Advertisement

Translational Stroke Research

, Volume 10, Issue 1, pp 44–51 | Cite as

Small Vessel Disease Is Associated with Tissue Inhibitor of Matrix Metalloproteinase-4 After Ischaemic Stroke

  • Francesco Arba
  • Benedetta Piccardi
  • Vanessa Palumbo
  • Betti Giusti
  • Patrizia Nencini
  • Anna Maria Gori
  • Alice Sereni
  • Mascia Nesi
  • Giovanni Pracucci
  • Giorgio Bono
  • Paolo Bovi
  • Enrico Fainardi
  • Domenico Consoli
  • Antonia Nucera
  • Francesca Massaro
  • Giovanni Orlandi
  • Francesco Perini
  • Rossana Tassi
  • Maria Sessa
  • Danilo Toni
  • Rosanna Abbate
  • Domenico Inzitari
  • on behalf of the MAGIC Study Group
Original Article
  • 74 Downloads

Abstract

Small vessel disease (SVD) is frequent in aging and stroke patients. Inflammation and remodeling of extracellular matrix have been suggested as concurrent mechanisms of SVD. We investigated the relationship between imaging features of SVD and circulating metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in patients with ischaemic stroke. In patients treated with intravenous thrombolysis, we took blood samples before intravenous thrombolysis and 90 days after the acute stroke and analysed levels of MMPs and TIMPs. We assessed leukoaraiosis, number of lacunes and brain atrophy on pre-treatment CT scan and graded global SVD burden combining such features. We investigated associations between single features, global SVD and MMPs and TIMPs at baseline and at follow-up, retaining univariate statistically significant associations in multivariate linear regression analysis and adjusting for clinical confounders. A total of 255 patients [mean (±SD) = 68.6 (± 12.7) years, 154 (59%) males] were included, 107 (42%) had no signs of SVD; 47 (19%) had from moderate to severe SVD burden. A total of 107 (42%) patients had no signs of SVD; 47 (19%) had from moderate to severe SVD burden. After adjustment, only TIMP-4 proved associations with SVD features. Brain atrophy was associated with baseline TIMP-4 (β = 0.20;p = 0.019) and leukoaraiosis with 90 days TIMP-4 (β = 0.19; p = 0.013). Global SVD score was not associated with baseline TIMP-4 levels (β = 0.10; p = 0.072), whereas was associated with 90 days TIMP-4 levels (β = 0.21; p = 0.003). Total SVD burden was associated with higher TIMP-4 levels 90 days after stroke, whereas was not during the acute phase. Our results support a biological relationship between SVD grade and TIMP-4.

Keywords

Small vessel disease Matrix metalloproteinase Tissue inhibitor of matrix metalloproteinase Acute stroke 

Notes

Acknowledgments

We thank the hospital staff for data collection: M. Acampa, Siena; M. Bacigaluppi, Milano; A. Chiti, Pisa; A. De Boni, Vicenza; M.L. De Lodovici, Varese; F. Galati, Vibo Valentia; N. Marcello, Reggio Emilia; N. Micheletti, Verona; F. Muscia, Como; E. Paolino, Ferrara; P. Palumbo, Prato; P. Tosi, Rozzano; E. Mossello, Firenze; M.R. Tola, Ferrara; M. Torri, Firenze.

Funding

Biological Markers Associated with Acute Ischemic Stroke (MAGIC) Study was funded by grants from Italian Ministry of Health, 2006 Finalized Research Programmes (RFPS-2006-1-336520) and Ente Cassa di Risparmio di Firenze (2010.06.03).

Compliance with Ethical Standards

Study protocol was approved from local ethic committees. Each patient gave written informed consent.

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Supplementary material

12975_2018_627_MOESM1_ESM.pptx (51 kb)
ESM 1 (PPTX 50.8 kb)
12975_2018_627_MOESM2_ESM.pptx (69 kb)
ESM 2 (PPTX 69 kb)
12975_2018_627_MOESM3_ESM.docx (17 kb)
ESM 3 (DOCX 17.4 kb)

References

  1. 1.
    Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9:689–701.CrossRefGoogle Scholar
  2. 2.
    Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, et al. STandards for ReportIng vascular changes on nEuroimaging (STRIVE v1). Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12:822–38.CrossRefGoogle Scholar
  3. 3.
    Rosenberg GA. Inflammation and white matter damage in vascular cognitive impairment. Stroke. 2009;40:S20–3.CrossRefGoogle Scholar
  4. 4.
    Shoamanesh A, Preis SR, Beiser AS, Vasan RS, Benjamin EJ, Kase CS, et al. Inflammatory biomarkers, cerebral microbleeds, and small vessel disease: Framingham Heart Study. Neurology. 2015;84:825–32.CrossRefGoogle Scholar
  5. 5.
    Wiseman SJ, Doubal FN, Chappell FM, Valdés-Hernández MC, Wang X, Rumley A, et al. Plasma biomarkers of inflammation, endothelial function and hemostasis in cerebral small vessel disease. Cerebrovasc Dis. 2015;40:157–64.CrossRefGoogle Scholar
  6. 6.
    Topakian R, Garrick TR, Howe FA, et al. Blood-brain barrier permeability is increased in normal-appearing white matter in patients with lacunar stroke and leukoaraiosis. J Neurol Neurosurg Psychiatry. 2010;81:192–7.CrossRefGoogle Scholar
  7. 7.
    Wardlaw JM, Sandercock PAG, Dennis MS, Starr J, Kalimo H. Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia? Stroke. 2003;34:806–12.CrossRefGoogle Scholar
  8. 8.
    Candelario-Jalil E, Thompson J, Taheri S, Grossetete M, Adair JC, Edmonds E, et al. Matrix metalloproteinases are associated with increased blood-brain barrier opening in vascular cognitive impairment. Stroke. 2011;42:1345–50.CrossRefGoogle Scholar
  9. 9.
    Heo JH, Lucero J, Abumiya T, Koziol JA, Copeland BR, del Zoppo GJ. Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J Cereb Blood Flow Metab. 1999;19:624–33.CrossRefGoogle Scholar
  10. 10.
    Inzitari D, Giusti B, Nencini P, Gori AM, Nesi M, Palumbo V, et al. MAGIC study group. MMP9 variation after thrombolysis is associated with hemorrhagic transformation of lesion and death. Stroke. 2013;44:2901–3.CrossRefGoogle Scholar
  11. 11.
    Montaner J, Molina CA, Monasterio J, Abilleira S, Arenillas JF, Ribó M, et al. Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation. 2003;107:598–603.CrossRefGoogle Scholar
  12. 12.
    Wahlgren N, Ahmed N, Dávalos A, Ford GA, Grond M, Hacke W, Hennerici MG, Kaste M, Kuelkens S, Larrue V, Lees KR, Roine RO, Soinne L, Toni D, Vanhooren G; SITS-MOST investigators. Thrombolysis with alteplase for acute ischaemic stroke in the safe implementation of thrombolysis in stroke-monitoring study (SITS-MOST): an observational study. Lancet 2007; 369:275–282.Google Scholar
  13. 13.
    Van Swieten JC, Hijdra A, Koudstaal PJ, van Gijn J. Grading white matter lesions on CT and MRI: a simple scale. J Neurol Neurosurg Psychiatry. 1990;53:1080–3.CrossRefGoogle Scholar
  14. 14.
    IST-3 collaborative group. Association between brain imaging signs, early and late outcomes, and response to intravenous alteplase after acute ischaemic stroke in the third international stroke trial (IST-3): secondary analysis of a randomised controlled trial. Lancet Neurol. 2015;14:485–96.CrossRefGoogle Scholar
  15. 15.
    Arba F, Leigh R, Inzitari D, Warach S, Luby M, Lees KR. On behalf of STIR/VISTA imaging collaboration. Blood-brain barrier leakage increases with small vessel disease in acute ischemic stroke. Neurology. 2017;89:2143–50.CrossRefGoogle Scholar
  16. 16.
    Arba F, Mair G, Carpenter T, Sakka E, Sandercock PA, Lindley RI, et al. Cerebral white matter hypoperfusion increases with small vessel disease burden. Data from the third international stroke trial. J Stroke Cerebrovasc Dis. 2017;26:1506–13.CrossRefGoogle Scholar
  17. 17.
    Arba F, Inzitari D, Ali M, Warach SJ, Luby M, Lees KR. STIR/VISTA imaging collaboration. Small vessel disease and clinical outcomes after IV rt-PA treatment. Acta Neurol Scand. 2017;136:72–7.CrossRefGoogle Scholar
  18. 18.
    Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Royal Statistical Society1995; Series B. 57:289–300.Google Scholar
  19. 19.
    Staals J, Booth T, Morris Z, Bastin ME, Gow AJ, Corley J, et al. Total MRI load of cerebral small vessel disease and cognitive ability in older people. Neurobiol Aging. 2015;36:2806–11.CrossRefGoogle Scholar
  20. 20.
    Staals J, Makin SD, Doubal FN, Dennis MS, Wardlaw JM. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Neurology. 2014;83:1228–34.CrossRefGoogle Scholar
  21. 21.
    Arba F, Palumbo V, Boulanger JM, Pracucci G, Inzitari D, Buchan AM, et al. Leukoaraiosis and lacunes are associated with poor clinical outcomes in ischemic stroke patients treated with intravenous thrombolysis. Int J Stroke. 2016;11:62–7.CrossRefGoogle Scholar
  22. 22.
    Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol. 2013;12:483–97.CrossRefGoogle Scholar
  23. 23.
    Fernando MS, Simpson JE, Matthews F, Brayne C, Lewis CE, Barber R, et al. White matter lesions in an unselected cohort of the elderly: molecular pathology suggests origin from chronic hypoperfusion injury. Stroke. 2006;37:1391–8.CrossRefGoogle Scholar
  24. 24.
    Simpson JE, Fernando MS, Clark L, Ince PG, Matthews F, Forster G, et al. White matter lesions in an unselected cohort of the elderly: astrocytic, microglial and oligodendrocyte precursor cell responses. Neuropathol Appl Neurobiol. 2007;33:410–9.CrossRefGoogle Scholar
  25. 25.
    Rosenberg GA, Sullivan N, Esiri MM. White matter damage is associated with matrix metalloproteinases in vascular dementia. Stroke. 2001;32:1162–8.CrossRefGoogle Scholar
  26. 26.
    Aribisala BS, Wiseman S, Morris Z, Valdés-Hernández MC, Royle NA, Maniega SM, et al. Circulating inflammatory markers are associated with magnetic resonance imaging-visible perivascular spaces but not directly with white matter hyperintensities. Stroke. 2014;45:605–7.CrossRefGoogle Scholar
  27. 27.
    Rouhl RP, Damoiseaux JG, Lodder J, Theunissen RO, Knottnerus IL, Staals J, et al. Vascular inflammation in cerebral small vessel disease. Neurobiol Aging. 2012;33:1800–6.CrossRefGoogle Scholar
  28. 28.
    Romero JR, Vasan RS, Beiser AS, Au R, Benjamin EJ, DeCarli C, et al. Association of matrix metalloproteinases with MRI indices of brain ischemia and aging. Neurobiol Aging. 2010;31:2128–35.CrossRefGoogle Scholar
  29. 29.
    Leco KJ, Apte SS, Taniguchi GT, Hawkes SP, Khoukha R, Schultz GA, et al. Murine tissue inhibitor of metalloproteinases-4 (Timp-4): cDNA isolation and expression in adult mouse tissues. FEBS Lett. 1997;401:213–7.CrossRefGoogle Scholar
  30. 30.
    Ketsawatsomkron P, Keen HL, Davis DR. Lu KT, stump M, De Silva TM, Hilzendeger AM, Grobe JL, Faraci FM, Sigmund CD. Protective role for tissue inhibitor of Metalloproteinase-4, a novel peroxisome proliferator-activated receptor-γ target gene, in smooth muscle in Deoxycorticosterone acetate-salt hypertension. Hypertension. 2016;67:214–22.CrossRefGoogle Scholar
  31. 31.
    Radomski A, Jurasz P, Sanders EJ, Overall CM, Bigg HF, Edwards DR, et al. Identification, regulation and role of tissue inhibitor of metalloproteinases-4 (TIMP-4) in human platelets. Br J Pharmacol. 2002;137(8):1330–8.CrossRefGoogle Scholar
  32. 32.
    Tomimoto H, Akiguchi I, Wakita H, Osaki A, Hayashi M, Yamamoto Y. Coagulation activation in patients with Binswanger disease. Arch Neurol. 1999;56:1104–8.CrossRefGoogle Scholar
  33. 33.
    Iwamoto T, Kubo H, Takasaki M. Platelet activation in the cerebral circulation in different subtypes of ischaemic stroke and Binswanger's disease. Stroke. 1995;26:52–6.CrossRefGoogle Scholar
  34. 34.
    Wattjes MP, Henneman WJ, van der Flier WM, de Vries O, Träber F, Geurts JJ, et al. Diagnostic imaging of patients in a memory clinic: comparison of MR imaging and 64-detector row CT. Radiology. 2009;253:174–83.CrossRefGoogle Scholar
  35. 35.
    Potter GM, Doubal FN, Jackson CA, Chappell FM, Sudlow CL, Dennis MS, et al. Counting cavitating lacunes underestimates the burden of lacunar infarction. Stroke. 2010;4:267–72.CrossRefGoogle Scholar
  36. 36.
    Curtze S, Melkas S, Sibolt G, Haapaniemi E, Mustanoja S, Putaala J, et al. Cerebral computed tomography-graded white matter lesions are associated with worse outcome after thrombolysis in patients with stroke. Stroke. 2015;46:1554–60.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Francesco Arba
    • 1
    • 2
  • Benedetta Piccardi
    • 1
    • 2
  • Vanessa Palumbo
    • 2
  • Betti Giusti
    • 3
  • Patrizia Nencini
    • 2
  • Anna Maria Gori
    • 3
  • Alice Sereni
    • 3
  • Mascia Nesi
    • 2
  • Giovanni Pracucci
    • 1
  • Giorgio Bono
    • 4
  • Paolo Bovi
    • 5
  • Enrico Fainardi
    • 6
  • Domenico Consoli
    • 7
  • Antonia Nucera
    • 8
  • Francesca Massaro
    • 9
  • Giovanni Orlandi
    • 10
  • Francesco Perini
    • 11
  • Rossana Tassi
    • 12
  • Maria Sessa
    • 13
  • Danilo Toni
    • 14
  • Rosanna Abbate
    • 15
  • Domenico Inzitari
    • 16
  • on behalf of the MAGIC Study Group
  1. 1.Department of NEUROFARBA, Neuroscience SectionUniversity of FlorenceFlorenceItaly
  2. 2.Stroke Unit and NeurologyCareggi University HospitalFlorenceItaly
  3. 3.Department of Experimental and Clinical Medicine, Atherothrombotic Diseases Center, AOU CareggiUniversity of FlorenceFlorenceItaly
  4. 4.Stroke Unit, Department of NeurologyOspedale di Circolo e Fondazione MacchiVareseItaly
  5. 5.SSO Stroke Unit, Department of NeurosciencesAzienda Ospedaliera IntegrataVeronaItaly
  6. 6.Department of NeuroradiologyCareggi University HospitalFlorenceItaly
  7. 7.U.O. NeurologiaG. Jazzolino HospitalVibo ValentiaItaly
  8. 8.Department of Clinical Neurological Sciences, London Health Sciences CentreWestern UniversityLondonCanada
  9. 9.Neurology UnitSanto Stefano HospitalPratoItaly
  10. 10.Department of Neurosciences, Neurological ClinicUniversity of PisaPisaItaly
  11. 11.UOC di Neurologia e Stroke UnitOspedale San BortoloVicenzaItaly
  12. 12.U.O.C. Stroke Unit, Dipartimento di Scienze Neurologiche e NeurosensorialiAzienda Ospedaliera Universitaria SeneseSienaItaly
  13. 13.U.O. Neurologia, DAI Neuroscienze-RiabilitazioneAzienda Ospedaliera-Universitaria S. AnnaFerraraItaly
  14. 14.Emergency Department Stroke Unit, Department of Neurological SciencesSapienza University of RomeRomeItaly
  15. 15.Centro Studi Medicina Avanzata (CESMAV)FlorenceItaly
  16. 16.Institute of NeuroscienceItalian National Research CouncilFlorenceItaly

Personalised recommendations