An IL-18-centered inflammatory network as a biomarker for cerebral white matter injury

English version

Autoři: Marie Altendahl ^aff001; Pauline Maillard ^aff002; Danielle Harvey ^aff003; Devyn Cotter ^aff001; Samantha Walters ^aff001; Amy Wolf ^aff001; Baljeet Singh ^aff002; Visesha Kakarla ^aff004; Ida Azizkhanian ^aff005; Sunil A. Sheth ^aff006; Guanxi Xiao ^aff004; Emily Fox ^aff001; Michelle You ^aff001; Mei Leng ^aff007; David Elashoff ^aff007; Joel H. Kramer ^aff001; Charlie Decarli ^aff002; Fanny Elahi ^aff001; Jason D. Hinman ^aff004
Působiště autorů: Memory & Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA, United States of America ^aff001; Department of Neurology and Center for Neurosciences, University of California, Davis, CA, United States of America ^aff002; Department of Public Health Sciences, University of California, Davis, CA, United States of America ^aff003; Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States of America ^aff004; School of Medicine, New York Medical College, Vahalla, NY, United States of America ^aff005; University of Texas Health McGovern School of Medicine, Department of Neurology, Houston, TX, United States of America ^aff006; Department of Medicine Statistics Core, Department of Medicine, University of California Los Angeles, Los Angeles, CA, United States of America ^aff007; Department of Psychiatry, University of California San Francisco, San Francisco, CA, United States of America ^aff008
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0227835

Souhrn

Chronic systemic sterile inflammation is implicated in the pathogenesis of cerebrovascular disease and white matter injury. Non-invasive blood markers for risk stratification and dissection of inflammatory molecular substrates in vivo are lacking. We sought to identify whether an interconnected network of inflammatory biomarkers centered on IL-18 and all previously associated with white matter lesions could detect overt and antecedent white matter changes in two populations at risk for cerebral small vessel disease. In a cohort of 167 older adults (mean age: 76, SD 7.1, 83 females) that completed a cognitive battery, physical examination, and blood draw in parallel with MR imaging including DTI, we measured cerebral white matter hyperintensities (WMH) and free water (FW). Concurrently, serum levels of a biologic network of inflammation molecules including MPO, GDF-15, RAGE, ST2, IL-18, and MCP-1 were measured. The ability of a log-transformed population mean-adjusted inflammatory composite score (ICS) to associate with MR variables was demonstrated in an age and total intracranial volume adjusted model. In this cohort, ICS was significantly associated with WMH (β = 0.222, p = 0.013), FW (β = 0.3, p = 0.01), and with the number of vascular risk factor diagnoses (r = 0.36, p<0.001). In a second cohort of 131 subjects presenting for the evaluation of acute neurologic deficits concerning for stroke, we used serum levels of 11 inflammatory biomarkers in an unbiased principal component analysis which identified a single factor significantly associated with WMH. This single factor was strongly correlated with the six component ICS identified in the first cohort and was associated with WMH in a generalized linear regression model adjusted for age and gender (p = 0.027) but not acute stroke. A network of inflammatory molecules driven by IL-18 is associated with overt and antecedent white matter injury resulting from cerebrovascular disease and may be a promising peripheral biomarker for vascular white matter injury.

Klíčová slova:

Biomarkers – Central nervous system – Cognitive impairment – Diffusion tensor imaging – Inflammation – Inflammatory diseases – Magnetic resonance imaging – stroke

Zdroje

1. Fu Y, Yan Y. Emerging Role of Immunity in Cerebral Small Vessel Disease. Front Immunol. 2018;9:67. Epub 2018/02/10. doi: 10.3389/fimmu.2018.00067 29422904; PubMed Central PMCID: PMC5788893.

2. Elahi FM, Casaletto KB, Altendahl M, Staffaroni AM, Fletcher E, Filshtein TJ, et al. "Liquid Biopsy" of White Matter Hyperintensity in Functionally Normal Elders. Front Aging Neurosci. 2018;10:343. Epub 2018/11/30. doi: 10.3389/fnagi.2018.00343 30483114; PubMed Central PMCID: PMC6244607.

3. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9(7):689–701. Epub 2010/07/09. doi: 10.1016/S1474-4422(10)70104-6 20610345.

4. Uiterwijk R, van Oostenbrugge RJ, Huijts M, De Leeuw PW, Kroon AA, Staals J. Total Cerebral Small Vessel Disease MRI Score Is Associated with Cognitive Decline in Executive Function in Patients with Hypertension. Front Aging Neurosci. 2016;8:301. Epub 2016/12/27. doi: 10.3389/fnagi.2016.00301 28018214; PubMed Central PMCID: PMC5149514.

5. Staszewski J, Piusinska-Macoch R, Skrobowska E, Brodacki B, Pawlik R, Dutkiewicz T, et al. Significance of Haemodynamic and Haemostatic Factors in the Course of Different Manifestations of Cerebral Small Vessel Disease: The SHEF-CSVD Study-Study Rationale and Protocol. Neurosci J. 2013;2013:424695. Epub 2013/01/01. doi: 10.1155/2013/424695 26317092; PubMed Central PMCID: PMC4437267.

6. Yang S, Yuan J, Qin W, Yang L, Fan H, Li Y, et al. Twenty-four-hour ambulatory blood pressure variability is associated with total magnetic resonance imaging burden of cerebral small-vessel disease. Clin Interv Aging. 2018;13:1419–27. Epub 2018/08/22. doi: 10.2147/CIA.S171261 30127599; PubMed Central PMCID: PMC6089119.

7. Group SMIftSR, Nasrallah IM, Pajewski NM, Auchus AP, Chelune G, Cheung AK, et al. Association of Intensive vs Standard Blood Pressure Control With Cerebral White Matter Lesions. JAMA. 2019;322(6):524–34. Epub 2019/08/14. doi: 10.1001/jama.2019.10551 31408137; PubMed Central PMCID: PMC6692679.

8. Group SMIftSR, Williamson JD, Pajewski NM, Auchus AP, Bryan RN, Chelune G, et al. Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial. JAMA. 2019;321(6):553–61. Epub 2019/01/29. doi: 10.1001/jama.2018.21442 30688979; PubMed Central PMCID: PMC6439590.

9. Fazekas F, Kleinert R, Offenbacher H, Schmidt R, Kleinert G, Payer F, et al. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology. 1993;43(9):1683–9. Epub 1993/09/01. doi: 10.1212/wnl.43.9.1683 8414012.

10. Hinman JD, Lee MD, Tung S, Vinters HV, Carmichael ST. Molecular disorganization of axons adjacent to human lacunar infarcts. Brain. 2015;138(Pt 3):736–45. Epub 2015/01/24. doi: 10.1093/brain/awu398 25614025; PubMed Central PMCID: PMC4339777.

11. Maillard P, Mitchell GF, Himali JJ, Beiser A, Fletcher E, Tsao CW, et al. Aortic Stiffness, Increased White Matter Free Water, and Altered Microstructural Integrity: A Continuum of Injury. Stroke. 2017;48(6):1567–73. Epub 2017/05/06. doi: 10.1161/STROKEAHA.116.016321 28473633; PubMed Central PMCID: PMC5502744.

12. Maillard P, Seshadri S, Beiser A, Himali JJ, Au R, Fletcher E, et al. Effects of systolic blood pressure on white-matter integrity in young adults in the Framingham Heart Study: a cross-sectional study. Lancet Neurol. 2012;11(12):1039–47. Epub 2012/11/06. doi: 10.1016/S1474-4422(12)70241-7 23122892; PubMed Central PMCID: PMC3510663.

13. Maillard P, Fletcher E, Singh B, Martinez O, Johnson DK, Olichney JM, et al. Cerebral white matter free water: A sensitive biomarker of cognition and function. Neurology. 2019;92(19):e2221–e31. Epub 2019/04/07. doi: 10.1212/WNL.0000000000007449 30952798; PubMed Central PMCID: PMC6537135.

14. Staszewski J, Skrobowska E, Piusinska-Macoch R, Brodacki B, Stepien A. IL-1alpha and IL-6 predict vascular events or death in patients with cerebral small vessel disease-Data from the SHEF-CSVD study. Adv Med Sci. 2019;64(2):258–66. Epub 2019/03/08. doi: 10.1016/j.advms.2019.02.003 30844663.

15. Staszewski J, Skrobowska E, Piusinska-Macoch R, Brodacki B, Stepien A. Cerebral and Extracerebral Vasoreactivity in Patients With Different Clinical Manifestations of Cerebral Small-Vessel Disease: Data From the Significance of Hemodynamic and Hemostatic Factors in the Course of Different Manifestations of Cerebral Small-Vessel Disease Study. J Ultrasound Med. 2019;38(4):975–87. Epub 2018/09/13. doi: 10.1002/jum.14782 30208231.

16. Low A, Mak E, Rowe JB, Markus HS, O'Brien JT. Inflammation and cerebral small vessel disease: A systematic review. Ageing Res Rev. 2019;53:100916. Epub 2019/06/11. doi: 10.1016/j.arr.2019.100916 31181331.

17. Walker KA, Power MC, Hoogeveen RC, Folsom AR, Ballantyne CM, Knopman DS, et al. Midlife Systemic Inflammation, Late-Life White Matter Integrity, and Cerebral Small Vessel Disease: The Atherosclerosis Risk in Communities Study. Stroke. 2017;48(12):3196–202. Epub 2017/11/05. doi: 10.1161/STROKEAHA.117.018675 29101255; PubMed Central PMCID: PMC5705320.

18. 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(8):825–32. Epub 2015/01/30. doi: 10.1212/WNL.0000000000001279 25632086; PubMed Central PMCID: PMC4345647.

19. Rabkin SW. The role of interleukin 18 in the pathogenesis of hypertension-induced vascular disease. Nat Clin Pract Cardiovasc Med. 2009;6(3):192–9. Epub 2009/02/24. doi: 10.1038/ncpcardio1453 19234499.

20. Jefferis BJ, Papacosta O, Owen CG, Wannamethee SG, Humphries SE, Woodward M, et al. Interleukin 18 and coronary heart disease: prospective study and systematic review. Atherosclerosis. 2011;217(1):227–33. Epub 2011/04/13. doi: 10.1016/j.atherosclerosis.2011.03.015 21481392; PubMed Central PMCID: PMC3146704.

21. Blankenberg S, Tiret L, Bickel C, Peetz D, Cambien F, Meyer J, et al. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation. 2002;106(1):24–30. Epub 2002/07/03. doi: 10.1161/01.cir.0000020546.30940.92 12093765.

22. Vidal-Vanaclocha F, Fantuzzi G, Mendoza L, Fuentes AM, Anasagasti MJ, Martin J, et al. IL-18 regulates IL-1beta-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1. Proc Natl Acad Sci U S A. 2000;97(2):734–9. Epub 2000/01/19. doi: 10.1073/pnas.97.2.734 10639148; PubMed Central PMCID: PMC15399.

23. Kaplanski G. Interleukin-18: Biological properties and role in disease pathogenesis. Immunol Rev. 2018;281(1):138–53. Epub 2017/12/17. doi: 10.1111/imr.12616 29247988.

24. Miwa K, Tanaka M, Okazaki S, Furukado S, Sakaguchi M, Kitagawa K. Relations of blood inflammatory marker levels with cerebral microbleeds. Stroke. 2011;42(11):3202–6. Epub 2011/08/27. doi: 10.1161/STROKEAHA.111.621193 21868735.

25. Hudson BI, Moon YP, Kalea AZ, Khatri M, Marquez C, Schmidt AM, et al. Association of serum soluble receptor for advanced glycation end-products with subclinical cerebrovascular disease: the Northern Manhattan Study (NOMAS). Atherosclerosis. 2011;216(1):192–8. Epub 2011/02/15. doi: 10.1016/j.atherosclerosis.2011.01.024 21316677; PubMed Central PMCID: PMC3089661.

26. Andersson C, Preis SR, Beiser A, DeCarli C, Wollert KC, Wang TJ, et al. Associations of Circulating Growth Differentiation Factor-15 and ST2 Concentrations With Subclinical Vascular Brain Injury and Incident Stroke. Stroke. 2015;46(9):2568–75. Epub 2015/07/30. doi: 10.1161/STROKEAHA.115.009026 26219649; PubMed Central PMCID: PMC4550531.

27. Bettcher BM, Fitch R, Wynn MJ, Lalli MA, Elofson J, Jastrzab L, et al. MCP-1 and eotaxin-1 selectively and negatively associate with memory in MCI and Alzheimer's disease dementia phenotypes. Alzheimers Dement (Amst). 2016;3:91–7. Epub 2016/07/28. doi: 10.1016/j.dadm.2016.05.004 27453930; PubMed Central PMCID: PMC4941041.

28. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47(D1):D607–D13. Epub 2018/11/27. doi: 10.1093/nar/gky1131 30476243; PubMed Central PMCID: PMC6323986.

29. Jenkinson M, Beckmann CF, Behrens TE, Woolrich MW, Smith SM. Fsl. Neuroimage. 2012;62(2):782–90. Epub 2011/10/08. doi: 10.1016/j.neuroimage.2011.09.015 21979382.

30. Jack CR Jr., O'Brien PC, Rettman DW, Shiung MM, Xu Y, Muthupillai R, et al. FLAIR histogram segmentation for measurement of leukoaraiosis volume. J Magn Reson Imaging. 2001;14(6):668–76. Epub 2001/12/18. doi: 10.1002/jmri.10011 11747022; PubMed Central PMCID: PMC2755497.

31. DeCarli C, Fletcher E, Ramey V, Harvey D, Jagust WJ. Anatomical mapping of white matter hyperintensities (WMH): exploring the relationships between periventricular WMH, deep WMH, and total WMH burden. Stroke. 2005;36(1):50–5. Epub 2004/12/04. doi: 10.1161/01.STR.0000150668.58689.f2 15576652; PubMed Central PMCID: PMC3816357.

32. Fletcher E, Singh B, Harvey D, Carmichael O, DeCarli C. Adaptive image segmentation for robust measurement of longitudinal brain tissue change. Conf Proc IEEE Eng Med Biol Soc. 2012;2012:5319–22. Epub 2013/02/01. doi: 10.1109/EMBC.2012.6347195 23367130; PubMed Central PMCID: PMC3776590.

33. Carmichael O, McLaren DG, Tommet D, Mungas D, Jones RN, Alzheimer's Disease Neuroimaging I. Coevolution of brain structures in amnestic mild cognitive impairment. Neuroimage. 2013;66:449–56. Epub 2012/10/30. doi: 10.1016/j.neuroimage.2012.10.029 23103689; PubMed Central PMCID: PMC3593811.

34. Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. AJR Am J Roentgenol. 1987;149(2):351–6. Epub 1987/08/01. doi: 10.2214/ajr.149.2.351 3496763.

35. Wahlund LO, Barkhof F, Fazekas F, Bronge L, Augustin M, Sjogren M, et al. A new rating scale for age-related white matter changes applicable to MRI and CT. Stroke. 2001;32(6):1318–22. Epub 2001/06/02. doi: 10.1161/01.str.32.6.1318 11387493.

36. Yilmaz P, Ikram MK, Niessen WJ, Ikram MA, Vernooij MW. Practical Small Vessel Disease Score Relates to Stroke, Dementia, and Death. Stroke. 2018;49(12):2857–65. Epub 2018/12/21. doi: 10.1161/STROKEAHA.118.022485 30571403.

37. Debette S, Markus HS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ. 2010;341:c3666. Epub 2010/07/28. doi: 10.1136/bmj.c3666 20660506; PubMed Central PMCID: PMC2910261.

38. Kissela B, Lindsell CJ, Kleindorfer D, Alwell K, Moomaw CJ, Woo D, et al. Clinical prediction of functional outcome after ischemic stroke: the surprising importance of periventricular white matter disease and race. Stroke. 2009;40(2):530–6. Epub 2008/12/26. doi: 10.1161/STROKEAHA.108.521906 19109548; PubMed Central PMCID: PMC2766300.

39. 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(8):1800–6. Epub 2011/05/24. doi: 10.1016/j.neurobiolaging.2011.04.008 21601314.

40. Boehme AK, McClure LA, Zhang Y, Luna JM, Del Brutto OH, Benavente OR, et al. Inflammatory Markers and Outcomes After Lacunar Stroke: Levels of Inflammatory Markers in Treatment of Stroke Study. Stroke. 2016;47(3):659–67. Epub 2016/02/19. doi: 10.1161/STROKEAHA.115.012166 26888535; PubMed Central PMCID: PMC4766076.

41. Welsh P, Barber M, Langhorne P, Rumley A, Lowe GD, Stott DJ. Associations of inflammatory and haemostatic biomarkers with poor outcome in acute ischaemic stroke. Cerebrovasc Dis. 2009;27(3):247–53. Epub 2009/01/30. doi: 10.1159/000196823 19176958.

42. Rost NS, Wolf PA, Kase CS, Kelly-Hayes M, Silbershatz H, Massaro JM, et al. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study. Stroke. 2001;32(11):2575–9. Epub 2001/11/03. doi: 10.1161/hs1101.098151 11692019.

43. Elkind MS, Luna JM, McClure LA, Zhang Y, Coffey CS, Roldan A, et al. C-reactive protein as a prognostic marker after lacunar stroke: levels of inflammatory markers in the treatment of stroke study. Stroke. 2014;45(3):707–16. Epub 2014/02/14. doi: 10.1161/STROKEAHA.113.004562 24523037; PubMed Central PMCID: PMC4114338.

44. Dinarello CA, Novick D, Kim S, Kaplanski G. Interleukin-18 and IL-18 binding protein. Front Immunol. 2013;4:289. Epub 2013/10/12. doi: 10.3389/fimmu.2013.00289 24115947; PubMed Central PMCID: PMC3792554.

45. Zaremba J, Losy J. Interleukin-18 in acute ischaemic stroke patients. Neurol Sci. 2003;24(3):117–24. Epub 2003/11/06. doi: 10.1007/s10072-003-0096-0 14600822.

46. Alboni S, Cervia D, Sugama S, Conti B. Interleukin 18 in the CNS. J Neuroinflammation. 2010;7:9. Epub 2010/02/02. doi: 10.1186/1742-2094-7-9 20113500; PubMed Central PMCID: PMC2830964.

47. Culhane AC, Hall MD, Rothwell NJ, Luheshi GN. Cloning of rat brain interleukin-18 cDNA. Mol Psychiatry. 1998;3(4):362–6. Epub 1998/08/14. doi: 10.1038/sj.mp.4000389 9702748.

48. Wheeler RD, Culhane AC, Hall MD, Pickering-Brown S, Rothwell NJ, Luheshi GN. Detection of the interleukin 18 family in rat brain by RT-PCR. Brain Res Mol Brain Res. 2000;77(2):290–3. Epub 2000/06/06. doi: 10.1016/s0169-328x(00)00069-3 10837926.

49. Jander S, Schroeter M, Stoll G. Interleukin-18 expression after focal ischemia of the rat brain: association with the late-stage inflammatory response. J Cereb Blood Flow Metab. 2002;22(1):62–70. Epub 2002/01/25. doi: 10.1097/00004647-200201000-00008 11807395.

50. Abulafia DP, de Rivero Vaccari JP, Lozano JD, Lotocki G, Keane RW, Dietrich WD. Inhibition of the inflammasome complex reduces the inflammatory response after thromboembolic stroke in mice. J Cereb Blood Flow Metab. 2009;29(3):534–44. Epub 2008/12/11. doi: 10.1038/jcbfm.2008.143 19066616.

51. Kim SH, Eisenstein M, Reznikov L, Fantuzzi G, Novick D, Rubinstein M, et al. Structural requirements of six naturally occurring isoforms of the IL-18 binding protein to inhibit IL-18. Proc Natl Acad Sci U S A. 2000;97(3):1190–5. Epub 2000/02/03. doi: 10.1073/pnas.97.3.1190 10655506; PubMed Central PMCID: PMC15564.

52. Mazodier K, Marin V, Novick D, Farnarier C, Robitail S, Schleinitz N, et al. Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome. Blood. 2005;106(10):3483–9. Epub 2005/07/16. doi: 10.1182/blood-2005-05-1980 16020503; PubMed Central PMCID: PMC1895045.

53. Novick D, Elbirt D, Dinarello CA, Rubinstein M, Sthoeger ZM. Interleukin-18 binding protein in the sera of patients with Wegener's granulomatosis. J Clin Immunol. 2009;29(1):38–45. Epub 2008/07/03. doi: 10.1007/s10875-008-9217-0 18594952.

54. Novick D, Elbirt D, Miller G, Dinarello CA, Rubinstein M, Sthoeger ZM. High circulating levels of free interleukin-18 in patients with active SLE in the presence of elevated levels of interleukin-18 binding protein. J Autoimmun. 2010;34(2):121–6. Epub 2009/08/25. doi: 10.1016/j.jaut.2009.08.002 19699611.

55. Gabay C, Fautrel B, Rech J, Spertini F, Feist E, Kotter I, et al. Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still's disease. Ann Rheum Dis. 2018;77(6):840–7. Epub 2018/02/24. doi: 10.1136/annrheumdis-2017-212608 29472362; PubMed Central PMCID: PMC5965361.

56. Canna SW, Girard C, Malle L, de Jesus A, Romberg N, Kelsen J, et al. Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition. J Allergy Clin Immunol. 2017;139(5):1698–701. Epub 2016/11/24. doi: 10.1016/j.jaci.2016.10.022 27876626; PubMed Central PMCID: PMC5846100.

57. Willerson JT, Ridker PM. Inflammation as a cardiovascular risk factor. Circulation. 2004;109(21 Suppl 1):II2–10. Epub 2004/06/03. doi: 10.1161/01.CIR.0000129535.04194.38 15173056.

58. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377(12):1119–31. Epub 2017/08/29. doi: 10.1056/NEJMoa1707914 28845751.

59. Hinman JD, Rost NS, Leung TW, Montaner J, Muir KW, Brown S, et al. Principles of precision medicine in stroke. J Neurol Neurosurg Psychiatry. 2017;88(1):54–61. Epub 2016/12/06. doi: 10.1136/jnnp-2016-314587 27919057.

60. Thrippleton MJ, Backes WH, Sourbron S, Ingrisch M, van Osch MJP, Dichgans M, et al. Quantifying blood-brain barrier leakage in small vessel disease: Review and consensus recommendations. Alzheimers Dement. 2019;15(6):840–58. Epub 2019/04/30. doi: 10.1016/j.jalz.2019.01.013 31031101; PubMed Central PMCID: PMC6565805.

61. Wardlaw J, Makin S, Valdes Hernandez Mdel C, Armitage PA, Heye AK, Chappell F, et al. Blood-brain barrier failure as a core mechanism in cerebral small vessel disease and dementia: evidence from a cohort study. Alzheimers Dement. 2017;13(6):634–43. doi: 10.1016/j.jalz.2016.09.006 PubMed Central PMCID: PMC5472180.

An IL-18-centered inflammatory network as a biomarker for cerebral white matter injury

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Zdroje

PLOS One

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