, Tojo T, Ako J (2018) Endothelial dysfunction is associated with cognitive impairment of elderly cardiovascular disease patients. Int Heart J 59:1034–1040. https://doi.org/10.1536/ihj.17-610

  9. He J, Zhang Y, Xu T, Zhao Q, Wang D, Chen CS, Tong W, Liu C, Xu T, Ju Z, Peng Y, Peng H, Li Q, Geng D, Zhang J, Li D, Zhang F, Guo L, Sun Y, Wang X, Cui Y, Li Y, Ma D, Yang G, Gao Y, Yuan X, Bazzano LA, Chen J, Investigators C (2014) Effects of immediate blood pressure reduction on death and major disability in patients with acute ischemic stroke: the CATIS randomized clinical trial. JAMA 311:479–489. https://doi.org/10.1001/jama.2013.282543

  10. Kanbay M, Afsar B, Siriopol D, Unal HU, Karaman M, Saglam M, Gezer M, Tas A, Eyileten T, Guler AK, Aydin I, Oguz Y, Tarim K, Covic A, Yilmaz MI (2016) Endostatin in chronic kidney disease: associations with inflammation, vascular abnormalities, cardiovascular events and survival. Eur J Intern Med 33:81–87. https://doi.org/10.1016/j.ejim.2016.06.033

  11. Machuca-Parra AI, Bigger-Allen AA, Sanchez AV, Boutabla A, Cardona-Velez J, Amarnani D, Saint-Geniez M, Siebel CW, Kim LA, D'Amore PA, Arboleda-Velasquez JF (2017) Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL. J Exp Med 214:2271–2282. https://doi.org/10.1084/jem.20161715

  12. Mijajlovic MD, Pavlovic A, Brainin M, Heiss WD, Quinn TJ, Ihle-Hansen HB, Hermann DM, Assayag EB, Richard E, Thiel A, Kliper E, Shin YI, Kim YH, Choi S, Jung S, Lee YB, Sinanovic O, Levine DA, Schlesinger I, Mead G, Milosevic V, Leys D, Hagberg G, Ursin MH, Teuschl Y, Prokopenko S, Mozheyko E, Bezdenezhnykh A, Matz K, Aleksic V, Muresanu D, Korczyn AD, Bornstein NM (2017) Post-stroke dementia - a comprehensive review. BMC Med 15:11. https://doi.org/10.1186/s12916-017-0779-7

  13. Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H (2005) The Montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 53:695–699. https://doi.org/10.1111/j.1532-5415.2005.53221.x

  14. Navarro-Sobrino M, Rosell A, Hernandez-Guillamon M, Penalba A, Boada C, Domingues-Montanari S, Ribo M, Alvarez-Sabin J, Montaner J (2011) A large screening of angiogenesis biomarkers and their association with neurological outcome after ischemic stroke. Atherosclerosis 216:205–211. https://doi.org/10.1016/j.atherosclerosis.2011.01.030

  15. O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277–285

  16. Pendlebury ST, Cuthbertson FC, Welch SJ, Mehta Z, Rothwell PM (2010) Underestimation of cognitive impairment by mini-mental state examination versus the Montreal cognitive assessment in patients with transient ischemic attack and stroke: a population-based study. Stroke 41:1290–1293. https://doi.org/10.1161/STROKEAHA.110.579888

  17. Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves JW, Hill MN, Jones DH, Kurtz T, Sheps SG, Roccella EJ (2005) Recommendations for blood pressure measurement in humans: an AHA scientific statement from the council on high blood pressure research professional and public education subcommittee. J Clin Hypertens (Greenwich) 7:102–109

  18. Primo V, Graham M, Bigger-Allen AA, Chick JM, Ospina C, Quiroz YT, Manent J, Gygi SP, Lopera F, D'Amore PA, Arboleda-Velasquez JF (2016) Blood biomarkers in a mouse model of CADASIL. Brain Res 1644:118–126. https://doi.org/10.1016/j.brainres.2016.05.008

  19. Qu Y, Zhuo L, Li N, Hu Y, Chen W, Zhou Y, Wang J, Tao Q, Hu J, Nie X, Zhan S (2015) Prevalence of post-stroke cognitive impairment in China: a community-based, cross-sectional study. PLoS One 10:e0122864. https://doi.org/10.1371/journal.pone.0122864

  20. Ruge T, Carlsson AC, Kjoller E, Hilden J, Kolmos HJ, Sajadieh A, Kastrup J, Jensen GB, Larsson A, Nowak C, Jakobsen JC, Winkel P, Gluud C, Arnlov J (2019) Circulating endostatin as a risk factor for cardiovascular events in patients with stable coronary heart disease: a CLARICOR trial sub-study. Atherosclerosis 284:202–208. https://doi.org/10.1016/j.atherosclerosis.2019.02.031

  21. Salza R, Oudart JB, Ramont L, Maquart FX, Bakchine S, Thoannes H, Ricard-Blum S (2015) Endostatin level in cerebrospinal fluid of patients with Alzheimer's disease. J Alzheimers Dis 44:1253–1261. https://doi.org/10.3233/JAD-142544

  22. Swartz RH, Bayley M, Lanctot KL, Murray BJ, Cayley ML, Lien K, Sicard MN, Thorpe KE, Dowlatshahi D, Mandzia JL, Casaubon LK, Saposnik G, Perez Y, Sahlas DJ, Herrmann N (2016) Post-stroke depression, obstructive sleep apnea, and cognitive impairment: rationale for, and barriers to, routine screening. Int J Stroke 11:509–518. https://doi.org/10.1177/1747493016641968

  23. Tian HL, Chen H, Cui YH, Xu T, Zhou LF (2007) Increased protein and mRNA expression of endostatin in the ischemic brain tissue of rabbits after middle cerebral artery occlusion. Neurosci Bull 23:35–40. https://doi.org/10.1007/s12264-007-0005-2

  24. Tikka S, Baumann M, Siitonen M, Pasanen P, Poyhonen M, Myllykangas L, Viitanen M, Fukutake T, Cognat E, Joutel A, Kalimo H (2014) CADASIL and CARASIL. Brain Pathol 24:525–544. https://doi.org/10.1111/bpa.12181

  25. Walia A, Yang JF, Huang YH, Rosenblatt MI, Chang JH, Azar DT (2015) Endostatin’s emerging roles in angiogenesis, lymphangiogenesis, disease, and clinical applications. Biochim Biophys Acta 1850:2422–2438. https://doi.org/10.1016/j.bbagen.2015.09.007

  26. Wang L, Wang F, Liu S, Yang X, Yang J, Ming D (2018) VEGF attenuates 2-VO induced cognitive impairment and neuronal injury associated with the activation of PI3K/Akt and Notch1 pathway. Exp Gerontol 102:93–100. https://doi.org/10.1016/j.exger.2017.12.010

  27. Xue L, Chen H, Zhang T, Chen J, Geng Z, Zhao Y (2017) Changes in serum vascular endothelial growth factor and endostatin concentrations associated with circulating endothelial progenitor cells after acute ischemic stroke. Metab Brain Dis 32:641–648. https://doi.org/10.1007/s11011-017-9953-z

  28. Yang J, Yao Y, Chen T, Zhang T (2014) VEGF ameliorates cognitive impairment in in vivo and in vitro ischemia via improving neuronal viability and function. NeuroMolecular Med 16:376–388. https://doi.org/10.1007/s12017-013-8284-4

  29. Zhang C, Qian S, Zhang R, Guo D, Wang A, Peng Y, Peng H, Li Q, Ju Z, Geng D, Chen J, Zhang Y, He J, Zhong C, Xu T (2019) Endostatin as a novel prognostic biomarker in acute ischemic stroke. Atherosclerosis 293:42–48. https://doi.org/10.1016/j.atherosclerosis.2019.11.032

  30. Zhong C, Bu X, Xu T, Guo L, Wang X, Zhang J, Cui Y, Li D, Zhang J, Ju Z, Chen CS, Chen J, Zhang Y, He J (2018) Serum matrix Metalloproteinase-9 and cognitive impairment after acute ischemic stroke. J Am Heart Assoc 7. https://doi.org/10.1161/JAHA.117.007776

  31. Zhou M, Wang H, Zeng X, Yin P, Zhu J, Chen W, Li X, Wang L, Wang L, Liu Y, Liu J, Zhang M, Qi J, Yu S, Afshin A, Gakidou E, Glenn S, Krish VS, Miller-Petrie MK, Mountjoy-Venning WC, Mullany EC, Redford SB, Liu H, Naghavi M, Hay SI, Wang L, Murray CJL, Liang X (2019) Mortality, morbidity, and risk factors in China and its provinces, 1990-2017: a systematic analysis for the global burden of disease study 2017. Lancet. https://doi.org/10.1016/s0140-6736(19)30427-1

Download references

Acknowledgments

We thank the study participants and their relatives and the clinical staff at all participating hospitals for their support and contribution to this project.

Funding

This study was supported by the National Natural Science Foundation of China (grant: 81773522); Undergraduate Training Program for Innovation and Entrepreneurship, Soochow University (grant: 201910285131Y); and a Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions, China; Tulane University and Collins C. Diboll Private Foundation, both in New Orleans, LA.

Author information

Correspondence to Tan Xu or Chongke Zhong.

Ethics declarations

This study was approved by the ethical committee at Soochow University in China and Tulane University in the USA, as well as ethical committees at the participating hospitals. All participants provided written informed consent. The CATIS trial was registered at clinicaltrials.gov (NCT01840072).

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

ESM1

(PDF 131 kb).

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Qian, S., Li, R., Zhang, C. et al. Plasma Endostatin Levels at Acute Phase of Ischemic Stroke Are Associated with Post-Stroke Cognitive Impairment. Neurotox Res (2020). https://doi.org/10.1007/s12640-020-00173-5

Download citation

Keywords

  • Cognitive impairment
  • Ischemic stroke
  • Endostatin
  • Montreal cognitive assessment