Efficacy and Safety of Citicoline to Prevent Cognitive Deficiency Progression in First-Degree Relatives of Patients with Alzheimer’s Disease: Prospective Study

Objective: study of the prolonged effects of a three-month course of therapy with citicoline, carried out three times for three years, to prevent the progression of cognitive deficit in 1st-degree relatives of patients with Alzheimer’s disease (AD).

Study participants: the study involved first-degree relatives of patients with an established diagnosis of AD.

Study design: an openlabel comparative three-year prospective study of the dynamics of cognitive status in two groups of relatives, one of whom received citicoline therapy (1st group), and the other did not (2nd group). The 1st group made up 48 relatives (11 — with mild cognitive impairment syndrome and 37 — with signs of minimal cognitive dysfunction). 32 relatives who had not received drug treatment for 3 years (8 of them had objectively confirmed signs of minimal cognitive dysfunction, in 24 people — cognitive functioning corresponded to the normal aging) were included to 2nd group. The groups did not have significant differences in demographic characteristics and distribution of the ApoE4(+) genotype carriers.

Methods: clinical and psychological, psychometric, ApoE genotyping, statistical.

Results: in the therapeutic group, a significant improvement in the cognitive status was found in 75.0% of the treated relatives with cognitive disfunction on most scales and tests, with the exception of the clock drawing test. In the group of relatives who did not receive drug therapy, there was a significant deterioration of cognitive functioning — in 2 cases with the formation of mild cognitive impairment syndrome, in 21 cases — with the appearance of minimal cognitive signs.

Conclusion: the results of a three-year preventive course of citicoline therapy showed a significant positive effect of the drug on the cognitive status of the 1st degree relatives of AD patients who had signs of cognitive impairment that did not reach the level of dementia.

1. McGuffin P, Owen MC, O’Donovan AT, Gottesman Gaskell II. Seminars in Psychiatric Genetics. 1994. London: Gaskell. DOI: 10.1136/bmj.309.6957.818a

2. 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. DOI: 10.1080/13803399508406582

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

4. 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. DOI: 10.1212/01.wnl.0000129533.26544.bf

5. Levy JA, Bergeson J, Putnam K, Rosen V. Context-specific 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. DOI: 10.1017/s1355617704103044

6. 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. DOI: 10.1177/0891988705281882

7. 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. Zhurnal nevrologii i psihiatrii imeni S.S. Korsakova. 2015;115(12):110–117. DOI: 10.17116/jnevro2015115112110-117 (In Russ.).

8. Agnoli A, Bruno G, Fioravanti M, Yanagi M. Therapeutic approach to senile memory impairment: a double-blind clinical trial with CDP choline. In: Alzheimer’s Disease: Proceedings of the Fifth Meeting of the International Study Group on the Pharmacology of Memory Disorders Associated with Aging. Eds. R. Wurtman, S. Corkin, J. Growden, Boston, MA: Birkhauser. 1989;649–654.

9. 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. 2011;111(12):16–20. WOS:000301827600003 (In Russ.).

10. Lopez-Coviella I, Agut J, Savci V, Alonso Ortiz J, Richard J. Wurtman. Evidence that 5’-cytidinediphosphocholine can affect brain phospholipids composition by increasing choline and cytidine plasma levels. J. Neurochem. 1995;65:889–894.

11. Spiers PA, Myers M, Hochanadel GS, Lieberman HR, Wurtman RJ. Citicoline improves verbal memory in aging. Arch. Neurol. 1996;53:441–448. DOI: 10.1001/archneur.1996.00550050071026

12. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical character ization and outcome. Arch. Neurol. 1999;56:303–308. DOI: 10.1001/archneur. 56.3.303

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

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

15. Korovaytseva GI, Chipped TV, Seleznеva ND, Gavrilova SI, Golimbet VE, Voskresenskaya NI, Rogayev EI. Genetic association between alleles of a gene of E (APOE) apolipoprotein and various forms of Alzheimer’s disease. Genetics. 2001;37(4):529–533. (In Russ.). DOI: 10.1023/A:1016610727938

16. 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. DOI: 10.1111/j.1600-0447.1987.tb10566