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Citicoline and Memory Function in Healthy Older Adults: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial



Background Supplementation of citicoline (CDP-choline), a naturally occurring mononucleotide, has shown beneficial effects on memory function and behavior in populations with a wide range of impairments. However, few studies have investigated its effect in healthy older populations. Objective The objective of this study was to investigate the effects of citicoline (Cognizin®), on memory in healthy elderly populations with age-associated memory impairment (AAMI). Methods 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. Results 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 = 0.0025). 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 = 0.0052). Conclusions 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 as NCT03369925.
The Journal of Nutrition
Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions
Citicoline and Memory Function in Healthy
Older Adults: A Randomized, Double-Blind,
Placebo-Controlled Clinical Trial
Eri Nakazaki,1Eunice Mah,2Kristen Sanoshy,2Danielle Citrolo,3and Fumiko Watanabe1
1Research & Innovation Center, Kyowa Hakko Bio Co., Ltd, Tsukuba, Ibaraki, 305–0841, Japan; 2Biofortis Innovation Services, Addison,
IL 60101, USA; and 3Scientic and Regulatory Affairs, Kyowa Hakko USA Inc., New York, NY 10016, USA
Background: Supplementation of citicoline (CDP-choline), a naturally occurring mononucleotide, has shown benecial
effects on memory function and behavior in populations with a wide range of impairments. However, few studies have
investigated its effect in healthy older populations.
Objective: The objective of this study was to investigate the effects of citicoline (Cognizin®), on memory in healthy
elderly populations with age-associated memory impairment (AAMI).
Methods: 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.
Results: A total of 99 out of 100 participants completed the study in its entirety. After the 12-wk intervention, participants
supplemented with citicoline showed signicantly 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=0.0025).
Composite memory (secondary outcome), calculated using the scores of 4 memor y tests, also signicantly improved
to a greater extent following citicoline supplementation (mean: 3.78) compared with placebo (mean: 0.72, P=0.0052).
Conclusions: Dietary supplementation of citicoline for 12 wk improved overall memory performance, especially
episodic memory, in healthy older males and females with AAMI. The ndings suggest that regular consumption
of citicoline may be safe and potentially benecial against memory loss due to aging. This trial was registered at as NCT03369925. J Nutr 2021;151:2153–2160.
Keywords: 5-cytidine diphosphate choline, citicoline, aging, brain, memory loss
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 2050 (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, socioe-
conomic, 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
specic 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
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 cholin-
ergic neurotransmission and the structural integrity of cell
membranes (6). Brain choline uptake is decreased in older
The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition. This is an Open Access article distributed under the
terms of the Creative Commons Attribution License (, which permits unrestricted reuse, distribution, and reproduction
in any medium, provided the original work is properly cited.
Manuscript received November 30, 2020. Initial review completed January 8, 2021. Revision accepted April 5, 2021.
First published online May 12, 2021; doi: 2153
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. Com-
pared 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 benecial 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
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 supplementa-
tion (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 inefcient memory [i.e., scored below
average of all recruited participants (17)]. Another open-
label clinical trial demonstrated a signicant 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
This research was sponsored by Kyowa Hakko Bio Co., Ltd. This research did
not receive any specic grant from funding agencies in the public, commercial,
or not-for-prot sectors. Kyowa Hakko Bio Co., Ltd funded the study and
participated in study design, but was not involved in the intervention, data
collection, and statistical analysis. The views expressed in this manuscript are
those of the authors and do not necessarily reect the position or policy of
Kyowa Hakko Bio Co., Ltd.
Author disclosures: EN and FW are current employees of Kyowa Hakko Bio Co.,
Ltd. EM and KS are current employees of Biofortis Innovation Ser vices. DC is a
current employee of Kyowa Hakko USA, Inc.
Supplemental Tables 1 and 2 are available from the “Supplementar y data” link
in the online posting of the article and from the same link in the online table of
contents at
Address correspondence to EN (e-mail:
Abbreviations used: AAMI, age-associated memory impairment; AE, adverse
event; CFR, Code of Federal Regulations; GCP, Good Clinical Practices; ITT,
intent-to-treat; TMA, trimethylamine; TMAO, trimethylamine N-oxide.
Study design
This randomized, double-blind, placebo-controlled trial of citicoline
was conducted at Biofortis Inc. (Addison, IL) between January 2018
and December 2018. 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 (2013 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-specic procedures were carried out. This
trial was registered at with identier NCT03369925.
Study participants
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
denition 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 fullling 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 dened 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
Study product and treatment
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.
Study supplements consisted of encapsulated microcrystalline cellu-
lose (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 dened as
consumption of <80% or >120% of the scheduled intake upon study
completion. Overall compliance was determined at Week 12.
Study procedures
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
2154 Nakazaki et al.
and diastolic BP measured using an automated blood pressure monitor
(Welch Allyn 53000; 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/m2. 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.
Cognitive assessments
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 dened 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 stratied 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.
Safety assessments
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 phone 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-3100 Automated Hematology
System (Sysmex America, Inc., Lincolnshire, IL), respectively.
Statistical analysis
Sample size calculations were performed using GPower (Version, for ANCOVA (xed effects, main effects, and interactions)
with the following parameters: αerr prob =0.05, power (1-βerr
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 signicant difference between groups and a total of 100 participants
were randomized to account for possible attrition.
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
(SSscore), Monkey Ladder (MLscore), Paired Associates (PAscore), and
Digit Span (DSscore) raw scores using the following formula provided
by Cambridge Brain Sciences:
Com pos it eM emor yS core =˜
Q= SSscore6.11
1.07 ·0.69+ MLscore7.8
1.16 ·0.69+ PAscore5.24
1.11 ·0.58+ DSscore7.15
1.48 ·0.26
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 signicance, unless otherwise stated, were performed at
alpha =0.00625 (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 signicant 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 signicance with the Shapiro-Wilk test (23).
For hematology and metabolic panels, continuous measures were
compared between groups with the Wilcoxon rank sum test. At each
time point, the Pvalues were adjusted for multiple comparisons with
the false discovery rate. Data of unadjusted means ±SD are presented
for each test group.
Finally, differences between groups for baseline characteristics
(Tab l e 1), were analyzed using independent t-test for continuous
variables and Fisher’s exact for categorical variables.
Participant characteristics
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
dened 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 Tabl e 1 .
Compliance over the 12-wk supplementation period was 99.2 ±
0.5% for the 99 participants who completed the study.
Cognitive performance
The results on cognitive function tests at Weeks 0 (baseline),
and 12 (end of study) are shown in Tabl e 2 . Within-
group analysis indicated that the citicoline group, but not
Citicoline on memory in healthy older adults 2155
TABLE 1 Characteristics of the 100 study participants enrolled in this randomized controlled trial1
Placebo Citicoline
(n=51) (n=49) P
Age,2y 65.5 ±1.13 63.2 ±1.12 0.53
Male 16 (31.4) 19 (38.8)
Female 35 (68.6) 30 (61.2) 0.16
Race,3n(%) 0.17
White 47 (92.2) 41 (83.7)
Black/African American 3 (5.88) 7 (14.3)
American Indian or Alaskan Native 0 (0.00) 1 (2.04)
Asian 0 (0.00) 0 (0.00)
Native Hawaiian or other Pacic Islander 1 (1.92) 0 (0.00)
Ethnicity,3n(%) 1.00
Not Hispanic/Latino 49 (96.1) 48 (98.0)
Hispanic/Latino 2 (3.92) 1 (2.04)
BMI,2kg/m229.6 ±0.96 30.7 ±0.91 0.35
Systolic BP,2mm Hg 127 ±2.06 130 ±1.83 0.25
Diastolic BP,2mm Hg 74.4 ±1.64 76.1 ±1.38 0.44
MMSE227.6 ±0.22 27.8 ±0.21 0.50
KBIT-22101 ±1.45 98.9 ±1.26 0.30
Geriatric Depression Scale20.784 ±0.144 0.796 ±0.124 0.95
Spatial Span score (at screening)23.71 ±0.08 3.80 ±0.06 0.35
Hours of sleep (at Week 0),2h7.32±0.12 7.20 ±0.11 0.47
1Values are means ±SEMs or frequency (%). Differences between placebo and citicoline groups for all characteristics were analyzed using independent t-test for continuous
variables and Fisher’s exact test for categorical variables. BP, blood pressure; kg, kilogram; KBIT-2, Kaufman Brief Intelligence Test, Second Edition; m, meter; mm Hg,
millimeter mercury; MMSE, Mini-Mental State Examination.
2Independent t-test.
3Fisher’s exact test.
the placebo group, had a statistically signicant improvement
in Spatial Span, Feature Match, and Composite Memory
scores from baseline. Between-group analysis indicated that
the changes from baseline scores were statistically signif-
icantly different (P<0.00625) between test groups for
Paired Associates and Composite Memory whereby the citi-
coline group demonstrated greater improvements in these
tests compared with the placebo group (Figures 2 and
3). No additional statistically signicant cognitive effects
were detected in Monkey Ladder, Digit Span, Interlocking
Polygon Task, and Sustained Attention to Response Task
according to multiple comparisons with Bonferroni correc-
Safety assessments
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 atulence
(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 “denitely”
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
Tabl e 1 and Supplemental Table 2, respectively. There were
no statistically signicant differences in mean values between
groups at baseline or at end of study. None of the values fell
outside the normal range.
To our knowledge, this is the rst 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 signicant 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
benecial effects of citicoline on memory (17,18).
Episodic memory describes the ability to remember and
recall specic 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 rst to demonstrate a benecial effect of citicoline
supplementation in maintaining and/or improving episodic
memory that may decline with age.
In addition to a statistically signicant improvement in
Paired Associates, we also observed a tendency toward
improvement in the citicoline group for the Spatial Span task.
2156 Nakazaki et al.
FIGURE 1 CONSORT participant ow diagram.
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 ndings 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 specic 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 signicant
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
benecial effect of citicoline on attention that warrants further
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 phos-
phatidylcholine 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 exibility in healthy older adults, and the inferior
prefrontal cortex mediates the relationship between plasma
phosphatidylcholine and cognitive exibility (39). Increase in
phosphodiesters correlated with improvement on the California
Verbal Learning Test, an assessment of verbal learning and
memory decits, in healthy older adults (34). Taken together,
these ndings suggest that citicoline may slow or prevent AAMI
by inuencing specic 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 ndings, 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 ndings 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 benecial effects of citicoline on memory last following
cessation of citicoline supplementation.
Citicoline on memory in healthy older adults 2157
TABLE 2 Results for cognitive performance of the citicoline supplementation group and the placebo group in the ITT population at
Weeks 0 and 121
Tes t Baseline (Week 0) End of study (Week 12)
Spatial Span
Placebo 4.75 ±0.11 4.67 ±0.13
Citicoline 4.65 ±0.09 4.90 ±0.12
Monkey Ladder
Placebo 6.43 ±0.12 6.51 ±0.13
Citicoline 6.65 ±0.14 6.88 ±0.17
Digit Span
Placebo 5.94 ±0.18 6.22 ±0.18
Citicoline 5.88 ±0.16 5.94 ±0.17
Paired Associate
Placebo 3.86 ±0.13 3.92 ±0.14
Citicoline 3.92 ±0.11 4.04 ±0.11†
Composite Memory
Placebo 74.8 ±1.5 75.5 ±1.8
Citicoline 75.6 ±1.4 79.1 ±1.7
Feature Match
Placebo 83.8 ±3.0 88.6 ±3.3
Citicoline 86.7 ±2.8 96.8 ±3.5
Interlocking Polygon Task
Placebo 26.2 ±2.3 28.0 ±2.3
Citicoline 22.8 ±2.4 25.3 ±2.8
Sustained Attention to Response Task
Placebo 174 ±7 185 ±2
Citicoline 181 ±4 177 ±6
1Values are means ±SEMs of test score. n=51 for placebo and n=49–48 for citicoline. An increase composite memory score and all of each individual cognitive tests score
indicates an improvement. P<0.05 within-group difference (baseline vs. end of study) using paired t-test. †P<0.05 between-group difference for the raw change score
analyzed 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 study has some limitations worth noting. Participants
were specically 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
FIGURE 2 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
Pvalue 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.
studies with a wider range of ethnicity are warranted to
understand if the benecial 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
FIGURE 3 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
Pvalue 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.
2158 Nakazaki et al.
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 conrm 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 ndings suggest that
regular consumption of citicoline (Cognizin) may be safe and
potentially benecial against memory loss due to aging.
The authors’ contributions were as follows—EN, EM, DC, and
FW: designed research; KS: conducted research; EM: analyzed
data; EN: wrote the rst draft of the manuscript; EN: had
primary responsibility for nal content; and all authors: read
and approved the nal manuscript. The authors would also
like to thank Dr Libertie Mantilla for statistical analysis and
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... A randomized, double-blind, placebo-controlled trial studied the effects of citicoline (Cognizin ® ) on memory in healthy older adult participants with age-associated memory impairment [27]. One hundred participants aged between 50 and 85 years were randomized to receive either a placebo or 500 mg/d of citicoline for 12 weeks. ...
... Memory was measured using computerized tests at baseline and 12 weeks. The treatment group was found to have a statistically significant higher score on episodic memory, measured by the Paired Association test, and composite memory, which was assessed using 4 memory tests, at the end of the 12 weeks compared to the placebo group (p = 0.0025 and p = 0.0052, respectively) [27]. ...
... Heterogeneity of the populations sampled is also a common problem among these studies [86]. [23] An update of the previous review also yielded mixed results [22] A clinical recommendation for the use of carnitine supplementation for memory cannot be made due to the lack of consistent evidence for its benefit Choline A randomized, double-blind, placebo-controlled trial in 100 adults ages 50-85 years with age-associated memory impairment were found to have statistically significantly improved episodic memory after 12 weeks of treatment with 500 mg/d of citicoline [27] The Kuopio Ischemic Heart Disease Risk Factor Study included 2682 non-demented patients aged 42-60 years and found that patients with the highest intake of phosphatidylcholine had a statistically significant lower incidence of dementia compared to those with the lowest intake [28] A systematic review of 14 RCTs involving choline supplementation in patients with cognitive deficits concluded that there is some evidence of short-to-medium term memory benefits from choline supplementations [29] There is some evidence of short-to-medium term memory benefit from choline supplementation ...
Full-text available
In 2021, the Global Brain Health Supplement Industry Market size was valued at US$7.6 billion. It is predicted to increase to US$15.59 billion by 2030. Memory and its enhancement are a segment of the market that comprised the highest global revenue share in 2021. In the USA alone, dietary supplement sales reached US$18 billion in 2018. The US Food and Drug Administration (FDA) does not have the authority to approve dietary supplements' safety, effectiveness, or labeling before products go on the market. The FDA often does not even review supplements before they go to market. Supplement manufacturers are thus responsible for ensuring their products are safe and that their claims are truthful. An extensive review of current supplements on the market was performed by surveying memory products for sale at local and national pharmacies and grocery stores. A list of 103 supplements was compiled and the ingredients in these memory supplements were reviewed. The 18 most common ingredients in these supplements were identified. Each of the supplements included at least one of the 18 most common ingredients. Scientific data relative to these ingredients and their effect on memory was searched using PubMed and Cochrane library databases. Currently, there is no compelling evidence for use of apoaequorin, coenzyme Q10, coffee extracts, L-theanine, omega-3 fatty acids, vitamin B6, vitamin B9, or vitamin B12 supplementation for memory. On the other hand, there is some current evidence for memory benefit from supplementation with ashwagandha, choline, curcumin, ginger, Lion's Mane, polyphenols, phosphatidylserine, and turmeric. There are current studies with mixed results regarding the benefit of carnitine, gingko biloba, Huperzine A, vitamin D, and vitamin E supplementation for memory. Dietary supplements geared toward improving cognition are a billion-dollar industry that continues to grow despite lacking a solid scientific foundation for their marketing claims. More rigorous studies are needed relative to the long-term use of these supplements in homogenous populations with standardized measurements of cognition. Health care providers need to be aware of any and all supplements their older adult patients may be consuming and be educated about their side effects and interactions with prescription medications. Lastly, the FDA needs to take an active position relative to monitoring marketed supplements regarding safety, purity and claims of efficacy.
... Each nootropic currently available varies in terms of the ingredients but there is some commonality across products. Mind Lab Pro contains 250 mg of Citicoline which has been found to improve memory and attention by activating biosynthesis in the neural membranes and increasing specific hormone levels in the central nervous system to protect cell membranes [5,8,9]. Bacopa Monnieri has been found to increase dendritic branching and pruning, which in turn can lead to improved cognitive function [9], specifically in older patients. ...
... Despite this, significant improvements were made by the experimental group from pre to post. It may be that ingredients such as Citicoline, Bacopa Monnieri, Lion's Mane Mushroom, Maritime pine bark extract, Tyrosine and Phosphatidylserine may have assisted participants focus and attention as found in previous studies [7,8,3,21]. As the control group did not improve, it can be assumed that the improvement in SRT in the experimental group was not as a result of learning. ...
... It was encouraging to see this in older participants as this has also been shown by other studies [48]. Citicoline, Bacopa Monnieri, Lion's Mane Mushroom, Tyrosine and Phosphatidylserine taken in combination have been shown to with improve focus and attention which is important when performing choice reaction type tasks [8,12,13,15]. The vitamins in Mind Lab Pro have also been shown to improve cognitive functioning especially in older populations [23,25,26]. ...
... Another form of choline, known as citicoline or CDP-choline, was measured for its effects on elderly populations with age-associated memory impairment. This form of choline also showed significant improvements in overall memory, especially episodic memory, compared to the placebo group [41]. ...
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Aging results in more health challenges, including neurodegeneration. Healthy aging is possible through nutrition as well as other lifestyle changes. One-carbon (1C) metabolism is a key metabolic network that integrates nutritional signals with several processes in the human body. Dietary supplementation of 1C components, such as folic acid, vitamin B12, and choline are reported to have beneficial effects on normal and diseased brain function. The aim of this review is to summarize the current clinical studies investigating dietary supplementation of 1C, specifically folic acid, choline, and vitamin B12, and its effects on healthy aging. Preclinical studies using model systems have been included to discuss supplementation mechanisms of action. This article will also discuss future steps to consider for supplementation. Dietary supplementation of folic acid, vitamin B12, or choline has positive effects on normal and diseased brain function. Considerations for dietary supplementation to promote healthy aging include using precision medicine for individualized plans, avoiding over-supplementation, and combining therapies.
... Citicoline (CL) is a naturally occurring endogenous compound that belongs to the phospholipid cytidine and choline; it is also an essential structural component of the cell membrane [12]. The lack of availability of phosphatidylcholine, an essential component for neuronal cell health, is a consequence of cell membrane damage and impaired phospholipid metabolism [13,14]. According to a study by Navarro-Sobrino M et al., only CL can effectively provide neurorepair and neuroprotection [15]. ...
Insufficiency of a choline derivative (acetylcholine) can lead to the development of cognitive impairment (CI). One of the most well-known and well-studied medical drugs (MD) containing choline and having neuroprotective properties is citicoline (Recognan). A number of studies have demonstrated the effectiveness of Recognan in relation to mild CI, chronic cerebrovascular diseases (CVD), acute vascular disorders (including post-traumatic genesis). Recognan improves memory and other cognitive functions in healthy young people against the background of asthenia due to stress or increased cognitive and emotional stress or infection, and also has a preventive effect on fading cognitive functions in the process of age-related changes. The duration of neuroprotection can reach 6 months or more - up to 12 months, depending on the patient's condition. Therapy regimens include two-stage Recognan prescribing: with CVD intramuscularly (i/m) at 1000 mg /d for 30 days, in the acute period of ischemic stroke, i/m or intravenously (i/v) at 1000 mg every 12 hours from the first day after diagnosis, 3-5 days after the start of therapy, with preservation functions of swallowing, it is possible to switch to per oral (p/o) drug administration.
В обзоре представлена нейропротекторная способность пиримидиновых нуклеотидов на основе анализа литературных данных относительно их цереброваскулярных, метаболических и функциональных эффектов в условиях нарушений кровоснабжения мозга, являющихся одной из главных причин смертности и основной причиной инвалидизации населения. Принимая во внимание возрастающий интерес к эндогенным соединениям, пиримидиновые нуклеотиды представлены как потенциальные нейропротекторы для терапии инсульта – наиболее часто встречающейся патологии нарушений мозгового кровообращения. Показано участие пиримидиновых нуклеотидов в формировании миелиновой оболочки, синтезе гликогена в мозговой ткани, передаче нервных импульсов, так же как и в различных функциях головного мозга. Благодаря своей разносторонней биологической активности, пиримидиновые нуклеотиды нашли широкое применение в виде различных лекарственных средств и лекарственных комбинаций в качестве нейропротекторов, особенно для лечения заболеваний периферической и центральной нервной системы. Представлены так же и выявленные новые свойства уридин- и цитидинфосфатов относительно их способности стимулировать локальный мозговой кровоток в условиях одностороннего нарушения кровоснабжения мозга, а также их участия в предотвращении нейроповеденческих последствий и морфологических изменений в тканях головного мозга, вызванных локальной ишемией. Presented review describes the neuroprotective ability of pyrimidine nucleotides based on the analysis of literature data regarding their cerebrovascular, metabolic and functional effects in conditions of impaired brain blood flow, which is one of the main causes of death and disability all over the world. Taking into account the growing interest in endogenous compounds, pyrimidine nucleotides are presented as potential neuroprotectors for the treatment of stroke - the most common pathology of cerebrovascular disorders. The participation of pyrimidine nucleotides in the formation of the myelin sheath, the synthesis of glycogen in the brain tissue, the transmission of nerve impulses, as well as in various functions of the brain, has been demonstrated. Due to their diverse biological activity, pyrimidine nucleotides have found wide application in the dosage form of various drugs and drug combinations as neuroprotectors, especially for the treatment of the peripheral and central nervous system diseases. New discovered properties of uridine and cytidine phosphates regarding their ability to stimulate local cerebral blood flow in the conditions of unilateral disturbances of brain blood supply, as well as their participation in prevention of neurobehavioral consequences and morphological changes in brain tissues caused by local ischemia, are also presented.
Objectives: This study aimed to investigate the efficacy of taking Mind Lab Pro, a plant-based nootropic on memory in a group of healthy adults. Auditory, visual, visual working memory, immediate and delayed recall (DR) were assessed. Methods: The study employed a pseudo randomised, double blinded, placebo-controlled design. A total of 49 healthy individuals completed the study with 36 in the experimental group and 13 in the control group. Participants ranged between 20 and 68 years with a mean age of 31.4 ± 14.4 years. Pre and post taking either the Mind Lab Pro supplement or placebo for 30 days. All participants completed the Wechsler Memory Scale Fourth UK Edition (WSM-IV UK). Results: We found that the experimental group significantly improved in all memory subtests assessed (p < 0.05) whilst the control group only significantly improved in auditory memory and immediate recall (p = 0.004 and p = 0.014 respectively). A significant difference in immediate and DR was also found between the control and experimental group (p = 0.005 and 0.034 respectively). Conclusion: The use of Mind Lab Pro for 4 weeks improves memory with the experimental group significantly improving in all sub areas of memory as assessed by the WSM-IV UK.
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Failed proteostasis is a well-documented feature of Alzheimer’s disease, particularly, reduced protein degradation and clearance. However, the contribution of failed proteostasis to neuronal circuit dysfunction is an emerging concept in neurodegenerative research and will prove critical in understanding cognitive decline. Our objective is to convey Alzheimer’s disease progression with the growing evidence for a bidirectional relationship of sleep disruption and proteostasis failure. Proteostasis dysfunction and tauopathy in Alzheimer’s disease disrupts neurons that regulate the sleep–wake cycle, which presents behavior as impaired slow wave and rapid eye movement sleep patterns. Subsequent sleep loss further impairs protein clearance. Sleep loss is a defined feature seen early in many neurodegenerative disorders and contributes to memory impairments in Alzheimer’s disease. Canonical pathological hallmarks, β-amyloid, and tau, directly disrupt sleep, and neurodegeneration of locus coeruleus, hippocampal and hypothalamic neurons from tau proteinopathy causes disruption of the neuronal circuitry of sleep. Acting in a positive-feedback-loop, sleep loss and circadian rhythm disruption then increase spread of β-amyloid and tau, through impairments of proteasome, autophagy, unfolded protein response and glymphatic clearance. This phenomenon extends beyond β-amyloid and tau, with interactions of sleep impairment with the homeostasis of TDP-43, α-synuclein, FUS, and huntingtin proteins, implicating sleep loss as an important consideration in an array of neurodegenerative diseases and in cases of mixed neuropathology. Critically, the dynamics of this interaction in the neurodegenerative environment are not fully elucidated and are deserving of further discussion and research. Finally, we propose sleep-enhancing therapeutics as potential interventions for promoting healthy proteostasis, including β-amyloid and tau clearance, mechanistically linking these processes. With further clinical and preclinical research, we propose this dynamic interaction as a diagnostic and therapeutic framework, informing precise single- and combinatorial-treatments for Alzheimer’s disease and other brain disorders. Graphical Abstract
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In this comprehensive review, we examine the main preclinical and clinical investigations assessing the effects of different forms of choline supplementation currently available, including choline alfoscerate (C8H20NO6P), also known as alpha-glycerophosphocholine (α-GPC, or GPC), choline bitartrate, lecithin, and citicoline, which are cholinergic compounds and precursors of acetylcholine. Extensively used as food supplements, they have been shown to represent an effective strategy for boosting memory and enhancing cognitive function.
Choline is an essential nutrient affects brain development in early life. However, evidence is lacking regarding its potential neuroprotective effects in later life from community-based cohorts. This study assessed the relationship between choline intake and cognitive functioning in a sample of older adults 60 years + from the National Health and Nutrition Examination Survey 2011–2012 and 2013–2014 waves (n = 2,796). Choline intake was assessed using two nonconsecutive 24-hour dietary recalls. Cognitive assessments included immediate and delayed word recalls, Animal Fluency, and Digit Symbol Substitution Test. The average daily dietary choline intake was 307.5 mg, and the total intake (including intake from dietary supplements) was 330.9 mg, both below the Adequate Intake level. Neither dietary OR = 0.94, 95% CI (0.75, 1.17) nor total choline intake OR = 0.87, 95% CI (0.70, 1.09) was associated with changes in cognitive test scores. Further investigation adopting longitudinal or experimental designs may shed light on the issue.
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Trimethylamine-N-oxide (TMAO) is generated in a microbial-mammalian co-metabolic pathway mainly from the digestion of meat-containing food and dietary quaternary amines such as phosphatidylcholine, choline, betaine, or L-carnitine. Fish intake provides a direct significant source of TMAO. Human observational studies previously reported a positive relationship between plasma TMAO concentrations and cardiometabolic diseases. Discrepancies and inconsistencies of recent investigations and previous studies questioned the role of TMAO in these diseases. Several animal studies reported neutral or even beneficial effects of TMAO or its precursors in cardiovascular disease model systems, supporting the clinically proven beneficial effects of its precursor, L-carnitine, or a sea-food rich diet (naturally containing TMAO) on cardiometabolic health. In this review, we summarize recent preclinical and epidemiological evidence on the effects of TMAO, in order to shed some light on the role of TMAO in cardiometabolic diseases, particularly as related to the microbiome.
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As people age they become increasingly susceptible to chronic and extremely debilitating brain diseases. The precise cause of the neuronal degeneration underlying these disorders, and indeed normal brain ageing remains however elusive. Considering the limits of existing preventive methods, there is a desire to develop effective and safe strategies. Growing preclinical and clinical research in healthy individuals or at the early stage of cognitive decline has demonstrated the beneficial impact of nutrition on cognitive functions. The present review is the most recent in a series produced by the Nutrition and Mental Performance Task Force under the auspice of the International Life Sciences Institute Europe (ILSI Europe). The latest scientific advances specific to how dietary nutrients and non-nutrient may affect cognitive ageing are presented. Furthermore, several key points related to mechanisms contributing to brain ageing, pathological conditions affecting brain function, and brain biomarkers are also discussed. Overall, findings are inconsistent and fragmented and more research is warranted to determine the underlying mechanisms and to establish dose-response relationships for optimal brain maintenance in different population subgroups. Such approaches are likely to provide the necessary evidence to develop research portfolios that will inform about new dietary recommendations on how to prevent cognitive decline.
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Objectives: This study examines the neural mechanisms that mediate the relationship between phosphatidylcholine and executive functions in cognitively intact older adults. We hypothesized that higher plasma levels of phosphatidylcholine are associated with better performance on a particular component of the executive functions, namely cognitive flexibility, and that this relationship is mediated by gray matter structure of regions within the prefrontal cortex (PFC) that have been implicated in cognitive flexibility. Methods: We examined 72 cognitively intact adults between the ages of 65 and 75 in an observational, cross-sectional study to investigate the relationship between blood biomarkers of phosphatidylcholine, tests of cognitive flexibility (measured by the Delis-Kaplan Executive Function System Trail Making Test), and gray matter structure of regions within the PFC. A three-step mediation analysis was implemented using multivariate linear regressions and we controlled for age, sex, education, income, depression status, and body mass index. Results: The mediation analysis revealed that gray matter thickness of one region within the PFC, the left inferior PFC (Brodmann’s Area 45), mediates the relationship between phosphatidylcholine blood biomarkers and cognitive flexibility. Conclusion: These results suggest that the inferior PFC acts as a mediator of the relationship between phosphatidylcholine and cognitive flexibility in cognitively intact older adults. This report demonstrates a novel structural mediation between plasma phosphatidylcholine levels and cognitive flexibility. Future work should examine the potential mechanisms underlying this mediation, including phosphatidylcholine-dependent cell membrane integrity of the inferior PFC and phosphatidylcholine-dependent cholinergic projections to the inferior PFC.
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Significance Human blood provides a rich source of information about metabolites that reflects individual differences in health, disease, diet, and lifestyle. The coefficient of variation for human blood metabolites enriched in red blood cells or plasma was quantified after careful preparation. We identified 14 age-related metabolites. Metabolites that decline strikingly in the elderly include antioxidants and compounds involved in high physical activity, including carnosine, UDP-acetyl-glucosamine, ophthalmic acid,1,5-anhydroglucitol, NAD ⁺ , and leucine. Metabolites that increase significantly in the elderly include compounds related to declining renal and liver function. Statistical analysis suggests that certain age-related compounds that either increased or decreased in the elderly are correlated. Individual variability in blood metabolites may lead to identify candidates for markers of human aging or relevant diseases.
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Background: Citicoline is able to potentiate neuroplasticity and is a natural precursor of phospholipid synthesis, or rather serves as a choline source in the metabolic pathways for biosynthesis of acetylcholine. Several studies have shown that it can have beneficial effects both in degenerative and in vascular cognitive decline. The aim of the present study was to review the pharmacokinetics and pharmacodynamics of this drug and its role in cognitive impairment according to the present medical literature. Methods: A MEDLINE(®) search was made using the following key words: citicoline, pharmacokinetics, pharmacodynamics, elderly, cognitive impairment, vascular dementia, and Alzheimer's disease. Recent studies on the possible role of citicoline in increasing sirtuin 1 (SIRT1) expression were assessed. Some personal studies were also considered, such as the VITA study and the IDEALE study. Results: Administered by both oral and intravenous routes, citicoline is converted into two major circulating metabolites, cytidine and choline. It is metabolized in the gut wall and liver. Pharmacokinetic studies suggested that it is well absorbed and highly bioavailable with oral dosing. A number of studies have clearly shown the possible role of citicoline in cognitive impairment of diverse etiology. It can also modulate the activity/expression of some protein kinases involved in neuronal death and increases SIRT1 expression in the central nervous system. The VITA study and the IDEALE study suggested that both parenteral and oral citicoline are effective and safe. Other studies have clearly demonstrated citicoline's effects on several cognitive domains. Conversely, some studies did not point out any evidence of efficacy of this drug. Conclusion: Citicoline appears to be a promising agent to improve cognitive impairment, especially of vascular origin. In fact, so far it appears as a drug with the ability to promote "safe" neuroprotection, capable of enhancing endogenous protective. Large clinical trials are needed to confirm its benefits.
Cognitive impairment results from a complex interplay of many factors. The most important independent predictor of cognitive decline is age but other contributing factors include demographic, genetic, socio-economic, and environmental parameters, including nutrition. The number of persons with cognitive decline and dementia will increase in the next decades in parallel with aging of the world population. Effective pharmaceutical treatments for age-related cognitive decline are lacking, emphasizing the importance of prevention strategies. There is extensive evidence supporting a relationship between diet and cognitive functions. Thus, nutritional approaches to prevent or slow cognitive decline could have a remarkable public health impact. Several dietary components and supplements have been examined in relation to their association with the development of cognitive decline. A number of studies have examined the role of dietary patterns on late-life cognition, with accumulating evidence that combinations of foods and nutrients may act synergistically to provide stronger benefit than those conferred by individual dietary components. Higher adherence to the Mediterranean dietary pattern has been associated with decreased cognitive decline and incident AD. Another dietary pattern with neuroprotective actions is the Dietary Approach to Stop Hypertension (DASH). The combination of these two dietary patterns has been associated with slower rates of cognitive decline and significant reduction in incident AD. This review evaluates the evidence for the effects of some dietary components, supplements, and dietary patterns as neuroprotective, with potential to delay cognitive decline and the onset of dementia.
The episodic long-term memory system supports remembering of events. It is considered to be the most age-sensitive system, with an average onset of decline around 60 years of age. However, there is marked interindividual variability, such that some individuals show faster than average change and others show no or very little change. This variability may be related to the risk of developing dementia, with elevated risk for individuals with accelerated episodic memory decline. Brain imaging with functional magnetic resonance imaging (MRI) of blood oxygen level-dependent (BOLD) signalling or positron emission tomography (PET) has been used to reveal the brain bases of declining episodic memory in ageing. Several studies have demonstrated a link between age-related episodic memory decline and the hippocampus during active mnemonic processing, which is further supported by studies of hippocampal functional connectivity in the resting state. The hippocampus interacts with anterior and posterior neocortical regions to support episodic memory, and alterations in hippocampus–neocortex connectivity have been shown to contribute to impaired episodic memory. Multimodal MRI studies and more recently hybrid MRI/PET studies allow consideration of various factors that can influence the association between the hippocampal BOLD signal and memory performance. These include neurovascular factors, grey and white matter structural alterations, dopaminergic neurotransmission, amyloid-Β and glucose metabolism. Knowledge about the brain bases of episodic memory decline can guide interventions to strengthen memory in older adults, particularly in those with an elevated risk of developing dementia, with promising results for combinations of cognitive and physical stimulation.
Background: CDP-choline has a widespread, but not exclusive use in the treatment of disorders of a cerebrovascular nature. The many years of its use have caused an evolution in dosage, method of administration, and selection of patients to which the treatment was given. Design of the clinical studies, including length of observation, severity of disease, and methodology of evaluation of the results have also varied. In spite of uncertainties about its efficacy, CDP-choline is frequently prescribed for cognitive impairment in several continental European countries, especially when the clinical picture is predominantly one of cerebrovascular disease. Objectives: The objective is to assess the efficacy of CDP-choline (cytidinediphosphocholine) in the treatment of cognitive, emotional, and behavioural deficits associated with chronic cerebral disorders of older people. Search strategy: The CDCIG register of trials and other databases were searched in July 2000 for all relevant, non-animal randomized controlled trials using the terms CDP-choline/CDP, Citicoline, Cytidine Diphosphate choline and Diphosphocholine. The Psychlit (1974-1996), Psychiatry (1980-1996) and MEDLINE electronic databases have been searched independently by the reviewers. The reviewers have also contacted manufacturers of CDP-choline. Selection criteria: All relevant, non-animal, unconfounded, double-blind, placebo-controlled, randomized trials of CDP-choline for patients with cognitive impairment due to chronic cerebral disorders are considered for inclusion in the review. Data collection and analysis: Two reviewers independently reviewed the included studies, extracted the data, and pooled when appropriate and possible. The pooled odd ratios (95% CI) or the average differences (95% CI) were estimated. No intention-to-treat data were available from the studies included. Main results: Seven of the included studies observed the subjects for a period between 20 to 30 days, one study was of 6 weeks duration, 3 studies used cycles extending over 2 and 3 months and one study observed continuous administration over 3 months. The studies differed in dose, inclusion criteria for subjects, and outcome measures. Results are reported for the domains of attention, memory testing, behavioural rating scales, global clinical impression and tolerability. There is no significant evidence of a beneficial effect of CDP-choline on attention. There are modest, but statistically significant, beneficial effects of CDP-choline on memory function and behaviour. For the outcome of clinical global impression, the odds ratio for improvement in the subjects treated with CDP-choline as opposed to the subjects treated with placebo is 8.89 [5.19 to 15.22]. The drug is well tolerated. Reviewer's conclusions: There is some evidence that CDP-choline has a positive effect on memory and behaviour in at least the short term. The evidence of benefit from global impression is stronger, but is still limited by the duration of the studies. There is evidence that the effect of treatment is more homogeneous for patients with cognitive impairment secondary to cerebrovascular disorder. Further studies with a more appropriate length of treatment are recommended owing to the chronic and irreversible nature of the disorders for which this treatment is indicated.