Advertisement

Journal of Neurology

, Volume 260, Issue 10, pp 2642–2649 | Cite as

Alpha2-macroglobulin as a promising biomarker for cerebral small vessel disease in acute ischemic stroke patients

  • Tomohisa Nezu
  • Naohisa HosomiEmail author
  • Shiro Aoki
  • Kazushi Deguchi
  • Hisashi Masugata
  • Noriko Ichihara
  • Hideo Ohyama
  • Toshiho Ohtsuki
  • Masakazu Kohno
  • Masayasu Matsumoto
Original Communication

Abstract

Alpha2-macroglobulin is a protease inhibitor that enhances procoagulant properties via the neutralization of plasmin, plasminogen activators and metalloproteinases. Additionally, alpha2-macroglobulin is thought to be involved in inflammatory reactions as a carrier protein for interleukin-6 (IL-6). The objective of this study was to evaluate the usefulness of alpha2-macroglobulin as a biomarker for cerebrovascular diseases. Patients with acute ischemic stroke (n = 159; 93 male and 66 female, 71.6 ± 10.3 years) and patients with no previous history of stroke (n = 77; 38 male and 39 female, 70.7 ± 9.5 years) were consecutively enrolled in this study. White matter lesions were assessed via the fluid-attenuated inversion recovery image of magnetic resonance images using the Fazekas classification. The serum alpha2-macroglobulin levels were measured by nephelometry. The serum alpha2-macroglobulin levels at admission in patients with acute ischemic stroke were higher than those in the control patients (230.2 ± 73.7 vs. 205.0 ± 55.8 mg/dl, p = 0.009). The serum alpha2-macroglobulin levels were positively correlated with age and the severity of the white matter lesions (R 2 = 0.048, p < 0.001 and R 2 = 0.058, p < 0.001, respectively), although there was no significant association between serum alpha2-macroglobulin levels and IL-6 levels. In addition, multivariate analysis showed that increased serum alpha2-macroglobulin levels were independently associated with the severity of white matter lesions [standardized partial regression coefficient (β) 0.102, p = 0.026]. Increased serum alpha2-macroglobulin levels might be involved in the pathophysiology of acute ischemic stroke. Furthermore, serum alpha2-macroglobulin levels, which were associated with high-grade white matter lesions, may reflect the chronic pathophysiological condition of cerebral small vessel disease.

Keywords

Neurology Biological markers Stroke Inflammation Leukoaraiosis 

Notes

Acknowledgments

We would like to express our gratitude to Kobayashi, Furuno, Sasanishi and Hironaka for their technical assistance. This study was supported in part by research grants from the Smoking Research Foundation, the Tsuchiya Foundation, the Japan Science and Technology Agency and the Japan Heart Foundation.

Conflicts of interest

None.

References

  1. 1.
    LaMarre J, Wollenberg GK, Gauldie J, Hayes MA (1990) Alpha 2-macroglobulin and serum preferentially counteract the mito-inhibitory effect of transforming growth factor-beta 2 in rat hepatocytes. Lab Invest 62:545–551PubMedGoogle Scholar
  2. 2.
    Sottrup-Jensen L (1989) Alpha-macroglobulins: structure, shape, and mechanism of proteinase complex formation. J Biol Chem 264:11539–11542PubMedGoogle Scholar
  3. 3.
    Herz J, Kowal RC, Ho YK, Brown MS, Goldstein JL (1990) Low density lipoprotein receptor-related protein mediates endocytosis of monoclonal antibodies in cultured cells and rabbit liver. J Biol Chem 265:21355–21362PubMedGoogle Scholar
  4. 4.
    Herz J, Strickland DK (2001) LRP: a multifunctional scavenger and signaling receptor. J Clin Invest 108:779–784PubMedGoogle Scholar
  5. 5.
    Hoogendoorn H, Toh CH, Nesheim ME, Giles AR (1991) Alpha 2-macroglobulin binds and inhibits activated protein C. Blood 78:2283–2290PubMedGoogle Scholar
  6. 6.
    Cvirn G, Gallistl S, Koestenberger M, Kutschera J, Leschnik B, Muntean W (2002) Alpha 2-macroglobulin enhances prothrombin activation and thrombin potential by inhibiting the anticoagulant protein C/protein S system in cord and adult plasma. Thromb Res 105:433–439PubMedCrossRefGoogle Scholar
  7. 7.
    Cvirn G, Gallistl S, Muntean W (2001) Effects of alpha(2)-macroglobulin and antithrombin on thrombin generation and inhibition in cord and adult plasma. Thromb Res 101:183–191PubMedCrossRefGoogle Scholar
  8. 8.
    Beheiri A, Langer C, Düring C, Krümpel A, Thedieck S, Nowak-Göttl U (2007) Role of elevated alpha2-macroglobulin revisited: results of a case-control study in children with symptomatic thromboembolism. J Thromb Haemost 5:1179–1184PubMedCrossRefGoogle Scholar
  9. 9.
    Arbeláez LF, Bergmann U, Tuuttila A, Shanbhag VP, Stigbrand T (1997) Interaction of matrix metalloproteinases-2 and -9 with pregnancy zone protein and alpha2-macroglobulin. Arch Biochem Biophy 347:62–68CrossRefGoogle Scholar
  10. 10.
    Cáceres LC, Bonacci GR, Sánchez MC, Chiabrando GA (2010) Activated α(2) macroglobulin induces matrix metalloproteinase 9 expression by low-density lipoprotein receptor-related protein 1 through MAPK-ERK1/2 and NF-κB activation in macrophage-derived cell lines. J Cell Biochem 111:607–617PubMedCrossRefGoogle Scholar
  11. 11.
    Matsuda T, Hirano T, Nagasawa S, Kishimoto T (1989) Identification of alpha 2-macroglobulin as a carrier protein for IL-6. J Immunol 142:148–152PubMedGoogle Scholar
  12. 12.
    Ahmad J, Singh M, Saleemuddin M (2001) A study of plasma alpha-2-macroglobulin levels in type 2 diabetic subjects with micro albuminuria. J Assoc Physic India 49:1062–1065Google Scholar
  13. 13.
    Watzke H, Schernthaner G, Schnack C, Schwarz HP, Prskavec F, Freyler H (1988) Coagulation factors of contact phase of haemostasis are normal in well-controlled type-I diabetic patients despite presence of diabetic retinopathy. Diabet Res 7:197–200Google Scholar
  14. 14.
    Hosomi N, Aoki S, Matsuo K, Deguchi K, Masugata H, Murao K, Ichihara N, Ohyama H, Dobashi H, Nezu T, Ohtsuki T, Yasuda O, Soejima H, Ogawa H, Izumi Y, Kohno M, Tanaka J, Matsumoto M (2012) Association of serum anti-periodontal pathogen antibody with ischemic stroke. Cerebrovasc Dis 34:385–392PubMedCrossRefGoogle Scholar
  15. 15.
    Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE (1993) Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of org 10172 in acute stroke treatment. Stroke 24:35–41PubMedCrossRefGoogle Scholar
  16. 16.
    Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA (1987) MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. AJR Am J Roentgenol 149:351–356PubMedCrossRefGoogle Scholar
  17. 17.
    Kothari RU, Brott T, Broderick JP, Barsan WG, Sauerbeck LR, Zuccarello M, Khoury J (1996) The ABCs of measuring intracerebral hemorrhage volumes. Stroke 27:1304–1305PubMedCrossRefGoogle Scholar
  18. 18.
    Ritchie RF, Palomaki GE, Neveux LM, Navolotskaia O (2004) Reference distributions for alpha2-macroglobulin: a comparison of a large cohort to the world’s literature. J Clin Lab Anal 18:148–152PubMedCrossRefGoogle Scholar
  19. 19.
    Patterson CC, Smith AE, Yarnell JW, Rumley A, Ben-Shlomo Y, Lowe GD (2010) The associations of interleukin-6 (IL-6) and downstream inflammatory markers with risk of cardiovascular disease: the caerphilly study. Atherosclerosis 209:551–557PubMedCrossRefGoogle Scholar
  20. 20.
    Rehman AA, Ahsan H, Khan FH (2013) Alpha-2-macroglobulin: a physiological guardian. J Cell Physiol 228:1665–1675PubMedCrossRefGoogle Scholar
  21. 21.
    Prins ND, van Dijk EJ, den Heijer T, Vermeer SE, Jolles J, Koudstaal PJ, Hofman A, Breteler MM (2005) Cerebral small-vessel disease and decline in information processing speed, executive function and memory. Brain 128:2034–2041PubMedCrossRefGoogle Scholar
  22. 22.
    Pantoni L, Garcia JH (1997) Pathogenesis of leukoaraiosis: a review. Stroke 28:652–659PubMedCrossRefGoogle Scholar
  23. 23.
    Fornage M, Chiang YA, O’Meara ES, Psaty BM, Reiner AP, Siscovick DS, Tracy RP, Longstreth WT (2008) Biomarkers of inflammation and MRI-defined small vessel disease of the brain: the cardiovascular health study. Stroke 39:1952–1959PubMedCrossRefGoogle Scholar
  24. 24.
    Satizabal CL, Zhu YC, Mazoyer B, Dufouil C, Tzourio C (2012) Circulating IL-6 and CRP are associated with MRI findings in the elderly: the 3C-dijon study. Neurology 78:720–727PubMedCrossRefGoogle Scholar
  25. 25.
    Pantoni L (2010) Cerebral small vessel disease: from pathogenesis to clinical characteristics to therapeutic challenges. Lancet Neurol 9:689–701PubMedCrossRefGoogle Scholar
  26. 26.
    Carmichael O, Schwarz C, Drucker D, Fletcher E, Harvey D, Beckett L, Jack CR, Weiner M, DeCarli C, Initiative AsDN (2010) Longitudinal changes in white matter disease and cognition in the first year of the Alzheimer disease neuroimaging initiative. Arch Neurol 67:1370–1378PubMedCrossRefGoogle Scholar
  27. 27.
    Qiu WQ, Borth W, Ye Z, Haass C, Teplow DB, Selkoe DJ (1996) Degradation of amyloid beta-protein by a serine protease–alpha2-macroglobulin complex. J Biol Chem 271:8443–8451PubMedCrossRefGoogle Scholar
  28. 28.
    Du Y, Ni B, Glinn M, Dodel RC, Bales KR, Zhang Z, Hyslop PA, Paul SM (1997) alpha2-macroglobulin as a beta-amyloid peptide-binding plasma protein. J Neurochem 69:299–305PubMedCrossRefGoogle Scholar
  29. 29.
    Grinberg LT, Thal DR (2010) Vascular pathology in the aged human brain. Acta Neuropathol 119:277–290PubMedCrossRefGoogle Scholar
  30. 30.
    Myllykangas L, Polvikoski T, Sulkava R, Verkkoniemi A, Crook R, Tienari PJ, Pusa AK, Niinistö L, O’Brien P, Kontula K, Hardy J, Haltia M, Pérez-Tur J (1999) Genetic association of alpha2-macroglobulin with Alzheimer’s disease in a Finnish elderly population. Ann Neurol 46:382–390PubMedCrossRefGoogle Scholar
  31. 31.
    Blacker D, Wilcox MA, Laird NM, Rodes L, Horvath SM, Go RC, Perry R, Watson B, Bassett SS, McInnis MG, Albert MS, Hyman BT, Tanzi RE (1998) Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nat Genet 19:357–360PubMedCrossRefGoogle Scholar
  32. 32.
    Poduslo SE, Shook B, Drigalenko E, Yin X (2002) Lack of association of the two polymorphisms in alpha-2 macroglobulin with Alzheimer disease. Am J Med Genet 110:30–35PubMedCrossRefGoogle Scholar
  33. 33.
    Rudrasingham V, Wavrant-De Vrièze F, Lambert JC, Chakraverty S, Kehoe P, Crook R, Amouyel P, Wu W, Rice F, Pérez-Tur J, Frigard B, Morris JC, Carty S, Petersen R, Cottel D, Tunstall N, Holmans P, Lovestone S, Chartier-Harlin MC, Goate A, Hardy J, Owen MJ, Williams J (1999) Alpha-2 macroglobulin gene and Alzheimer disease. Nat Genet 22:17–19PubMedCrossRefGoogle Scholar
  34. 34.
    Avilés-Santa L, Alpern R, Raskin P (2002) Reversible acute renal failure and nephrotic syndrome in a type 1 diabetic patient. J Diabetes Compl 16:249–254CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Tomohisa Nezu
    • 1
  • Naohisa Hosomi
    • 1
    • 2
    Email author
  • Shiro Aoki
    • 1
  • Kazushi Deguchi
    • 2
  • Hisashi Masugata
    • 2
  • Noriko Ichihara
    • 3
  • Hideo Ohyama
    • 4
  • Toshiho Ohtsuki
    • 1
  • Masakazu Kohno
    • 2
  • Masayasu Matsumoto
    • 1
  1. 1.Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health SciencesHiroshimaJapan
  2. 2.Department of Internal MedicineKagawa University School of MedicineKagawaJapan
  3. 3.Department of NeurologyNational Hospital Takamatsu Medical CenterKagawaJapan
  4. 4.Department of StrokologyOsaka Neurosurgical HospitalKagawaJapan

Personalised recommendations