The main mechanisms of development of cognitive impairment

Bogolepova A.N.

doi:https://doi.org/10.17116/jnevro202512504213

Recommended articles:

Modern approaches to diagnosis and treatment of syndrome of autonomic dysfunction in children. S.S. Korsakov Journal of Neurology and Psychiatry. 2024;(11-2):66-75

Oxidative stress in the pathogenesis of chronic headache. S.S. Korsakov Journal of Neurology and Psychiatry. 2024;(10):35-40

Resolution of the expert council «Possibilities of neuroprotective therapy in patients with arterial hypertension and cognitive disorders». Russian Journal of Preventive Medicine. 2024;(11):85-93

Alterations in the activity of glutathione-dependent enzymes in erythrocytes of patients with acute pancreatitis of varying severity. Russian Journal of Evidence-Based Gastroenterology. 2024;(4):10-15

Neurochemical mechanisms of tremor in Parkinson’s disease. S.S. Korsakov Journal of Neurology and Psychiatry. 2024;(11):64-72

Cognitive impairment in patients with Parkinson’s disease. S.S. Korsakov Journal of Neurology and Psychiatry. 2024;(11):81-90

Comorbidity of depression and dementia: epidemiological, biological and therapeutic aspects. S.S. Korsakov Journal of Neurology and Psychiatry. 2024;(11):113-121

Differentiated approach to cognitive rehabilitation of patients after stroke. Problems of Balneology, Physiotherapy and Exercise Therapy. 2024;(6):5-11

Neuroprotective therapy for age-related macular degeneration. Russian Annals of Ophthalmology. 2024;(6):152-158

Activation of endogenous mechanisms of sanogenesis in cognitive impairment in cerebral small vessel disease. S.S. Korsakov Journal of Neurology and Psychiatry. 2024;(12):7-13

Abstract:

Cognitive impairments (CI) are one of the most important problems of modern clinical neurology, which is due to their high prevalence and degree of disability. In most cases, cognitive impairments progress. The development of CI is inevitably associated with the loss of neurons and interneuronal synaptic connections. Possible mechanisms for the development of CI include a deficiency of neurotrophic factors, disorders of neurotransmitter systems, impaired energy metabolism and mitochondrial dysfunction, oxidative stress, neuroinflammation, and damage to the blood-brain barrier. Chronic cerebral hypoperfusion is probably one of the main causes, since it occurs at the initial stages of not only cerebrovascular but also neurodegenerative damage. It links together some of the mechanisms of cognitive impairment, such as chronic inflammation, oxidative stress, neurodegeneration, and brain atrophy. One of the drugs for the treatment of CI is Mexidol, a drug with a multimodal effect, including antioxidant, antihypoxant and membrane-protective properties. The clinical efficacy of Mexidol in relation to moderate CI was confirmed by meta-analysis data from 10 prospective clinical studies.

Keywords:

cognitive impairment

dementia

oxidative stress

neurotransmitters

neurotrophic factors

ethylmethylhydroxypyridine succinate

Mexidol

Authors:

Bogolepova A.N.

Pirogov Russian National Research Medical University (Pirogov University);
Federal Center of Brain and Neurotechnologies

SPIN RSCI: 6775-0279
Scopus AuthorID: 6602240836
ORCID: 0000-0002-6327-3546

Received:

13.03.2025

Accepted:

14.03.2025

Close metadata

References:

Petersen RC, Lopez O, Armstrong MJ, et al. Practice guideline update summary: Mild cognitive impairment: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(3):126-135 https://doi.org/10.1212/WNL.0000000000004826
Campbell NL, Unverzagt F, LaMantia MA, et al. Risk factors for the progression of mild cognitive impairment to dementia. Clin Geriatr Med. 2013;29(4):873-93. https://doi.org/10.1016/j.cger.2013.07.009
Jia L, Du Y, Chu L, et al.; COAST Group. Prevalence, risk factors, and management of dementia and mild cognitive impairment in adults aged 60 years or older in China: a cross-sectional study. Lancet Public Health. 2020;5(12):e661-e671. https://doi.org/10.1016/S2468-2667(20)30185-7
Roberts R, Knopman DS. Classification and epidemiology of MCI. Clin Geriatr Med. 2013;29(4):753-72. https://doi.org/10.1016/j.cger.2013.07.003
Kim TA, Syty MD, Wu K, Ge S. Adult hippocampal neurogenesis and its impairment in Alzheimer’s disease. Zool Res. 2022;43(3):481-496. https://doi.org/10.24272/j.issn.2095-8137.2021.479
Pisani A, Paciello F, Del Vecchio V, et al. The Role of BDNF as a Biomarker in Cognitive and Sensory Neurodegeneration. J Pers Med. 2023;13(4):652. https://doi.org/10.3390/jpm13040652
Kumar A, Foster TC. Alteration in NMDA receptor mediated glutamatergic neurotransmission in the hippocampus during senescence. Neurochem Res. 2019;44:38-48. https://doi.org/10.1007/s11064-018-2634-4
Luo Z, Ahlers-Dannen KE, Spicer MM, et al. Age-dependent nigral dopaminergic neurodegeneration and α-synuclein accumulation in RGS6-deficient mice. JCI Insight. 2019;5:e126769. https://doi.org/10.1172/jci.insight.126769
Gasiorowska A, Wydrych M, Drapich P, et al. The Biology and Pathobiology of Glutamatergic, Cholinergic, and Dopaminergic Signaling in the Aging Brain. Front Aging Neurosci. 2021;13:654931. https://doi.org/10.3389/fnagi.2021.654931
Bukke VN, Archana M, Villani R, et al. The dual role of glutamatergic neurotransmission in Alzheimer’s disease: from pathophysiology to pharmacotherapy. Int J Mol Sci. 2020;21:7452. https://doi.org/10.3390/ijms21207452
Speranza L, di Porzio U, Viggiano D, et al. Dopamine: The Neuromodulator of Long-Term Synaptic Plasticity, Reward and Movement Control. Cells. 2021;10(4):735. https://doi.org/10.3390/cells10040735
Sorensen A, Blazhenets G, Rucker G, et al. Prognosis of conversion of mild cognitive impairment to Alzheimer’s dementia by voxel-wise cox regression based on FDG PET data. Neuroimage Clin. 2019;21:101637. https://doi.org/10.1016/j.nicl.2018.101637
Kellar D, Craft S. Brain insulin resistance in Alzheimer’s disease and related disorders: mechanisms and therapeutic approaches. Lancet Neurol. 2020;19(9):758-766. https://doi.org/10.1016/S1474-4422(20)30231-3
Wang W, Zhao F, Ma X, et al. Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances. Mol Neurodegener. 2020;15(1):30. https://doi.org/10.1186/s13024-020-00376-6
Swerdlow RH. Mitochondria and mitochondrial cascades in Alzheimer’s disease. J Alzheimers Dis. 2018;62(3):1403-1416. https://doi.org/10.3233/JAD-170585
Belkhelfa M, Beder N, Mouhoub D, et al. The involvement of neuroinflammation and necroptosis in the hippocampus during vascular dementia. J Neuroimmunol. 2018; 34(7):34-39. https://doi.org/10.1016/j.jneuroim.2018.04.004
Tang D, Kang R, Berghe TV, et al. The molecular machinery of regulated cell death. Cell Res. 2019;29:347-364. https://doi.org/10.1038/s41422-019-0164-5
Poh L, Fann DY, Wong P, et al. AIM2 inflammasome mediates hallmark neuropathological alterations and cognitive impairment in a mouse model of vascular dementia. Mol Psychiatry. 2021;26:4544-4560. https://doi.org/10.1038/s41380-020-00971-5
Wang XX, Zhang B, Xia R, Jia QY. Inflammation, apoptosis and autophagy as critical players in vascular dementia. Eur Rev Med Pharmacol Sci. 2020;24(18):9601-9614. https://doi.org/10.26355/eurrev_202009_23048
Wu M, Li D, Qiu F, et al. Aging aggravates cognitive dysfunction in spontaneously hypertensive rats by inducing cerebral microvascular endothelial dysfunction. PLoS One. 2025 Mar 13;20(3):e0316383. https://doi.org/10.1371/journal.pone.0316383
Nation DA, Sweeney MD, Montagne A, et al. Violation of the blood-brain barrier is an early biomarker of human cognitive dysfunction. Nat Med. 2019;25(2):270-276. https://doi.org/10.1038/s41591-018-0297-y
Rajeev V, Chai YL, Poh L, et al. Chronic cerebral hypoperfusion: a critical feature in unravelling the etiology of vascular cognitive impairment. Acta Neuropathol Commun. 2023;11(1):93. https://doi.org/10.1186/s40478-023-01590-1
Wang X, Cui L, Ji X. Cognitive impairment caused by hypoxia: from clinical evidences to molecular mechanisms. Metab Brain Dis. 2022;37(1):51-66. https://doi.org/10.1007/s11011-021-00796-3
Voronina TA. Mexidol: the spectrum of pharmacological effects. SS. Korsakov Journal of Neurology and Psychiatry. 2012;112(12):86-90. (In Russ.).
Schulkin AV. The effect of Mexidol on the development of the phenomenon of excitotoxicity of neurons in vitro. SS. Korsakov Journal of Neurology and Psychiatry. 2012;112:2:35-39 (In Russ.).
Schulkin AV. A modern concept of antihypoxic and antioxidant effects of mexidol. SS. Korsakov Journal of Neurology and Psychiatry. 2018;118(12-2):87-93 (In Russ.). https://doi.org/10.17116/jnevro201811812287
Miroshnichenko II, Smirnov LD, Voronin AE et al. The effect of Mexidol on the content of mediator monoamines and amino acids in the structures of the rat brain. Bulletin of Experimental Biology and Medicine 1996;2:170-172. (In Russ.).
Gromova OA, Torshin IYu, Sorokin AI, et al. Chemotranscriptome analysis of the ethylmethylhydroxypyridine succinate molecule in the context of postgenomic pharmacology. Nevrologiya, neiropsikhiatriya, psikhosomatika=Neurology, Neuropsychiatry, Psychosomatics. 2020;12(5):130-137. https://doi.org/10.14412/2074-2711-2020-5-130-137
Kirova YuI, Germanova EL. New aspects of the energy-tropic action of mexidol. Patologicheskaya Fiziologiya i Eksperimental’naya Terapiya. 2018;62(4):42-46. (In Russ.). https://doi.org/10.25557/0031-2991.2018.04.36-40
Shchulkin AV, Yakusheva EN, Chernykh IV. The distribution of mexidol in the rat’s brain and its subcellular fractions. SS. Korsakov Journal of Neurology and Psychiatry. 2014;114:8:70-73.
Shetekauri SA. Modern possibilities of antioxidant therapy and experience in the treatment of patients with chronic cerebrovascular insufficiency with mexidol. Bulletin of Experimental Biology and Medicine. 2006;1:156-15 (In Russ.).
Yanishevsky SN. The experience of using the drug “Mexidol” in the treatment of chronic cerebrovascular insufficiency in patients with stenosing-occlusive lesion of the main brachycephalic vessels. Bulletin of Experimental Biology and Medicine. 2006;1:159-163 (In Russ.).
Abramenko YuV. Assessment of the clinical efficacy, vasoactive and metabolic effects of Mexidol in elderly patients with discirculatory encephalopathy. SS. Korsakov Journal of Neurology and Psychiatry. 2011;111(11):35-41 (In Russ.).
Antipenko EA, Shulyndin AV, Belyakov KM. Neurometabolic therapy of mild cognitive impairment in patients with chronic cerebral ischemia. SS. Korsakov Journal of Neurology and Psychiatry. 2024;124(3):42-51. (In Russ.). https://doi.org/10.17116/jnevro202412403142
Vizilo TL, Arefieva EG. Improving the effectiveness of pharmacotherapy in comorbid patients with chronic cerebral ischemia on an outpatient basis. SS. Korsakov Journal of Neurology and Psychiatry. 2023;123(3):51-55. (In Russ.). https://doi.org/10.17116/jnevro202312303151
Shchepankevich LA, Nicolaev YuA, Taneeva EV, et al. The efficacy and safety study of Mexidol and Mexidol FORTE 250 in patients with chronic cerebral ischemia. SS. Korsakov Journal of Neurology and Psychiatry. 2021;121(10):32-37. (In Russ.). https://doi.org/10.17116/jnevro202112110132
Chukanova EI, Chukanova AS. Efficacy and safety of the drug mexidol FORTE 250 as part of sequential therapy in patients with chronic ischemia of the brain. SS. Korsakov Journal of Neurology and Psychiatry. 2019;119(9):39-45. (In Russ.). https://doi.org/10.17116/jnevro201911909139
Fedin AI, Zakharov VV, Tanashyan MM, et al. Results of an international multicenter, randomized, double-blind, placebo-controlled study assessing the efficacy and safety of sequential therapy with Mexidol and Mexidol FORTE 250 in patients with chronic brain ischemia (MEMO). SS. Korsakov Journal of Neurology and Psychiatry. 2021;121(11):7-16. (In Russ.). https://doi.org/10.17116/jnevro20211211117
Zakharov VV, Vakhnina NV. The use of Mexidol in patients with mild (moderate) cognitive impairment: results of a meta-analysis. SS. Korsakov Journal of Neurology and Psychiatry. 2024;124(1):82-88. (In Russ.). https://doi.org/10.17116/jnevro202412401182