Cognitive risks in arterial hypertension: From mechanisms to prevention

Dementia remains one of the leading causes of global mortality and disability. Current evidence suggests that 40% of dementia cases could potentially be prevented or delayed by addressing modifiable risk factors, including arterial hypertension (AH). This review examines the pathophysiological relationship between AH and cognitive impairment (CI), along with practical approaches to patient management. Extensive epidemiological studies have established AH as a significant independent risk factor for CI, with cognitive deficits detected in 73.7% of hypertensive patients. The risk of CI increases by 7–16% with every 10 mm Hg elevation in systolic blood pressure (SBP), while severe dementia risk escalates 4.8 – fold when SBP exceeds 160 mmHg. The underlying mechanisms involve cerebral microangiopathy, white matter lesions, and neurodegenerative processes, which become particularly pronounced in cases of chronic uncontrolled hypertension. The cognitive impact of antihypertensive therapy remain controversial: while blood pressure control demonstrates neuroprotective potential, aggressive antihypertensive treatment in elderly patients may compromise cerebral perfusion. In this context, the combined neuroprotective agent containing a combination of extract from the leaves of Ginkgo biloba (EGb) and nicotinoyl gamma-aminobutyric acid (nicotinoyl GABA) – integrating vasoactive, neuroprotective and metabolic properties – emerges as a promising therapeutic option for AH patients with cognitive concerns. Clinical trial and observational data confirm that this unique combination of nicotinoyl GABA and EGb not only enhances cognitive performance but also alleviates anxiety and improves sleep quality. The drug demonstrates excellent compatibility with standard antihypertensive regimens, requires no dose adjustments for concomitant cardiovascular medications and shows efficacy across diverse age groups. Incorporating the complex drug containing nicotinoyl GABA and EGb into comprehensive AH management protocols may offer dual benefits: ameliorating existing cognitive deficits and potentially slowing their progression.

1. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413–446. https://doi.org/10.1016/S0140-6736(20)30367-6.

2. Starchina YuA, Parfyonov VA, Chazova IE, Pustovitova TS, Yakhno NN. Cognitive disturbances in patients with arterial hypertension. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2008;108(4):19–23. (In Russ.) Available at: https://www.elibrary.ru/isjlpd.

3. Launer LJ, Ross GW, Petrovitch H, Masaki K, Foley D, White LR, Havlik RJ. Midlife blood pressure and dementia: the Honolulu-Asia aging study. Neurobiol Aging. 2000;21(1):49–55. https://doi.org/10.1016/s0197-4580(00)00096-8.

4. Whitmer RA, Sidney S, Selby J, Johnston SC, Yaffe K. Midlife cardiovascular risk factors and risk of dementia in late life. Neurology. 2005;64(2):277–281. https://doi.org/10.1212/01.WNL.0000149519.47454.F2.

5. Yamada M, Kasagi F, Sasaki H, Masunari N, Mimori Y, Suzuki G. Association between dementia and midlife risk factors: the Radiation Effects Research Foundation Adult Health Study. J Am Geriatr Soc. 2003;51(3):410–414. https://doi.org/10.1046/j.1532-5415.2003.51117.x.

6. Yoshitake T, Kiyohara Y, Kato I, Ohmura T, Iwamoto H, Nakayama K et al. Incidence and risk factors of vascular dementia and Alzheimer’s disease in a defined elderly Japanese population: the Hisayama Study. Neurology. 1995;45(6):1161–1168. https://doi.org/10.1212/wnl.45.6.1161.

7. Posner HB, Tang MX, Luchsinger J, Lantigua R, Stern Y, Mayeux R. The relationship of hypertension in the elderly to AD, vascular dementia, and cognitive function. Neurology. 2002;58(8):1175–1181. https://doi.org/10.1212/wnl.58.8.1175.

8. McGrath ER, Beiser AS, DeCarli C, Plourde KL, Vasan RS, Greenberg SM, Seshadri S. Blood pressure from midto late life and risk of incident dementia. Neurology. 2017;89(24):2447–2454. https://doi.org/10.1212/WNL.0000000000004741.

9. Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K et al. Midlife vascular risk factors and Alzheimer’s disease in later life: longitudinal, population based study. BMJ. 2001;322(7300):1447–1451. https://doi.org/10.1136/bmj.322.7300.1447.

10. Shim YS, Shin HE. Impact of the ambulatory blood pressure monitoring profile on cognitive and imaging findings of cerebral small-vessel disease in older adults with cognitive complaints. J Hum Hypertens. 2022;36(1):14–23. https://doi.org/10.1038/s41371-021-00490-y.

11. Skoog I, Lernfelt B, Landahl S, Palmertz B, Andreasson LA, Nilsson L et al. 15year longitudinal study of blood pressure and dementia. Lancet. 1996;347(9009):1141–1145. https://doi.org/10.1016/s0140-6736(96)90608-x.

12. Qiu C, von Strauss E, Fastbom J, Winblad B, Fratiglioni L. Low blood pressure and risk of dementia in the Kungsholmen project: a 6-year follow-up study. Arch Neurol. 2003;60(2):223–228. https://doi.org/10.1001/ archneur.60.2.223.

13. Li G, Rhew IC, Shofer JB, Kukull WA, Breitner JC, Peskind E et al. Age-varying association between blood pressure and risk of dementia in those aged 65 and older: a community-based prospective cohort study. J Am Geriatr Soc. 2007;55(8):1161–1167. https://doi.org/10.1111/j.1532--5415.2007.01233.x.

14. Walker KA, Sharrett AR, Wu A, Schneider ALC, Albert M, Lutsey PL et al. Association of Midlife to Late-Life Blood Pressure Patterns With Incident Dementia. JAMA. 2019;322(6):535–545. https://doi.org/10.1001/jama.2019.10575.

15. Swan GE, DeCarli C, Miller BL, Reed T, Wolf PA, Jack LM, Carmelli D. Association of midlife blood pressure to late-life cognitive decline and brain morphology. Neurology. 1998;51(4):986–993. https://doi.org/10.1212/wnl.51.4.986.

16. Lopez OL, Jagust WJ, Dulberg C, Becker JT, DeKosky ST, Fitzpatrick A et al. Risk factors for mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 2. Arch Neurol. 2003;60(10):1394–1399. https://doi.org/10.1001/archneur.60.10.1394.

17. Zúñiga-Salazar GA, Hincapié-Arias SM, Salazar-Bolaños EE, Lara-Terán JJ, Cáceres-Vinueza SV, Duarte-Vera YC. Impact of arterial hypertension on the cognitive function of patients between 45 and 65 years. Luis Vernaza Hospital, Guayaquil, Ecuador. Arch Cardiol Mex. 2020;90(3):284–292. https://doi.org/10.24875/ACM.20000350.

18. Antonazzo B, Marano G, Romagnoli E, Ronzoni S, Frati G, Sani G, Janiri L, Mazza M. Impact of arterial hypertension and its management strategies on cognitive function and dementia: a comprehensive umbrella review. Minerva Cardiol Angiol. 2022;70(3):285–297. https://doi.org/10.23736/S2724-5683.20.05452-3.

19. Suzuki K, Masawa N, Sakata N, Takatama M. Pathologic evidence of microvascular rarefaction in the brain of renal hypertensive rats. J Stroke Cerebrovasc Dis. 2003;12(1):8–16. https://doi.org/10.1053/jscd.2003.1.

20. Zhang M, Mao Y, Ramirez SH, Tuma RF, Chabrashvili T. Angiotensin II induced cerebral microvascular inflammation and increased blood-brain barrier permeability via oxidative stress. Neuroscience. 2010;171(3):852–858. https://doi.org/10.1016/j.neuroscience.2010.09.029.

21. Toth P, Tucsek Z, Sosnowska D, Gautam T, Mitschelen M, Tarantini S et al. Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension. J Cereb Blood Flow Metab. 2013;33(11):1732–1742. https://doi.org/10.1038/jcbfm.2013.143.

22. Jiménez-Balado J, Riba-Llena I, Garde E, Valor M, Gutiérrez B, Pujadas F, Delgado P. Prevalence of hippocampal enlarged perivascular spaces in a sample of patients with hypertension and their relation with vascular risk factors and cognitive function. J Neurol Neurosurg Psychiatry. 2018;89(6):651–656. https://doi.org/10.1136/jnnp-2017-316724.

23. Alber J, Alladi S, Bae HJ, Barton DA, Beckett LA, Bell JM et al. White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): Knowledge gaps and opportunities. Alzheimers Dement. 2019;5:107–117. https://doi.org/10.1016/j.trci.2019.02.001.

24. Geerlings MI, Appelman AP, Vincken KL, Mali WP, van der Graaf Y. Association of white matter lesions and lacunar infarcts with executive functioning: the SMART-MR study. Am J Epidemiol. 2009;170(9):1147–1155. https://doi.org/10.1093/aje/kwp256.

25. Biesbroek JM, Weaver NA, Biessels GJ. Lesion location and cognitive impact of cerebral small vessel disease. Clin Sci. 2017;131(8):715–728. https://doi.org/10.1042/CS20160452.

26. Carnevale L, D’Angelosante V, Landolfi A, Grillea G, Selvetella G, Storto M et al. Brain MRI fiber-tracking reveals white matter alterations in hypertensive patients without damage at conventional neuroimaging. Cardiovasc Res. 2018;114(11):1536–1546. https://doi.org/10.1093/cvr/cvy104.

27. Ungvari Z, Tarantini S, Kirkpatrick AC, Csiszar A, Prodan CI. Cerebral microhemorrhages: mechanisms, consequences, and prevention. Am J Physiol Heart Circ Physiol. 2017;312(6):H1128–H1143. https://doi.org/10.1152/ajpheart.00780.2016.

28. Petrea RE, O’Donnell A, Beiser AS, Habes M, Aparicio H, DeCarli C et al. Mid to Late Life Hypertension Trends and Cerebral Small Vessel Disease in the Framingham Heart Study. Hypertension. 2020;76(3):707–714. https://doi.org/10.1161/HYPERTENSIONAHA.120.15073.

29. Petrovitch H, White LR, Izmirilian G, Ross GW, Havlik RJ, Markesbery W et al. Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS. Honolulu-Asia aging Study. Neurobiol Aging. 2000;21(1):57–62. https://doi.org/10.1016/s0197-4580(00)00106-8.

30. Iadecola C, Yaffe K, Biller J, Bratzke LC, Faraci FM, Gorelick PB et al. Impact of Hypertension on Cognitive Function: A Scientific Statement From the American Heart Association. Hypertension. 2016;68(6):e67–e94. https://doi.org/10.1161/HYP.0000000000000053.

31. Smits LL, van Harten AC, Pijnenburg YA, Koedam EL, Bouwman FH, Sistermans N et al. Trajectories of cognitive decline in different types of dementia. Psychol Med. 2015;45(5):1051–1059. https://doi.org/10.1017/S0033291714002153.

32. Sikaroodi H, Yadegari S, Miri SR. Cognitive impairments in patients with cerebrovascular risk factors: a comparison of Mini Mental Status Exam and Montreal Cognitive Assessment. Clin Neurol Neurosurg. 2013;115(8):1276–1280. https://doi.org/10.1016/j.clineuro.2012.11.026.

33. Smith EE, Muzikansky A, McCreary CR, Batool S, Viswanathan A, Dickerson BC et al. Impaired memory is more closely associated with brain beta-amyloid than leukoaraiosis in hypertensive patients with cognitive symptoms. PLoS ONE. 2018;13(1):e0191345. https://doi.org/10.1371/journal.pone.0191345.

34. Reed BR, Mungas DM, Kramer JH, Ellis W, Vinters HV, Zarow C et al. Profiles of neuropsychological impairment in autopsy-defined Alzheimer’s disease and cerebrovascular disease. Brain. 2007;130(Pt 3):731–739. https://doi.org/10.1093/brain/awl385.

35. Noh J, Kim HC, Shin A, Yeom H, Jang SY, Lee JH et al. Prevalence of Comorbidity among People with Hypertension: The Korea National Health and Nutrition Examination Survey 2007–2013. Korean Circ J. 2016;46(5):672–680. https://doi.org/10.4070/kcj.2016.46.5.672.

36. Trauernicht AK, Sun H, Patel KP, Mayhan WG. Enalapril prevents impaired nitric oxide synthase-dependent dilatation of cerebral arterioles in diabetic rats. Stroke. 2003;34(11):2698–26703. https://doi.org/10.1161/01.STR.0000092121.62649.DC.

37. Valcarcel-Ares MN, Tucsek Z, Kiss T, Giles CB, Tarantini S, Yabluchanskiy A et al. Obesity in Aging Exacerbates Neuroinflammation, Dysregulating Synaptic Function-Related Genes and Altering Eicosanoid Synthesis in the Mouse Hippocampus: Potential Role in Impaired Synaptic Plasticity and Cognitive Decline. J Gerontol A Biol Sci Med Sci. 2019;74(3):290–298. https://doi.org/10.1093/gerona/gly127.

38. Viggiano D, Wagner CA, Martino G, Nedergaard M, Zoccali C, Unwin R, Capasso G. Mechanisms of cognitive dysfunction in CKD. Nat Rev Nephrol. 2020;16(8):452–469. https://doi.org/10.1038/s41581-020-0266-9.

39. Hooghiemstra AM, Leeuwis AE, Bertens AS, Biessels GJ, Bots ML, BrunnerLa Rocca HP et al. Frequent Cognitive Impairment in Patients With Disorders Along the Heart-Brain Axis. Stroke. 2019;50(12):3369–3375. https://doi.org/10.1161/STROKEAHA.119.026031.

40. Gottesman RF, Schneider AL, Albert M, Alonso A, Bandeen-Roche K, Coker L et al. Midlife hypertension and 20-year cognitive change: the atherosclerosis risk in communities neurocognitive study. JAMA Neurol. 2014;71(10):1218–1227. https://doi.org/10.1001/jamaneurol.2014.1646.

41. Derby CA, Hutchins F, Greendale GA, Matthews KA, Sternfeld B, EversonRose SA et al. Cardiovascular risk and midlife cognitive decline in the Study of Women’s Health Across the Nation. Alzheimers Dement. 2021;17(8):1342–1352. https://doi.org/10.1002/alz.12300.

42. Lande MB, Kupferman JC. Blood Pressure and Cognitive Function in Children and Adolescents. Hypertension. 2019;73(3):532–540. https://doi.org/10.1161/HYPERTENSIONAHA.118.11686.

43. Yaffe K, Vittinghoff E, Pletcher MJ, Hoang TD, Launer LJ, Whitmer R, Coker LH, Sidney S. Early adult to midlife cardiovascular risk factors and cognitive function. Circulation. 2014;129(15):1560–1567. https://doi.org/10.1161/CIRCULATIONAHA.113.004798.

44. Mahinrad S, Kurian S, Garner CR, Sedaghat S, Nemeth AJ, Moscufo N et al. Cumulative Blood Pressure Exposure During Young Adulthood and Mobility and Cognitive Function in Midlife. Circulation. 2020;141(9):712–724. https://doi.org/10.1161/CIRCULATIONAHA.119.042502.

45. Nordström P, Nordström A, Eriksson M, Wahlund LO, Gustafson Y. Risk factors in late adolescence for young-onset dementia in men: a nationwide cohort study. JAMA Intern Med. 2013;173(17):1612–1628. https://doi.org/10.1001/jamainternmed.2013.9079.

46. Qiu C, Winblad B, Fratiglioni L. The age-dependent relation of blood pressure to cognitive function and dementia. Lancet Neurol. 2005;4(8):487–499. https://doi.org/10.1016/S1474-4422(05)70141-1.

47. Waldstein SR, Giggey PP, Thayer JF, Zonderman AB. Nonlinear relations of blood pressure to cognitive function: the Baltimore Longitudinal Study of Aging. Hypertension. 2005;45(3):374–379. https://doi.org/10.1161/01.HYP.0000156744.44218.74.

48. Legdeur N, Heymans MW, Comijs HC, Huisman M, Maier AB, Visser PJ. Age dependency of risk factors for cognitive decline. BMC Geriatr. 2018;18(1):187. https://doi.org/10.1186/s12877-018-0876-2.

49. Emdin CA, Rothwell PM, Salimi-Khorshidi G, Kiran A, Conrad N, Callender T et al. Blood Pressure and Risk of Vascular Dementia: Evidence From a Primary Care Registry and a Cohort Study of Transient Ischemic Attack and Stroke. Stroke. 2016;47(6):1429–1435. https://doi.org/10.1161/STROKEAHA.116.012658.

50. Ungvari Z, Yabluchanskiy A, Tarantini S, Toth P, Kirkpatrick AC, Csiszar A, Prodan CI. Repeated Valsalva maneuvers promote symptomatic manifestations of cerebral microhemorrhages: implications for the pathogenesis of vascular cognitive impairment in older adults. Geroscience. 2018;40(5-6): 485–496. https://doi.org/10.1007/s11357-018-0044-9.

51. Levine DA, Galecki AT, Langa KM, Unverzagt FW, Kabeto MU, Giordani B et al. Blood Pressure and Cognitive Decline Over 8 Years in Middle-Aged and Older Black and White Americans. Hypertension. 2019;73(2):310–318. https://doi.org/10.1161/HYPERTENSIONAHA.118.12062.

52. Forette F, Seux ML, Staessen JA, Thijs L, Birkenhäger WH, Babarskiene MR et al. Prevention of dementia in randomised double-blind placebocontrolled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet. 1998;352(9137):1347–1351. https://doi.org/10.1016/s0140-6736(98)03086-4.

53. Peters R, Beckett N, Forette F, Tuomilehto J, Clarke R, Ritchie C et al. Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a doubleblind, placebo controlled trial. Lancet Neurol. 2008;7(8):683–689. https://doi.org/10.1016/S1474-4422(08)70143-1.

54. Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association/ american stroke association. Stroke. 2011;42(9):2672–2713. https://doi.org/10.1161/STR.0b013e3182299496.

55. Rouch L, Cestac P, Hanon O, Cool C, Helmer C, Bouhanick B et al. Antihypertensive drugs, prevention of cognitive decline and dementia: a systematic review of observational studies, randomized controlled trials and meta-analyses, with discussion of potential mechanisms. CNS Drugs. 2015;29(2):113–130. https://doi.org/10.1007/s40263-015-0230-6.

56. de Menezes ST, Giatti L, Brant LCC, Griep RH, Schmidt MI, Duncan BB et al. Hypertension, Prehypertension, and Hypertension Control: Association With Decline in Cognitive Performance in the ELSA-Brasil Cohort. Hypertension. 2021;77(2):672–681. https://doi.org/10.1161/HYPERTENSIONAHA.120.16080.

57. Tzourio C, Anderson C, Chapman N, Woodward M, Neal B, MacMahon S et al. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med. 2003;163(9):1069–1075. https://doi.org/10.1001/archinte.163.9.1069.

58. Tzourio C, Dufouil C, Ducimetière P, Alpérovitch A. Cognitive decline in individuals with high blood pressure: a longitudinal study in the elderly. EVA Study Group. Epidemiology of Vascular Aging. Neurology. 1999;53(9):1948–1952. https://doi.org/10.1212/wnl.53.9.1948.

59. Barthold D, Joyce G, Wharton W, Kehoe P, Zissimopoulos J. The association of multiple anti-hypertensive medication classes with Alzheimer’s disease incidence across sex, race, and ethnicity. PLoS ONE. 2018;13(11):e0206705. https://doi.org/10.1371/journal.pone.0206705.

60. Hughes D, Judge C, Murphy R, Loughlin E, Costello M, Whiteley W et al. Association of Blood Pressure Lowering With Incident Dementia or Cognitive Impairment: A Systematic Review and Meta-analysis. JAMA. 2020;323(19):1934–1944. https://doi.org/10.1001/jama.2020.4249.

61. Tu K, Anderson LN, Butt DA, Quan H, Hemmelgarn BR, Campbell NR et al. Antihypertensive drug prescribing and persistence among new elderly users: implications for persistence improvement interventions. Can J Cardiol. 2014;30(6):647–652. https://doi.org/10.1016/j.cjca.2014.03.017.

62. Quitterer U, AbdAlla S. Improvements of symptoms of Alzheimer`s disease by inhibition of the angiotensin system. Pharmacol Res. 2020;154:104230. https://doi.org/10.1016/j.phrs.2019.04.014.

63. Hachinski V, Einhäupl K, Ganten D, Alladi S, Brayne C, Stephan BCM et al. Preventing dementia by preventing stroke: The Berlin Manifesto. Alzheimers Dement. 2019;15(7):961–984. https://doi.org/10.1016/j.jalz.2019.06.001.

64. Friberg L, Rosenqvist M. Less dementia with oral anticoagulation in atrial fibrillation. Eur Heart J. 2018;39(6):453–460. https://doi.org/10.1093/ eurheartj/ehx579.

65. de Leeuw FE, de Groot JC, Oudkerk M, Witteman JC, Hofman A, van Gijn J, Breteler MM. Hypertension and cerebral white matter lesions in a prospective cohort study. Brain. 2002;125(Pt 4):765–772. https://doi.org/10.1093/brain/awf077.

66. van Dijk EJ, Breteler MM, Schmidt R, Berger K, Nilsson LG, Oudkerk M et al. The association between blood pressure, hypertension, and cerebral white matter lesions: cardiovascular determinants of dementia study. Hypertension. 2004;44(5):625–630. https://doi.org/10.1161/01.HYP.0000145857.98904.20.

67. Williamson JD, Pajewski NM, Auchus AP, Bryan RN, Chelune G, Cheung AK et al. Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial. JAMA. 2019;321(6):553–561. https://doi.org/10.1001/jama.2018.21442.

68. Lv YB, Zhu PF, Yin ZX, Kraus VB, Threapleton D, Chei CL et al. A U-shaped Association Between Blood Pressure and Cognitive Impairment in Chinese Elderly. J Am Med Dir Assoc. 2017;18(2):193.e7–193.e13. https://doi.org/10.1016/j.jamda.2016.11.011.

69. Nilsson SE, Read S, Berg S, Johansson B, Melander A, Lindblad U. Low systolic blood pressure is associated with impaired cognitive function in the oldest old: longitudinal observations in a population-based sample 80 years and older. Aging Clin Exp Res. 2007;19(1):41–47. https://doi.org/ 10.1007/BF03325209.

70. Prince MJ, Bird AS, Blizard RA, Mann AH. Is the cognitive function of older patients affected by antihypertensive treatment? Results from 54 months of the Medical Research Council’s trial of hypertension in older adults. BMJ. 1996;312(7034):801–805. https://doi.org/10.1136/bmj.312.7034.801.

71. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265(24):3255–3264. Available at: https://pubmed.ncbi.nlm.nih.gov/2046107/.

72. Bosch J, O’Donnell M, Swaminathan B, Lonn EM, Sharma M, Dagenais G et al. Effects of blood pressure and lipid lowering on cognition: Results from the HOPE-3 study. Neurology. 2019;92(13):e1435–e1446. https://doi.org/10.1212/WNL.0000000000007174.

73. Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003;21(5):875–886. https://doi.org/10.1097/00004872-200305000-00011.

74. Peters R, Warwick J, Anstey KJ, Anderson CS. Blood pressure and dementia: What the SPRINT-MIND trial adds and what we still need to know. Neurology. 2019;92(21):1017–1018. https://doi.org/10.1212/WNL.0000000000007543.

75. Fryar CD, Ostchega Y, Hales CM, Zhang G, Kruszon-Moran D. Hypertension Prevalence and Control Among Adults: United States, 2015–2016. NCHS Data Brief. 2017;(289):1–8. Available at: https://pubmed.ncbi.nlm.nih.gov/29155682/.

76. Putilina MV. Arterial hypertension as a global neurological problem and the prospect of multifactorial cerebroprotection: Focus on combination drugs. Meditsinskiy Sovet. 2024;(12):15–20. (In Russ.) https://doi.org/10.21518/ms2024-278.

77. Noor-E-Tabassum, Das R, Lami MS, Chakraborty AJ, Mitra S, Tallei TE et al. Ginkgo biloba: A Treasure of Functional Phytochemicals with Multimedicinal Applications. Evid Based Complement Alternat Med. 2022;2022:8288818. https://doi.org/10.1155/2022/8288818.

78. Abdel-Zaher AO, Farghaly HSM, El-Refaiy AEM, Abd-Eldayem AM. Protective effect of the standardized extract of ginkgo biloba (EGb761) against hypertension with hypercholesterolemia-induced renal injury in rats: Insights in the underlying mechanisms. Biomed Pharmacother. 2017;95:944–955. https://doi.org/10.1016/j.biopha.2017.08.078.

79. Amieva H, Meillon C, Helmer C, Barberger-Gateau P, Dartigues JF. Ginkgo biloba extract and long-term cognitive decline: a 20-year follow-up population-based study. PLoS ONE. 2013;8(1):e52755. https://doi.org/10.1371/journal.pone.0052755.

80. DeKosky ST, Williamson JD, Fitzpatrick AL, Kronmal RA, Ives DG, Saxton JA et al. Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA. 2008;300(19):2253–2262. https://doi.org/10.1001/jama.2008.683.

81. Vellas B, Coley N, Ousset PJ, Berrut G, Dartigues JF, Dubois B et al. Longterm use of standardised Ginkgo biloba extract for the prevention of Alzheimer’s disease (GuidAge): a randomised placebo-controlled trial. Lancet Neurol. 2012;11(10):851–859. https://doi.org/10.1016/S1474-4422(12)70206-5.

82. Silkina IV, Gan’shina TS, Seredenin SB, Mirzoyan RS. Gabaergic mechanism of cerebrovascular and neuroprotective effects of afobazole and picamilon. Eksperimentalnaya i Klinicheskaya Farmakologiya. 2005;1(68):2–24. (In Russ.) Available at: https://www.ekf.folium.ru/index.php/ekf/article/ view/1082.

83. Lihodeeva VA, Spasov AA, Isupov IB, Mandrikov VB. The influence of picamilon parameters of cerebral microcirculation of disadaptation swimmers in the types systemic hemodynamics. Journal of New Medical Technologies. 2011;18(1):150–153. (In Russ.) Available at: https://med-click.ru/uploads/files/docs/vliyanie-pikamilona-na-parametry-tserebralnogo-krovotoka-dizadaptirovannyh-plovtsov-s-raznymi-tipami-sistemnoy-gemodinamiki.pdf.

84. emianovskaya EG, Vasilev AS, Shmyrev VI. Cognitive impairments in young and middle-aged patients. Lechaschi Vrach. 2023;26(5):48–54. (In Russ.) https://doi.org/10.51793/OS.2023.26.5.008.

85. Putilina MV. A young patient at a neurologist’s appointment: features of diagnostics and therapy. Meditsinskiy Sovet. 2023;17(10):146–152. (In Russ.) https://doi.org/10.21518/ms2023-225.

86. Zakharov VV, Borodulina IV, Vakhnina NV. Treatment of patients with chronic cerebral ischemia: experience of using the combined neuroprotective drug Picamilon Ginkgo. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2022;122(9):95–103. (In Russ.) https://doi.org/10.17116/jnevro202212209195.

87. Yakhno NN, Zakharov VV, Koberskaya NN, Mkhitaryan EA, Grishina DA, Lokshina AB et al. Premild (subjective and subtle) cognitive disorders. Nevrologicheskii Zhurnal. 2017;22(4):198–204. (In Russ.) https://doi.org/10.18821/1560-9545-2017-22-4-198-204.

88. Baranova EI, Katsap AA, Kolesnik OS, Lebedeva EV. Hypertension in periand postmenopausal women – pathophysiological mechanisms and approaches to treatment. Russian Journal of Cardiology. 2023;28(5):5439. (In Russ.) https://doi.org/10.15829/1560-4071-2023-5439.

89. Gasparyan SA, Chotchaeva AM, Karpov SM. Cognitive and psychoemotional changes in menopausal transition: The possibility of medical correction. Problemy Endokrinologii. 2023;69(1):86–95. (In Russ.) https://doi.org/10.14341/probl13205.

90. Bone KM. Potential interaction of Ginkgo biloba leaf with antiplatelet or anticoagulant drugs: what is the evidence? Mol Nutr Food Res. 2008;52(7):764–771. https://doi.org/10.1002/mnfr.200700098.

91. Chan AL, Leung HW, Wu JW, Chien TW. Risk of hemorrhage associated with co-prescriptions for Ginkgo biloba and antiplatelet or anticoagulant drugs. J Altern Complement Med. 2011;17(6):513–517. https://doi.org/10.1089/acm.2010.0295.

92. Wolf HR. Does Ginkgo biloba special extract EGb 761 provide additional effects on coagulation and bleeding when added to acetylsalicylic acid 500 mg daily? Drugs R D. 2006;7(3):163–172. https://doi.org/10.2165/00126839-200607030-00003.

93. Katunina EA. Ginkgo biloba: Results of Half a Century of Clinical Use. Polymodal Effects of Ginkgo biloba: Experimental and Clinical Studies. Rheumatology Science and Practice. 2013;(2):53–57. (In Russ.) Available at: https://omnidoctor.ru/upload/iblock/a59/a5924627a37e263a664ccd673bdc5dc7.pdf.