Abstract
Background and Objective: D-dimer prompts fibrinolysis system, which is involved in Alzheimer’s disease and the complications of type 2 diabetic patients, especially among those with carotid artery plaques. Hence, this study aims to investigate the role of D-dimer in early cognitive impairment among type 2 diabetic patients with carotid artery plaques.
Methods: A total of 175 Chinese patients with type 2 diabetes were recruited and divided into two groups according to the Montreal Cognitive Assessment score. Demographic data were collected, plasma D-dimer was tested through VIDAS D-dimer New, neuropsychological tests were examined, and carotid artery plaques were detected by ultrasound and further stratified by vulnerability and level.
Results: A total of 67 types 2 diabetic patients with Mild Cognitive Impairment (MCI) displayed significantly increased plasma D-dimer levels compared with their health-cognition controls (p = 0.011). Plasma D-dimer concentration was negatively related with Digit Span Test scores in diabetic patients with vulnerable plaques (r=-0.471, p=0.023) and Stroop Color Word Test C (number) in diabetic patients with stable plaques (r=-0.482, p<0.001). Multivariable regression analysis further showed that D-dimer concentration was an independent factor of diabetic MCI with carotid artery plaque (p=0.005), and D-dimer concentration especially contributed to the high risk of MCI with vulnerable plaques (p=0.028) or high levels of carotid plaque (p=0.023).
Conclusion: Elevated D-dimer level predicts the high risk of early cognitive impairment in type 2 diabetic patients with carotid artery plaques, especially vulnerable plaques or high levels of carotid plaques.
Keywords: Carotid artery plaques, vulnerable plaques, D-dimer, fibrinolysis system, mild cognitive impairment, type 2 diabetes mellitus.
[1]
van Harten B, de Leeuw FE, Weinstein HC, Scheltens P, Biessels GJ. Brain imaging in patients with diabetes: a systematic review. Diabetes Care 29(11): 2539-48. (2006).
[2]
Zhou H, Lu W, Shi Y, Bai F, Chang J, Yuan Y, et al. Impairments in cognition and resting-state connectivity of the hippocampus in elderly subjects with type 2 diabetes. Neurosci Lett 473(1): 5-10. (2010).
[3]
Vazzana N, Ranalli P, Cuccurullo C, Davi G. Diabetes mellitus and thrombosis. Thromb Res 129(3): 371-7. (2012).
[4]
Ahmed AS, Elgharabawy RM, Al-Najjar AH. Ameliorating effect of anti-Alzheimer’s drugs on the bidirectional association between type 2 diabetes mellitus and Alzheimer’s disease. Exp Biol Med (Maywood) 242(13): 1335-44. (2017).
[5]
Xiang J, Zhang T, Yang QW, Liu J, Chen Y, Cui M, et al. Carotid artery atherosclerosis is correlated with cognitive impairment in an elderly urban Chinese non-stroke population. J Clin Neurosci 20(11): 1571-5. (2013).
[6]
Rogne SO, Solbu MD, Arntzen KA, Herder M, Mathiesen EB, Schirmer H. Albuminuria and carotid atherosclerosis as predictors of cognitive function in a general population. Eur Neurol 70(5-6): 340-8. (2013).
[7]
Hess K, Grant PJ. Inflammation and thrombosis in diabetes. Thromb Haemost 105(1): S43-54. (2011).
[8]
Adam SS, Key NS, Greenberg CS. D-dimer antigen: current concepts and future prospects. Blood 113(13): 2878-87. (2009).
[9]
Nwose EU, Richards RS, Jelinek HF, Kerr PG. D-dimer identifies stages in the progression of diabetes mellitus from family history of diabetes to cardiovascular complications. Pathology 39(2): 252-7. (2007).
[10]
Long ZF, Qu GY, Xu M. Relationship between the level of plasma D-dimer and diabetic microangiopathy. Hunan Yi Ke Da Xue Xue Bao 26(5): 434-6. (2001).
[11]
Wakabayashi I, Masuda H. Association of D-dimer with microalbuminuria in patients with type 2 diabetes mellitus. J Thromb Thrombolysis 27(1): 29-35. (2009).
[12]
Bhatia S, Jenner AM, Li H, Ruberu K, Spiro AS, Shepherd CE, et al. Increased apolipoprotein D dimer formation in Alzheimer’s disease hippocampus is associated with lipid conjugated diene levels. J Alzheimers Dis 35(3): 475-86. (2013).
[13]
Sutton R, Keohane ME, Vanderberg SR, Gonias SL. Plasminogen activator inhibitor-1 in the cerebrospinal fluid as an index of neurological disease. Blood Coagul Fibrinolysis 5(2): 167. (1994).
[14]
Carcaillon L, Gaussem P, Ducimetiere P, Giroud M, Ritchie K, Dartigues JF, et al. Elevated plasma fibrin D-dimer as a risk factor for vascular dementia: the Three-City cohort study. J Thromb Haemost 7(12): 1972-8. (2009).
[15]
Stott DJ, Robertson M, Rumley A, Welsh P, Sattar N, Packard CJ, et al. Activation of hemostasis and decline in cognitive function in older people. Arterioscler Thromb Vasc Biol 30(3): 605-11. (2010).
[16]
Krupinski J, Turu M, Font M, Ahmed N, Sullivan M, Rubio F, et al. Increased tissue factor, MMP-8, and D-dimer expression in diabetic patients with unstable advanced carotid atherosclerosis. Vasc Health Risk Manag 3(4): 405-12. (2007).
[17]
Lepedda AJ, Lobina O, Rocchiccioli S, Nieddu G, Ucciferri N, De Muro P, et al. Identification of differentially expressed plasma proteins in atherosclerotic patients with type 2 diabetes. J Diabetes Complications 30(5): 880-6. (2016).
[18]
Soares AL, Kazmi RS, Borges MA, Rosario PW, Fernandes AP, Sousa MO, et al. Elevated plasma factor VIII and von Willebrand factor in women with type 2 diabetes: inflammatory reaction, endothelial perturbation or else? Blood Coagul Fibrinolysis 22(7): 600-5. (2011).
[19]
Agewall S, Wikstrand J, Suurkula M, Tengborn L, Fagerberg B. Carotid artery wall morphology, haemostatic factors and cardiovascular disease. An ultrasound study in men at high and low risk for atherosclerotic disease. Blood Coagul Fibrinolysis 5(6): 895-904. (1994).
[20]
Vigili de Kreutzenberg S, Fadini GP, Guzzinati S, Mazzucato M, Volpi A, Coracina A, et al. Carotid plaque calcification predicts future cardiovascular events in type 2 diabetes. Diabetes Care 38(10): 1937-44. (2015).
[21]
Bosevski M, Lazarova-Trajkovska E. Carotid artery disease in patients with type 2 diabetes. Angiol Sosud Khir 21(3): 17-26. (2015).
[22]
Arntzen KA, Schirmer H, Johnsen SH, Wilsgaard T, Mathiesen EB. Carotid artery plaque progression and cognitive decline: the Tromso Study 1994-2008. Eur J Neurol 19(10): 1318-24. (2012).
[23]
Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15(7): 539-53. (1998).
[24]
Portet F, Ousset PJ, Visser PJ, Frisoni GB, Nobili F, Scheltens P, et al. Mild cognitive impairment (MCI) in medical practice: a critical review of the concept and new diagnostic procedure. Report of the MCI Working Group of the European Consortium on Alzheimer’s Disease. J Neurol Neurosurg Psychiatry 77(6): 714-8. (2006).
[25]
Grant EG, Benson CB, Moneta GL, Alexandrov AV, Baker JD, Bluth EI, et al. Carotid artery stenosis: gray-scale and Doppler US diagnosis--Society of Radiologists in Ultrasound Consensus Conference. Radiology 229(2): 340-6. (2003).
[26]
Robinson ML, Sacks D, Perlmutter GS, Marinelli DL. Diagnostic criteria for carotid duplex sonography. Am J Roentgenol 151(5): 1045-9. (1988).
[27]
Tonizzo M, Fisicaro M, Bussani R, Bollini M, Da CP, Fonda M, et al. Carotid atherosclerosis: echographic patterns versus histological findings. Int Angiol 13(3): 208-14. (1994).
[29]
Alagiakrishnan K, Zhao N, Mereu L, Senior P, Senthilselvan A. Montreal Cognitive Assessment is superior to Standardized Mini-Mental Status Exam in detecting mild cognitive impairment in the middle-aged and elderly patients with type 2 diabetes mellitus. BioMed Res Int 2013: 186106. (2013).
[30]
Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, et al. The montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 53(4): 695-9. (2005).
[31]
van den Berg E, Reijmer YD, de Bresser J, Kessels RP, Kappelle LJ, Biessels GJA. 4 year follow-up study of cognitive functioning in patients with type 2 diabetes mellitus. Diabetologia 53(1): 58-65. (2010).
[32]
Wang J, Yuan Y, Cai R, Huang R, Tian S, Lin H, et al. Association between plasma levels of PAI-1, tPA/PAI-1 molar ratio, and mild cognitive impairment in chinese patients with type 2 Diabetes Mellitus. J Alzheimers Dis 63(2): 835-45. (2018).
[33]
Wang P, Huang R, Lu S, Xia W, Cai R, Sun H, et al. RAGE and AGEs in mild cognitive impairment of diabetic patients: a cross-sectional study. PLoS One 11(1): e0145521. (2016).
[34]
Barber M, Tait RC, Scott J, Rumley A, Lowe GD, Stott DJ. Dementia in subjects with atrial fibrillation: hemostatic function and the role of anticoagulation. J Thromb Haemost 2(11): 1873-8. (2004).
[35]
Vishnu VY, Modi M, Garg VK, Mohanty M, Goyal MK, Lal V, et al. Role of inflammatory and hemostatic biomarkers in Alzheimer’s and vascular dementia - a pilot study from a tertiary center in Northern India. Asian J Psychiatr 29: 59-62. (2017).
[36]
Rafnsson SB, Deary IJ, Smith FB, Whiteman MC, Rumley A, Lowe GD, et al. Cognitive decline and markers of inflammation and hemostasis: the Edinburgh Artery Study. J Am Geriatr Soc 55(5): 700-7. (2007).
[37]
Grober E, Hall CB, Hahn SR, Lipton RB. Memory impairment and executive dysfunction are associated with inadequately controlled diabetes in older adults. J Prim Care Community Health 2(4): 229-33. (2011).
[39]
Griffin WS, Sheng JG, Royston MC, Gentleman SM, McKenzie JE, Graham DI, et al. Glial-neuronal interactions in Alzheimer’s disease: the potential role of a ‘cytokine cycle’ in disease progression. Brain Pathol (Zurich, Switzerland) 8(1): 65-72. (1998).
[40]
Robson SC, Shephard EG, Kirsch RE. Fibrin degradation product D-dimer induces the synthesis and release of biologically active IL-1 beta, IL-6 and plasminogen activator inhibitors from monocytes in vitro. Br J Haematol 86(2): 322-6. (1994).
[41]
Dunn AJ, Wang J, Ando T. Effects of cytokines on cerebral neurotransmission. Comparison with the effects of stress. Adv Exp Med Biol 461: 117-27. (1999).
[42]
McCann SM, Kimura M, Karanth S, Yu WH, Mastronardi CA, Rettori V. The mechanism of action of cytokines to control the release of hypothalamic and pituitary hormones in infection. Ann N Y Acad Sci 917: 4-18. (2000).
[43]
Soares AL, Rosario PW, Borges MA, Sousa MO, Fernandes AP, Carvalho M. PAI-1 and D-dimer in type 2 diabetic women with asymptomatic macrovascular disease assessed by carotid Doppler. Clin Appl Thromb Hemost 16(2): 204-8. (2010).
[44]
Romero JR, Beiser A, Seshadri S, Benjamin EJ, Polak JF, Vasan RS, et al. Carotid artery atherosclerosis, MRI indices of brain ischemia, aging, and cognitive impairment: the Framingham study. Stroke 40(5): 1590-6. (2009).
[45]
Yew B, Nation DA. Cerebrovascular resistance: effects on cognitive decline, cortical atrophy, and progression to dementia. Brain 140(7): 1987-2001. (2017).
[46]
Safouris A, Hambye AS, Sculier C, Papageorgiou SG, Vasdekis SN, Gazagnes MD, et al. Chronic brain hypoperfusion due to multi-vessel extracranial atherosclerotic disease: a potentially reversible cause of cognitive impairment. J Alzheimers Dis 43(1): 23-7. (2015).
[47]
Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404(6779): 787-90. (2000).
Related Books
Frontiers in Clinical Drug Research - CNS and Neurological Disorders
Frontiers in Clinical Drug Research - CNS and Neurological Disorders
Frontiers in Clinical Drug Research - CNS and Neurological Disorders
Frontiers in Clinical Drug Research-Dementia
Frontiers in Clinical Drug Research - CNS and Neurological Disorders
Article Metrics
61
3
1