Phosphodiesterase 4D Single-nucleotide Polymorphism 83 and Cognitive Dysfunction in Carotid Endarterectomy Patients

Overview

Journal Neurosurgery

Specialty Neurosurgery

Date 2013 Jul 19

PMID 23863764

Citations 3

Authors

Eric J Heyer

Joanna L Mergeche

Justin T Ward

Hani R Malone

Christopher Kellner

Samuel S Bruce

E Sander Connolly

Affiliations

Soon will be listed here.

Abstract

Background: Phosphodiesterase 4D (PDE4D), through the regulation of cyclic AMP, modulates inflammation and other processes that affect atherosclerosis and stroke. A PDE4D polymorphism, single-nucleotide polymorphism (SNP) 83 (rs966221), is associated with ischemic stroke. The association of SNP 83 with postoperative cognitive dysfunction has never been investigated.

Objective: To determine whether SNP 83 is associated with cognitive dysfunction 1 day and 1 month following carotid endarterectomy (CEA).

Methods: Three hundred fourteen patients with high-grade carotid stenosis scheduled for CEA consented to participate in this single-center cohort study of cognitive dysfunction.

Results: Patients with the C/C genotype of SNP 83 exhibited significantly more cognitive dysfunction at 1 day (29.7%) than the C/T (15.8%, P = .008) and T/T (12.7%, P = .01) genotypes. In a multivariate logistic regression model, C/T and T/T genotypes were both associated with significantly decreased odds of cognitive dysfunction compared with the C/C genotype (odds ratio, 0.45 [0.24-0.83], P = .01 and odds ratio, 0.33 [0.12-0.77], P = .02). There were no significant associations at 1 month.

Conclusion: The C/C genotype of SNP 83 is significantly associated with the highest incidence of cognitive dysfunction 1 day following CEA in comparison with the C/T and T/T genotypes. This PDE4D genotype may lead to accelerated cyclic AMP degradation and subsequently elevated inflammation 1 day after CEA. These observations, in conjunction with previous studies, suggest that elevated inflammatory states may be partially responsible for the development of cognitive dysfunction after CEA, but more investigation is required.

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References

Moller J, Cluitmans P, Rasmussen L, Houx P, Rasmussen H, Canet J . Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet. 1998; 351(9106):857-61. DOI: 10.1016/s0140-6736(97)07382-0. View

Woo D, Kaushal R, Kissela B, Sekar P, Wolujewicz M, Pal P . Association of Phosphodiesterase 4D with ischemic stroke: a population-based case-control study. Stroke. 2005; 37(2):371-6. DOI: 10.1161/01.STR.0000198843.72824.0a. View

Rasmussen L . Postoperative cognitive dysfunction: incidence and prevention. Best Pract Res Clin Anaesthesiol. 2006; 20(2):315-30. DOI: 10.1016/j.bpa.2005.10.011. View

Gigante P, Kotchetkov I, Kellner C, Haque R, Ducruet A, Hwang B . Polymorphisms in complement component 3 (C3F) and complement factor H (Y402H) increase the risk of postoperative neurocognitive dysfunction following carotid endarterectomy. J Neurol Neurosurg Psychiatry. 2010; 82(3):247-53. PMC: 3245519. DOI: 10.1136/jnnp.2010.211144. View

Banner K, Trevethick M . PDE4 inhibition: a novel approach for the treatment of inflammatory bowel disease. Trends Pharmacol Sci. 2004; 25(8):430-6. DOI: 10.1016/j.tips.2004.06.008. View

Heyer E, Mergeche J, Bruce S, Connolly E . Inflammation and cognitive dysfunction in type 2 diabetic carotid endarterectomy patients. Diabetes Care. 2013; 36(10):3283-6. PMC: 3781521. DOI: 10.2337/dc12-2507. View

Heyer E, Sharma R, Rampersad A, Winfree C, Mack W, Solomon R . A controlled prospective study of neuropsychological dysfunction following carotid endarterectomy. Arch Neurol. 2002; 59(2):217-22. PMC: 2435245. DOI: 10.1001/archneur.59.2.217. View

Bevan S, Dichgans M, Gschwendtner A, Kuhlenbaumer G, Ringelstein E, Markus H . Variation in the PDE4D gene and ischemic stroke risk: a systematic review and meta-analysis on 5200 cases and 6600 controls. Stroke. 2008; 39(7):1966-71. DOI: 10.1161/STROKEAHA.107.509992. View

Ariga M, Neitzert B, Nakae S, Mottin G, Bertrand C, Pruniaux M . Nonredundant function of phosphodiesterases 4D and 4B in neutrophil recruitment to the site of inflammation. J Immunol. 2004; 173(12):7531-8. DOI: 10.4049/jimmunol.173.12.7531. View

10.

Fukumoto S, Koyama H, Hosoi M, Yamakawa K, Tanaka S, Morii H . Distinct role of cAMP and cGMP in the cell cycle control of vascular smooth muscle cells: cGMP delays cell cycle transition through suppression of cyclin D1 and cyclin-dependent kinase 4 activation. Circ Res. 1999; 85(11):985-91. DOI: 10.1161/01.res.85.11.985. View

11.

Xu X, Li X, Li J, Ou R, Sheng W . Meta-analysis of association between variation in the PDE4D gene and ischemic cerebral infarction risk in Asian populations. Neurogenetics. 2010; 11(3):327-33. DOI: 10.1007/s10048-010-0235-8. View

12.

Heyer E, Mergeche J, Bruce S, Ward J, Stern Y, Anastasian Z . Statins reduce neurologic injury in asymptomatic carotid endarterectomy patients. Stroke. 2013; 44(4):1150-2. PMC: 3609915. DOI: 10.1161/STROKEAHA.111.000362. View

13.

Heyer E, DeLaPaz R, Halazun H, Rampersad A, Sciacca R, Zurica J . Neuropsychological dysfunction in the absence of structural evidence for cerebral ischemia after uncomplicated carotid endarterectomy. Neurosurgery. 2006; 58(3):474-80. PMC: 1449740. DOI: 10.1227/01.NEU.0000197123.09972.EA. View

14.

Mocco J, Choudhri T, Mack W, Laufer I, Lee J, Kiss S . Elevation of soluble intercellular adhesion molecule-1 levels in symptomatic and asymptomatic carotid atherosclerosis. Neurosurgery. 2001; 48(4):718-21; discussion 721-2. DOI: 10.1097/00006123-200104000-00002. View

15.

Staton J, Sayer M, Hankey G, Attia J, Thakkinstian A, Yi Q . Association between phosphodiesterase 4D gene and ischaemic stroke. J Neurol Neurosurg Psychiatry. 2006; 77(9):1067-9. PMC: 2077747. DOI: 10.1136/jnnp.2006.092106. View

16.

Houslay M, Baillie G, Maurice D . cAMP-Specific phosphodiesterase-4 enzymes in the cardiovascular system: a molecular toolbox for generating compartmentalized cAMP signaling. Circ Res. 2007; 100(7):950-66. DOI: 10.1161/01.RES.0000261934.56938.38. View

17.

de Borst G, Moll F, van de Pavoordt H, Mauser H, Kelder J, Ackerstaf R . Stroke from carotid endarterectomy: when and how to reduce perioperative stroke rate?. Eur J Vasc Endovasc Surg. 2001; 21(6):484-9. DOI: 10.1053/ejvs.2001.1360. View

18.

Indolfi C, Di Lorenzo E, Rapacciuolo A, Stingone A, Stabile E, Leccia A . 8-chloro-cAMP inhibits smooth muscle cell proliferation in vitro and neointima formation induced by balloon injury in vivo. J Am Coll Cardiol. 2000; 36(1):288-93. DOI: 10.1016/s0735-1097(00)00679-3. View

19.

Heyer E, Wilson D, Sahlein D, Mocco J, Williams S, Sciacca R . APOE-epsilon4 predisposes to cognitive dysfunction following uncomplicated carotid endarterectomy. Neurology. 2005; 65(11):1759-63. PMC: 1524823. DOI: 10.1212/01.wnl.0000184579.23624.6b. View

20.

Mocco J, Wilson D, Ducruet A, Komotar R, Mack W, Zurica J . Elevations in preoperative monocyte count predispose to acute neurocognitive decline after carotid endarterectomy for asymptomatic carotid artery stenosis. Stroke. 2005; 37(1):240-2. PMC: 1413966. DOI: 10.1161/01.STR.0000195183.04978.4f. View