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Improved Attentional Performance Following Citicoline Administration in Healthy Adult Women

January 2012
Food and Nutrition Sciences 03(06)

DOI:10.4236/fns.2012.36103

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CC BY 4.0

Authors:

Allison E Locatelli

University of Utah

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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.

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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

, Julia Hardy

, Toshikazu Kamiya

, Masahiko Morita

Koji Morishita

, Yoichiro Sugimura

, Deborah Yurgelun-Todd

1,2

Brain Institute, University of Utah, Salt Lake City, USA;

Department of Psychiatry, University of Utah, Salt Lake City, USA;

Kyowa Hakko USA, Inc., New York, USA;

Kyowa Hakko Bio Co., Ltd., Tokyo, Japan.

Email: erin.mcglade@hsc.utah.edu

Received February 23

, 2012; revises April 16

, 2012; accepted April 23

, 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

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

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

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

Article

Full-text available

May 2021

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.

Citicoline: pharmacological and clinical review, 2022 update

Article

Full-text available

Dec 2022

This review is based on the previous one published in 2016 (Secades JJ. Citicoline: pharmacological and clinical review, 2016 update. Rev Neurol 2016; 63 (Supl 3): S1-S73), incorporating 176 new references, having all the information available in the same document to facilitate the access to the information 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.

Citicoline: pharmacological and clinical review, 2022 update

Article

Full-text available

Nov 2022

10 powodów, dla których warto stosować cytykolinę [10 reasons why to use citicoline]

Article

Apr 2022

Marcin Kopka

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.

10 reasons why to use citicoline

Article

Mar 2022

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.

Citicoline (CDP-choline).

Chapter

Full-text available

Sep 2020

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.

Efficacy of the nootropic supplement Mind Lab Pro on memory in adults: Double blind, placebo-controlled study

Article

May 2023
HUM PSYCHOPHARM CLIN

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.

Pharmacological Approaches in the Augmentation and Recovery of Brain Function

Chapter

Full-text available

Aug 2021

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.

Ultrareines Citicolin in Kombination mit Homotaurin und Vitamin E bei Normaldruckglaukom: ein Fallbericht

Article

May 2021

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.

Stroop Performance in Healthy Younger and Older Adults and in Individuals With Dementia of the Alzheimer’s Type

Article

Full-text available

Apr 1996

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.

Citicoline Preclinical and Clinical Update 2009-2010

Article

Full-text available

Jan 2011
STROKE

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.

Conners' continuous performance test II manual

Article

Jan 2000

Article

Feb 2004
CEREB CORTEX

David J. Madden

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.

Choline increases acetylcholine release and protects against the stimulation-induced decease in phosphatide levels within membranes of rat corpus striatum

Article

May 1989
BRAIN RES

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.

Association between decline in brain dopamine activity with age and cognitive and motor impairment in healthy individuals

Article

Mar 1998

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.

Evidence of the neuroprotective role of citicoline in glaucoma patients

Article

Feb 2008

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.

Citicoline enhances frontal lobe bioenergetics as measured by phosphorus magnetic resonance spectroscopy

Article

Dec 2008

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.

Changes in brain striatum dopamine and acetylcholine receptors induced by chronic CDP‐choline treatment of aging mice

Article

Dec 1991

Spiroperidol binding (dopamine D 2 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. 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. 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. 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. 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.

Differential effect of CDP-choline on brain cytosolic choline levels in younger and older subjects as measured by proton magnetic resonance spectroscopy

Article

Oct 1996

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.