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Improved Attentional Performance Following Citicoline Administration in Healthy Adult Women

Authors:

Abstract

Objectives: The present study assessed the potential cognitive-enhancing effects of citicoline, a dietary supplement, in healthy adult women. Specifically, it was hypothesized that citicoline supplementation would be associated with im-proved attention compared to placebo. Methods: The investigation was a double-blind, randomized, placebo-controlled three-arm study. Sixty healthy adult women ages 40 -60 completed a clinical screening visit, including a medical exam. After study enrollment each subject was randomly assigned to one of three groups: a daily oral dose of 250 mg citi-coline, 500 mg citicoline, or placebo for 28 days. Participants were evaluated with the Continuous Performance Test II (CPT-II), a measure sensitive to attentional function, during a baseline visit and 28 days after baseline. Results: All 60 participants were included in the analyses, which included an ANOVA with Tukey's post-hoc tests and t-tests. After 28 days of supplementation, individuals in the 250 mg group made fewer omission (p = 0.04) and commission (p = 0.03) errors compared to those in the placebo group. Individuals in the 500 mg group made significantly fewer commission errors compared to those in the placebo group (p = 0.03) and trended toward making fewer omission errors (p = 0.07). Conclusion: After 28 days of daily citicoline supplementation, participants who were administered either the 250 mg or the 500 mg citicoline doses showed significantly better ability to produce correct responses on the CPT-II, likely due to improved cognitive inhibition. Our findings suggest that citicoline may improve attentional performance in middle-aged women and may ameliorate attentional deficits associated with central nervous system disorders.
Food and Nutrition Sciences, 2012, 3, 769-773
doi:10.4236/fns.2012.36103 Published Online June 2012 (http://www.SciRP.org/journal/fns)
769
Improved Attentional Performance Following Citicoline
Administration in Healthy Adult Women
Erin McGlade
1,2
, Allison Locatelli
1
, Julia Hardy
1
, Toshikazu Kamiya
3
, Masahiko Morita
4
,
Koji Morishita
4
, Yoichiro Sugimura
4
, Deborah Yurgelun-Todd
1,2
1
Brain Institute, University of Utah, Salt Lake City, USA;
2
Department of Psychiatry, University of Utah, Salt Lake City, USA;
3
Kyowa Hakko USA, Inc., New York, USA;
4
Kyowa Hakko Bio Co., Ltd., Tokyo, Japan.
Email: erin.mcglade@hsc.utah.edu
Received February 23
rd
, 2012; revises April 16
th
, 2012; accepted April 23
rd
, 2012
ABSTRACT
Objectives: The present study assessed the potential cognitive-enhancing effects of citicoline, a dietary supplement, in
healthy adult women. Specifically, it was hypothesized that citicoline supplementation would be associated with im-
proved attention compared to placebo. Methods: The investigation was a double-blind, randomized, placebo-controlled
three-arm study. Sixty healthy adult women ages 40 - 60 completed a clinical screening visit, including a medical exam.
After study enrollment each subject was randomly assigned to one of three groups: a daily oral dose of 250 mg citi-
coline, 500 mg citicoline, or placebo for 28 days. Participants were evaluated with the Continuous Performance Test II
(CPT-II), a measure sensitive to attentional function, during a baseline visit and 28 days after baseline. Results: All 60
participants were included in the analyses, which included an ANOVA with Tukey’s post-hoc tests and t-tests. After 28
days of supplementation, individuals in the 250 mg group made fewer omission (p = 0.04) and commission (p = 0.03)
errors compared to those in the placebo group. Individuals in the 500 mg group made significantly fewer commission
errors compared to those in the placebo group (p = 0.03) and trended toward making fewer omission errors (p = 0.07).
Conclusion: After 28 days of daily citicoline supplementation, participants who were administered either the 250 mg or
the 500 mg citicoline doses showed significantly better ability to produce correct responses on the CPT-II, likely due to
improved cognitive inhibition. Our findings suggest that citicoline may improve attentional performance in middle-aged
women and may ameliorate attentional deficits associated with central nervous system disorders.
Keywords: Citicoline; Continuous Performance Test; Attention
1. Introduction
Citicoline is a natural product that is marketed as a nutri-
tional supplement in the United States. Exogenous ad-
ministration of citicoline (CDP-choline; cytidine 5’-di-
phosphocholine) has been shown to influence brain cel-
lular metabolism and citicoline has demonstrated a vari-
ety of cognitive-enhancing and neuroprotective proper-
ties in pre-clinical and clinical studies [1-3]. A compound
composed of choline and cytidine, citicoline is instru-
mental in the synthesis of cell membrane phospholipids
that aid in neuronal membrane repair [3,4], and provides
a choline source needed for acetylcholine (ACh) and
phosphatidylcholine synthesis [3,5].
Pharmacokinetic studies on the absorption of citicoline
through the oral route have shown that the drug is rapidly
absorbed with less than one percent excreted in the feces.
Citicoline is metabolized during intestinal absorption
yielding choline and uridine [6]. After metabolism, citi-
coline is distributed throughout the body by way of sys-
temic circulation in the form of choline and uridine for
utilization in many biosynthetic pathways. After crossing
the blood-brain barrier, uridine is synthesized into uri-
dine 5’-triphosphate, which can be further metabolized to
cytidine triphosphate and CDP-choline [6].
Previous studies on supplementation with citicoline
have shown an increase in choline-containing compounds
associated with improved bioenergetics. Specifically,
Babb and colleagues applied proton magnetic resonance
spectroscopy (MRS) to measure in-vivo brain chemistry
and found that a single oral dose of CDP-choline resulted
in increased plasma choline in older (mean age 59 years)
and younger (mean age 25) participants three hours after
supplementation [7]. These investigators subsequently [8]
applied phosphorous MRS to measure changes in brain
chemistry in healthy older adults following 6 weeks of
500 mg citicoline supplementation. The study findings
showed an increase in brain phosphodiesters that corre-
lated with memory improvement as measured by the
Copyright © 2012 SciRes. FNS
Improved Attentional Performance Following Citicoline Administration in Healthy Adult Women
770
California Verbal Learning Test [8]. To further examine
the potential effects of citicoline supplementation on
brain metabolism, Silveri and colleagues used phosphor-
rus MRS [9] to measure brain metabolites in healthy
adults 40 - 60 years old who received citicoline supple-
mentation for six weeks at doses of either 500 or 2000
mg/day. Increased phosphocreatine levels were observed
in the anterior cingulate, suggesting improved bioener-
getics and enhanced phospholipid membrane mainte-
nance in the frontal lobe. Animal study results have
complemented these data on human brain changes by
indicating a potential role of citicoline in the moderation
of neurotransmitters. In a study involving exogenous citi-
coline administration to rats for 28 days, supplementation
increased dopamine release in the striatum [10].
A number of investigations have focused on the thera-
peutic effects of citicoline in patients who have suffered
from stroke or a traumatic brain injury. Patients with
neurocognitive decline following an initial stroke have
shown improvement in both attention and executive
functioning after six months of 1000 mg/day citicoline
treatment [4,11,12]. In addition, Agnoli and colleagues
[12] showed that citicoline supplementation in an elderly
sample of individuals with mild to moderate memory
deficits resulted in significantly improved memory and
attention. They found that individuals who took 1000 mg
of citicoline for six weeks showed improved acquisition
efficiency and global memory efficiency, as measured by
the Randt Memory Test, compared to individuals who
took the placebo. The authors interpreted these findings
as indicative of memory processing and attentional im-
provement associated with dopaminergic stimulation
from citicoline consumption [12].
While previous studies of citicoline have focused on
study populations with neurological conditions or sig-
nificant cognitive deficits, there is a paucity of data on
the effects of citicoline in normal aging. Aging in the
absence of acute or chronic medical conditions has been
associated with decreased attentional capacity and in-
creased distractibility [13,14]. Research examining brain
structure and function as well as cognitive performance
has shown a number of changes in healthy aging adults.
For example, Madden and colleagues [15] found that
older and younger adults showed similar prefrontal acti-
vation during a visual target response task; however,
older adults also showed increased deep gray matter ac-
tivation. Regression analyses suggested that younger
adults’ performance on the visual target response task
was mediated by the prefrontal cortex, whereas deep gray
matter structures were more involved in older adults’ task
performance. In addition, older adults showed slower
response times compared to the younger adults. Vaidya
and colleagues [16] applied brain imaging methods and
showed smaller rostral ACC gray matter volume and
decreased blood flow in dorsal and rostral ACC regions
associated with age. These findings are consitent with
other neuroimaging studies that have reported reduced
brain activity and decreased cerebral glucose metabolism,
as well as reduced performance on response inhibition
tasks with age [17-20]. The brain changes observed dur-
ing aging in healthy adults suggest a potential role for
citicoline supplementation.
The current study is a double-blind, placebo-controlled,
three-arm study designed to evaluate the effect of two
doses of citicoline on attention after four weeks of supple-
mentation. Attentional performance measures in healthy,
aging adult women were monitored in a trial involving
two different doses of oral citicoline (250 mg/day and
500 mg/day) or a placebo. The study population was lim-
ited to women to decrease heterogeneity given hormonal
changes that males and females experience between 40
and 60 years old. It was hypothesized that the women
who received citicoline would demonstrate improved
attentional performance on a computerized attention task
compared to the women who received the placebo.
2. Subjects and Methods
2.1. Subjects
Sixty healthy female adults ranging from 40 to 60 years
of age (M = 47.38, SD = 5.48) were recruited from Salt
Lake City, UT (Table 1). The participants were screened
prior to enrollment to ensure that they met the inclusion
criteria for the study. Potential participants were enrolled
if they had no significant medical conditions, no history
of psychiatric disorders, no current Axis I or II diagnosis,
and no history of previous participation in a pharmaco-
therapeutic trial. The study was conducted under the
guidelines of the University of Utah Institutional Review
Board. All participants provided written informed consent
per the IRB and Declaration of Helsinki, and participants
were compensated financially for their time.
2.2. Study Design
All participants who were screened positive for study
Table 1. Baseline subject demographics.
250 mg
(N = 20)
500 mg
(N = 20)
Placebo
(N = 20)
Age ± SD 46.00 ± 4.60 48.20 ± 5.99 47.95 ± 5.74
Education ± SD
(years)
16.53 ± 2.37 17.75 ± 1.92 16.30 ± 2.54
Height (in) ± SD 64.22 ± 3.59 63.93 ± 2.28 64.30 ± 3.18
Weight (lbs) ± SD 158.38 ± 26.67 147.25 ± 40.15 154.80 ± 34.74
Vocabulary
Score ± SD
105.15 ± 17.64 109.75 ± 11.48 103.60 ± 11.55
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Improved Attentional Performance Following Citicoline Administration in Healthy Adult Women
771
entry then completed a clinical screening visit, including
a medical exam. Participants also completed a diagnostic
interview, lifestyle questionnaires, vocabulary subtest of
the Wechsler Adult Intelligence Scale-Fourth Edition
(WAIS-IV), California Verbal Learning Test (CVLT), and
the Continuous Performance Test II (CPT-II) during their
initial visit. Following the completion of this first visit,
subjects were randomly assigned to a dosing group of
250 mg, 500 mg, or placebo and given their 28-day sup-
ply of oral citicoline (Cognizin
®
Kyowa Hakko Kogyo
Co., Ltd., Japan) or placebo. Both participants and re-
searchers remained blind to the treatment condition for
the duration of data collection. Participants were in-
structed to take one capsule per day every day for the
next 28 days. Participants returned on day 28 to repeat
assessment measures, including the CPT-II and the medi-
cal exam.
The CPT-II is a test of sustained attention that has
been adapted for computerized administration. It has
been shown to be a reliable measure for sustained and
selective attention [21,22]. The CPT-II was completed on
an IBM-compatible laptop computer. The task begins
with a short practice exercise then proceeds into the full
test, which lasts for 14 minutes. For both the practice test
and the full test, participants are instructed to press the
spacebar as quickly and as accurately as possible when
any letter other than X appears on the screen. Letters
appear on the computer screen 1 letter at a time for 250
milliseconds. Inter-stimulus intervals between letter dis-
plays vary between 1, 2, and 4 seconds. Measures that
are provided by the CPT-II assessment include omission
and commission errors. Omission errors occur when the
participant does not respond when they should respond
(i.e., not pressing the spacebar when a letter other than X
appears), and commission errors occur when the partici-
pant fails to inhibit a response (i.e., pressing the spacebar
when the letter X appears). Computerized scoring is
completed automatically after the administration of the
CPT-II [23]. The CPT-II was administered at baseline
and at day 28, which was the last day of oral supplemen-
tation.
3. Results
Sixty healthy adult women participated in the study.
Three additional women enrolled in the study but were
discontinued due to study-unrelated events. The sixty
women were divided into three groups of 20. One group
took the low dose of citicoline (250 mg), one group took
the high dose of citicoline (500 mg), and one group took
a placebo for 28 days.
Between-group analyses prior to supplementation
showed no group difference on estimated intelligence as
measured by WAIS-IV Vocabulary (p = 0.35). Mean
estimated IQs for each group fell within the average
range (250 mg = 105.15, 500 mg = 109.75, placebo =
103.60). Baseline measures of verbal memory, as as-
sessed by CVLT, also indicated no between-group differ-
ences in performance (p = 0.23 on CVLT Lists 1 - 5,
indicating similar memory before supplementation).
Additionally, analyses of CPT-II response results from
baseline and day 28 were performed with SPSS (PASW
Statistics 18.0). All p-values are reported as one-tailed
because a priori hypotheses specified improvement on
CPT-II scores after supplementation. Additionally, one
woman in the 500 mg group was excluded from CPT-II
analyses due to the fact that her attention performance
score at visit 3 was a clear outlier (49 standard deviations
above the group mean).
Comparisons between Groups for Day 28 Scores
An ANOVA and t-tests were completed to assess be-
tween group differences at visit 3. Analysis of attentional
performance at visit 3 that included all three groups
showed overall significant between group differences on
commission (p = 0.02) and omission errors (p = 0.03).
Tukey’s post-hoc tests showed that individuals in the 250
mg group performed fewer omission (p = 0.04) and
commission (p = 0.03) errors compared to those in the
placebo group. Individuals in the 500 mg group also
made significantly fewer commission errors compared to
those in the placebo group (p = 0.03) and trended toward
significance making fewer omission errors (p = 0.07)
(Tables 2 and 3).
T-tests were also completed to compare the 250 mg
group to the placebo group and the 500 mg group to the
placebo group individually. Similar to the results of the
ANOVA, individuals in the 250 mg group made fewer
omission (p = 0.04) and commission (p = 0.02) errors
compared to those in the placebo group. Individuals in
the 500 mg group made fewer commission errors com-
pared to those in the placebo group (p = 0.02) and
trended toward making fewer omission errors (p = 0.06).
4. Discussion
Our study findings indicate that citicoline supplementa-
tion was associated with improved attentional focus and
inhibition, as measured by the CPT-II, in a group of
healthy female adult volunteers. Participants in the three
groups showed no differences in age, years of education,
height, weight, or estimated levels of global cognitive
functioning at baseline. After 28 days both supplementa-
tion groups (250 mg and 500 mg) evidenced improved
inhibition. Additionally, the 250 mg group evidenced
improved attentional focus at time 3, while the 500 mg
group trended toward showing improved focus. These
results indicate that citicoline enhanced two aspects of
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Improved Attentional Performance Following Citicoline Administration in Healthy Adult Women
772
Table 2
. 250 mg compared to placebo: CPT-II omission and
commission errors at time 3.
250 mg (N = 20) Placebo (N = 20)
Time 3 CPT-II Omission
Errors Mean ± SE
0.90 ± 0.25 6.70 ± 3.11
Time 3 CPT-II Commission
Errors Mean ± SE
2.70 ± 0.77 5.50 ± 1.03
Table 3. 500 mg compared to placebo: CPT-II omission and
commission errors at time 3.
500 mg (N = 19) Placebo (N = 20)
Time 3 CPT-II Omission
Errors Mean ± SE
1.47 ± 0.66 6.70 ± 3.11
Time 3 CPT-II Commission
Errors Mean ± SE
2.68 ± 0.75 5.50 ± 1.03
attention—attentional focus and inhibition in healthy
women ages 40 - 60.
Prior research has shown that citicoline administration
improves attention in a variety of patient populations,
including individuals with neurocognitive degeneration
after a stroke [4,11] and elderly participants [12]. How-
ever, the population of the current study differs from
previous studies, as the current study included only
healthy middle-aged women rather than clinical patient
populations. Whereas prior researchers have focused on
populations with deficits in cognitive performance, in-
cluding impaired memory or attention, the current study
examined women with estimated intelligence and verbal
memory within the average range. Findings from this
study extend previous research by showing that citicoline
administration improves attention not only in clinical
populations but also in healthy female adults. Addition-
ally, previous studies have focused on higher doses of
citicoline, generally between 1000 and 2000 mg. How-
ever, the current study shows improved attention in
healthy women between the ages of 40 and 60 who re-
ceived significantly smaller amounts of citicoline, spe-
cifically 250 and 500 mg. In addition to extending find-
ings from patient populations to healthy aging women
using smaller doses of citicoline, the current study also
provides behavioral support for prior studies suggesting
improved bioenergetics in the frontal lobe [9], where
much of attentional focus is believed to occur.
One mechanism underlying the observed improvement
in performance in the current study is likely related to
dopamine transmission. As individuals age, dopaminer-
gic transmission and the availability of dopamine recep-
tors decrease, contributing to decreased performance on
attention and executive function measures that occurs as
individuals age [24,25]. Conversely, dopaminergic up-
take has been associated with improved performance on
working memory and executive function tasks requiring
attention [25,26]. Previous investigations have shown
that citicoline increases dopamine [10,27], increases do-
pamine receptor densities [28], and aids in protection of
neurons related to dopamine [29]. While dopamine was
not measured in the current study, it seems likely that
dopamine increases identified with citicoline supple-
mentation may explain the improved performance on
attention tasks shown in the present study.
Given the evidence for improved attention with citi-
coline supplementation provided by the current study,
this study could be extended in multiple ways. The cur-
rent study includes women between the ages of 40 and
60, which limits generalizability to a broader population.
It is possible that the effects of citicoline supplementa-
tion may be different for men given biological differ-
ences, especially considering hormonal changes occur-
ring in middle age. However, the effects of citicoline
supplementation at lower doses (e.g. 250 and 500 mg)
with healthy men could be examined in future studies.
Future research examining the effects of citicoline on a
more diverse sample is warranted as well, given the fact
that the current sample consisted primarily of Caucasian
individuals. Because the participants in this study were
healthy, it is unclear to what extent the results of the cur-
rent study may be used to inform the effects of citicoline
supplementation with more ill populations, including
individuals with brain injury or psychiatric disorders.
Given the significant role of dopamine in a number of
psychiatric disorders, and research suggesting that citi-
coline affects dopaminergic systems, additional research
focused on citicoline supplementation with psychiatric
populations is warranted.
To our knowledge, the current study is the first to ex-
amine the effects of low doses of citicoline on cognitive
performance in healthy female adults. Women who re-
ceived citicoline showed improved attentional perform-
ance after 28 days of supplementation. Results of the
current study are consistent with prior studies showing
improved cognitive performance after citicoline supple-
mentation in individuals with cognitive deficits. Practical
applications of this research include the possible use of
citicoline supplementation to ameliorate cognitive defi-
cits associated with healthy aging, but also to ameliorate
cognitive deficits associated with psychiatric disorders.
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Neuroscience, Vol. 117, No. 7, 2007, pp. 985-998.
... 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)]. ...
... 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. ...
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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 clinicaltrials.gov as NCT03369925.
... PoPRAWA PAMIĘCI I uWAgI u ZDRoWyCH oSóB W badaniach przeprowadzonych wśród 95 zdrowych ochotników (w wieku 59-85 lat) wykazano korzystny wpływ na poprawę pamięci po 3 miesiącach terapii cytykoliną (w dawce 1000 mg/24 h) [20]. Cytykolina stosowana w dawce 500 mg/24 h przez okres 28 dni w porównaniu z grupą placebo poprawiła uwagę i zmniejszyła impulsywność u zdrowych kobiet [21]. 3 lata później ci sami autorzy wykazali podobne korzyści ze stosowania cytykoliny (500 mg/24 h przez 28 dni) u zdrowych nastolatków płci męskiej [22]. ...
Article
Cytykolina jest substancją endogenną odgrywającą rolę w metabolizmie komórkowym. Może być pomocna w leczeniu udaru mózgu, chorób Parkinsona i Alzheimera, jaskry, po urazach głowy itd. Bezpieczeństwo stosowania cytykoliny zostało potwierdzone w wielu badaniach. Citicoline is an endogenous compound and play important role in cellular metabolism. It may be helpful in treatment of stroke, Parkinson and Alzheimer disease, glaucoma, after head injury etc. The safety of citicoline was confirmed in many studies.
... The groups receiving citicoline exhibited improved cognitive attentional performance by committing significantly fewer commission errors on the Conners' Continuous Performance Test II (CPT-II) compared with the placebo group. 27 A similar study was performed in healthy male individuals ranging from 13 to 18 years of age, in which either 250 or 500 mg/day of citicoline was administered, or placebo, for 28 days. Significant improvements in attentional task and motor function were measured. ...
Chapter
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Citicoline is an endogenous mononucleotide composed of ribose, cytosine, pyrophosphate, and choline, and an essential precursor for the synthesis of neuronal plasma membrane phospholipids, important as a rate-limiting step in phosphatidylcholine synthesis. Choline is a component of the diet and is produced in the brain, albeit in small amounts. The chapter discusses the broad spectrum of benefits in conditions associated with neurological disorders and dysfunctions that citicoline plays a role in, in addition to toxicological studies that lend support to its use as an oral dietary source.
... The groups receiving citicoline exhibited improved cognitive attentional performance by committing significantly fewer commission errors on the Conners' Continuous Performance Test II (CPT-II) compared with the placebo group. 27 A similar study was performed in healthy male individuals ranging from 13 to 18 years of age, in which either 250 or 500 mg/day of citicoline was administered, or placebo, for 28 days. Significant improvements in attentional task and motor function were measured. ...
Chapter
Full-text available
Difference between citicoline and choline; bioavailability/pharmacokinetics; mechanism of action; clinical applications for its use in learning and memory, attention, Alzheimer's disease, and dementia, Parkinson's disease, stroke, and cerebral ischemia, traumatic head injuries; eye health and visual function, including amblyopia, glaucoma, ischemic optic neuropathy; substance abuse, infectious diseases, as well as, toxicology and safety, dosage, and drug interactions.
... Its neuroprotective action has been proven in many neurodegenerative disorders such as Alzheimer disease, Parkinson disease and glaucoma [10]. Ultrapure citicoline has also shown to improve attentional performances in healthy adult women and to improve psychomotor speed in adolescent males [11,12]. ...
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Normal tension glaucoma (NTG) remains a therapeutic challenge for the ophthalmologist since there are no effective therapies as the main therapeutic target, i.e., the intraocular pressure (IOP) increase, is missed. We report on the effectiveness of two neuroprotective molecules (ultrapure citicoline plus homotaurine), in combination with a topical hypotensive approach, in the management of NTG in a long-term follow-up (30 months). A 38-year-old Caucasian woman with no significant medical history and a diagnosis of NTG, after an extensive 30-month treatment with oral dietary supplement containing ultrapure citicoline 500 mg, homotaurine 50 mg and vitamin E once per day and topical glaucoma medication (brimonidine + brinzolamide drops twice per day), presented a significantly improved automated 24-2 visual field with a controlled tonometric measurement associated with a stabilization of retinal fiber layer and ganglion cells at OCT examination with patient satisfaction. This finding suggests that ultrapure citicoline together with homotaurine and vitamin E, through a synergistic neuroprotective effect, could be a promising approach in the management of NTG.
... The usage of cAMP in SED or in dietary supplements could be related to airway smooth muscle relaxation and antiinflammatory effects as a result of cAMP raising (Yan et al., 2016). Small numbers of clinical trials highlighted cognitive performance enhancement of citicoline in healthy female adults (McGlade et al., 2012) or improvement of attention and psychomotor speed in adolescent males (McGlade et al., 2015). Unexpected oral ingestion of ATP, a very rare SED ingredient, had not ergogenic effect most probably due to low bioavailability (Arts et al., 2012). ...
... Using magnetic resonance spectroscopy techniques, citicoline has been shown to stimulate phosphatidylcholine synthesis in the brain [537][538][539][540] and improves the energetic cerebral metabolism of elderly subjects [541], which is related to an improvement in their cognitive capacities [542], particularly memory [543][544][545] and reaction time [546]. In healthy volunteers, the administration of citicoline has been associated with improvement in attention [547,548], memory [549,550] and in some neurophysiological parameters [551][552][553][554]. ...
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Summary. This review is based on the previous one published in 2006 –Secades JJ, Lorenzo JL. Citicoline: pharmacological and clinical review, 2006 update. Methods Find Exp Clin Pharmacol 2006; 28 (Suppl B): S1-56–, incorporating the new references until now, having all the information available to facilitate the access to the información in one document. This review is focused on the main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment, and traumatic brain injury and its sequelae. There are retrieved the most important experimental and clinical data in both indications. Key words. Alcoholism. Alzheimer disease. Amblyopia. Apoptosis. CDP-choline. Cerebral edema. Cerebral ischemia. Citicoline. Cognitive disorder. Drug addiction. Glaucoma. Head injury. Memory. Neuronal membrane. Neuroplasticity. Neuroprotection. Neurorepair. Neurotransmission. Parkinson disease. Phosphatidylcholine. Phospholipase. Senile dementia. Stroke. Structural phospholipids. Traumatic brain injury.
Chapter
Pharmacological intervention for the augmentation of brain function in healthy individuals and for recovery after neurological conditions has reached new horizons. The advent of neuro-technologies, such as advanced functional imaging techniques and neurostimulation methods, offers valuable new data about the multiple levels of organization within the brain, uncovering crucial insights about the dynamic cross talk between cerebral networks. From nutritional components and traditional natural remedies to synthetic psychostimulants or multimodal agents, a wide range of interventions are currently used to enhance brain function. Of these, some have raised questions concerning safety, efficacy, and overall effectiveness. In response to increasing demands for cognitive performance or to an internal insult, the nervous system relies on the endogenous defense activity: a process of continuous modulation of neurobiological processes of neurotrophicity, neuroprotection, neuroplasticity, and neurogenesis. In this chapter, several pharmacological brain enhancers are reviewed to assess their capacity to support the brain’s anticorrelated endogenous defense mechanisms.
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Das Normaldruckglaukom ist nach wie vor eine therapeutische Herausforderung für Ophthalmologen, da in Abwesenheit des sonst üblichen Haupt-Behandlungsziels, des erhöhten Augeninnendrucks, keine effektiven Therapien bekannt sind. Wir berichten über die Wirksamkeit von zwei neuroprotektiven Molekülen (ultrapures Citicolin plus Homotaurin) in Kombination mit einer topischen drucksenkenden Therapie zur Behandlung des NTG in einer langfristigen Nachbeobachtung (30 Monate). Eine 38-jährige Frau kaukasischen Ursprungs ohne signifikante medizinische Vorgeschichte und mit diagnostiziertem NTG zeigte nach umfassender, 30-monatiger Anwendung von oraler Nahrungsergänzung mit ultrareinem Citicolin 500 mg, Homotaurin 50 mg und Vitamin E einmal täglich sowie von topischer Glaukom-Medikation (Brimonidin + Brinzolamid als Tropfen zweimal täglich) signifikante Verbesserungen des Gesichtsfelds laut automatisierter 24–2-Untersuchung mit kontrollierter tonometrischer Messung, begleitet von einer Stabilisierung der retinalen Nervenfaserschicht und der Ganglionzellen laut OCT-Untersuchung sowie von der Zufriedenheit der Patientin. Diese Ergebnisse deuten darauf hin, dass ultrareines Citicolin in Kombination mit Homotaurin und Vitamin E durch einen synergetischen neuroprotektiven Effekt einen vielversprechenden Ansatz für das NTG-Management darstellen könnte.
Article
The analysis of mechanisms of the neuroprotective effect of choline precursors reveals the primary effects of citicoline on the processes of repair of neuronal membranes, a decrease in the degeneration of free fatty acids, and choline alfoscerate, an increase in the production of the neurotransmitter acetylcholine. Although citicoline has a lesser effect on choline secretion than choline alfoscerate, the combination of choline and cytidine in its composition is a universal tool to reduce symptoms of cerebral ischemia, to stabilize cognitive status, superior to the standard benefits of choline. Various mechanisms of the action of citicoline enable to recommend it as a drug effective both in the acute phase of the disease and in the delayed period, giving it the status of a universal nootropic compound.
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Citicoline is a neuroprotectant and neurorestorative drug that is used in the treatment of acute ischemic stroke in some countries. The research with this compound continues. In this review, we focus on the latest publications or communications or both and on the major ongoing experimental and clinical projects involving citicoline in stroke recovery.
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Components of the Stroop task were examined to investigate the role that inhibitory processes play in cognitive changes in healthy older adults and in individuals with dementia of the Alzheimer's type (DAT). Inhibitory breakdowns should result in an increase in Stroop interference. The results indicate that older adults show a disproportionate increase in interference compared with younger adults. DAT individuals show interference proportionate to older adults but a disproportionate increase in facilitation for congruent color-word trials, and an increased intrusion of word naming on incongruent color naming trials. An ex-Gaussian analysis of response time distributions indicated that the increased interference observed in older adults was due to an increase in the tail of the distribution. Application of the process dissociation analysis of the Stroop task (D.S. Lindsay & L.L. Jacoby, 1994) indicated that older adults showed increased word process estimates, whereas DAT individuals showed differences in both color and word process estimates. Taken together, the results are consistent with an inhibitory breakdown in normal aging and an accelerated breakdown in inhibition in DAT individuals.
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We used functional magnetic resonance imaging (fMRI) of a visual target detection (oddball) task to investigate age differences in neural activation for the detection of two types of infrequent events: visually simple items requiring a response shift (targets) and visually complex items that did not entail a response shift (novels). Targets activated several prefrontal regions (e.g. middle frontal gyrus), as well as deep gray matter regions (caudate, putamen, thalamus and insula). Prefrontal activation was similar for younger and older adults, whereas deep gray matter activation was relatively greater for the older adults. Novels activated occipital regions (fusiform and lateral occipital gyri), and this activation was relatively reduced for older adults. The changes in behavioral performance across the task conditions were similar for the two age groups, although the older adults’ responses were slower overall. Regression analyses of the relation between neural activation and task performance (response time) indicated that whereas performance was mediated most directly by prefrontal cortex for younger adults, older adults’ performance was influenced to a greater extent by deep gray matter structures. Older adults may place relatively greater emphasis on the attentional control of response regulation, in compensation for the age-related decline in visual processing efficiency.
Article
This study examined the possibility that membrane phospholipids might be a source of choline used for acetylcholine (ACh) synthesis. Slices of rat striatum or cerebellum were superfused with a choline-free or choline-containing (10, 20 or 40 μM) physiological solution with eserine, for alternating 20 min periods of rest or electrical stimulation. Superfusion media were assayed for choline and ACh, and slice samples taken before and after stimulation were assayed for choline, ACh, various phospholipids, protein and DNA. The striatal slices were able to sustain the stimulation-induced release of ACh, releasing a total of about 3 times their initial ACh contents during the 8 periods of stimulation and rest. During these 8 cycles, 885 pmol/μg DNA free choline was released from the slices into the medium, an amount about 45-fold higher than the initial or final free choline levels in the slices. Although repeated stimulation of the striatal slices failed to affect tissue levels of free choline or ACh, this treatment did cause significant, dose-related (i.e., number of stimulation periods) stoichiometric decreases in tissue levels of phosphatidylcholine (PC) and of the other major phospholipids; tissue protein levels also declined significantly. Addition of exogenous choline to the superfusion medium produced dose-related increases in resting and evoked ACh release. The choline also fully protected the striatal slices from phospholipid depletion for as many as 6 stimulation periods. Cerebellar slices liberated large amounts of free choline into the medium but did not release measurable quantities of ACh; their phospholipid and protein levels did not decline with electrical stimulation. These data show that membrane phospholipids constitute a reservoir of free choline that can be used for ACh synthesis. When free choline is in short supply, ACh synthesis and release are sustained at the expense of this reservoir. The consequent reduction in membrane PC apparently is associated with a depletion of cellular membrane. The use of free choline by cholinergic neurons for two purposes, the syntheses of both ACh and membrane phospholipids, may thus impart vulnerability to them in situations where the supply of free choline is less than that needed for acetylation.
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Although it is documented that brain dopamine activity declines with age, the functional significance of this is not known. This study assessed the relation between measures of brain dopamine activity and indexes of motor and cognitive function in healthy individuals. Thirty healthy volunteers aged 24-86 years were studied with positron emission tomography and [11C]raclopride to assess dopamine D2 receptors. All subjects underwent a neuropsychological test battery that included tasks found to be sensitive to dopamine alterations in patients with neurodegenerative disease and control tasks. Transfer of [11C]raclopride from plasma to brain in the striatum and cerebellum was not affected by age. In contrast, D2 receptor availability in the caudate and putamen declined with age. Correlations between D2 receptors and neuropsychological test performance were strongest for the motor task (Finger Tapping Test) and were also significant for most tasks involving frontal brain regions, including measures of abstraction and mental flexibility (Wisconsin Card Sorting Test) and attention and response inhibition (Stroop Color-Word Test, interference score). These relationships remained significant after control for age effects. Age-related decreases in brain dopamine activity are associated with a decline in motor function and may also contribute to impaired performance on tasks that involve frontal brain regions. Interventions that enhance dopamine activity may improve performance and quality of life for the elderly. The fact that correlations remained significant after age effects were partialed out suggests that dopamine activity may influence motor and cognitive performance irrespective of age.
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The glaucomatous disease is currently considered a disease involving ocular and visual brain structures. This new approach to glaucoma introduces the possibility of inducing an improvement by means of a pharmacological approach similar to that used in different degenerative brain disorders. In line with this hypothesis, we studied the effects of oral (1600 mg/die, Cebrolux, Tubilux Pharma, Pomezia, Rome, Italy) or intramuscular (1000 mg/die, Cebroton, Tubilux Pharma) cytidine-5'-diphosphocholine (citicoline) treatment on retinal function and neural conduction in the visual pathways of glaucoma patients with moderate visual defects. Improvement of retinal function (objectively evaluated by pattern electroretinogram recordings) and of neural conduction along visual pathways (objectively evaluated by visual evoked potential recordings) were observed in glaucoma patients after two 60-day periods of oral or intramuscular treatment with citicoline. However, partial regression of this improvement was detected after two 120-day periods of washout. This suggests that the beneficial effects observed are in part treatment-dependent. The extension of citicoline treatment up to a period of 8 years lead to the stabilization or improvement of the glaucomatous visual dysfunction. These results suggest potential neuroprotective effects of citicoline in the glaucomatous disease.
Article
Citicoline supplementation has been used to ameliorate memory disturbances in older people and those with Alzheimer's disease. This study used MRS to characterize the effects of citicoline on high-energy phosphate metabolites and constituents of membrane synthesis in the frontal lobe. Phosphorus ((31)P) metabolite data were acquired using a three-dimensional chemical-shift imaging protocol at 4 T from 16 healthy men and women (mean +/- SD age 47.3 +/- 5.4 years) who orally self-administered 500 mg or 2000 mg Cognizin Citicoline (Kyowa Hakko Kogyo Co., Ltd, Ibaraki, Japan) for 6 weeks. Individual (31)P metabolites were quantified in the frontal lobe (anterior cingulate cortex) and a comparison region (parieto-occipital cortex). Significant increases in phosphocreatine (+7%), beta-nucleoside triphosphates (largely ATP in brain, +14%) and the ratio of phosphocreatine to inorganic phosphate (+32%), as well as significant changes in membrane phospholipids, were observed in the anterior cingulate cortex after 6 weeks of citicoline treatment. These treatment-related alterations in phosphorus metabolites were not only regionally specific, but tended to be of greater magnitude in subjects who received the lower dose. These data show that citicoline improves frontal lobe bioenergetics and alters phospholipid membrane turnover. Citicoline supplementation may therefore help to mitigate cognitive declines associated with aging by increasing energy reserves and utilization, as well as increasing the amount of essential phospholipid membrane components needed to synthesize and maintain cell membranes.
Article
1. Spiroperidol binding (dopamine D2 receptors) and quinuclidinyl benzilate binding (muscarinic receptors) in striata of 19-month old mice was analyzed for animals that had received chronic administration of cytidine 5'-diphosphocholine (CDP-choline) incorporated into the chow consumed (100 or 500 mg kg-1 added per day) for the 7 months before they were killed. 2. Treated animals displayed an increase in the dopamine receptor densities of 11% for those receiving 100 mg kg-1 and 18% for those receiving 500 mg kg-1 as compared to the control aged animals that had received no CDP-choline. Control animals showed, from 2 months to 19 months of life, a 28% decrease in the receptor density. No change in the affinity of the receptors for spiroperidol was found in the treated or untreated animals. 3. Muscarinic acetylcholine receptor densities were also partially recovered by the same treatment in aged animals that showed a 14% decrease of these receptors in this case. The muscarinic receptor density increased 6% for the animals that received 100 mg kg-1 and 17% for the animals that received 500 mg kg-1 without any change in the affinity of the receptor for quinuclidinyl benzilate. 4. Aged animals displayed a slight increase in brain membrane fluidity as indicated by a decrease in the polarization value of the non-polar fluorophore 1,6-diphenyl-1,3,5-hexatriene. Interestingly, in the treated animals a greater increase in membrane fluidity was determined and found to be very similar for the two doses.5. It is concluded that chronic administration of CDP-choline to aged animals promoted a partial recovery of the striatum dopamine and acetylcholine receptor function normally reduced with aging, which might be explicable in terms of mechanisms involving fluidity of the brain neuronal membrane.
Article
Phosphatidylcholine (PtdCho), which is essential for membrane integrity and repair, is reduced in brain cell membranes with age. Evidence from both animal and in vitro studies indicates that cytidine 5' diphosphate choline (CDP-choline) can increase the synthesis of PtdCho; however, the effect of CDP-choline on brain choline metabolism has not previously been studied in human subjects. In this study, in vivo proton magnetic resonance spectroscopy (1H-MRS) was used to measure brain levels of cytosolic, choline-containing compounds before and after single oral doses of CDP-choline. Three hours after dosing, plasma choline increased similarly in younger (mean age 25 years) and older subjects (mean age 59 years). However, while the choline resonance in brain increased by 18% on average in younger subjects, it decreased by almost 6% in older subjects (P = 0.028). These results may be explained by a previously observed decrease in brain choline uptake, but not cytidine uptake, in older subjects. Additional intracellular cytidine following the administration of CDP-choline should lead to the increased incorporation of choline already present in brain into membrane PtdCho, which is not MRS-visible, consequently lowering the brain choline resonance below that of pre-treatment values. These results suggest that the cytidine moiety of CDP-choline stimulates phosphatidylcholine synthesis in human brain cell membranes in older subjects.