Citicoline Improves Verbal Memory in Aging

ORIGIl'Al COl'TRIBUTlOl'

Paul A. Spiers. PhD; Diane Myers. MA; Gail S. Hochanadd. PhD; Harris R. Liebennan, PhD; Richard J. Wurtman, MD

Obiectlve: To test the verbal memory of older volun- line concentrations were measured at baseline; at days 30, teers given citicoline. 60, and 90 in the initial study; and at day 60 of each treatment condition in the crossover study. Plasma choline Design: A randomized, double-blind, placebo-controlled, concentrations and memory scores were analyzed using parallel group design was employed in the initial study. Af- repeated-measures analysis of variance and covariance, fol- ter data analysis, a subgroup was identified whose members lowed by planned comparisons when appropriate. had relatively inefficient memories. These subjects were recruited for a second study that used a crossover design. The Results: In the initial study, citicoline therapy im- subjects took either placebo or citicoline, 1000 mg/d, for 3 proved delayed recall on logical memory only for the months in the initial study. In the crossover study, subjects subjects with relativelyinefficientmemories. In the cross- took both placebo and citicoline, 2000 mg/d, each for 2 over study, the higher dosage of citicoline was clearly months. associated with improved immediate and delayed logical memory. Subiects: The subjects were 47 female and 48 male volunteers 50 to 85 years old. They were screened for de- Conclusions: Citicolinetherapyimproved verbalmemory mentia, memory disorders, and other neurological prob- functioning in older individuals with relatively ineffi- lems. Of the subjects with relativelyinefficientmemories, cient memories. Citicoline may prove effective in treat- 32 participated in the crossover study. ing age-related cognitive decline that may be the precursor of dementia. Main Ovtco.e Measure: Verbalmemorywastested at eachstudy visitusinga logicalmemorypassage.Plasmacho- (Arch Neurol. 1996;53:441-448)

HOLINERGICbrain neu- The purpose of the present study was rons playa central role in to determine whether oral administration learning and memory. 1.2 of citicoline (cytidine diphosphocholine) " These functions can be dis- (Ferrer Internacional, Barcelona,Spain), a rupted by giving normal metabolic intermediate that completely volunteers anticholinergic agents, such as dissociates to choline and cytidine on en- scopolamine,).~c and can be restored byace- teringthebody,IOimprovesmemoryin well- tylcholinesterase inhibitors. ).7 It is un- functioning older subjects. Besides pro- clear, however, whether the administra- motingacetylcholinebiosynthesis,thisdrug tion of choline, acetylcholine's precursor, mayalso enhance synaptic transmissionby can improve human memory. In some stud- facilitating the formation of neural mem- ies, oral choline therapy producea only branes. Choline and cytidine,actingin con- modest effects~.8; in another study, high cert, enhance phosphatidylcholine synthe- from the Clinical Research doses of phosphatidylcholine, the princi- sis in cultured cells, II rat brain slices, 12 and Center (Drs Spiers. pal dietary choline source, significantly re- whole brain in vivo, I) and this increase is Hochanadel. and Wurtman and duced the number of trials required by nor- followed by proportionate changes in lev- Ms Myers) and Department of mal subjects to learn a list of nonsense els of the other major membrane phospho- Brain and Cognitive Sciences (Dr Wurtman). Massachusetts syllables. Q This effect was greatest among subjects who had initially required more tri- lnstitute of Technology. als to learn a similar list. Otherwise nor- Cambridge; and US Army Research lnstitute of mal individuals with relatively poor memory See Subjects and Methods Environmental Medicine, function may, therefore, be the best candi- on next page Natich. Mass (Dr Lieberman). dates for choline supplementation.

.\RCli SEUROUVOL 53. ~tAY 1996 HI

.,~.-. ------noncompliance during screening, and those data were not SUBJECTS AND METHODS included in the baseline comparisons (n=94). The age and educational characteristics of the 2 experimental groups and SUBJECTS their baseline performance on the criterion measure are presented in Tall.e 1 . Subjects ranged in age from 50 to 85 The total study population was composed of 95 older sub- years, with a mean (~SD) age of 67.2 (~9.3) years. There jects (47 women and 48 men) who were recruited through was no significant difference in the mean age of male print advertisements or from a population that had previ- (67.9~8.2 years) vs female (66.4~ lO.3 years) subjects or ously participated in studies at the Clinical Research Cen- in the mean age of subjects randomly assigned to the pla- ter (CRC) of the Massachusetts Institute of Technology, cebo group (67.9~9.5 years) vs the citicoline group Cambridge. Exclusion criteria precluding participation in (66.2~9.0 years). The sample was well educated, with a this study included active medical, neurological, or psy- mean of 14.3 years of schooling. Men had significantly chiatric illness or a history ofany condition that might sig- (t=2.23,P<.03) more years ofschooling (l5.3~2.7 years) nificantly influence performance on cognitive testing. than women (l4.1~2.6years). Subjects assignedbythe ran- Subjects were screened by medical history, physical domization process to the placebo group had significantly examination, blood work, and electrocardiogram as well (t=- 2.28, P<.02) more years ofeducation (l5.3~2. 7 years) as bysinglephoton emissioncomputed tomography;allfind- than subjects assigned to the citicoline group (l4.1~2.6 ings and values had to fallwithin normal limits for the sub- years). There was no drug group-by-sex interaction when ject's age. Subjects also had to score 26 or greater (out of a these data were subjected to analysis ofvariance (ANOVA), possible score of 30, which is considered normal) on the however, since the mean years of education ofthe men and Mini-Mental State Examination. The Vocabulary subtest women in each drug group were not significantly differ- of the Wechsler Adult Intelligence Scale-Revised was ad- ent. There were no significant differencesin baseline plasma ministered to assessgeneral intelligence, with a score at the choline concentrations between men and women or be- 25th percentile (averagerange) or better required. The Logi- tween the citicoline and placebo groups. There were no sig- cal Memory subtest of the Wechsler Memory Scaleand the nificant differences between baseline performances on im- Rey-Osterreith Complex Figure Test were administered to mediate and delayed logical memory. assess verbal and nonverballeaming; scores on these mea- Baselineperformance on a logical memory passage was sures also had to be at least in the average range for age used to classify subjects as having relatively inefficient (see LezakJOfor descriptions of all of these tests). memories. As described above, the sample was stratified Informed consent was obtained from each subjectafter into age groups, and the mean (SD) performance for each the experimentalproceduresand risksassociatedwiththecon- age group at baseline was calculated for immediate recall. sumption of citicoline had been fully explained. Subjectre- Based on whether they scored below the mean relative to cruitment, informedconsent procedures, and allexperimen- their peers, the subjects were then classified as having ei- tal methods were approved by the Massachusetts Institute of ther average or relatively inefficient memories. Forty-nine Technology Committee on the Use of Humans as Experi- subjects (22 in the citicolinegroup, 27 in the placebo group) mental Subjects. Citicoline is an Investigational New Drug were classified as having relatively inefficient memories approved for human research bythe Food and Drug Admin- based on these criteria, and this group's performance was istration. Subjectswere monitOredclosely for adverseexpe- still within the normal range on this task. riences and encouraged to report any health complaints. A A total of 32 subjectswere recruited from this pool who study physician was available on 24-hour call. Adverseex- were willing and able to participate in the relatively ineffi- periences were recorded on case report forms, and subjects cient memory crossover study, 16 from the group assigned were followedup until such adverseexperiences resolvedor by the initial randomization to drug treatment and 16 from the subjectwasdropped from the stUdy.Anysubjectdropped the group assigned to the placebo condition. The ages and asa result ofan adverseexperienceor fornoncompliancewas educational characteristics of these 2 groups and their base- debriefed according to the guidelines of the Committee on line performances on the criterion measures are presented the Use of Humans as Experimental Subjects. Any adverse in Table 1.Two-tailed t tests and analyses ofvariance did not event ofsufficientseveritytoresult ina subject beingdropped reveal any significant comparisons or interactions between from the study and believed to be related to treatment with these 2 groups by gender, age, or years of education. These the experimental compound was to be reported to the Food subjects ranged in age from 54 to 86 years, with a mean of and Drug Administration. No such event occurred. 73.1 years. These groups, like the initial sample, were well Subjects were assigned to either the placebo or active educated, with 14.3 mean years of schooling. drug condition according to a blind randomization sched- There were no significant differences in baseline ule that was applied to successively recruited subjects plasma choline concentrations between men and women without regard to age, education, or baseline performance (t=-O.23, P<.83) or between the citicoline and on screening measures. One subject was dropped for placebo groups (t=O.92, P<.36). There was no drug lipids.13 In addition, citicoline may enhance dopaminer- Citicoline has been reported to accelerate recovery gic neurotransmission. Ii This action could also facilitate from strokelOand from traumatic brain injury.19,ll.13In a memory improvement, given that the arousal and atten- 1989 study, Agnoli et ap4 tested the potential of this tion components of this function depend on catechol- compound for improving memory in elderly patients aminergic systems.Ii Oral dose tolerance and pharmaco- (mean age, 74 years) complaining of mild to moderate kinetic studies suggest that citicoline is well tolerated and memory problems. While the authors did not clearly safe,1j.18 producingonlyinfrequent, minor sideeffects,even define their criteria for memory impairment, the mean during 15 months of daily administration.l~ Mini-Mental State Examination score for their sample

ARCH NEUROUVOL j3, MAY 1996 2

------group-by-sex interaction. There was no significant differ- subject's immediate oral recall. Approximately 30 min- ence between men and women in their baseline perfor- utes later, delayedrecallwasmeasured. The LogicalMemory mance on logical memory (1=1.77,P<.09). Similarly, there subtest stories ofthe Wechsler MemoryScaleand the Wech- was no significant differencebetween the citicoline and pla- sler MemoryScale-Revised,which contained the same num- cebo subgroups in their baseline perfonnance on logical ber of target bits of information, were used at the various memory (1=0.71, P<.48). There was no drug group-by- testing sessions. Alternate fonns were used at the different sex interaction. stUdyvisits, but the same fonn was used for all subjects at each specific study visit. For example. all subjects heard PROCEDURE the American tiner story at baseline and the Police Dogs story at day 30. All tests were administered and scored us- Citicoline and placebo tablets were fonnulated by Ferrer ing standard criteria by the same examiner, who remained lntemacional SAin Barcelona, Spain. Tablets were identi- blind to treatment conditions. Scoring and data entry were cal in appearance, taste, and packaging. Once accepted verified by the principal investigator, who was also blind into the protocol, all subjects took 1 tablet of placebo to treatments, and initial data analyses were conducted be- twice daily for 1 week prior to baseline studies to become fore the treatment assignment code was broken. acclimated to the experimental regimen. Subjects were then assigned to either the citicoline or placebo group STATISTICAL ANALYSIS according to the randomization schedule and were supplied with either placebo or citicoline tablets (500 mg), Four subjects were dropped from the initial study as a re- which they took twice daily for 3 months. If they contin- sult of adverse experiences (see below) and 1 subject for ued in the crossover study, subjects were supplied with noncompliance during screening; data from the remain- either placebo or citicoline tablets at the beginning of each ing 90 subjects were included in the statistical analysis.Cho- treatment condition. They took 2 tablets twice daily for 2 line assay results for all remaining subjects in each drug monthS during each condition, with a lO-day washout group (44 in the citicoline group, 46 in the placebo group) period prior to crossing over. were compared by 2-factor (timeXdrug) repeated- Subjects were required to spend 1 morning per month measures ANOVA,followed by planned comparisons (1- at the CRC,beginning at the end ofthe initialplacebo week, tailed 1tests). This analysis was used to determine whether for a total of 4 visits (baseline and days 30, 60, and 90) in there were any significantdifferencesin plasma choline con- the initial study and 5 more visits (days 30 and 60, wash- centrations betWeenthe 2 experimental groups at days 30, out, and days 30 and 60) in the crossover study. At these 60, and 90. Performance on immediate and delayed logi- monthly visits, vital signs were measured, health histories cal memory was also compared at days 30 and 90 by re- were recorded, and blood samples were taken by CRC nurs- peated-measures analysis of covariance (ANCOVA), with ing staffwho were blind to treatment assignment. After their baseline performance controlled to account for the signifi- nursing visit, at baseline, day 30, and day 90 in the initial cant difference in years of education between the experi- study and at day 60 ofeach condition in the crossover study, mental samples in this parallel group design. Two-factor a battery of cognitive tests was administered by a trained repeated-measures ANCOVAs were also applied to the technician who was also blind to treatment assignment. memory data of subjects classified in the relatively inefficient memory groups, followed by planned comparisons MEASURES (1-tailed 1tests). For the crossover stUdy, plasma choline assays were Subjects had fasting blood samples drawn, consumed a compared by 2-factor (timeXgroup) repeated-measures normal breakfast, and then took their morning tablet; ANOVA,followedby planned comparisons (1-tailed 1tests). approximately 2 hours later, second blood samples were This analysis was used to determine whether there were obtained. Laboratory tests performed included urinalysis, any significant differences in plasma choline concentra- complete blood cellcount, platelet count, and partial throm- tions betWeenthe 2 groups at washout and day 60 during boplastin time, and the following concentrations were either condition. Performance on immediate and delayed measured: blood glucose, serum urea nitrogen, creatinine, logicalmemory was compared by charting the subjects' per- electrolytes, calcium, phosphorus, plasma proteins, biliru- fonnance at baseline and day 90 of the initial study and at bin, alkaline phosphatase, aspartate aminotransferase, amy- day 60 during each condition of the crossover study using lase, and creatine kinase. Plasma was also obtained and 2-factor(timeXgroup) repeated-measures ANOVAs.If there frozen for later assay to determine choline concentrations. was a significant group-by-time interaction, single-factor The verbal memory task was administered at the base- (time) ANOVAswere used to compare the performance of line, day 30, and day 90 visits in the initial study and at each group at baseline and during each treatment condi- both day 60 visits in the crossover study. A narrative pas- tion, followedby planned comparisons (Student-Newman- sage was read aloud to the subject once, followed by the Keuls test).

'f was 20.1 (SD, 3.25). In the standardization research for The results were considered promising, with citicoline- a the Mini-Mental State Examination, a score of 20 or treated subjects showing a specific, statistically signifi- s less was found to be consistent with dementia, cant improvement in acquisition efficiency, although s delirium, or affective disorder but not with normal they did not differ from placebo-treated subjects in c aging.25After receiving citicoline, 1000 mg/d, or pla- overall memory performance. ~. cebo for 3 and 6 weeks, subjects were tested using the The present studies were designed to extend the :1 Randt Memory Test, a measure that was specifically initial findings of Agnoli et alH in a population of nor- ~ designed for longitudinal pharmacological studies.26 mal older volunteers using a more widely available

ARCH NEUROlJVOL 53. MAY 1996 +0 Table1. DemographicCharacteristicsandBaselinePerfonnances01Subjects In the Initial Studyandthe RelativelyInefficientMemoryCrossoverStudy.

StudyGroup Age" Education, , Initial Study 9.6(3.7) Citicoline (n=48) 66.2(9.0) 14.1(2.6) 10.6(3.4) 9.6(2.9) Placebo (n=46) 67.9(9.5) 15.3(2.7) 10.8(2.9) -0.91 -2.29 -0.21 -O.Ot Unpaired t <.83 <.99 2-Tailed P <.37 <.02

Crossover Study Received citicoline in the initial study (n=16) 74.0(8.7) 13.7(1.9) 9.4(8.8) U(2.8) 7.8(2.5) Received placebo in the initial study (n= 16) 72.2(9.6) 14.8 (2.6) 8.8(2.4) -1.32 -0.71 0.73 Unpairedt -0.58 2-TailedP <.57 <.20 <.48 <.

·Valuesaremean(SO). standardized measure of memory function: passages each age group at baseline was calculated for immediate from the logical Memory subtest of the Wechsler recall. Third, subjects were classified as having either av- Memory Scale and the Wechsler Memory Scale- erage or relatively inefficient memory, based on whether Revised.27This task more closely resembles the memory they scored below the mean relative to their peers. The requirements of real life, as the subject is read a selected logical memory data were then analyzed separately for passage aloud and then asked to repeat it, as opposed the relatively inefficient memory group. to being drilled repeatedly on a list of related or unrelated words. This task is also more like the demands of RESl"LTS normal human memory, in that subjects are asked to recall what they have heard and then, after a delay, to ADVERSE EXPERIENCES retrieve it. Although a few of our subjects reported mild for- Subjects were encouraged to report any health com- getfulness, none complained of malignant memory dis- plaints to the CRC nursing staff and were queried for ad- orders or showed evidence of memory impairment on verse symptoms during their monthly visits. Forty such screening examinations. Furthermore, none met the op- complaints or adverse experiences were reported in the erational criteria for age-associated memory impair- initial study. Of these, 4 were clearly the result of con- ment (complaint of poor memory and objective evi- current medical problems unrelated to the subjects' par- dence of memory performance 1 SD or more below the ticipation in the protocol (eg, cerebral aneurysm). These mean for young adults).l8 Subtypes of memory changes subjects were dropped from the study, leaving a total of associated with senescence other than age-associated 36 adverse experiences reported by 90 subjects during 3 memory impairment havebeen proposed,l9including age- months receiving either placebo or citicoline. These com- consistent memory impairment (test performance within plaints were grouped into categories, including insom- 1SDbelow the mean for the patient's agegroup) and late- nia, epigastric distress (diarrhea, constipation, nausea), lifeforgetfulness(testperformance> 1SDbelow the mean headache (head pain, blurred vision), rash, and cardiac for the patient's age group). In DSM-1V(Diagnosticand complaints (palpitations, chest pain), none of which oc- Statistical Manual of Mental Disorders, Fourth Edition), curred with significantly greater frequency among citi- it is proposed that the term age-relatedcognitivedecline coline-treated subjects. In fact, the total number of ad- be used to classify such conditions; however, no spe- verse experiences in the initial study was greater among cific criteria are proposed, and no specific definition is subjects receiving placebo than among those receiving provided for the memory-related changes. However,any citicoline ('I 2). subject whose performance was below the mean for his In the crossover study, only 9 adverse experiences or her peers might be considered to have a relativelY-in- were reported by the 32 subjects. Of these, 3 were clearly efficient memory. Consequently, once the data from the the result of concurrent medical problems unrelated to entire sample had been analyzed, we tested the hypoth- the subjects' participation in the protocol (eg, macular esis that subjects with normal but relatively less effi- degeneration). These subjects were dropped from the cient memory were more likely to benefit from choline study, leaving a total of 6 adverse experiences reported supplementation. by 29 subjects in 6 months. These 6 adverse experi- Relatively inefficient memory was defined as a per- ences included 9 symptoms that could be grouped ac- formance score that fellbelow the mean for the subject's cording to the categories used for the initial study. There peers within our sample. Subjects with relatively ineffi- were 4 episodes ofepigastric distress, 2 ofrash, 2of head- cient memory were identified as follows:First, the sample ache, and 1 of insomnia. The insomnia episode oc- was stratified into 3 age groups (50 to 64. 65 to 74, and curred during the placeboperiod, but all others took place 75 to 85 years). Second, the mean (SO) performance for during citicoline treatment. Two other subjects also had

ARCH ~EL'ROLNOL 53. MAY 1'1'16 4....

------to be dropped from the a~alysis of the crossover study results. One subject was dropped for incomplete data be- Table2. AdverseExperienC8$Reported cause of noncompliance during cognitive testing at his bySubjectsDuringtheInitialStudy last visit. The other subject was dropped beca,use a brain No.of Subjects tumor was diagnosed shortly after he completed partici- I I pation in the crossover study. This left 27 crossover sub- Complaint Placebo Clticollne jects (14 in the citicoline group, 13 in the placebo group) Insomnia 3 1 from whom data could be used for treatment analyses. Epigastricdistress In summary, no adverse events were judged by CRC phy- Diarrhea 4 3 sicians to be related to citicoline treatment in either the Constipation 1 1 Nausea 5 4 initial study or the crossover study that required medi- Headache cal intervention, termination from the stUdy. or an emer- Headpain 2 1 gent report to the Food and Drug Administration. Blurredvision 4 1 Allergicrash 2 1 CHOLINE Cardiac Palpitations 0 1 Chestpain 1 1 Repeated-measures ANOVA of plasma choline concen- Total 22 14 trations yielded a significantmain effectfordrug (F=7.71, P<.OO7) in the initial stUdy. There was no main effect for time comparing results over days 30, 60, and 90, and the interaction term was not significant. Planned com- ANOVA of the 2 groups under each treatment condition parisons (I-tailed t tests) showed that at each study visit, showed a significant main effect of treatment condition citicoline-treated subjects had significantly higher mean (F=23.7S, P<.OOl) and a significant group-by-treatment plasma choline concentrations than placebo-treated sub- interaction (F=3S.24, P<.OOl) for immediate recall. For jects (t=2.26, P<.02; t=0.77, P<.04; and t=1.97, P<.03 delayed recall, 2-factor repeated-measures ANOVA also at days 30, 60, and 90, respectively). showed a significant main effect of treatment condition In the crossover study, repeated-measures ANOVA (F=9.9S,P<.OOl) and a significantgroup-by-treatment in- ofplasma choline concentrations comparing placebo with teraction (F=lS.OS, P<.OOl). Single-factor repeated- citicoline yielded a significant main effect by drug measures ANOVAs showed a significant main effect for (F=Sl.S2, P<.OOl). There was no significant subgroup- treatment condition in the citicoline (F=32.36, P<.OOl) by-drug interaction (citicoline vs placebo) and no group- and placebo (F=30.42, P<.OOl) subgroups on immedi- by-drug interaction. Planned comparisons showed that ate recall as well as significant main effects of treatment citicoline treatment resulted in much higher plasma cho- condition in the citicoline (F=9.47, P<.OOl) and placebo line concentrations than placebotreatment forboth groups (F=24.36, P<.OOl) subgroups on delayed recall. Planned of subjects (t=2.26, P<.OOl). comparisons revealed that for both the immediate and delayed recall tasks, the best performance of both the LOGICAL MEMORY citicoline and placebo subgroups (P<.OS) was during the citicoline treatment condition (Tab.e 4, Figure I, Repeated-measures ANCOVAs for all subjects in the ini- and Figure 2). tial study yielded a main effect for time on both the immediate (F=S.22, P<.03) and delayed (F=7.0S, P<.Ol) logical memory tasks. There was no main effect for drug, nor was there a drug-by-time interaction. The main ef- Allsubjects,regardlessofexperimental treatment, showed fect for time showed that all subjects improved their per- a practice effect, improving their verbal memory perfor- formance compared with baseline. mance compared with the baseline. When the data were For the relatively inefficient memory group in the analyzed forthe relativelyinefficientmemory group, there initial study, repeated-measures ANCOVAs yielded no was no significant main effect for treatment, illustrating main effects and no interaction effects on the immediate the importance of practice effects in such a repeated- logical memory task. On delayed logical memory, there measuresdesign.There werestatisticaltrends in the analy- were no main effects, but a trend (F=2.7S, P<.lO) was sis, however, which planned comparisons showed were observed toward a drug-by-time interaction, suggesting related to a significant difference on delayed recall per- that citicoline-treated subjects consistently improved in formance. Thesubjects with relativelyinefficientmemory their performance compared with baselinewhen theywere who received citicoline maintained their improvement tested at days 30 and 90. Planned comparisons applied L from day 30 to day 90, whereas subjects who received to improvement in recall from baseline scores revealed placebo showed initial improvement at day 30, consis- that this trend was caused by a significant difference in tent with practice, but subsequently stayed the same or favor of citicoline for delayed logical memory at day 90 declined in performance by day 90. This finding sug- (t=1.6S, P<.OS). These data regarding performance im- gested that the resultsobservedwith citicolinewere caused provement for the whole sample vs the relatively ineffi- by more than a simple practice effect. cient memory group on immediate and delayed logical When subjects with relatively inefficient memory memory at days 30 and 90 are presented in Tab.e 3. 1 were studied while receiving a higher dose of cHico- In the crossover study, 2-factor repeated-measures line, verbal memory clearly improved. This effect was

ARCH NEUROUVOl53. MAY 1996 5

. -- Table3. ImprovementFromBaselineIn ImmediateandDelayedLogicalMemoryInthe Initial Study.

ImpmementInLogicalMemoryScore Day30 I All SublectsWIthRelltlvely All Sublects lneft1dentMemory SUblects StudyGroup (N=90) (N-49) (11=90) immediate Citicoline 1.95 (3.90) 3.23(3.57) 3.16 (3.41) Placebo 2.17 (3.52) 2.78(3.65) 2.76 (2.47) Unpairedt -0.28 0.43 0.64 Hailed P <.39 <.33 <.26 Delayed Citicoline 1.43(3.69) 2.50(3.4) 2.93 (3.41) Placebo 2.17 (3.62) 2.60(3.90) 2.72 (2.78) Unpairedt -0.96 -0.17 0.33 Hailed P <.17 <.43 <$I

·Valuesaremean(SO).

Tlble 4. ImmediateInd DelayedlogicalMemoryInthe InlUalStudyInd the RtIatIwfr 1DdIcIeIt""'::1::~:;~._~. "" I.8gIcaIIlllllary ~ DayII.IIIIIIIIIIIIIJ I I StudyGroup Baseline PIIceIIo CIIIC8III8 IauD8dIaI8 Receivedciticoline In the initial study (1I=14)t 9.14(2.68) ... 12.93(2.23) Receivedplacebo in the initialstudy (n=13)t 9.07(2.56) 13.38(2.81) Delayed Receivedciticolinein theinitialstudy(n=14)t 8.43(2.93) ... 11.21(2.29) ReceivedplaceboIntheInitialstudy(n=13)t 8.08(2.53) 12.00(3.39)

· Valuesare mean (SO). tP<.05 by the 5tudent.Newman-Keulstest.

a Baseline C Baseline

. Day90.CiIicoIine-lnilial Study . Day 90, PIacebo-IniIiaI Study C Day60.~Study . Day 60. CiticoIine-Crossover Study . Day60.CiticolinH:rossoverStudy .. Day 60. I'IacebcH:rosso Study 20 20

:! 15

i:' 0 E.. 10 2 3

0 o Immediate Memory Delayed Memory Immediate Memory Delayed Memcxy

Figure 1. Performanceon immediateand delayedlogical memory for Figure 2. Performanceon immediateand delayedlogical memory for sUbjectswho took citicoline in the initial study. subjects who took placebo in the initial study.

attributable to the citicoline. since performance was although still well within tolerance limits, given the significantly lower when the same subjects were tak- absence of serious side effects observed in this and ing placebo. This suggests that the optimal dose of other studies. citicoline for producing cognitive effects in this popu- This study was designed to test the earlier report by lation may be higher than was previously supposed. Agnoli et alzi that citicoline facilitates memory acquisi-

ARCH "IEUROUVOL n. MAY1996 6

------._u n_ .._____

tion in the elderly. We did not observe such an effect in Accepted for publication February 16. 1996. our overall population; however, this sample was higher- This work was supported in part by a grant from the functioning than that studied by Agnoli et al,H accord- Center for Brain Sciences and Metabolism Charitable Trust, ing to their mean Mini-Mental State Examination scores. Cambridge. Mass, by grant MH-2878J from the National When we studied subjects with relatively inefficient Institutes of Health, Bethesda, Md, and by grant MOl- memory, we did find that citicoline facilitated memory RR-00088 from the National Institutes of Health to the acquisition and retention, confirming the findings of Ag- CRC of the Massachusetts Institute of Technology. Cam- noli et aL Since plasma choline concentrations were sig- bridge. nificantly higher for subjects when they were receiving The authors thank John Growdon. MD. John Gabri- citicoline, these findings confinn that subjects were com- elli, PhD, Andrew Sat/in, PhD, Donald Schomer, MD, Keith pliant during the treatment condition and support the Johnson, MD, William Abend, MD, Antoine EI-Khoury, MD, view that the drug's memory effect may result from and David August, MD, as well as Susan Blackburn, re- changes in brain choline metabolism mediated by ace- search assistant, Pauline Marchant, RN, nursing coordina- tylcholine and phosphatidylcholine. tor, and the CRC Nursing and Dietary Staff for assistance Overall, this study showed that citicoline im- in carrying out this study. The authors also thank Jess Torres- proved verbal memory in elderly subjects whose perfor- Herrera, MD, and]. Alfonso Ortiz-Hernandez, MD,for their mance was below that of their peers. Our test sample was critical reading of the manuscript. composed of well-educated, functionally independent Reprints: Paul A. Spiers, PhD, CRC: E17-4J8, Mas- older adults. None of the subjects exhibited dementia, sachusetts Institute of Technology, 77 Massachusetts Ave, although a few might have met the criteria for age- . Cambridge, MA 02139. associatedmemory impainnent. Mostofour subjects were perfonning above average for their age on this memory RHLRL:\CLS task at baseline. For those who were not performing as well astheir high-functioning peers, however,results were 1. Bartus RT. Dean RL. Beer B. Uppa AS. The cholinergic hypothesis of geriatric dramatic in the relatively inefficient memory crossover memory dysfunction. Science. 1982;217:408-417. study. The mean age of subjects with relatively ineffi- 2. Bartus RT. Dean RL. Pontecorvo MJ. Ricker C. The cholinergic hypothesis: a cient memory was 6 to 8 years older than the mean age historical overview. current perspective. and Mure directions. Ann N Y Acad Sci. 1985;444:332-35B. of the population for the initial study, with most of the 3. Drachman D. Sahakian BJ. Effects of cholinergic agents on human learning former in their early 70s. The mean level ofeducation of and memory. In: Barbeau S. Growdon JH. Wurtman RJ. eds. Nutrition andthe the subjects with relatively inefficient memory, how- Brain. New York. NY: Raven Press; 1979;5:351-366. ever, was not different from that of the initial study popu- 4. Sitaram N. Weingartner H. Gillin JC. Human serial learning: enhancement with arecholine and choline and impairment with scopolamine. Science. 1978;201: lation. Thus, the finding that verbal memory was im- 274-276. proved by thedose ofciticolineused in the crossoverstudy 5. Rusted JM. Warburton DM. The effects of scopolamine on working memory suggests that this compound may be useful in the treat- in healthy young volunteers. Psychopharmacology. 1988;96:145-152. ment of individuals who experience reduced memory 6. Meador KJ. Loring OW. Davis HC. et at Cholinergic and serotonergic effects on the P3 potential and recent memory. J Clin Exp Neuropsychol. 1989;11: functioning with advancing age. While certain au- 252.260. thorsJ1havesuggested that this should be viewed as a nor- 7. Molchan SE. Mellows AM. Lawlor BA, et al. TRH attenuates scopolamine- mal, inevitable consequence ofsenescence, othersJ2have induced memory impairment in humans. Psychopharmacology. 1990;100:84- maintained that age-related changes in cognitive func- 89. tion should no more be tolerated than declining visual B. Sorgatz H. Effects of lecithin on memory and learning. In: Hanin I. Ansell GB. eds. Lecithin: Technological.Biologicaland TherapeuticAspects: Proceedings acuity observed with aging and should not remain un- of the FourthInternationalCOlloquiumonLecithin.NewYork.NY:PlenumPress; treated. 1987:147-153. This study suggests that citicoline should also prove 9. LaddSl Sommer55. Phospatidylc/lolineenhancesshort-termmemoryinslow helpful forelderlywho are more typicalintellectually than leamers.Presentedatthe 95thannualmeetingof theAmericanPsychological the sample described here. Furthermore, citicoline may Association;August20. 1990;Boston.Mass. 10. LopezG.-CoviellaI.AgutJ. VonBorstelR.WurtmanRJ. Metabolismof cyti- provide considerable benefit to older individuals with age- dine(5')-diphosphocholine(Citicoline)followingoralandintravenousadmin- associatedmemoryimpainnent or other symptoms of mild istrationto the humanand the rat. NeurochemInt.1987;11:293.297. cognitive impairment-symptoms that may herald the 11. LopezG.-CoviellaI.WurtmanRJ.Enhancementbycytidineof membranephos- onset of progressive cognitive decline and may in fact be pholipidsynthesis.J Neurochem.1992;59:338-343. 12.SavciV.WurtmanRJW.Effectofcytidineon membranephospholipidsynthe- the precursors of dementia. HResearch to discover those sis in rat striatalslices.BrainRes.1995;64:378-384. abilities that would be most predictive of such impend- 13. Lopez G.-Coviella I. Agut J. Ortiz A. Wurtman RJ. Effects of orally- ing progressive declineHidentifiedverbal memory. While administeredcytidine5'-diphosphatecholineon brain phospholipidcontent. the verbal memory task identified differed from that used J Nutr Biochem. 1992;3:313-315. in the present study, it remains to be determined whether 14. FonluptP.MartinetM. PachecoH.Effectof CDP-cholineondopamineme- citicoline could improve performance on verbal memory tabolismincentralnervoussystem.In:ZappiaV.KennedyEP.NilssonBI.GaI- ettiP.eds.Novel Biochemical,Pharmacological,and ClinicalAspects of COP- tasks other than logical memory, specifically for pa- Choline.NewYork.NY:ElsevierSciencePublishingCo Inc; 1985:169-177. tients experiencing mild cognitive impainnent. To the 15. DinsdaleJRM.GriffithsGK.CastelloJ. DrtizJA, MaddockJ.AylwardM.C-GDP- extent that citicoline can reverse such impairments and choline:repeatedoraldosetolerancestudiesin adulthealthyvolunteers.Drug may delay the onset of such dementing conditions, fur- Res.1983;33:1061-1065. 16. DinsdaleJRM. GriffithsGK.RowlandsC. et al. Pharmacokineticsof C-GDP- ther research should be conducted with this compound choline.Drug Res.1983;33:1066-1070. in patients who are experiencing memory loss or other 17. CanonicoPL.SortinoMA. SpecialeC. Phospholipidsandprolactinsecretion: forms of mild cognitive impairment. theeffectof CDP-choline.In:ZappiaV. KennedyEP.NilssonBI.GalettiP.eds.

ARCH NEUROUVOL 53. MAY 19Q6 7 NovelBiochemical.Pharmacological.andClinicalAspectsof COP-Choline.New AssociatedWithAging.Boston.Mass:Birkhauser:1989:649-654. York. NY:ElsevierSciencePublishingCo Inc; 1985:251-258. 25. FolsteinMF.FolsteinSE.McHughPR.'Mini-MentalState':a practicalmethod 18. ZornetzerSF.Brainsubstratesof senescentmemorydecline.In:SquireL. But- for gradingthe cognitivestate of patientsfor the clinician.J PsychiatrRes. tersN.eds.NeuropsychologyofMemory.NewYor\(,NY:GuilfordPress;1984: 1975; 12: 189-198. 588-600. 26. RandtCT,BrownER.OsborneOJ.Citedby: LezakMO,ed.Neuropsychotogi- 19. Lozano-FernandezR.Efficacyandsafetyof oralCOP-choline.DrugRes.1983; cal Assessment.2nded. NewYork.NY:OxfordUniversityPress;1983:469. 33:1073-1080. 27. WechslerMemoryScale:WechslerMemoryScale-Revised.NewYork,NY:Har- 20. TazakiY. SakaiF. OtomoE,et al. Trealmenlof acutecerebralinfarctionwith court BraceJovanovich-ThePsychologicalCorp;1987. acholineprecursorina multicenterdouble-blindplacebo-controlledstudy.Stroke. 28. CrookTH,BartusRT.FerrisSH,WhitehouseP, CohenGO.GershonS. Age- 1988;19:211-216. associatedmemoryimpairment:proposeddiagnosticcriteriaandmeasuresof 21. CatalyadMaldonadoV. CatalyudPerezJB. Aso EscarioJ. Effectsof COP- clinicalchange-report of a NationalInstituteof MentalHealthwork group. cholineon the recoveryof patientswith headinjury. J NeurolSci. 1991;103 DevNeuropsychol.1986;2:261-276. (suppl):SI5-S18. . 29. BlackfordRC.La RueA. Crileriafor diagnosingage-associatedmemoryim- 22. LozanoR.COP-cholinein thetrealmentof cranio-cephalictraumata.J Neurol pairment:proposedimprovementsfromthe field. DevNeuropsychol.1989;5: Sci. 1991;103(suppl):S43-S47. 295-306. 23. LevinHS.Trealmentof postconcussionalsymptomswith COP-choline.J Neu- 30. LezakM. NeuropsychologicalAssessment.2nded.NewYork,NY:OxfordUni- rol Sci.1991;103(suppl):S39-S42. versityPress;1983. 24. AgnoliA. BrunoG.FioravantiM. Therapeuticapproachto senilememoryim- 31. O'BrienJT,LevyR.Ageassociatedmemoryimpairment.BMJ.1992;304:5-6. pairment:a double-blindclinicaltrial with COP-choline.In:WurtmanRJ,Cor- 32. CrookTH.FerrisSH.Ageassociatedmemoryimpairment.BMJ.1992;304:714. kin S. GrowdonJH. eds.Alzheimer'sDisease:Proceedingsof theFifthMeet- 33. FlickerC. FerrisSH,ReisbergB. Mildcognitiveimpairmentin theelderly:pre- ing of theInternationalStudyGrouponthePharmacologyofMemoryDisorders dictors of dementia.Neurology.1991;41:1006-1009.

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