Dietary supplementation of citicoline for 12 wk improved overall memory performance, especially episodic memory, in healthy older males and females with AAMI. The findings suggest that regular consumption of citicoline may be safe and potentially beneficial against memory loss due to aging. This trial was registered at clinicaltrials.gov as NCT .
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A total of 99 out of 100 participants completed the study in its entirety. After the 12-wk intervention, participants supplemented with citicoline showed significantly greater improvements in secondary outcomes of episodic memory (assessed by the Paired Associate test), compared with those on placebo (mean: 0.15 vs. 0.06, respectively, P = 0.). Composite memory (secondary outcome), calculated using the scores of 4 memory tests, also significantly improved to a greater extent following citicoline supplementation (mean: 3.78) compared with placebo (mean: 0.72, P = 0.).
A total of 100 healthy men and women aged between 50 and 85 y with AAMI participated in this randomized, double-blind, placebo-controlled trial. Participants were randomized to receive placebo (n = 51) or citicoline (n = 49; 500 mg/d) for 12 wk. Memory function was assessed at baseline and end of the intervention (12 wk) using computerized tests (Cambridge Brain Sciences, Ontario, Canada). Safety measurements included adverse events query, body weight, blood pressure, and hematology and metabolic panel. Intent-to-treat analysis was conducted using ANCOVA for the primary and secondary outcome variables with Bonferroni correction for multiple comparisons.
In healthy populations, oral intake of a citicoline supplement (Cognizin), improved attention compared with placebo in middle-aged women [250 mg/d for 1 mo, age 40&#;60 y ( 15 )] and in adolescent males [250 and 500 mg/d for 28 d, n = 24/group ( 16 )]. Additionally, oral citicoline supplementation (1 g/d for 3 mo) improved logical memory score compared with placebo in men and women (n = 49/group, age 50&#;85 y) with relatively inefficient memory [i.e., scored below average of all recruited participants ( 17 )]. Another open-label clinical trial demonstrated a significant improvement in word and object recalls after citicoline supplementation (1 g/d) for 28 d ( 18 ). To date, no studies have investigated the effects of citicoline supplementation at 500 mg/d on memory in healthy elderly adults with age-associated memory impairment (AAMI). Thus, the objective of this study was to investigate the effects of citicoline supplementation at 500 mg/d on memory in healthy elderly populations with AAMI.
An important nutrient that is known to affect brain development and aging is choline. Choline is essential for several biological functions of cells. For example, choline metabolites acetylcholine and phosphatidylcholine, respectively, contribute to proper signaling functions for normal cholinergic neurotransmission and the structural integrity of cell membranes ( 6 ). Brain choline uptake is decreased in older adults ( 7 ) and the lower supply of extracellular choline may contribute to aging-related cognitive decline. Not surprisingly, higher dietary choline is associated with better cognitive performance in elderly individuals ( 8 , 9 ). One method to increase dietary choline is through supplementation with citicoline (CDP-choline or cytidine-5&#;-diphosphate choline), choline salts, such as choline chloride and choline bitartrate, glycerophosphocholine, as well as phosphatidylcholine. Compared with choline moiety obtained through other dietary sources such as phosphatidylcholine, choline in citicoline has been suggested to be less prone to conversion to trimethylamine (TMA) and trimethylamine N-oxide (TMAO), which have been implicated in the pathogenesis of cardiovascular disease ( 10 ). Citicoline is a naturally occurring mononucleotide comprised of cytosine, ribose, pyrophosphate, and choline. It is produced by the body as an intermediate product of phosphatidylcholine and sphingomyelin biosynthesis ( 11 , 12 ). The neuroprotective actions of citicoline include activating the biosynthesis of structural phospholipids in the neuronal membranes, increasing cerebral metabolism, noradrenaline, and dopamine levels in the central nervous system, preventing the loss of cardiolipin (an exclusive inner mitochondrial phospholipid enriched with unsaturated fatty acids), and protecting cell membranes by accelerating re-synthesis of phospholipids ( 13 ). Unsurprisingly, citicoline supplementation has shown beneficial effects on memory function and behavior in populations with a wide range of impairments such as those with mild to moderate vascular cognitive impairment, vascular dementia, or senile dementia ( 14 ).
The world's population is aging with almost every country experiencing a growth in the number and proportion of older persons. Projections of the World Population Prospects by the United Nations suggest that 1 in 6 people (16%) in the world will be aged over 65 y by ( 1 ). An expected challenge of an aging population is the increased rates of health issues associated with aging, such as age-related cognitive decline. Although age is the most important predictor of cognitive decline, this process is a complex interplay of many contributing factors including demographic, genetic, socioeconomic, environmental, and nutritional parameters ( 2 ). No effective pharmaceutical treatments for age-related cognitive decline are available, emphasizing the importance of prevention strategies against cognitive decline. There is extensive evidence on how nutrients and bioactive compounds may impact on cognitive decline due to aging ( 3 ). Some evidence points to specific dietary patterns (e.g., ketogenic or Mediterranean diets) as having strong potential to combat age-related cognitive decline ( 4 ). Additionally, individual nutrients such as B vitamins, antioxidant polyphenols, selenium, vitamin D, medium-chain triglycerides, and long-chain omega-3 fatty acids have been investigated for their potential cognitive-enhancing properties ( 5 ).
For hematology and metabolic panels, continuous measures were compared between groups with the Wilcoxon rank sum test. At each time point, the P values were adjusted for multiple comparisons with the false discovery rate. Data of unadjusted means ± SD are presented for each test group.
All statistical analyses were conducted using SAS for Windows (version 9.4, Cary, NC) on the intent-to-treat (ITT) population, which included all participants who were randomized into the study. All tests of significance, unless otherwise stated, were performed at alpha = 0. (2-sided), which accounted for multiple comparisons with Bonferroni correction. ANCOVA was used to assess differences between test groups for the primary and secondary outcome variables. Initial ANCOVA models contained terms for test group, Spatial Span screening score (i.e., 4, 3, 2), sex, BMI, 2-way interaction terms &#;test group by sex,&#; &#;test group by second Spatial Span screening score,&#; &#;test group by BMI,&#; and &#;test group by age,&#; with age and baseline test scores as covariates. Models were reduced using a backward selection method until only terms for test group, Spatial Span screening score (i.e., 4, 3, 2), sex, age, baseline test scores, and significant 2-way interaction terms (if there are any) remained in the model. Data of unadjusted means ± SEM were presented for each test group. Assumption of normality of residuals was investigated for each outcome variable at the 5% level of significance with the Shapiro-Wilk test ( 23 ).
The primary outcome variable was the raw change in Spatial Span scores, calculated as the difference in baseline score and end of the test period (Week 12) score for each participant. Secondary outcome variables included the raw change in test scores for the remaining 6 cognitive tasks. Additionally, the composite memory score was calculated for overall memory function based on the Spatial Span (SS score ), Monkey Ladder (ML score ), Paired Associates (PA score ), and Digit Span (DS score ) raw scores using the following formula provided by Cambridge Brain Sciences:
Sample size calculations were performed using G*Power (Version 3.1.9.2), for ANCOVA (fixed effects, main effects, and interactions) with the following parameters: α err prob = 0.05, power (1-β err prob) = 0.80, numerator df = 1, number of groups = 2, number of covariates = 2. Sample size calculations also used proprietary normative data (obtained from >74,000 adults) for Spatial Span provided by Cambridge Brain Sciences and estimated improvement difference of 9.9% and distribution in scores following citicoline supplementation between groups based on using data from a previous study on citicoline and memory ( 17 ), while taking into account 2 covariates (age and baseline scores). An evaluable sample size of 82 was needed to detect a significant difference between groups and a total of 100 participants were randomized to account for possible attrition.
Safety was assessed by adverse events (AEs) reported by participants, as well as assessment of vital signs, body weight, and hematology and metabolic panels. Inquiry of AEs was conducted using an open-ended question at Weeks 0, 6, and 12, and during calls between each visit. The Clinical Investigator evaluated all AEs with respect to their severity, according to the World Health Organization Adverse Reaction Terminology (WHO-ART) dictionary ( 21 ). The Clinical Investigator also judged the likelihood that the AE was related to the study product in accordance with Reviewer Guidance on Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review ( 22 ). Finally, metabolic and hematology panels were evaluated by Elmhurst Memorial Reference Laboratory (Elmhurst, IL) from heparin plasma samples using the Dimension Vista 500 System (Siemens Medical Solutions USA, Inc., Malvern, PA) and from whole blood samples using the Sysmex XN- Automated Hematology System (Sysmex America, Inc., Lincolnshire, IL), respectively.
Cognitive performance was assessed using Cambridge Brain Sciences (Toronto, Ontario, Canada) computerized tests. This computerized testing battery was publicly available and was validated by the Medical Research Council and Brain Sciences Unit [Cambridge, UK ( 20 )]. The testing battery was used to assess working memory (Monkey Ladder task), short-term spatial memory (Spatial Span), short-term verbal memory (Digit Span task), episodic memory (Paired Associate task), selective attention (Feature Match and Interlocking Polygons tasks), and sustained attention (Sustained Attention to Response Task). Normative data from >74,000 participants aged between 11 and 100 y provided by Cambridge Brain Sciences showed a decrease in Spatial Span score with age. Thus, it was used at screening to identify participants with compromised memory function defined as scoring at least 1 standard deviation below the mean established for young adults (based on normative data provided by Cambridge Brain Sciences). Additionally, screening Spatial Span scores were also used during randomization whereby participants were stratified into 3 Spatial Span test score strata (score of 2, 3, or 4). All 7 tasks were administered at Week 0 and Week 12, but not administered at Week 6. Participants were given the opportunity to practice all cognitive tasks during the screening visit.
This study consisted of 1 screening visit, 2 test visits (Week 0 and Week 12), and 1 compliance visit (Week 6). To minimize the impact of lifestyle changes on cognition, participants were instructed to maintain their habitual diet, exercise routines, and sleep duration throughout the study and any major change/life stress event that could impact cognition was inquired and documented. At screening, participants were screened for inclusion and exclusion criteria. Additionally, evaluations of medical history, prior/current medication/supplement use, height, body weight measured using a digital scale (Health-O-Meter 349KLX; Sunbeam Products, Inc., Boca Raton, FL), vital signs including systolic and diastolic BP measured using an automated blood pressure monitor (Welch Allyn ; Hill-Rom Holdings, Inc., Chicago, IL), Mini-Mental State Examination, Kaufman Brief Intelligence Test - Second Edition, Geriatric Depression Scale, and sleep and smoking habits were assessed. The 24-h diet record was collected and reviewed to compare food and beverage consumption up to the day before test visits (Weeks 0 and 12) for consistency. BMI was calculated as kg/m 2 . At baseline (Week 0) and end of study (Week 12), participants arrived at the clinic fasted (10&#;14 h), consumed a standard breakfast, and completed the cognitive assessments test battery. Fasting (10&#;14 h) blood samples were collected at the screening and end of study visits for hematology and metabolic panel assessments.
Study supplements consisted of encapsulated microcrystalline cellulose (placebo), or 250 mg/capsule of citicoline (Cognizin; Kyowa Hakko Bio Co., Ltd). Placebo and citicoline capsules were identical in color and size. Participants were instructed to consume 2 capsules with breakfast for 12 wk; thus participants in the citicoline group consumed a total of 500 mg/d of citicoline. Compliance was documented as a percentage of study product consumed calculated based on scheduled product intakes and number of returned study product. Non-compliance was defined as consumption of <80% or >120% of the scheduled intake upon study completion. Overall compliance was determined at Week 12.
Eligible participants were randomly assigned 1:1 to oral citicoline (500 mg/d) or placebo in a double-blind design using a randomization sequence prepared by the lead study statistician. The randomization sequence was designed such that it allowed approximately equal distribution of baseline spatial span test score and sex among the 2 test groups. A randomization number was assigned to eligible participants using an electronic randomization module (Medrio, Inc., San Francisco, CA). Participants, research staff, and outcome assessors were blinded to group allocations until data analyses had been completed.
Healthy men and women (aged 50 to 85 y) with AAMI were recruited by the Biofortis Clinical Research team by using an established database of volunteers and local advertisements. While there is no agreed-upon definition for AAMI, we based our recruitment on the criteria for AAMI suggested by the US National Institutes of Health ( 19 ). Thus, the inclusion criteria for this study included: age 50&#;85 y, scored &#;24 on the Mini-Mental State Examination, &#;85 on the Kaufman Brief Intelligence Test - Second Edition, &#;5 on the Geriatric Depression Scale, and 4, 3, or 2 on the Spatial Span test, and no health conditions that would prevent him or her from fulfilling the study requirements on the basis of medical history and routine laboratory test results. Exclusion criteria included color blindness, abnormal laboratory test results that fell outside of the normal range as defined by the analytical laboratory (Elmhurst Memorial Reference Laboratory, Elmhurst, IL), major medical or neurological illness including, but not limited to, hyperparathyroidism, type 1 or 2 diabetes mellitus, hypoglycemia, myocardial infarction, peripheral arterial disease, uncontrolled asthma, Alzheimer's disease, Parkinson's disease, stroke, intracranial hemorrhage, and local brain lesions, females who were pregnant or planning to be pregnant during the study period, and medications that may have interfered with the interpretation of the study results (e.g., medications known to affect cognition).
This randomized, double-blind, placebo-controlled trial of citicoline was conducted at Biofortis Inc. (Addison, IL) between January and December . This study was carried out in compliance with the protocol and in accordance with Good Clinical Practices (GCP), the applicable US Code of Federal Regulations (CFR), and the Declaration of Helsinki ( Version). The study protocol was approved by an Institutional Review Board (IntegReview, Austin, TX). Signed written informed consent for participation in the study was obtained from all participants before protocol-specific procedures were carried out. This trial was registered at ClinicalTrials.gov with identifier NCT .
No AEs were judged to be serious. Eight mild AEs were judged to be &#;possibly&#; related to 1 of the study products, with 2 occurring in the placebo group and 6 occurring in the citicoline group. All 6 of the AEs in the citicoline group [increased appetite, weight gain, increased flatulence (2 instances), headache, and increased burping] were mild and transient, and were not unexpected based on previous studies with the product ( 15 , 16 ). No AEs were deemed &#;definitely&#; or &#;probably&#; related to the ingestion of study product. Data from the hematology and metabolic panels obtained at baseline and end of study are presented in Supplemental Table 1 and Supplemental Table 2 , respectively. There were no statistically significant differences in mean values between groups at baseline or at end of study. None of the values fell outside the normal range.
Paired Associates scores after 12 wk of citicoline supplementation of the citicoline supplementation group and the placebo group in the ITT population. Participants were healthy older-aged males and females with AAMI. Data shown are unadjusted means ± SEMs for each test group. n = 51 for placebo and n = 49&#;48 for citicoline. An increased score indicates improvement. The P value shows between-group difference (vs. placebo) for the raw change score using ANCOVA with Bonferroni correction for multiple comparisons. The raw change was calculated as the difference in scores at baseline to the end of the test period for each participant.
Composite memory scores after 12 wk of citicoline supplementation of the citicoline supplementation group and the placebo group in the ITT population. Participants were healthy older-aged males and females with AAMI. Data shown are unadjusted means ± SEMs for each test group. n = 51 for placebo and n = 49&#;48 for citicoline. An increased score indicates improvement. The P value shows between-group difference (vs. placebo) for the raw change score using ANCOVA with Bonferroni correction for multiple comparisons. The raw change was calculated as the difference in scores at baseline to the end of the test period for each participant.
The results on cognitive function tests at Weeks 0 (baseline), and 12 (end of study) are shown in Table 2 . Within-group analysis indicated that the citicoline group, but not the placebo group, had a statistically significant improvement in Spatial Span, Feature Match, and Composite Memory scores from baseline. Between-group analysis indicated that the changes from baseline scores were statistically significantly different (P < 0.) between test groups for Paired Associates and Composite Memory whereby the citicoline group demonstrated greater improvements in these tests compared with the placebo group ( Figures 2 and 3 ). No additional statistically significant cognitive effects were detected in Monkey Ladder, Digit Span, Interlocking Polygon Task, and Sustained Attention to Response Task according to multiple comparisons with Bonferroni correction.
A CONSORT diagram illustrating participant recruitment and attrition during the trial is presented in Figure 1 . A total of 426 participants were screened for participation and 100 participants were randomized. A total of 99 participants completed the study in its entirety. One participant in the citicoline group withdrew from the study due to a headache, which was judged as possibly related to study product. As defined in the study protocol, the ITT sample population consisted of all randomized participants. In the ITT sample population, a total of n = 100 participants contributed to data at Week 0 and n = 99 participants contributed to data at Week 12. No premature unblinding occurred during the study. There were no differences in selected demographics, and baseline characteristics for sample populations are listed in Table 1 . Compliance over the 12-wk supplementation period was 99.2 ± 0.5% for the 99 participants who completed the study.
To our knowledge, this is the first randomized, double-blind, placebo-controlled parallel study to evaluate the effects of chronic (12 wk) supplementation of 500 mg/d of citicoline in healthy adults with AAMI on memory performance. Compared with those taking placebo, participants taking citicoline demonstrated a significant improvement in episodic memory assessed using the Paired Associate task and overall memory assessed by the composite memory score. Although each cognitive test assessed distinct components of memory and tapped into different processes, composite score provides for a single outcome variable combining each cognitive test. Our observations are consistent with previous studies demonstrating beneficial effects of citicoline on memory (17, 18).
Episodic memory describes the ability to remember and recall specific events, paired with the content in which they occurred, such as identifying when and where an object was encountered (24). A decline in episodic memory often manifests as the inability to recall past events or retrieve lessons from past experiences, which can lead to repeat error. Episodic memory is more vulnerable than other memory systems to decreases due to aging (25). Kinugawa et al. (26) reported that middle-aged (48&#;62 y) and aged (71&#;83 y) participants showed lower episodic memory score as compared with the young (21&#;45 y) participants with longitudinal studies demonstrating a decline after age 60 y (27, 28). To the best of our knowledge, our study is the first to demonstrate a beneficial effect of citicoline supplementation in maintaining and/or improving episodic memory that may decline with age.
In addition to a statistically significant improvement in Paired Associates, we also observed a tendency toward improvement in the citicoline group for the Spatial Span task. Owen (20) reported activation of the mid-ventrolateral frontal cortex during the Spatial Span and Paired Associates tasks. Citicoline has been shown to improve frontal lobe bioenergetics and alter phospholipid membrane turnover in humans (29). Age-related declines in cognitive abilities, particularly related to function in frontal lobe has been demonstrated in humans (30, 31). Taken together, the findings suggest that activation of the mid-ventrolateral frontal cortex is a possible mechanism of action by which citicoline improved cognition. Future studies may consider assessing regionally specific neuronal activation following citicoline supplementation to better understand its mechanism of action and effect on brain function.
We also observed an improvement in selective attention (assessed using Feature Match task) in the citicoline group compared with baseline; however, there was no significant difference between groups. The primary objective of this study was to assess the effect of citicoline on short-term spatial memory, and thus, is likely underpowered to assess difference in attention between groups. However, the within-group improvement that we observed along with the positive effect reported by a previous study (16), suggests a promising beneficial effect of citicoline on attention that warrants further investigation.
Citicoline is well known to increase the synthesis of phosphatidylcholine, which is the primary phospholipid of neuronal membrane. Studies in rodents have demonstrated increased phosphatidylcholine levels in the brain following repeated citicoline supplementation (32, 33). A clinical study in healthy participants consuming 500 mg/d of citicoline for 6 wk demonstrated increased levels of phosphodiesters, a noninvasive biomarker of phospholipid synthesis in the brain, thus supporting the ability of citicoline to increase brain phosphatidylcholine synthesis in humans (34). Phosphatidylcholine is essential for cell membrane integrity and repair (35, 36, 37), and is normally reduced in brain as a result of aging (38). Plasma phosphatidylcholine levels are positively associated with cognitive flexibility in healthy older adults, and the inferior prefrontal cortex mediates the relationship between plasma phosphatidylcholine and cognitive flexibility (39). Increase in phosphodiesters correlated with improvement on the California Verbal Learning Test, an assessment of verbal learning and memory deficits, in healthy older adults (34). Taken together, these findings suggest that citicoline may slow or prevent AAMI by influencing specific structures within the brain.
Citicoline is naturally present in humans (40), and is a nontoxic material determined by animal toxicology studies (41, 42, 43). In our study, we did not observe any serious adverse events following daily consumption of citicoline for 12 wk. Consistent with our findings, previous clinical trials involving oral citicoline supplementation of Alzheimer's disease patients for 6 wk at a dose of 500 mg/d or for 12 wk at a dose of 1 g/d reported no serious adverse drug reactions (44, 45). Thus, based on our findings and that of others, oral intake of citicoline at amounts up to 1 g/d is safe and well tolerated. Future investigations are required to determine the acute and longer-term effects of citicoline, in addition to the extent to which the beneficial effects of citicoline on memory last following cessation of citicoline supplementation.
The study has some limitations worth noting. Participants were specifically screened for AAMI, and thus, the effects observed may not be generalizable to young adults, and those with cognitive diseases such as dementia and Alzheimer's disease. Disparities in cognitive functioning by race/ethnicity have been suggested by several studies (46, 47). Thus, future studies with a wider range of ethnicity are warranted to understand if the beneficial effects of citicoline on memory observed in our mostly white Caucasian population may be extended to other ethnic and racial groups. In total, there were fewer males than females in this study (35:65 males:females) although effort was made to balance the number of males and females by intervention group to limit any confounding factors due to sex. Additionally, participants were instructed to maintain their habitual diet and lifestyle in an effort to minimize other confounding factors. The day before test visits (Weeks 0 and 12), information on diet intake and sleeping hours was collected to confirm whether participants maintained their habits. Care was taken to ensure that participants completed all cognitive assessments in a supervised environment where lighting and noise were controlled.
Taken together, dietary supplement of citicoline improves overall memory performance, especially episodic memory in healthy males and females with AAMI. The findings suggest that regular consumption of citicoline (Cognizin) may be safe and potentially beneficial against memory loss due to aging.
Citicoline is the generic name of CDP-choline, a natural metabolite presents in all living cells. Used in medicine as a drug since the -s, citicoline was recently pronounced a food ingredient. When ingested, citicoline breaks down to cytidine and choline, which become incorporated into their respective normal metabolic pathways. Choline is a precursor of acetylcholine and phospholipids; these is a neurotransmitter pivotal for learning and memory and important constituents of neuronal membranes and myelin sheaths, respectively. Cytidine in humans is readily converted to uridine, which exerts a positive effect on synaptic function and supports the formation of synaptic membranes. Choline deficiency has been found to be correlated with memory dysfunction. Magnetic resonance spectroscopy studies showed that citicoline intake improves brain uptake of choline in older persons, suggestive of that it shall help in reversing early age-related cognitive changes. In randomized, placebo-controlled trials of cognitively normal middle-aged and elderly persons, positive effects of citicoline on memory efficacy were found. Similar effects of citicoline on memory indices were also found in patients suffering from mild cognitive impairment and some other neurological diseases. Altogether, the aforementioned data provide complex and unambiguous evidence supporting the claim that oral citicoline intake positively influences memory function in humans who encounter age-related memory impairment also in the absence of any detectable neurological or psychiatric disease.
Keywords: citicoline, humans, aging, cognitive ability
Memory is the cognitive ability to maintain previously learned information so that it may be accessed and used at a later time. It is not a unitary construct but reflects a number of distinct cognitive processes (e.g., episodic memory, working memory, short-term memory, semantic memory, etc.). In the extended definition, memory is the capacity to store and retrieve information [1].
Although aging is characterized by the development of a broad spectrum of pathologies, traditionally, it has been viewed as a natural process and, consequently, not a disease. When aging is not complicated by neurological or psychiatric disease, cognitive functions are not impaired but become slowed. In particular, in middle-aged and elderly people the memory and its constituents are noticeably failing, which is considered physiological. Almost everybody will subjectively experience certain deterioration of memory with aging, manifested inter alia as prolongation of time required to memorize new information and to recall information previously remembered. A frequently encountered aspect of age-related failing of human memory is the impairment of episodic memory, i.e., the memory of everyday events that can be explicitly stated or conjured (for example, times, location geography, associated emotions, and other contextual information) [2]. The maintenance or reduced loss of one or more cognitive processes related to memory is considered a beneficial physiological effect [3].
Citicoline is the generic name of a substance identical to cytidine-5&#;-diphosphocholine (CDP-choline), a natural metabolite presents in minute amounts inside every living cell and playing a crucial role in the synthesis of cellular phospholipids [4]. CDP-choline from an exogenous source, known as citicoline, has been used in medicine since the -s as a prescription drug displaying neuroprotective effects, indicated for various chronic and acute neurological diseases (e.g., Parkinson&#;s disease, stroke, brain and spinal cord injury, glaucoma). [5]. More recently, one of its variants (citicoline inner salt) was pronounced a food constituent in the major world markets (USA, European Union) [6]. Therefore, citicoline became freely available over the counter as a food supplement that is considered a memory enhancer [7]. The aim of the present review is to critically discuss the evidence for positive effects of this substance on memory in middle-aged and elderly persons who do not suffer from any neurological or psychiatric disease. In humans, citicoline following ingestion is well absorbed and rapidly broken down into choline and cytidine. This results in a marked increase of blood choline level, whereas blood cytidine is quickly converted to uridine. Next, choline and uridine enter cells of the human body and join their appropriate metabolic pathways. In an analogy to the term &#;a prodrug&#; used in pharmacy to depict a compound which is metabolized in the body to produce an active drug, citicoline shall be called &#;a pro-nutrient&#; that in the human body produces choline and uridine as &#;active nutrients&#;.
The metabolic fate of citicoline and its hydrolysis/ dephosphorylation products have been extensively studied in experimental animals (see [8], and the references cited). In the central nervous system, the three most prominent pathways (schematically shown on Fig. 1) include (a) the synthesis of the neurotransmitter acetylcholine, (b) the aforementioned &#;Kennedy pathway&#; that also utilizes cytidine and leads to the synthesis of phosphatidylcholine, and (3) oxidation of betaine, providing one-carbon unit for the conversion of homocysteine to methionine.
Major metabolic pathways of citicoline following ingestion. 1. Hydrolysis and dephosphorylation of citicoline occur in blood and yield choline and cytidine (in humans converted to uridine) that enter brain. 2. In the brain cytidine is activated by phosphorylation to cytidine-triphosphate (CTP). Choline, which concomitantly enters the brain, follows three major paths: 3. activation by phosphorylation to phosphocholine; 4. conversion to betaine (N,N,N-trimethylglycine); 5. conversion to acetylcholine (a neurotransmitter). 6. CTP and phosphocholine rejoin to yield CDP-choline, which 7. is used to synthesize phosphatidylcholine, utilized to support membrane integrity and myelin metabolism.
During decades of medical use, it became apparent that the application of citicoline is not linked to any significant adverse effects, and no contraindication to its use has ever been indicated. Its almost perfect tolerance observed in human studies has been corroborated by results of a subchronic toxicological study performed on rats in which a dose of 1 gram per kg body weight per day given orally for 3 months produced only slight signs of toxicity related most likely to excess of phosphate [9]. In various clinical studies, patients were receiving daily citicoline doses of up to 2 grams, given either parenterally or orally. Recommended maximal dosing of citicoline (inner salt) as a food supplement is 500 mg per day and as dietary foods for special medical purposes as 1,000 mg.
References related to the scientific data pertinent to the issue of citicoline and memory in humans were identified with Pubmed, Scopus, and Web of Science databases, using a composition of key words: &#;citicoline pharmacokinetics and human&#;, &#;citicoline and human memory&#;, &#;choline and human memory&#;, and &#;uridine and human memory&#;. When required, the references concerning the aforementioned combinations of keywords are supplemented by the appropriate references concerning pertinent general issues, such as &#;definitions of the human memory&#;, &#;healthy aging&#; compared to &#;age-related pathology&#;, etc.
Only human studies were taken into account for two main reasons: First, human memory and related cognitive functions are qualitatively different from the memory and cognitive functions of laboratory animals (mostly rodents). Consequently, methods used to investigate the efficacy of human memory and cognition are vastly different from those used for testing the efficacy of memory of laboratory mice and rats, therefore extrapolation of the data from preclinical experiments to humans would not be appropriate. Second, in animal studies, citicoline and/or its catabolites (choline and cytidine/uridine) were almost always tested in doses severalfold larger than those that could be taken by humans, making extrapolation of the animal data to humans doubtful. Results of animal experiments are cited only exceptionally.
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There are four aspects of the scientific substantiation of the positive effect of oral citicoline intake on the maintenance, reduced loss, or improvement of memory in healthy middle-aged and elderly persons. The first aspect is related to choline insufficiency in age-dependent memory deterioration. Although choline is synthesized in the human body, its de novo synthesis is not adequate to meet the demand for this substance, making it an essential nutrient. The best-known effect of a choline-deficient diet, occurring concomitantly with diminished blood plasma choline and phosphatidylcholine concentrations, is the development of liver damage which is reversed by the reintroduction of choline supply. There is limited data concerning a similar &#;depletion-repletion&#; effect of choline on human memory and cognition. However, there is convincing evidence from large population studies that the availability of dietary choline is positively correlated with memory efficiency in adults and the elderly. The second aspect is related to the role of uridine as a precursor for phospholipids of neuronal cell membranes. This issue is relevant because in humans (unlike in rodents), cytidine released from citicoline after its oral intake is in circulating blood plasma readily and almost completely converted to uridine. The third aspect is related to the studies of choline uptake by the human brain following the intake of choline and citicoline and its metabolic disposal. Intensification of the brain choline uptake has been shown of particular importance in middle-aged and older human individuals. The fourth aspect focuses on interventional trials assessing oral intake of citicoline on memory in middle-aged or elderly persons considered healthy.
The references pertaining to the scientific substantiation of the effect of citicoline on memory functions in healthy middle-aged and older persons are supplemented by the selected references concerning the effects of citicoline on the memory of patients suffering from certain chronic neurological diseases. These data are presented as a part of the totality of the evidence for support of the claim concerning citicoline and human memory because citicoline effects on memory in these patients and in cognitively healthy elderly persons suffering from subjective memory impairment seem to be similar.
As previously mentioned, citicoline following ingestion is well absorbed and rapidly broken down into choline and cytidine, which in humans is quickly and almost completely metabolized to uridine. Food-borne choline and other choline-containing food ingredients (carnitine, betaine, etc.) are partially metabolized by intestine bacteria to a gaseous metabolite trimenthylamnie (TMA), which is further transformed in the liver to its oxide (TMAO). The latter substance is suspected to be atherogenic, and recently it has also been implicated in the development of Mild Cognitive Impairment and Alzheimer&#;s Disease [10,11]. Choline derivatives from ingested food may have different accessibility for the gut microbes due to their different moieties and intestinal absorption rates. It has been suggested that citicoline is a potentially safer form of choline because it may resist hydrolysis inside the intestinal lumen, possibly due to its pyrophosphate group [6].
In humans as well as in animal choline is a substrate for the synthesis of acetylcholine (ACh), the main neurotransmitter on which important neuronal circuits involved in memory depend. ACh is widely distributed in the nervous system and has been implicated to play a critical role in many aspects of brain functioning, including modulating cognitive performance, learning and memory processes. The basal forebrain cholinergic complex (comprising medial septum, horizontal and vertical diagonal band of Broca, and nucleus basalis of Meynert) provides the major cholinergic projections to the cerebral cortex and hippocampus. The synthesis of the neurotransmitter ACh in cholinergic neurons depends on the availability of its precursor choline, most of which is derived from the circulation and enters cholinergic neurons via a process catalyzed by a specific transporter (reviewed in [12]).
Animal studies indicate that citicoline may increase choline availability to cholinergic neurons not only directly by increasing blood plasma choline level, but also indirectly by modulating the expression of proteins relevant to ACh metabolism. In experiments on rats one week of daily intraperitoneal (i.p.) injections of citicoline (or the other choline containing compound, choline alfosclerate) resulted in enhanced expression of choline transporter (ChT) responsible for delivering choline to ACh-synthesizing neurons and vesicular acetylcholine transporter (VAChT) responsible for loading ACh into presynaptic vesicles [13]. The other mechanism by which citicoline could support memory could relate to enhanced sirtuin-1 (SIRT1) expression, which was observed in the rat brain one day after a single i.p. injection of citicoline [14]. In mice, normal cognitive function and synaptic plasticity were impaired by knocking out SIRT1 gene [15]. However, these effects may indicate advanced pathological rather than physiological brain aging. The level of SIRT1 protein in the human brain cortex investigated post-mortem appeared to decrease in Alzheimer&#;s disease patients but not in those who suffered from mild cognitive impairment [16].
When aging is not complicated with any detectable neurological disease, the cholinergic neurons of this complex undergo moderate degenerative changes, resulting in cholinergic hypofunction that has been related to the memory deficits progressing with age. Importantly, it has been found that in normal aging nearly no neural cell loss occurs, which is suggestive that functional decline associated with aging is mediated by mechanisms other than those involved in the development of dementia (reviewed in [17]). One of these relates to the fact that levels of ACh in the brain appear to decline with age. A general idea behind the use of choline donors (such as citicoline) as so-called &#;memory boosters&#; has been presented, according to which more ACh could be produced if the brain had more of choline, the substrate needed to make ACh [18].
In addition to being the precursor to ACh, choline also serves as the precursor of phospholipids sphingomyelin and phosphatidylcholine (PtdCho), which are structural components of cell membranes. PtdCho is also an important constituent of myelin, which in the brain is produced by oligodendrocytes. Myelin sheaths wrapped around axons enable rapid saltatory conduction of action potentials and contribute to the maintenance of axonal integrity. Human as well as rodent brain myelin is characterized by a high lipid content, its dry mass consisting of 70-85% lipids. Circa 45% of these lipids are phospholipids, mostly PtdCho (see [19] and the references cited). Very recent studies provided evidence that the experience-dependent formation of myelin in the circuits encoding memory is an important aspect of how memories are consolidated and recalled (reviewed in [20]). These observations further support the idea that adequate choline availability plays an important role in memory.
Humans deprived of choline develop liver damage, as clearly shown by &#;depletion-repletion&#; studies in patients dependent on parenteral nutrition. Only one pilot study of this type has been reported concerning choline and human memory. Buchman et al. [21] described memory abnormalities (delayed visual recall, verbal learning, and visual scanning ability/ psychomotor speed) in a group of eleven patients who before entry in the study covered more than 80% of their nutritional needs for at least 12 weeks with parenteral nutrition. The patients were randomly assigned to receive their usual total parenteral nutrition regimen that did not contain choline (n = 6) or their usual regimen plus 2 gram of choline chloride (n=5) and subjected to a battery of memory tests at the beginning of the experiment and after 24 weeks of supplementation with citicoline or placebo. Although the study group was very small, choline supplementation compared with placebo resulted in improvement of delayed visual recall, verbal learning, and visual scanning ability/psychomotor speed.
In agreement with the observations mentioned above, significant associations in the adults and elderly between dietary choline intake or plasma choline level and performance in memory and cognitive functions have been reported in 2 large population studies.
In 1,391 non-demented adults (mean age 60.9 years) Poly et al. [22] found the relation between dietary choline intake, brain morphology and cognition. Daily choline intake was estimated using the Harvard Food Frequency Questionnaire (FFQ, a validated method for assessing habitual dietary intake over a specified period of time). The results obtained were correlated with the Wechsler Memory Scale outcome measures of neuropsychological tests assessing different cognitive domains: verbal memory, visual memory, verbal learning, attention and executive function. Multivariate adjusted linear regressions performed to assess the linear trend in individual neuropsychological items across quartiles of choline intake showed that higher choline intake was significantly and positively related to verbal memory in both the immediate and delayed recall (adjusted average change across choline quartiles 0.28, 95% CI:0.05-0.51, P=0.02 and 0.30, 95% CI: 0.13-0.46, P=0.01, respectively). Higher choline intake was also significantly positively related to visual memory in both the immediate and delayed recall (adjusted average change across choline quartiles 0.25, 95% CI:0.05-0.45, P=0.01 and 0.26, 95% CI: 0.05-0.47, P=0.01, respectively).
In the other aspect of the Poly et al. study, the FFQ estimates of daily choline intake were correlated with magnetic resonance imaging (MRI) measures of the brain white matter hyperintensity volume (WMHV). Choline intake was inversely related to log-transformed WMHV (average change in log WMHV per 1-unit change in choline was 20.05, 95% CI:20.10-20.01, P=0.02), and to presence of large WMVH (OR: 0.56; 95% CI: 0.34, 0.92; P=0.01). MRI-detected white matter hyperintensities (WMHs), also known under the term leukoaraiosis, are detected in patients who have impaired performance in a wide range of cognitive domains characterized mainly by detrimental changes in processing speed and executive function [23]. However, leukoaraiosis is a frequent finding also in non-demented elderly people [24,25].
In the study of 2,195 subjects aged 70-74 years [26] it has been found that low plasma free choline concentrations were cross-sectionally associated with poor performance in validated tests for global cognition, sensorimotor speed, perceptual speed, and executive function after adjusting for other factors known to influence cognition. Compared with low choline concentrations, high plasma choline (>8·4μmol/l) was associated with better test scores in the Trail Making Test part A (56·0 v. 61·5, P<0·004), modified versions of the Digit Symbol Test (10·5 v. 9·8, P<0·005) and Mini Mental State Examination (11·5 v. 11·4, P<0·01).
The other recent study [27] was based on the data from the US National Health and Nutrition Examination Survey (NHANES), -. The analysis, which included data on 601 female and 530 healthy male seniors (aged >60 years), aimed at finding whether inadequate intake of micro-nutrients, as defined by the Institute of Medicine&#;s (IOM) Recommended Dietary Allowance (RDA) according to gender, is associated with lower working memory performance. Data on diet and supplement exposure were collected in person for the 24-h (midnight-to-midnight) period prior to administration of the survey, and daily intake of 8 micronutrients, namely vitamins B2, B6, B12, C, choline, folate, niacin, and zinc were assessed. Working memory was assessed with the Wechsler Adult Intelligence Scale (WAIS III)&#;s Digit Symbol Substitution Test (DSST). Logistic regression was used to estimate unadjusted and adjusted odds ratios for having a memory performance score in the lowest quartile for individuals with inadequate compared to adequate RDA levels. Unlike in the other studies, the correlation between inadequate choline consumption and less efficient memory was gender-dependent. The odds ratio of being in the lowest quartile of DSST scores when individual under-consumed choline was highly statistically significant in males (P<0.), but not significant in females.
The aforementioned population studies strongly suggest a cause-and-effect relationship between dietary choline availability and maintenance of memory function in middle-aged and elderly, cognitively healthy (non-demented) adults.
In humans, cytidine released from citicoline following its oral intake is in circulating blood plasma readily and almost completely converted to uridine due to plasma cytidine deaminase activity [28,29]. Uridine belongs, along with choline and docosohexanoic acid, to the compounds present in circulating blood which are required for brain phosphatide synthesis [30]. Higher uridine levels are thought to exert a positive effect on synaptic function, support synaptic membrane formation and alleviate synaptic dysfunction (see [31], and the references cited).
Agarwal et al. [32] reported an effect of uridine on membrane phospholipid precursors in the brains of 17 healthy male adults using phosphorous magnetic resonance spectroscopy (31P-MRS). Study participants took 1 g of uridine or placebo two times daily for seven days. Sustained administration of uridine appeared to increase brain phosphomonoesters in healthy subjects.
No study has been published to date showing that uridine per se supports memory in healthy elderly persons, but uridine (along with choline) is an ingredient in some proprietary products indicated for the dietary management of failing memory in the early Alzheimer&#;s disease (eg. Souvenaid® [33]).
Magnetic resonance spectroscopy (MRS) is a set of non-invasive techniques that allow for the quantification in the brain of several major metabolites. Two types of MRS techniques used in the studies assessing the effects of diet on cognition are proton resonance spectroscopy (1H-MRS) and phosphorous resonance spectroscopy (31P-MRS) [34]).
1H-MRS allows for quantification of the sum of water-soluble choline compounds, namely phosphor-choline (PC) and glycerophosphocholine (GPC), with small or negligible contributions from free choline and acetylcholine. The 1H-MRS signal does not include a contribution from cellular membrane-bound choline-containing phospholipids such as phosphatidylcholine (PtdCho) despite the fact that these comprise approximately 96% of brain choline-containing compounds. However, changes in phosphatidylcholine are reflected by changes in the H-MRS signal because PC is as a precursor of PtdCho, and GPC is a catabolite of PtdCho. 31P-MRS allows for the indirect quantification of membrane phospholipid metabolism. In this regard, the level of phospholipid anabolites (phosphomonoesters, PME), including phospholcholine (PC) and phosphoryl-ethanolamine (PE), is indicative for membrane synthesis, while the level of phospholipid catabolites (phosphor-diesters, PDE), mainly glycerolphosphocholine (GPC) and glycerolphosphoethanol-amine (GPE), is a measure of membrane breakdown. Consequently, the ratio of PME to PDE (PME/PDE) can be used to quantify membrane turnover.
Two 1H-MRS human studies showed the increase of 1H-MRS signals following oral choline bitartrate. Stoll et al. [35] followed the effects of ingesting a single dose of choline bitartrate equal to a free choline dose of 50 mg/kg body weight in four healthy young volunteers of unspecified age. The basal ganglia was chosen as the region to study because of its rich innervation with cholinergic neurons. The authors found that the choline resonance signal (expressed as a ratio to the creatine resonance signal) did not significantly change 1.25 hour after choline intake (mean change 7.7±15.1%), but it significantly increased at 3 hours (mean change 94.2±35.5%, P=0.008). In the follow-up investigation Cohen et al. [36] measured plasma and brain choline levels with 1H-MRS after a single dose of choline bitartrate in a dose equal to a free choline dose of 50 mg/kg body weight in young and aged healthy subjects. The results showed that, despite a similar choline increase in plasma in both groups, brain levels of choline measured by 1 H-MRS were lower in the aged group, suggestive of a decrease in choline uptake into the brain with age. Given the role of choline in cholinergic neuronal function supporting memory, the result was interpreted as a sign of reduced uptake of choline that may be involved in age-dependent altered memory function.
However, two other studies did not confirm the aforementioned observations. Tan et al. [37] claimed to repeat as closely, as possible, on a group of young healthy volunteers (average age 26 years) the protocol of the aforementioned study by Cohen et al. but failed to find a change in the choline resonance signal from basal ganglia as well, as from gray and white matter of parietal cortex, at 3h and 5h following oral intake of choline bitartrate. In this study along with 1H-MRS the authors used 31P-MRS to record four principal phosphorylated choline metabolites prior to and 3 h after choline ingestion, but they also found no change. Dechent et al. [38] used 1HMRS to follow choline resonance signals in young volunteers following ingestion of choline bitartrate given as a single dose of 50 mg/kg body weight, or phosphatidylcholine (soy lecithin), 16 g dose given twice daily for four weeks. Neither short-term choline nor monthly phosphatidylcholine supplementation resulted in statistically significant changes of choline resonance acquired from four different locations in the brain, paramedian parietal gray matter, parieto-occipital white matter, central cerebellum and thalamus.
In the last study in which H-MRS was used to follow choline resonance signal from the human brain following choline bitartrate ingestion (dose equivalent to 50 mg choline per kg body weight) [39], the authors for 2.5 h continuously acquired the spectroscopic data from the left putamen of 11 young male subjects. When the data obtained were compared with the effect of placebo ingestion, small increases of choline resonance signals relative to creatines or to N-acetylaspartate signals were noted following choline intake. The authors concluded that their study demonstrated that in humans, as in animals, ingested choline does get into the brain and may be important for the normal synthesis of acetylcholine and phosphatidylcholine.
Compared to the data on changes in brain choline compounds following oral choline or phosphatidylcholine intake which are ambiguous, the MRS data concerning the effects of citicoline ingestion on brain choline compounds are more cohesive. Babb et al. [40] investigated the effects of single doses of citicoline on choline H-MRS signal from the head of caudate and the putamen area in the brain. The study groups comprised six young male volunteers (age 25+3 years) and six older subjects (four males and two females, age 59+3 years). H-MRS spectra were recorded prior to and 3 h after the intake of 0.5, 2 or 4 g citicoline. The main finding of the study was that, in spite of similar increases in plasma choline following citicoline intake in older and younger subjects, the choline resonance signal (expressed as a ratio to the creatine signal) decreased by 4-16% in older subjects (P<0.05 after the highest citicoline dose only), whereas in the younger subjects it increased by 12-26% (changes statistically not significant). The authors explained these results as a consequence of older persons encountering decreased brain ability of choline uptake, whereas cytidine uptake was not affected. Increased choline availability from blood following citicoline intake improved brain uptake of choline in older persons, resulting in the increased incorporation of choline together with additional intracellular cytidine into membrane phospholipids not visible by 1H-MRS technique.
In two studies the effects of citicoline intake on brain phosphate compounds were investigated with 31P-MRS technique. Later the same group [41] recorded phosphorus resonance spectra from genu of corpus callosum prior to and after 6 weeks of the oral intake of 0.5 g citicoline daily. Treatment with citicoline resulted in a 7.3% increase of brain phosphodiesters (P=0.008), including an 11.6% increase in glycerophosphoethanolamine (P=0.002) and a 5.1% (but not significant) increase in glycerophosphocholine. The authors concluded that their study provided the first in vivo human data showing increased phosphatidylcholine synthesis in the brain following citicoline administration. Moreover, the correlation between increased concentrations of phosphodiesters and improved verbal learning in healthy older subjects suggested that the administration of oral citicoline may be of use in reversing age-related cognitive changes.
In the second study [42] 31P-MRS technique was employed to observe main phosphorous metabolites in two brain areas, anterior cingulate cortex (ACC) and parieto-occipital cortex (POC) of 16 healthy adults (mean age 47.3 years) following intake of citicoline in a daily dose of 500 mg or 2,000 mg for 6 weeks. Based on the preclinical data the authors hypothesized that citicoline may alter not only resonance-visible phospholipid metabolites, but also resonance signals of phosphometabolites related to energy production and utilization, namely inorganic phosphate, phosphocreatine, and beta-nucleoside triphosphates (β-NTP, which mostly is related to ATP). After 6 weeks of citicoline supplementation the main findings were significantly increased resonance signals of phosphocreatine (P<0.02) and β-NTP (P<0.05), two phospholipid membrane anabolites phosphocholine (P<0.02) and phosphoetanolamine (P<0.04), and one phospholipid membrane catabolite glycerophosphocholine (P <0.01). Importantly, citicoline-related changes were detected in ACC, but not in PCC.
Although the MRS data concerning citicoline effects on choline and phosphate metabolites in the brains of adult and elderly healthy humans are fragmentary, they correspond well to the other relevant observations. Significant increase following citicoline supplementation of glycerophosphoethanolamine resonance signal in the genu of the corpus callosum of middle-aged adults, interpreted as a reflection of increased phosphatidylcholine synthesis in this area, corresponds to the observation that citicoline intake attenuated the development of leukoaraiosis in the corpus callosum ([43], see below). The potential importance of signs of improvement in bioenergetics in the anterior cingulate cortex following citicoline intake are underscored with the data showing that during healthy aging ACC is function-wise among the most affected cortical regions [44].
Four scientific reports have been identified that describe prospective intervention trials designed to assess the effects of oral citicoline on indices of memory (three publications), and on a relevant radiological correlate of memory (leukoaraiosis, one publication).
The first study, which was placebo-controlled [45], was performed with 95 subjects (47 women and 48 men), age 50 to 85 years (mean 67.2±9.3 SD years). Exclusion criteria included, inter alia, active medical, neurological, or psychiatric illness, subjects also had to score 26 or greater (out of a possible score of 30) on the Mini-Mental State Examination. There were two stages of the study. The initial stage was randomized, double-blind, placebo-controlled, during which the subjects took either placebo or citicoline, 500 mg twice daily for 3 months. Citicoline-treated subjects had significantly higher mean blood plasma choline concentrations than placebo-treated subjects. Citicoline-treated subjects, but only those with relatively inefficient memories, exhibited a trend for improvement in the standardized measure of memory function that resembled the memory requirements of real life, which consisted of immediate recall and later recall of the passages from the Logical Memory subtest of the Wechsler Memory Scale and the Wechsler Memory Scale Revised. In the second part of the study a subgroup of 27 subjects with relatively inefficient memories received 1,000 mg twice daily or a placebo for 2 months, with a 10-day washout period prior to crossing over, and improvement of verbal memory functioning following citicoline intake was clearly confirmed.
In the second placebo-controlled, crossover study [46] the effects of oral citicoline (daily dose 500mg or 1,000mg) taken over 4 weeks by 24 elderly, non-demented subjects (18 male and 6 female, mean age 66.12 years, mean Mini-Mental Score 31.69) on memory performance were evaluated using neuropsychological tests assessing the following memory tasks: word recall, word recognition, immediate recall and delayed recall of objects, and recognition of objects. Prior to testing the effects of citicoline, the memory performance of the participants was compared to that of 24 younger persons (15 male and 9 females, mean age 29.20 years, mean Mini-Mental Score 34.41), and the memory of the older group was significantly less efficient in all 5 tests (P<0.001, except of P<0.005 in word recognition test). Following 4 weeks of citicoline treatment improvement was noted in 2 of 5 memory tasks, namely in word recall (P<0.02) and delayed object recall (P<0.001).
In the third study [43] Diffusion Tensor Imaging (DTI) technique has been used to investigate the effect of citicoline on the indices of the network connectivity of the corpus callosum in patients with leukoaraiosis. DTI allows to quantitatively describe water molecule diffusion patterns in the brain white matter which are related to microscopic details of tissue architecture, such as the integrity of myelin [47]. After excluding stroke history, central nervous system and mental diseases, neurodegenerative diseases, and addiction to alcohol or drugs, 30 persons were recruited diagnosed with moderate to severe leukoaraiosis. The participants were voluntarily assigned to the citicoline group (n=14) and the control group (n=16). In the citicoline group, patients received a daily dose of 600mg citicoline for one year, whereas the control group received no citicoline. Quantitative DTI of three parts of the corpus callosum, the genu, body, and splenium, were performed on recruitment and after one year of citicoline treatment, and the results were presented as the estimates of mean diffusivity (MD) which measures the overall water diffusivity in the tissue, and fractional anisotropy (FA) which measures the degree of directional restriction of the diffusion of water. Compared to the results obtained at the beginning of the trial, after one-year subjects belonging to the control group displayed increases of MD and decreases of FA in all three locations, indicative of pathology progression. Subjects who received citicoline did display decreases in FA as well, but at all three locations, they were markedly smaller than the changes noted in the control group (P=0.005 for genu of the corpus callosum, P=0.052 for the body of corpus callosum, and P=0.011 for splenium of corpus callosum). Citicoline intake over one year resulted in unchanged MD values, the effect was clearly different from that seen in the control group (P=0.007 for genu of the corpus callosum, P=0.002 for the body of corpus callosum and P=0.002 for splenium of corpus callosum). These data are suggestive of that in subjects with leukoaraiosis, citicoline may attenuate the damage to the axons and myelin and promote the repair of the corpus callosum.
In the fourth, most recent, randomized, double-blind, placebo-controlled study [48], the effects of oral citicoline intake on memory in healthy elderly subjects displaying age-associated memory impairment (AAMI) were evaluated. The study was carried out in compliance with the protocol and in accordance with Good Clinical Practices (GCP). Males and females aged between 50 and 85 years were randomized to receive placebo (n = 51) or citicoline (n = 49; dose 500 mg/day) for 12 weeks. Cognitive performance was assessed at baseline and end of the intervention using computerized tests developed and validated by the MRC and Brain Sciences Unit, University of Cambridge, Great Britain. These tests assess working memory, short-term spatial memory, short-term verbal memory, episodic memory, selective attention, and sustained attention. Compared with those taking placebo, participants taking citicoline demonstrated a significant improvement in episodic memory and overall memory assessed by the composite memory score. The authors concluded that their results were convergent with two previous studies indicating positive effects of citicoline on memory in middle-aged and elderly persons.
Before citicoline (inner salt) was accepted as a food constituent, citicoline (both inner salt and sodium salt) had been extensively used as a prescription drug used to treat neurological diseases, both acute (ischemic brain stroke, brain trauma) and chronic (dementias, Parkinson&#;s disease). In multiple prospective trials, patients suffering from various memory-impairing diseases have been treated with citicoline.
A final version of the Cochrane review concerning citicoline for cognitive and behavioral disturbances associated with chronic cerebral disorders in the elderly [49] included the analysis of 14 randomized, placebo-controlled studies on aged individuals with symptoms ranging from memory disorders to vascular mild cognitive impairment, vascular dementia, or senile dementia. The main findings of this review had been summarized [50] as follows: Duration of studies ranged between 20 and 30 days, 1 study lasted 6 weeks, 4 studies lasted 2 and 3 months, and 1 study lasted 12 months. Multiple doses and different inclusion criteria and outcome measures were used. Overall results (884 patients) showed evidence of the benefit of citicoline on memory and behavior but not on attention. There was a significant improvement in the global impression of change in comparison with the placebo group. Odds ratio (OR) for global improvement following active treatment compared to placebo was 8.89 (95% CI, 5.19-15.22; P<0.001), indicating a rather strong drug effect. Importantly, as noted by Fioravanti and Buckley [51], when results of memory tests were taken into account, the effect of citicoline on memory was also significantly different from the placebo effect, being not specifically dependent on the pathogenesis of the cerebral disorder (effect size 0.19; confidence interval [CI] 95% 0.06, 0.32; p<0.005). Moreover, when only cerebrovascular disorders studies were pooled together (for a total of 675 patients), the homogeneity and entity of results was about the same (effect size 0.22; CI 95% 0.07, 0.37; p<0.004). This indicates that the positive effect of citicoline on memory does not depend on the type of underlying brain pathology, and the mechanism responsible is probably the same as in cognitively unimpaired older adults.
Besides the data reviewed in the aforementioned Cochrane analysis, the results of an Italian open multicenter study (the IDEALE study) were published in [52]. Its aim was to assess the effectiveness and safety of oral citicoline in elderly people with mild vascular cognitive impairment. Of note is that the authors considered citicoline as a dietary supplement. The study group comprised 349 patients, 265 of whom (122 men and 143 women) were taking citicoline, and the remaining 84 who did not take it served as the control group. Inclusion criteria were age at least 65 years, subjective memory complaints, Mini-Mental State Examination (MMSE) score not less than 21 indicating a mild degree of cognitive impairment, and neuroradiological evidence of brain vascular lesions. Although memory is only one of few domains tested in MMSE, which also includes tests of orientation, attention, language and visual-spatial skills, the study is unique because the treatment has been conducted for a period of 9 months, longer than in most previous trials. Citicoline-treated patients encountered unchanged MMSE scores (22.4±4 at the beginning, 22.7±4 at 3 months and 22.9±4 at 9 months), whereas controls presented deterioration of MMSE score (21.5±6.9 at the beginning; 20.4±6.6 at 3 months and 19.6±6.3 at 9 months). The difference between the groups was statistically not significant at the beginning of the study but reached high significance at both 3 and 9 months of the study, P<0..
Leading world markets are currently flooded by hundreds of dietary supplements intended for enhancing brain health and improving cognitive performance. Such products are targeted to the aging persons concerned with or experiencing cognitive decline as well as to healthy adults seeking to improve or enhance memory performance or prevent a cognitive decline. Many authors indicate that these &#;memory boosters&#; should not be trusted because scientific evidence behind them is inadequate, studies are inconsistent and imprecise, and many trials are methodologically flawed (see for example, [53]).
A good example is the case of polyphenols, a diverse group of substances encountered in plant-based foods and considered micronutrients. Polyphenols (flavonoids and related phenolic compounds) are so-called secondary plant metabolites, i.e., compounds not necessary for the growth and reproduction of plants. After ingestion dietary polyphenols, which usually are sparingly water-soluble, appear in the circulatory system not as the parent compounds but as more water-soluble phase II metabolites, and their presence in plasma after dietary intake rarely exceeds nM concentrations [54]. Their role as components responsible in part for the putative protective effects of vegetable-rich diets against many chronic diseases has become an important area of human nutrition research.
The issue of polyphenols and human memory and cognition has recently been the subject of several systematic reviews and meta-analyses. In one of them [55], it was stated that the evidence from clinical trials is by no means conclusive, although there is tentative support for a relationship between regular polyphenol intake and cognitive benefits. The other [56] provided a bit more optimistic conclusion: of 66 randomized controlled trials testing the effects of polyphenols on memory, 33 found a significant improvement on at least one memory outcome measure, while 30 did not find any significant effects, and three reported a worsening.
How can we compare the strength of scientific evidence for the positive effects of citicoline and polyphenols on human memory? A scholarly article published recently by a group by Kirk Daffner from the Department of Neurology, Brigham and Women's Hospital, Harvard Medical School [57] prompted us a promising methodology to perform such a comparison. The said article concerns the issue of promoting successful human cognitive aging. The authors discuss the advantages and limitations of four different lines of evidence used to evaluate whether a proposed factor or intervention really may have an impact on cognitive aging. These are: 1) epidemiological/cohort studies, 2) animal/basic science studies, 3) human proof-of-concept studies, and 4) human intervention studies. To prove that a factor or intervention under consideration is efficacious, findings along all these lines shall converge. As we were trying to justify, in the case of citicoline and human memory, these four lines of evidence nicely converge (see Table 1). In the case of polyphenols and human memory, such convergence seems to be much less clear.
Converging lines of evidence for positive effects of citicoline on memory in cognitively normal middle aged and elderly humans.
Line of evidence Main findings References Epidemiological/cohort studies Reciprocal association between choline availability and memory efficacy 15, 16, 17, 20 Basic science/animal studies Citicoline is the efficacious source of bioavailable choline and cytidine/uridine 5, 6 Human &#;proof of concept&#; studies Citicoline supplementation improves brain MRS and MRI biomarkers 34, 35, 36, 37 Human intervention studies Citicoline supplementation positively influences human memory 39, 40, 42, 43, 44, 45, 46 Open in a new tabCurrently, the mainstream treatment of dementing diseases is based on the use of acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine), and/or a low affinity NMDA antagonist memantine. The use of these prescription drugs is burdened with side effects, and it is unlikely that they will be prescribed to cognitively competent persons suffering only from mild age-related memory troubles. However, it is worth mentioning a few clinical studies (reviewed recently by Gareri et al. [58]) which indicated that treatment of patients suffering from early Alzheimer&#;s disease or mixed dementia with citicoline combined with memantine and/or an AChE inhibitor resulted in slight but statistically significant improvement, whereas treatment with memantine and/or an AChEI, drugs formally indicated for the early dementias, resulted is a slight but statistically significant worsening of MMSE scores at 3 or 9 months. Although these studies were neither prospective, nor placebo-controlled, differences between avereage MMSE scores between the groups were impressive. For example, in the CITIMEM study [59] supplementing metantine with citicoline for 9 months resulted in the improvement of the average MMSE score from 16.2 to 17.7, whereas treatment with memantine alone resulted in the average MMSE score deterioration from 16.6 to 14.6. Such data are indicative of citicoline effect being larger than the suggested threshold of a minimal clinically important difference in an Alzheimer&#;s disease clinical trial [60]. These observations provide further confirmation that citicoline shall be seriously considered as an agent providing support for failing memory in middle-aged and elderly persons.
This project is partially supported by VMIX Limited Hong Kong.
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