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Dose–response association between plasma homocysteine and white matter lesions in patients with hypertension: a case–control study

Hypertension Research volume 45, pages 1794–1801 (2022)Cite this article

Abstract

White matter lesions (WMLs) are common MRI changes that are indicative of cerebral small vessel disease (CSVD). Elevated plasma homocysteine (Hcy) levels are related to an increased risk of vascular disease. We aimed to analyze the relationship between Hcy levels and WMLs in patients with hypertension. A total of 1961 patients with WMLs and 15,463 patients without WMLs were matched at a 1:1 ratio by age and sex. Hyperhomocysteinemia (HHcy) was defined as an abnormally high level (>15 µmol/l) of Hcy in a plasma sample. In total, 1888 (WML group) and 1888 (No-WMLs group) patients were enrolled, with 51.6% of the sample being male and a mean age of 63 years. Multivariate logistic regression analysis showed a significant association between a higher level of plasma Hcy and a higher prevalence of WMLs (OR 1.03 95% CI, 1.02–1.04) when the Hcy level was used as a continuous variable. Patients with Hcy levels of 15–20 µmol/l (OR 1.54, 95% CI 1.31–1.81) and >20 µmol/l (OR 1.51, 95% CI 1.26–1.82) also had a significantly higher risk of WMLs than patients with Hcy levels <15 µmol/l. Multivariable-adjusted spline regression models showed that the risk of WMLs started to increase only in patients with Hcy levels above 13.85 µmol/l (P < 0.001). In subgroup analyses of WMLs, there was no significant interaction between the Hcy group and subgroup heterogeneity for the prevalence of WMLs (P > 0.05). Our study found a dose–response association between plasma homocysteine levels, especially a Hcy level >13.85 µmol/l, and the prevalence of WMLs, implying that lowering Hcy levels might be a target for prevention.

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References

  1. Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12:822–38.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Caligiuri ME, Perrotta P, Augimeri A, Rocca F, Quattrone A, Cherubini A. Automatic detection of white matter hyperintensities in healthy aging and pathology using magnetic resollauce knagmg: a review. Neuromformatics. 2015;13:261–76.

    Article  Google Scholar 

  3. Kloppenborg RP, Nederkoorn PJ, Geerlings MI, van den Berg E. Presence and progression of white matter hyperintensities and cognition: a meta-analysis. Neurology. 2014;82:2127–38.

    Article  PubMed  Google Scholar 

  4. Hainsworth AH, Minett T, Andoh J, Forster G, Bhide I, Barrick TR, et al. Neuropathology of white matter lesions, blood-brain barrier dysfunction, and dementia. Stroke. 2017;48:2799–804.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Coutu JP, Goldblatt A, Rosas HD, Salat DH. Alzheimer’s Disease Neuroimaging Initiative (ADNI). White matter changes are associated with ventricular expansion in aging, mild cognitive impairment, and Alzheimer’S disease. J Alzheimers Dis. 2016;49:329–42.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Wang L, Leonards CO, Sterzer P, Ebinger M. White matter lesions and depression: a systematic review and meta-analysis. J Psychiatr Res. 2014;56:56–64.

    Article  PubMed  Google Scholar 

  7. Kuller LH, Longstreth WT Jr, Arnold AM, Bernick C, Bryan RN, Beauchamp NJ Jr. Cardiovascular Health Study Collaborative Research Group. White matter hyperintensity on cranial magnetic resonance imaging: a predictor of stroke. Stroke. 2004;35:1821–5.

    Article  PubMed  Google Scholar 

  8. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9:689–701.

    Article  PubMed  Google Scholar 

  9. Wolfson L, Wakefield DB, Moscufo N, Kaplan RF, Hall CB, Schmidt JA, et al. Rapid buildup of brain white matter hyperintensities over 4 years linked toambulatory blood pressure, mobility, cognition, and depression in old persons. J Gerontol A Biol Sci Med Sci. 2013;68:1387–94.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Guevarra AC, Ng SC, Saffari SE, Wong BYX, Chander RJ, Ng KP, et al. Age moderates associations of hypertension, white matter hyperintensities, and cognition. J Alzheimers Dis. 2020;75:1351–60.

    Article  PubMed  Google Scholar 

  11. Habes M, Erus G, Toledo JB, Zhang T, Bryan N, Launer LJ, et al. White matterhyperintensities and imaging patterns of brain ageing in the general population. Brain. 2016;139:1164–79.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Abraham HM, Wolfson L, Moscufo N, Guttmann CR, Kaplan RF, White WB. Cardiovascular risk factors and small vessel disease of the brain: blood pressure, white matter lesions, and functional decline in older persons. J Cereb Blood Flow Metab. 2016;36:132–42.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Gottesman RF, Schneider AL, Albert M, Alonso A, Bandeen-Roche K, Coker L, et al. Midlife hypertention and 20-year cognitive change: the atherosclerosis risk in communities neurocognitive study. JAMA Neurol. 2014;21287:1–10.

    Google Scholar 

  14. Godin O, Tzourio C, Maillard P, Mazoyer B, Dufouil C. Antihypertensive treatment and change in blood pressure are associated with the progression of white matter lesion volumes: the Three-City (3C)-Dijon Magnetic Resonance Imaging Study. Circulation. 2011;123:266–73.

    Article  PubMed  Google Scholar 

  15. Wang DQ, Wang L, Wei MM, Xia XS, Tian XL, Cui XH, et al. Relationship between type 2 diabetes and white matter hyperintensity: a systematic review. Front Endocrinol. 2020;11:595962.

    Article  Google Scholar 

  16. Rist PM, Buring JE, Rexrode KM, Cook NR, Rost NS. Prospectively collected lifestyle and health information as risk factors for white matter hyperintensity volume in stroke patients. Eur J Epidemiol. 2019;34:957–65.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Andreescu C, Tudorascu D, Sheu LK, Rangarajan A, Butters MA, Walker S, et al. Brain structural changes in late-life generalized anxiety disorder. Psychiatry Res Neuroimaging. 2017;268:15–21.

    Article  PubMed  Google Scholar 

  18. Karcher HS, Holzwarth R, Mueller HP, Ludolph AC, Huber R, Kassubek J, et al. Body fat distribution as a risk factor for cerebrovascular disease: an MRI-based body fat quantification study. Cerebrovasc Dis. 2013;35:341–8.

    Article  PubMed  Google Scholar 

  19. Smith AD, Refsum H. Homocysteine, B vitamins, and cognitive impairment. Annu Rev Nutr. 2016;36:211–39.

    Article  PubMed  CAS  Google Scholar 

  20. Tinelli C, Di Pino A, Ficulle E, Marcelli S, Feligioni M. Hyperhomocysteinemia as a risk factor and potential nutraceutical target for certain pathologies. Front Nutr. 2019;6:49.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Cao L, Guo Y, Zhu Z. Effects of hyperhomocysteinemia on ischemic cerebral small vessel disease and analysis of inflammatory mechanisms. Int J Neurosci. 2021;131:362–9.

    Article  PubMed  CAS  Google Scholar 

  22. Wang CY, Chen ZW, Zhang T, Liu J, Chen SH, Liu SY, et al. Elevated plasma homocysteine level is associated with ischemic stroke in Chinese hypertension patients. Eur J Intern Med. 2014;25:538–44.

    Article  PubMed  CAS  Google Scholar 

  23. Lorius N, Locascio JJ, Rentz DM, Johnson KA, Sperling RA, Viswanathan A, et al. Vascular disease and risk factors are associated with cognitive decline in the Alzheimer disease spectrum. Alzheimer Dis Assoc Disord. 2019;29:18–25.

    Article  Google Scholar 

  24. Nelson ME, Andel R, Nedelska Z, Martinkova J, Cechova K, Markova H, et al. The association between homocysteine and memory in older adults. J Alzheimer Dis. 2021;81:413–26.

    Article  CAS  Google Scholar 

  25. Smith AD, Refsum H, Bottiglieri T, Fenech M, Hooshmand B, McCaddon A, et al. Homocysteine and dementia: an international consensus statement. J Alzheimers Dis. 2018;62:561–70.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Tu W, Yan F, Chao B, Ji X, Wang L. Status of hyperhomocysteinemia in China: results from the China Stroke High-risk Population Screening Program, 2018. Front Med. 2021;15:903–12.

    Article  PubMed  Google Scholar 

  27. Zhao W, Gao F, Lv L, Chen X. The interaction of hypertension and homocysteine increases the risk of mortality among middle-aged and older population in the United States. J Hypertens. 2022;40:254–63.

  28. Shokouhi M, Qiu D, Samman Tahhan A, Quyyumi AA, Hajjar I. Differential Associations of diastolic and systolic pressures with cerebral measures in older individuals with mild cognitive impairment. Am J Hypertens. 2018;31:1268–77.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Gottesman RF, Schneider AL, Albert M, Alonso A, Bandeen-Roche K, Coker L, et al. Midlife hypertention and 20-year cognitive change: the atherosclerosis risk in communities neurocognitive study. JAMA Neurol. 2014;21287:1–10.

    Google Scholar 

  30. Li M, Fu B, Dong W. Correlations between plasma homocysteine and MTHFR gene polymorphism and white matter lesions. Folia Neuropathol. 2018;56:301–7.

    Article  PubMed  Google Scholar 

  31. Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet. 1999;354:407–13. 31

    Article  PubMed  CAS  Google Scholar 

  32. Katsiki N, Perez-Martinez P, Mikhailidis DP. Homocysteine and non-cardiac vascular disease. Curr Pharm Des. 2017;23:3224–32.

    Article  PubMed  CAS  Google Scholar 

  33. Khan U, Crossley C, Kalra L, Rudd A, Wolfe CD, Collinson P, et al. Homocysteine and its relationship to stroke subtypes in a UK black population: the South London Ethnicity and Stroke Study. Stroke. 2008;39:2943–9.

    Article  PubMed  CAS  Google Scholar 

  34. Linnebank M, Moskau S, Jürgens A, Simon M, Semmler A, Orlopp K, et al. Association of genetic variants of methionine metabolism with methotrexate‐induced CNS white matter changes in patients with primary CNS lymphoma. Neuro Oncol. 2009;11:2–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Hong ED, Taylor WD, McQuoid DR, Potter GG, Payne ME, Ashley‐Koch A, et al. Influence of the MTHFR C677T polymorphism on magnetic resonance imaging hyperintensity volume and cognition in geriatric depression. Am J Geriatr Psychiatry. 2009;17:847–55.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Cuadrado-Godia E, Dwivedi P, Sharma S, Ois Santiago A, Roquer Gonzalez J, Balcells M, et al. Cerebral small vessel disease: a review focusing on pathophysiology, biomarkers, and machine learning strategies. J Stroke. 2018;20:302–20.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Moretti R, Caruso P. The controversial role of homocysteine in neurology: from labs to clinical practice. Int J Mol Sci. 2019;20:231.

    Article  PubMed Central  Google Scholar 

  38. Cao L, Guo Y, Zhu Z. Effects of hyperhomocysteinemia on ischemic cerebral small vessel disease and analysis of inflammatory mechanisms. Int J Neurosci. 2021;131:362–9.

    Article  PubMed  CAS  Google Scholar 

  39. Pang X, Liu J, Zhao J, Mao J, Zhang X, Feng L, et al. Homocysteine induces the expression of C-reactive protein via NMDAr-ROS-MAPK-NF-KB signal pathway in rat vascular smooth muscle cells. Atherosclerosis. 2014;236:73–81.

    Article  PubMed  CAS  Google Scholar 

  40. Ma Y, Zhao X, Zhang W, Liu L, Wang Y, Fang R, et al. Homocysteine and ischemic stroke subtype: a relationship study in Chinese patients. Neurol Res. 2010;32:636–41.

    Article  PubMed  CAS  Google Scholar 

  41. Feng C, Bai X, Xu Y, Hua T, Huang J, Liu XY. Hyperhomocysteinemia associates with small vessel disease more closely than large vessel disease. Int J Med Sci. 2013;10:408–12.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Shi Z, Guan Y, Huo YR, Liu S, Zhang M, Lu H, et al. Elevated total homocysteine levels in acute ischemic stroke are associated with long-term mortality. Stroke. 2015;46:2419–25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Cavalieri M, Schmidt R, Chen C, Mok V, deFreitas GR, Song S, et al. VITATOPS Trial Study Group. B vitamins and magnetic resonance imaging-detected ischemic brain lesions in patients with recent transient ischemic attack or stroke: the VITAmins TO Prevent Stroke (VITATOPS) MRI-substudy. Stroke. 2012;43:3266–70.

    Article  PubMed  CAS  Google Scholar 

  44. Ting SKS, Earnest A, Li H, Hameed S, Chang HM, Chen CLH, et al. B vitamins and cognition in subjects with small vessel disease: a substudy of VITATOPS, a randomized, placebo-controlled trial. J Neurol Sci. 2017;379:124–6.

    Article  PubMed  CAS  Google Scholar 

  45. Larsson SC, Traylor M, Markus HS. Homocysteine and small vessel stroke: a mendelian randomization analysis. Ann Neurol. 2019;85:495–501.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

Study concept and design: Yujuan Yuan. Data collection: Yujuan Yuan, Xintian Cai, Yan Liu. Drafting the manuscript: Yujuan Yuan. Data interpretation: all authors. Critical revision of the manuscript: all authors. All the authors have read and approved the final manuscript. The Ethics Committee of the People’s Hospital of Xinjiang Uygur Autonomous Region approved the study. Due to the retrospective nature of the study and the use of anonymized data, the need for informed consent was waived.

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  1. Xinjiang Medical University, Urumqi, China

    Yujuan Yuan & Xintian Cai

  2. Hypertension Center of People’s Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hypertension Institute, National Health Committee Key Laboratory of Hypertension Clinical Research, Key Laboratory of Xinjiang Uygur Autonomous Region “Hypertension Research Laboratory, Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, China

    Yan Liu & Nanfang Li

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Yuan, Y., Cai, X., Liu, Y. et al. Dose–response association between plasma homocysteine and white matter lesions in patients with hypertension: a case–control study. Hypertens Res 45, 1794–1801 (2022). https://doi.org/10.1038/s41440-022-00999-w

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