Citicoline in the Treatment of Mild Cognitive Impairment in Blood Relatives of Patients with Alzheimer’s Disease: Immediate and Long-Term Effects of Course Therapy

The aim was to study immediate and long-term (post-therapeutic) effects of a three-month course of therapy with citicoline in 1st-degree relatives of patients with Alzheimer’s disease (AD). All the included relatives of patients with AD revealed signs of minimal cognitive dysfunction (MCD) and mild cognitive decline syndrome (MCI — Mild Cognitive Impairment, ICD-10 code F06.7). Study participants: the study involved 90 first-degree relatives: 24 with MCI and 66 with MCD. Study design: an open-label comparative multidisciplinary study of the six-month dynamics of cognitive functioning of two groups of relatives who received a three-month course of citicoline therapy. The baseline indicators of the cognitive functioning of relatives with MCI syndrome and MKD were compared with the indicators at the end of the three-month course of therapy with citicoline at a daily dose of 1000 mg as well as 3 months after the end of the course of treatment. Methods: clinical, psychopathological, neuropsychological, psychometric, genetic, statistical ones. Results: а significant positive effect of the course therapy with citicoline on the cognitive impairment of 1st degree AD-patients’ relatives with minimal cognitive dysfunction and more pronounced cognitive impairments met the diagnostic criteria for MCI syndrome has been found. A significantly greater value of both immediate and long-term therapeutic effect of MKD compared with MCI in relatives was established by psychometric and neuropsychological indicators characterizing voluntary memorization of verbal and visual stimuli, optical and spatial activity, voluntary attention, and associative verbal thinking. Conclusion: the results of the study can be used as the basis for a model of prevention of the progression of cognitive deficit and the development of dementia in persons with a high risk of developing AD, i.e. in individuals with both genetic risk and signs of cognitive impairment.

1. La Rue A, O’Hara R, Matsuyama SS, Jarvik LF. Cognitive changes in young-old adults: effect of family history of dementia. J Clin Exp Neuropsychol. 1995;17:60–70. https://doi.org/10.1080/13803399508406582

2. Small GW, Okonek A, Mandelkern MA, La Rue A, Chang L, Khonsary A, Ropchan J., Blahd WH. Age-associated memory loss: initial neuropsychological and cerebral metabolic findings of a longitudinal study. Int Psychogeriatr. 1994;6:23–44. https://doi.org/10.1017/S1041610294001596

3. Jarvik LF, Brazer D. Children of Alzheimer parents: An Overview. J Geriatr Psychiatry Neurol. 2005;18:181– 186. https://doi.org/10.1177/0891988705281859

4. Селезнева НД, Рощина ИФ, Гаврилова СИ, Федорова ЯБ, Гантман МВ, Коровайцева ГИ, Кунижева СС, Рогаев ЕИ. Психические нарушения когнитивного и некогнитивного спектра у родственников 1-й степени родства пациентов с болезнью Альцгеймера. Журнал неврологии и психиатрии им. С.С. Корсакова. 2012;112(10):8–13. Selezneva ND, Roshchina IF, Gavrilova SI, Fedorova YaB, Gantman M, Korovaytseva GI, Kunizheva SS, Rogayev EI. Mental disturbances of a cognitive and not cognitive range at relatives of 1 degree of relationship of patients with Alzheimer’s disease. Zhurnal nevrologii i psihiatrii im. S.S. Korsakova. 2012;112(10):8–13. (In Russ.).

5. Caselli RJ, Reiman EM, Osborne D, Hentz JG, Baxter LC, Hernandez JL Alexander GG. Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele. Neurology. 2004;62:1990–1995. https://doi.org/10.1212/01.wnl.0000129533.26544.bf

6. Levy JA, Bergeson J, Putnam K, Rosen V. Context-specic memory and apolipoprotein E (APOE) epsilon 4: cognitive evidence from the NIMH prospective study of risk for Alzheimer’s disease. J Int Neuropsychol Soc. 2004;10:362–370. https://doi.org/10.1017/s1355617704103044

7. Sager MA, Hermann B, La Rue A. Middle-aged children of persons with Alzheimer’s disease: APOE genotypes and cognitive function in the Wisconsin Registry for Alzheimer’s Prevention. J Geriatr Psychiatry Neurol. 2005;18(4):245–249. https://doi.org/10.1177/0891988705281882

8. Малашенкова ИК, Крынский СА, Мамошина МВ, Дидковский НА. Полиморфизм гена АРОЕ: влияние аллеля АРОЕ4 на системное воспаление и его роль в патогенезе болезни Альцгеймера. Медицинская иммунология. 2018;20(3):303–312. https://doi.org/10.15789/1563-0625-2018-3-303-31222 Malashenkova IK, Krynskij SA, Mamoshina MV, Didkovskij NA. Polimorfizm gena AROE: vliyanie allelya AROE4 na sistemnoe vospalenie i ego rol’ v patogeneze bolezni Al’cgejmera. Medicinskaya immunologiya. 2018;20(3):303–312. (In Russ.). https://doi.org/10.15789/1563-0625-2018-3-303-31222

9. Garcia-Cobos R, Frank-Garcia A, Gutierras-Fernandes M, Diez-Tejedor E. Citicoline, use in cognitive decline: vascular and degenerative. J. Neurol Sci. 2010;229 (1–2):188–192. https://doi:10.1016/j.jns.2010.08.027

10. Spiers PA, Myers D, Mochanadel GS, Lieberman HR, Wurman RJ. Citicoline improves verbal memory in aging. Arch Neurol. 1996;53:441–448. https://doi:10.1001/archneur.1996.00550050071026

11. Селезнева НД, Рощина ИФ, Коровайцева ГИ, Гаврилова СИ. Профилактика прогрессирования когнитивной недостаточности (у родственников 1-й степени родства) пациентов с болезнью Альцгеймера. Журнал неврологии и психиатрии им. С.С. Корсакова. 2018;118(10):30–36. https://doi.org/10.17116/ Jnevro201811810330 Selezneva ND, Roshchina IF, Korovaytseva GI, Gavrilova SI. Prevention of the progression of cognitive impairment (in 1st-degree relatives) of patients with Alzheimer’s disease. S.S. Korsakov Journal of Neurology and Psychiatry. 2018;118(10):30–36. (In Russ.). https://doi.org/10.17116/Jnevro201811810330

12. Селезнева НД, Колыхалов ИВ, Гаврилова СИ. Сравнительное проспективное мультидисциплинарное исследование эффективности холина альфосцерата в профилактике прогрессирования когнитивного дефицита у родственников пациентов с болезнью Альцгеймера. Психиатрия. 2020;18(1):6–15. https://doi.org/10.30629/2618-6667-2020-18-1-6-15 Selezneva ND, Kolykhalov IV, Gavrilova SI. Comparative prospective multidisciplinary study of the effectiveness of choline alfoscerate in the prevention of the progression of cognitive decit in relatives of patients with Alzheimer’s disease. Psychiatry (Moscow) (Psikhiatriya). (In Russ.). 2020;18(1):6– 15. https://doi.org/10.30629/2618-6667-2020-18-1-6-15

13. Гаврилова СИ, Федорова ЯБ, Гантман МВ, Калын ЯБ, Колыхалов ИВ. Цераксон (Цитиколин) в лечении синдрома мягкого когнитивного снижения. Журнал неврологии и психиатрии имени С.С. Корсакова. 2011;111(12):16–20. WOS:000301827600003 Gavrilova SI, Fedorova YaB, Gantman MV, Kalyn YaB, Kolykhalov IV. Ceraxon (Citicoline) in the treatment of mild cognitive decline syndrome. Zhurnal nevrologii i psihiatrii imeni S.S. Korsakova. (In Russ.). 2011;111(12):16–20. WOS:000301827600003

14. Журавин ИА, Наливаева НН, Козлова ДИ, Кочкина ЕГ, Федорова ЯБ, Гаврилова СИ. Активность холинэстераз и неприлизина плазмы крови как потенциальные биомаркеры синдрома мягкого когнитивного снижения и болезни Альцгеймера. Журнал неврологии и психиатрии имени С.С. Корсакова. 2015;115(12):110–117. https://doi.org/10.17116/jnevro2015115112110-117 Zhuravin IA, Nalivaeva NN, Kozlova DI, Kochkina EG, Fedorova YaB, Gavrilova SI. Plasma cholinesterase and neprilysin activity as potential biomarkers of mild cognitive decline syndrome and Alzheimer’s disease. S.S. Korsakov Journal of Neurology and Psychiatry/Zhurnal nevrologii i psihiatrii imeni S.S. Korsakova. 2015;115(12):110–117. (In Russ.). https://doi.org/10.17116/jnevro2015115112110-117

15. Rao AM, Hatcher JF, Dempsey RJ. Does CDP-choline modulate phospholipase activities after transient forebrain ischemia? Brain Res. 2001;893:268–272. https://doi.org/10.1016/S0006-8993(00)03280-7

16. Adibhatla RM, Hatcher JF. Citicoline decreases phospholipase A2 stimulation and hydroxyl radical generation in transient cerebral ischemia. J. Neurosci. Res. 2003;73:308–315. https://doi.org/10.1002/jnr.10672

17. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56(3):303–308. https://doi.org/10.1001/archneur.56.3.303

18. Корсакова НК, Балашова ЕЮ, Рощина ИФ. Экспресс-методика оценки когнитивных функций при нормальном старении. Журнал неврологии и психиатрии имени С.С. Корсакова. 2009;2:44–50. Korsakova NK, Balashova EYu, Roshchina IF. Express-method for assessing cognitive functions in normal aging. Zhurnal nevrologii i psihiatrii imeni S.S. Korsakova. 2009;2:44–50. (In Russ.).

19. Коровайцева ГИ, Щербатых ТВ, Селезнева НД, Гаврилова СИ, Голимбет ВЕ, Воскресенская НИ, Рогаев ЕИ. Генетическая ассоциация между аллелями гена аполипопротеина Е (АРОЕ) и различными формами болезни Альцгеймера. Генетика. 2001:37 (4):529– 533. https://doi.org/10.1023/A:1016610727938 Korovajceva GI, Shcherbatyh TV, Selezneva ND, Gavrilova SI, Golimbet VE, Voskresenskaya NI, Rogaev EI. Genetic association between alleles of the apolipoprotein E gene (APOE) and various forms of Alzheimer’s disease. Genetika. 2001;37(4):529–535. (In Russ.). https://doi.org/10.1023/A:1016610727938

20. Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K. The UKU Side Effect Rating Scale. Comprehensive Rating Scale for Psychotropic Drugs and a Cross-Sectional Study of Side Effects in Neuroleptic-Treated Patients. Acta Psychiatr Scand Suppl. 1987;334:1–100. https://doi.org/10.1111/j.1600-0447.1987.tb10566

21. Селезнева НД, Рощина ИФ, Гаврилова СИ. Методы нейрометаболической терапии в профилактике когнитивного дефицита у родственников 1-й степени родства пациентов с болезнью Альцгеймера. Современная терапия в психиатрии и неврологии. 2018;3–4:8–18. eLIBRARY ID: 36907661 Selezneva ND, Roshchina IF, Gavrilova SI. Methods of neurometabolic therapy in the prevention of cognitive deficits in 1st degree relatives of patients with Alzheimer’s disease. Sovremennaya terapiya v psikhiatrii i nevrologii. 2018;3–4:8–18. (In Russ.). eLIBRARY ID: 36907661

22. Селезнева НД, Гаврилова СИ, Пономарева ЕВ. Эффективность и безопасность цитиколина в профилактике прогрессирования когнитивного дефицита у родственников 1-й степени родства пациентов с болезнью Альцгеймера: проспективное исследование. Психиатрия. 2020;18(4):33–40. https://doi.org/10.30629/2618-6667-2020-18-4-33-40 Selezneva ND, Gavrilova SI, Ponomareva EV. The efficacy and safety of citicoline in preventing the progression of cognitive deficits in 1st-degree relatives of patients with Alzheimer’s disease: a prospective study. Psychiatry (Moscow) (Psikhiatriya). 2020;18(4):33–40. (In Russ.). https://doi.org/10.30629/2618-6667-2020-18-4-33-40