Double-blind placebo-controlled study with citicoline (CDP-choline) in APOE genotyped Alzheimer's disease patients. Effects on cognitive performance, brain bioelectrical activity and cerebral perfusion.

Alvarez XA, Mouzo R, Pichel V, Perez P, Laredo M, Fernandez-Novoa L, 
Corzo L, Zas R, Alcaraz M, Secades JJ, Lozano R, Cacabelos R.

EuroEspes Biomedical Research Center,
A Coruna, Barcelona, Spain.
Methods Find Exp Clin Pharmacol 1999 Nov;21(9):633-44


Cytidine 5'-diphosphocholine (CDP-choline) is a an endogenous intermediate in the biosynthesis of structural membrane phospholipids and brain acetylcholine. CDP-choline has been extensively used for the treatment of neurodegenerative disorders associated with head trauma, stroke, brain aging, cerebrovascular pathology and Alzheimer's disease. In this study we have investigated the efficacy and safety of the treatment with CDP-choline versus placebo in patients with Alzheimer disease. Thirty patients (age = 73.0 +/- 8.5 years; range = 57-87 years) with mild to moderate senile dementia (GDS: stages 3-6) of the Alzheimer type were included in a double-blind, randomized and placebo-controlled clinical trial. After a 2-week period of drug washout, patients were treated with i) placebo (n = 17; age = 73 +/- 5 years) or ii) 1,000 mg/day of citicoline (n = 13; age = 76 +/- 9 years) for 12 weeks (84 days). Examinations were done at baseline (T0) and after the 12 weeks of treatment (T12). As compared to placebo, CDP-choline improved cognitive performance in Alzheimer's disease patients with APOE E4 (ADAS: difference between groups = -3.2 +/- 1.8 scores, p < 0.05; ADAS-cog: difference between groups = -2.3 +/- 1.5, ns); and this improvement on cognition was more pronounced (ADAS, p < 0.01; ADAS-cog: difference between groups = -2.8 +/- 1.3, p < 0.06) in patients with mild dementia (GDS < 5).  CDP-choline also increased cerebral blood flow velocities in comparison with placebo (p < 0.05) when transcranial Doppler recordings from both hemispheres were considered together, as well as diastolic velocity in the left middle cerebral artery (p < 0.05). Patients treated with CDP-choline showed an increase in the percentage of brain bioelectrical activity of alpha (occipital electrodes) and theta type (left side electrodes), accompanied by a decrease in relative delta activity particularly marked in the left temporal lobe. Significant differences with respect to placebo (p < 0.05) were observed for theta activity in several fronto-parieto-temporal electrodes of the left hemisphere. Treatment with CDP-choline tended to reduce serum IL-1 beta levels, mainly after 4 weeks of administration, with no modified blood histamine content. In addition, neither adverse side effects nor alterations in biological and hematological parameters were induced by CDP-choline. The present data indicate that CDP-choline (1,000 mg/day) is well tolerated and improves cognitive performance, cerebral blood perfusion and the brain bioelectrical activity pattern in AD patients. According to our results, it seems that CDP-choline might be a useful treatment in Alzheimer's disease, and that the efficacy of this compound is greater in patients with mild mental deterioration and/or bearing the epsilon 4 allele of the APOE.

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