Psychopharmacology (2002) 161:248–254 DOI 10.1007/s00213-002-1045-y Abstract Rationale: Phosphatidylcholine (PtdCho) in brain cell membranes decreases with age. Evidence from both animal and in vitro studies indicates that CDP-cho- line (citicoline) administration may increase phosphati- dylcholine (PtdCho) synthesis and might reverse PtdCho loss. Objectives: We investigated whether oral citicoline can increase PtdCho synthesis in the brains of older sub- jects by measuring levels of phosphorus-containing metabolites using proton-decoupled phosphorus mag- netic resonance spectroscopy ( 31 P-MRS) before and after citicoline treatment. Methods: All subjects took 500 mg citicoline once orally each day for 6 weeks, then took either citicoline or placebo once orally per day for a sec- ond 6-week period. Subjects underwent a 31 P-MRS scan at baseline and following 6 and 12 weeks of treatment. Results: Treatment with citicoline for 6 weeks was asso- ciated with a 7.3% increase from baseline levels in brain phosphodiesters (P=0.008), including an 11.6% increase in glycerophosphoethanolamine (P=0.002) and a 5.1% increase in glycerophosphocholine (P=0.137). Subjects who continued to take citicoline for the second 6-week period did not show significant additional increases in the levels of these metabolites. No changes were seen in other phosphorus-containing metabolites. There was a correlation between improvement on the California Verbal Learning Test and increase in phosphodiesters. Conclusions: The increases in phosphodiesters seen in this study indicate that phospholipid synthesis and turn- over were stimulated by 6 weeks of oral citicoline. These results in humans support previous in vitro and animal studies and suggest that the administration of oral citico- line may be of use in reversing age-related changes in the brain. Keywords 5′-Cytidine diphosphate choline · Choline · Phosphatidylcholine · Aging · Brain · Magnetic resonance spectroscopy Introduction A decline in cognitive function is commonly seen with age and may be associated with biochemical and meta- bolic changes occurring in the central nervous system. These include alterations in cell membrane structure and function, decreases in the functioning of cholinergic neu- rons (Bartus et al. 1982; Pepeu and Giovannelli 1994) as well as compromised glucose and energy metabolism (Hoyer 1996). Many of these changes may be reflected in levels of phosphorus-containing metabolites in the brain, which can be detected by phosphorus magnetic resonance spectroscopy ( 31 P-MRS). Specifically, 31 P-MRS can identify phosphomonoesters (PME) and phosphodiesters (PDE), related to membrane lipids, as well as inorganic phosphate (Pi), phosphocreatine (PCr), and the α, β and γ phosphates of nucleoside triphosphates (NTPs), related to energy metabolism. If proton-decoupled 31 P-MRS is per- formed (Luyten et al. 1989; Murphy-Boesch et al. 1993), the PME resonance can be resolved into two peaks sub- stantially representing phosphocholine (PC) and pho- sphoethanolamine (PE), while the PDE resonance can be mainly resolved into two peaks substantially representing glycerophosphocholine (GPC) and glycerophosphoetha- nolamine (GPE); although, at 1.5 T, there is also a broad PDE component arising from mobile and bilayer pho- spholipids (Murphy et al. 1989; Kilby et al. 1990, 1991). S.M. Babb ( ✉ ) · B.M. Cohen · R.A. Villafuerte · S.A. Gruber D.A. Yurgelun-Todd · P.F. Renshaw Brain Imaging Center, McLean Hospital, 115 Mill St., Belmont, MA 02478, USA e-mail: sueb@mclean.harvard.edu Fax: +1-617-855-2770 S.M. Babb · B.M. Cohen · S.A. Gruber · D.A. Yurgelun-Todd P.F. Renshaw Consolidated Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA L.L. Wald Department of Radiology, MGH-NMR Center, Massachusetts General Hospital, 9 13th St, Charlestown, MA 02129, USA ORIGINAL INVESTIGATION S.M. Babb · L.L. Wald · B.M. Cohen R.A. Villafuerte · S.A. Gruber · D.A. Yurgelun-Todd P.F. Renshaw Chronic citicoline increases phosphodiesters in the brains of healthy older subjects: an in vivo phosphorus magnetic resonance spectroscopy study Received: 28 June 2001 / Accepted: 29 January 2002 / Published online: 22 March 2002 © Springer-Verlag 2002