Diagnosis and therapy of cognitive impairment in chronic cerebral ischemia

Chronic cerebral ischemia is a common condition associated with progressive brain damage that manifests itself in various neurological disorders, including cognitive impairment. One of the etiologic factors of vascular disorders is arterial hypertension. The article discusses types of cognitive impairment and pathogenetic mechanisms of their formation. The role of the glymphatic system of the brain, the role of neuroinflammation in the implementation of cognitive impairment are discussed. The described clinical case shows the need to supplement basic therapy in patients with hypertension with drugs of other groups, in particular pentoxifylline, to improve the effectiveness of therapy. The article reviews the latest clinical and experimental studies of pentoxifylline, which show its positive effect on inflammation, endothelial dysfunction and, as a result, improvement of cognitive functions. The neuroprotective effect of pentoxifylline, which has been confirmed in experimental and clinical studies, is discussed. The possibility of using pentoxifylline in patients with mood disorders, major depressive disorder, bipolar disorder as an adjunct to the main therapy, and in cognitive impairment as monotherapy is discussed.

1. Lobzin VYu, Kolmakova KA, Emelin AYu, Yanishevskiy SN. Arterial hypertension and Alzheimer’s disease. Prologue to neurodegeneration. Arterial Hypertension (Russian Federation). 2019;25(2):122–133. https://doi.org/10.18705/1607-419X-2019-25-2-122-133.

2. Ou YN, Tan CC, Shen XN, Xu W, Hou XH, Dong Q et al. Blood Pressure and Risks of Cognitive Impairment and Dementia: A Systematic Review and Meta-Analysis of 209 Prospective Studies. Hypertension. 2020;76(1): 217–225. https://doi.org/10.1161/HYPERTENSIONAHA.120.14993.

3. Skoog I, Lernfelt B, Landahl S, Palmertz B, Andreasson LA, Nilsson L et al. 15-year longitudinal study of blood pressure and dementia. Lancet. 1996;347(9009):1141–1145. https://doi.org/10.1016/S0140-6736(96)90608-X.

4. Abell JG, Kivimäki M, Dugravot A, Tabak AG, Fayosse A, Shipley M et al. Association between systolic blood pressure and dementia in the Whitehall II cohort study: role of age, duration, and threshold used to define hypertension. Eur Heart J. 2018;39(33):3119–3125. https://doi.org/10.1093/eurheartj/ehy288.

5. Gottesman RF, Albert MS, Alonso A, Coker LH, Coresh J, Davis SM et al. Associations Between Midlife Vascular Risk Factors and 25-Year Incident Dementia in the Atherosclerosis Risk in Communities (ARIC) Cohort. JAMA Neurol. 2017;74(10):1246–1254. https://doi.org/10.1001/jamaneurol.2017.1658.

6. Alpérovitch A, Blachier M, Soumaré A, Ritchie K, Dartigues JF, RichardHarston S, Tzourio C. Blood pressure variability and risk of dementia in an elderly cohort, the Three-City Study. Alzheimers Dement. 2014;10(Suppl. 5):S330–S337. https://doi.org/10.1016/j.jalz.2013.05.1777.

7. 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.

8. Dregan A, Stewart R, Gulliford MC. Cardiovascular risk factors and cognitive decline in adults aged 50 and over: a population-based cohort study. Age Ageing. 2013;42(3):338–345. https://doi.org/10.1093/ageing/afs166.

9. Yasar S, Ko JY, Nothelle S, Mielke MM, Carlson MC. Evaluation of the effect of systolic blood pressure and pulse pressure on cognitive function: the Women’s Health and Aging Study II. PLoS ONE. 2011;6(12):e27976. https://doi.org/10.1371/journal.pone.0027976.

10. Elias PK, Elias MF, Robbins MA, Budge MM. Blood pressure-related cognitive decline: does age make a difference? Hypertension. 2004;44(5):631–636. https://doi.org/10.1161/01.HYP.0000145858.07252.99.

11. Ungvari Z, Toth P, Tarantini S, Prodan CI, Sorond F, Merkely B, Csiszar A. Hypertension-induced cognitive impairment: from pathophysiology to public health. Nat Rev Nephrol. 2021;17(10):639–654. https://doi.org/10.1038/s41581-021-00430-6.

12. Iadecola C. The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease. Neuron. 2017;96(1):17–42. https://doi.org/10.1016/j.neuron.2017.07.030.

13. Silverman A, Petersen NH. Physiology, Cerebral Autoregulation. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023. Available at: https://pubmed.ncbi.nlm.nih.gov/31985976/.

14. Chirinos JA, Segers P, Hughes T, Townsend R. Large-Artery Stiffness in Health and Disease: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;74(9):1237–1263. https://doi.org/10.1016/j.jacc.2019.07.012.

15. Wei HS, Kang H, Rasheed ID, Zhou S, Lou N, Gershteyn A et al. Erythrocytes Are Oxygen-Sensing Regulators of the Cerebral Microcirculation. Neuron. 2016;91(4):851–862. https://doi.org/10.1016/j.neuron.2016.07.016.

16. Devor A, Sakadžić S, Saisan PA, Yaseen MA, Roussakis E, Srinivasan VJ et al. “Overshoot” of O2 is required to maintain baseline tissue oxygenation at locations distal to blood vessels. J Neurosci. 2011;31(38):13676–13681. https://doi.org/10.1523/JNEUROSCI.1968-11.2011.

17. Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV. Blood-Brain Barrier: From Physiology to Disease and Back. Physiol Rev. 2019;99(1):21–78. https://doi.org/10.1152/physrev.00050.2017.

18. Hill-Eubanks DC, Gonzales AL, Sonkusare SK, Nelson MT. Vascular TRP channels: performing under pressure and going with the flow. Physiology. 2014;29(5):343–360. https://doi.org/10.1152/physiol.00009.2014.

19. Santisteban MM, Ahn SJ, Lane D, Faraco G, Garcia-Bonilla L, Racchumi G et al. Endothelium-Macrophage Crosstalk Mediates Blood-Brain Barrier Dysfunction in Hypertension. Hypertension. 2020;76(3):795–807. https://doi.org/10.1161/HYPERTENSIONAHA.120.15581.

20. Iadecola C. The pathobiology of vascular dementia. Neuron. 2013;80(4):844–866. https://doi.org/10.1016/j.neuron.2013.10.008.

21. Sakagami K, Wu DM, Puro DG. Physiology of rat retinal pericytes: modulation of ion channel activity by serum-derived molecules. J Physiol. 1999;521(Pt 3):637–650. https://doi.org/10.1111/j.1469-7793.1999.00637.x.

22. 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.

23. Bowman GL, Dayon L, Kirkland R, Wojcik J, Peyratout G, Severin IC et al. Blood-brain barrier breakdown, neuroinflammation, and cognitive decline in older adults. Alzheimers Dement. 2018;14(12):1640–1650. https://doi.org/10.1016/j.jalz.2018.06.2857.

24. Qiu L, Ng G, Tan EK, Liao P, Kandiah N, Zeng L. Chronic cerebral hypoperfusion enhances Tau hyperphosphorylation and reduces autophagy in Alzheimer’s disease mice. Sci Rep. 2016;6:23964. https://doi.org/10.1038/srep23964.

25. Bennett SA, Pappas BA, Stevens WD, Davidson CM, Fortin T, Chen J. Cleavage of amyloid precursor protein elicited by chronic cerebral hypoperfusion. Neurobiol Aging. 2000;21(2):207–214. https://doi.org/10.1016/s0197-4580(00)00131-7.

26. Weller RO, Boche D, Nicoll JA. Microvasculature changes and cerebral amyloid angiopathy in Alzheimer’s disease and their potential impact on therapy. Acta Neuropathol. 2009;118(1):87–102. https://doi.org/10.1007/s00401-009-0498-z.

27. Iliff JJ, Nedergaard M. Is there a cerebral lymphatic system? Stroke. 2013;44(6 Suppl. 1):S93–S95. https://doi.org/10.1161/sTROKEAHA.112.678698.

28. Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342(6156):373–377. https://doi.org/10.1126/science.1241224.

29. Nagai M, Hoshide S, Ishikawa J, Shimada K, Kario K. Ambulatory blood pressure as an independent determinant of brain atrophy and cognitive function in elderly hypertension. J Hypertens. 2008;26(8):1636–1641. https://doi.org/10.1097/HJH.0b013e3283018333.

30. Bellelli G, Frisoni GB, Lucchi E, Guerini F, Geroldi C, Magnifico F et al. Blunted reduction in night-time blood pressure is associated with cognitive deterioration in subjects with long-standing hypertension. Blood Press Monit. 2004;9(2):71–76. https://doi.org/10.1097/00126097-200404000-00003.

31. van Boxtel MP, Henskens LH, Kroon AA, Hofman PA, Gronenschild EH, Jolles J, de Leeuw PW. Ambulatory blood pressure, asymptomatic cerebrovascular damage and cognitive function in essential hypertension. J Hum Hypertens. 2006;20(1):5–13. https://doi.org/10.1038/sj.jhh.1001934.

32. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition (DSM-5). Arlington, VA: American Psychiatric Publishing; 2013. Available at: https://repository.poltekkes-kaltim.ac.id/657/1/Diagnostic%20and%20statistical%20manual%20of%20mental%20disorders%20_%20DSM-5%20(%20PDFDrive.com%20).pdf.

33. Vakhnina NV. Cognitive disorders and therapy in patients with hypertension. Meditsinskiy Sovet. 2014;(5):30–37. (In Russ.) Available at: https://www.med-sovet.pro/jour/article/view/565/565.

34. Zakharov VV, Sleptsova KB, Martynova OO. Chronic cerebral ischemia: a view from the ХХI century. RMJ. 2021;(5):45–49. (In Russ.) Available at: https://www.rmj.ru/articles/nevrologiya/Hronicheskaya_ishemiya_mozga_vzglyad_iz_HHIveka.

35. Govorushina AA, Minakova MS, Kalmykova AD, Turusheva AV, Bogdanova TF. White Matter Hyperintensities According to Neuroimaging Analysis, Cognitive Impairment and Emotional Disorders: Is There a Link? Russian Journal of Geriatric Medicine. 2023;(2):121–126. (In Russ.) https://doi.org/10.37586/2686-8636-2-2023-121-126.

36. Yakhno NN, Levin OS, Damulin IV. Comparison of clinical and MRI data in cerebrovascular insufficiency. Message 2: Cognitive impairment. Nevrologicheskii Zhurnal. 2001;6(3):10–19. (In Russ.) Available at: https://www.elibrary.ru/shsmnl.

37. Sachdev P, Kalaria R, O’Brien J, Skoog I, Alladi S, Black SE et al. Diagnostic criteria for vascular cognitive disorders: a VASCOG statement. Alzheimer Dis Assoc Disord. 2014;28(3):206–218. https://doi.org/10.1097/WAD.0000000000000034.

38. Zakharov VV. Introduction to behavioral neurology. Behavioral Neurology. 2021;(1):8–16. (In Russ.) https://doi.org/10.46393/2712-9675_2021_1_8-16.

39. Cristofori I, Cohen-Zimerman S, Grafman J. Executive functions. Handb Clin Neurol. 2019;163:197–219. https://doi.org/10.1016/B978-0-12-804281-6.00011-2.

40. Starchina YuA, Zakharov VV. Cognitive impairment in hypertension. Neurology, Neuropsychiatry, Psychosomatics. 2021;13(1):113–118. (In Russ.). https://doi.org/10.14412/2074-2711-2021-1-113-118.

41. Román GC, Erkinjuntti T, Wallin A, Pantoni L, Chui HC. Subcortical ischaemic vascular dementia. Lancet Neurol. 2002;1(7):426–436. https://doi.org/10.1016/s1474-4422(02)00190-4.

42. Fladd D. Subcortical vascular dementia. Geriatr Nurs. 2005;26(2):117–121. https://doi.org/10.1016/j.gerinurse.2005.01.001.

43. Erkinjuntti T. Subcortical vascular dementia. Cerebrovasc Dis. 2002;13(Suppl. 2):58–60. https://doi.org/10.1159/000049152.

44. Menon U, Kelley RE. Subcortical ischemic cerebrovascular dementia. Int Rev Neurobiol. 2009;84:21–33. https://doi.org/10.1016/S0074-7742(09)00402-4.

45. Preobrazhenskaya IS, Yakhno NN. Vascular cognitive impairment – clinical manifestations, diagnostic approaches and treatment. Nevrologicheskii Zhurnal. 2007;12(5):45–50. (In Russ.) Available at: https://www.elibrary.ru/ibfjdx.

46. Zaharov VV, Vahnina NV. Cognitive disorders in arterial hypertension. Nervous Diseases. 2013;(3):16–21. (In Russ.) Available at: https://www.elibrary.ru/rhtulz.

47. Yakhno NN, Zakharov VV, Lokshina AB. Moderate cognitive impairment syndrome in cerebral vascular insufficiency. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2005;105(2):13–17. (In Russ.) Available at: https://www.elibrary.ru/hrxphz.

48. Sachdev PS, Lipnicki DM, Crawford JD, Brodaty H. The Vascular Behavioral and Cognitive Disorders criteria for vascular cognitive disorders: a validation study. Eur J Neurol. 2019;26(9):1161–1167. https://doi.org/10.1111/ene.13960.

49. Xie C, Zhong D, Zhang Y, Liu X, Zhang L, Luo X et al. Prevalence and risk factors of cognitive impairment in Chinese patients with hypertension: a systematic review and meta-analysis. Front Neurol. 2024;14:1271437. https://doi.org/10.3389/fneur.2023.1271437.

50. Sidorovich EK, Pavlovskaya TS, Liventseva MM. The abilities for early diagnosis of cognitive and motor impairments in chronic cerebral circulation insufficiency in patients with arterial hypertension. Lechebnoe Delo. 2020;(4):21–29. (In Russ.) Available at: https://www.elibrary.ru/btwljy.

51. Damulin IV. Cognitive and motor disorders in cerebrovascular insufficiency and vascular dementia. Vrach. 2005;(11):3–6. (In Russ.) Available at: https://www.elibrary.ru/mbcapj.

52. Bryzhakhina VG, Damulin IV, Yakhno NN. Gail and equilibrium disorders in dyscirculatory encephalopathy. Communication 1. Nevrologicheskii Zhurnal. 2004;9:(2):11–16. (In Russ.) Available at: https://www.elibrary.ru/onllxh.

53. Damulin IV, Bryzakhina VG, Shashkova EV, Yakhno NN. Disturbances in walking and balance in dyscirculatory encephalopathy. Message 2. Clinical, morphological and MRI comparisons. Nevrologicheskii Zhurnal. 2004;9(4):13–18. (In Russ.) Available at: https://www.elibrary.ru/onlmgx.

54. Yakhno NN, Zakharov VV. Cognitive and emotional-affective disorders in cerebrovascular insufficiency. RMJ. 2002;(12):539. (In Russ.) Available at: https://www.rmj.ru/articles/nevrologiya/Kognitivnye_i_emocionalynoaffektivnye_narusheniya_pri_discirkulyatornoy_encefalopatii/.

55. Bogolepova AN, Smirnova MYu, Semushkina EG, Gusev EI. Depression and cerebrovascular pathology. Doctor.Ru. 2010;(4):7–11. (In Russ.) Available at: https://www.elibrary.ru/mtzbit.

56. Ткачева ОН, Яхно НН, Незнанов НГ, Шпорт СВ, Шамалов НА, Левин ОС и др. Когнитивные расстройства у лиц пожилого и старческого возраста: клинические рекомендации. .; 2024. 330 с. Режим доступа: https://cr.minzdrav.gov.ru/preview-cr/617_5.

57. Chang-Quan H, Hui W, Chao-Min W, Zheng-Rong W, Jun-Wen G, Yong-Hong L et al. The association of antihypertensive medication use with risk of cognitive decline and dementia: a meta-analysis of longitudinal studies. Int J Clin Pract. 2011;65(12):1295–1305. https://doi.org/10.1111/j.1742-1241.2011.02810.x.

58. Kilander L, Nyman H, Boberg M, Hansson L, Lithell H. Hypertension is related to cognitive impairment: a 20-year follow-up of 999 men. Hypertension. 1998;31(3):780–786. https://doi.org/10.1161/01.hyp.31.3.780.

59. 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.

60. Levi Marpillat N, Macquin-Mavier I, Tropeano AI, Bachoud-Levi AC, Maison P. Antihypertensive classes, cognitive decline and incidence of dementia: a network meta-analysis. J Hypertens. 2013;31(6):1073–1082. https://doi.org/10.1097/HJH.0b013e3283603f53.

61. Jin BR, Liu HY. Comparative efficacy and safety of cognitive enhancers for treating vascular cognitive impairment: systematic review and Bayesian network meta-analysis. Neural Regen Res. 2019;14(5):805–816. https://doi.org/10.4103/1673-5374.249228.

62. Kavirajan H, Schneider LS. Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled trials. Lancet Neurol. 2007;6(9):782–792. https://doi.org/10.1016/S1474-4422(07)70195-3.

63. Baskys A, Hou AC. Vascular dementia: pharmacological treatment approaches and perspectives. Clin Interv Aging. 2007;2(3):327–335. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC2685259/.

64. Thomas SJ, Grossberg GT. Memantine: a review of studies into its safety and efficacy in treating Alzheimer’s disease and other dementias. Clin Interv Aging. 2009;4:367–377. https://doi.org/10.2147/cia.s6666.

65. Bär KJ, Boettger MK, Seidler N, Mentzel HJ, Terborg C, Sauer H. Influence of galantamine on vasomotor reactivity in Alzheimer’s disease and vascular dementia due to cerebral microangiopathy. Stroke. 2007;38(12):3186–3192. https://doi.org/10.1161/STROKEAHA.107.492033.

66. Frampton JE, Brogden RN. Pentoxifylline (oxpentifylline). A review of its therapeutic efficacy in the management of peripheral vascular and cerebrovascular disorders. Drugs Aging. 1995;7(6):480–503. https://doi.org/10.2165/00002512-199507060-00007.

67. Sha MC, Callahan CM. The efficacy of pentoxifylline in the treatment of vascular dementia: a systematic review. Alzheimer Dis Assoc Disord. 2003;17(1):46–54. https://doi.org/10.1097/00002093-200301000-00006.

68. Sergeev AV. Evidence-based basis for the effective use of pentoxifylline (Trental®) in neurological practice. Effective Pharmacotherapy. 2010;(19):32–35. (In Russ.) Available at: https://www.elibrary.ru/shronz.

69. Movassaghi S, Nadia Sharifi Z, Soleimani M, Joghataii MT, Hashemi M, Shafaroodi H, Mehdizadeh M. Effect of Pentoxifylline on Ischemiainduced Brain Damage and Spatial Memory Impairment in Rat. Iran J Basic Med Sci. 2012;15(5):1083–1090. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC3586929/.

70. Alzoubi KH, Khabour OF, Ahmed M. Pentoxifylline prevents post-traumatic stress disorder induced memory impairment. Brain Res Bull. 2018;139:263–268. https://doi.org/10.1016/j.brainresbull.2018.03.009.

71. Wang Y, Zhang T, Zhao H, Qi C, Ji X, Yan H et al. Pentoxifylline Enhances Antioxidative Capability and Promotes Mitochondrial Biogenesis in D-Galactose-Induced Aging Mice by Increasing Nrf2 and PGC-1α through the cAMP-CREB Pathway. Oxid Med Cell Longev. 2021;2021:6695613. https://doi.org/10.1155/2021/6695613.

72. Muhsen M, Alzoubi KH, Khabour OF, Mhaidat N, Rababa’h A, Ali S et al. Pentoxifylline protects memory performance in streptozotocin-induced diabetic rats. Brain Res. 2025;1847:149319. https://doi.org/10.1016/j.brainres.2024.149319.

73. Elseweidy MM, Mahrous M, Ali SI, Shaheen MA, Younis NN. Pentoxifylline as Add-On Treatment to Donepezil in Copper Sulphate-Induced Alzheimer’s Disease-Like Neurodegeneration in Rats. Neurotox Res. 2023;41(6):546–558. https://doi.org/10.1007/s12640-023-00672-1.

74. Erdoğan MA, Tunç KC, Daştan Aİ, Tomruk C, Uyanıkgil Y, Erbaş O. Therapeutic effects of pentoxifylline in propionic acid-induced autism symptoms in rat models: A behavioral, biochemical, and histopathological study. Int J Dev Neurosci. 2024;84(8):991–1005. https://doi.org/10.1002/jdn.10394.

75. Zheng L, Jia J, Chen Y, Liu R, Cao R, Duan M et al. Pentoxifylline alleviates ischemic white matter injury through up-regulating Mertk-mediated myelin clearance. J Neuroinflammation. 2022;19(1):128. https://doi.org/10.1186/s12974-022-02480-4.

76. Black RS, Barclay LL, Nolan KA, Thaler HT, Hardiman ST, Blass JP. Pentoxifylline in Cerebrovascular Dementia. J Am Geriatr Soc. 1992;40(3):237–244. https://doi.org/10.1111/j.1532-5415.1992.tb02075.x.

77. Siegel AN, Rodrigues N, Nasri F, Wilkialis L, Lipsitz O, Lee Y et al. Novel therapeutic targets in mood disorders: Pentoxifylline (PTX) as a candidate treatment. Prog Neuropsychopharmacol Biol Psychiatry. 2021;104:110032. https://doi.org/10.1016/j.pnpbp.2020.110032.

78. Nassar A, Azab AN. Effects of Dexamethasone and Pentoxifylline on Manialike and Depression-like Behaviors in Rats. Pharmaceuticals. 2022;15(9):1063. https://doi.org/10.3390/ph15091063.

79. Mohammad TAM, Mohammad TAM, Shawis TN. Efficacy of pentoxifylline for the treatment of bipolar I/II patients with treatment-resistant depression: A proof-of-concept, randomized, double-blind, placebo-controlled trial. Brain Res Bull. 2024;216:111047. https://doi.org/10.1016/j.brainresbull.2024.111047.

80. Ramzi A, Maya S, Balousha N, Amin M, Powell RC, Shiha MR. Effects of the anti-inflammatory pentoxifylline on psychiatric and neuropsychiatric conditions: exploring various off-label utilities with meta-analyses. Inflammopharmacology. 2025;33(1):105–119. https://doi.org/10.1007/s10787-024-01616-7.

81. Steele AR, Howe CA, Gibbons TD, Foster K, Williams AM, Caldwell HG et al. Hemorheological, cardiorespiratory, and cerebrovascular effects of pentoxifylline following acclimatization to 3,800 m. Am J Physiol Heart Circ Physiol. 2024;326(3):H705–H714. https://doi.org/10.1152/ajpheart.00783.2023.