STUDY PROTOCOL Open Access
A randomized controlled trial investigating the
neurocognitive effects of Lacprodan® PL-20, a
phospholipid-rich milk protein concentrate, in
elderly participants with age-associated memory
impairment: the Phospholipid Intervention for
Cognitive Ageing Reversal (PLICAR): study
protocol for a randomized controlled trial
Andrew B Scholey1*, David A Camfield1, Matthew E Hughes2, Will Woods2, Con K K Stough1, David J White1,
Shakuntla V Gondalia1and Pernille D Frederiksen3
Background: Age-related cognitive decline (ARCD) is of major societal concern in an ageing population, with the
development of dietary supplements providing a promising avenue for amelioration of associated deficits. Despite
initial interest in the use of phospholipids (PLs) for ARCD, in recent years there has been a hiatus in such research.
Because of safety concerns regarding PLs derived from bovine cortex, and the equivocal efficacy of soybean-derived
PLs, there is an important need for the development of new PL alternatives. Phospholipids derived from milk proteins
represent one potential candidate treatment.
Methods: In order to reduce the effects of age-associated memory impairment (AAMI) the Phospholipid Intervention
for Cognitive Ageing Reversal (PLICAR) was developed to test the efficacy of a milk protein concentrate rich in natural,
non-synthetic milk phospholipids (Lacprodan® PL-20). PLICAR is a randomized, double-blind, placebo-controlled
parallel-groups study where 150 (N=50/group) AAMI participants aged>55 years will be randomized to receive a daily
supplement of Lacprodan® PL-20 or one of two placebos (phospholipid-free milk protein concentrate or inert rice
starch) over a 6-month (180-day) period. Participants will undergo testing at baseline, 90 days and 180 days. The primary
outcome is a composite memory score from the Rey Auditory Verbal Learning Test. Secondary outcomes include
cognitive (verbal learning, working memory, prospective and retrospective memory, processing speed and attention),
mood (depression, anxiety, stress and visual analogue scales), cardiovascular (blood pressure, blood velocity and pulse
wave pressure), gastrointestinal microbiota and biochemical measures (oxidative stress, inflammation, B vitamins and
(Continued on next page)
* Correspondence: firstname.lastname@example.org
1Centre for Human Psychopharmacology, Swinburne University of
Technology, Melbourne 3122, Victoria, Australia
Full list of author information is available at the end of the article
© 2013 Scholey et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Scholey et al. Trials 2013, 14:404
(Continued from previous page)
Homocysteine, glucoregulation and serum choline). Allelic differences in the Apolipoprotein E and (APOE) and
Methylenetetrahydrofolate reductase (MTHFR) gene will be included for subgroup analysis. A subset (N=60; 20/group))
will undergo neuroimaging using functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG)
in order to further explore in vivo central mechanisms of action of Lacprodan® PL-20. This study will enable evaluation
of the efficacy of milk-derived phospholipids for AAMI, and their mechanisms of action.
Trial Registration: The trial is jointly funded by Arla Foods and Swinburne University of Technology, currently
recruiting and is registered on the Australian New Zealand Clinical Trials Registry as ACTRN12613000347763.
Cognitive deficits including learning and memory impair-
ment are one of the most prominent and debilitating con-
sequences of normal and pathological ageing in humans.
A consistent finding in research on ageing and cognition
is that performance across various tests of memory is
lower with increased age. Meta-analyses of cross-sectional
and longitudinal datasets have demonstrated approximately
40 to 60% decline in cognitive speed at age 80 compared to
age 20 years in non-demented adults . These cognitive
deficits are of considerable concern to elderly individuals,
with up to 50% of adults aged 64 years or older reporting
difficulties with their memory . There is an increasing
awareness of the possibility that dietary modification can
alter the course of age-related cognitive decline.
Frequent dairy food intake is associated with better
cognitive function, although the exact underlying mecha-
nisms are yet to be determined. The positive correlation
between increased dairy intake and cognitive function
seems partly to be a result of counteracting metabolic
syndrome, by reducing cardiovascular (CV) risk factors
such as type 2 diabetes, hypertension, obesity and hyper-
lipedimia [3-5]. In a recent paper by Crichton et al. ,
the authors support this link and in addition argue that
apart from counteracting the CV risk factors, dairy
consumption provides additional benefits in relation to
cognitive function (for example, after adjusting for CV
disease, lifestyle and dietary factors). Recent advances in
dairy manufacturing, which enable the enrichment of
phospholipid components in milk also offer a promising
new avenue for the treatment of age-related cognitive
Phospholipids and the amelioration of cognitive decline
Bovine milk contains a vast range of phospholipids
and complex lipids, with important biological functions.
Phospholipids are substances with both a hydrophilic
(water-liking) head and hydrophobic (water-repellent) tail
segment which are major building blocks for cellular
membranes, including neuronal cells, where they arrange
themselves into lipid bilayers . Relevant phospholipids
in relation to cognitive performance include phosphati-
dylserine (PS) and phosphatidylcholine (PC) as well as
the related substances sphingomyelin and the sialic-
acid-containing gangliosides. Pharmacokinetic studies
of PS have revealed good bioavailability when consumed
orally. Following ingestion, the headgroup is absorbed
intact through the intestinal wall into the bloodstream,
while the fatty-acid tail segments at position 2 are often
removed and later re-added. After crossing the blood–
brain barrier the fatty acid at position 2 is typically oc-
cupied by either oleic (C18:1) or docosahexaenoic acid
(DHA, C22:6) in the brain [8,9].
PS is a naturally occurring membrane phospholipid
that is found in high concentrations in brain tissue,
where it comprises 10 to 20% of the total phospho-
lipid pool . PS plays an important role in a host of
cellular functions including mitochondrial membrane
integrity, presynaptic neurotransmitter release, post-
synaptic receptor activity and activation of protein
kinase C in memory formation [7,11]. PS enhances the
activities of membrane-bound enzymes involved in signal
transduction  and plays a key role in the biosyn-
thesis and release of several neurotransmitters, including
acetylcholine [13,14], norepinephrine , serotonin and
dopamine . PS has also been found to elevate glucose
In relation to the cholinergic system, PS has been
found to restore age-related decreases in choline-
acetyltransferase-positive neurons  as well as dens-
ities of muscarinic and N-methyl-D-aspartate (NMDA)
receptors [19,20]. Increases in nerve growth factor (NGF)-
receptor density have been reported in aged animals
following PS supplementation, as well as increases in
neuronal numbers and size . Other beneficial effects of
PS supplementation include protection from cell death
 due to increased membrane fluidity  as well as
anti-inflammatory and antioxidant effects . Behavioural
animal experiments using PS have provided evidence of
improvements in spatial memory , retention of passive
avoidance , exploration and memory retrieval  as
well as improvement of avoidance performance . Pre-
vention of scopolamine-induced learning deficits have also
been reported [28-31], together with an attenuation of
Scholey et al. Trials 2013, 14:404
Page 2 of 15
memory deficits associated with reserpine-induced cat-
echolamine depletion .
PS is the most studied of the phospholipids in regards
to human clinical trials of dementia and cognitive de-
cline. Five double-blind randomized trials have been
conducted using PS in Alzheimer’s disease (AD) [33-37].
Clinical global impressions of change and activities of
daily living were found to be improved with daily doses
of 200 to 300 mg up to six months. In milder cases of
AD, significant improvements to concentration, learning
and memory for names, locations and recent events
were also observed [7,11]. In the largest of these studies
involving 494 elderly patients with moderate to severe
cognitive decline, Cenacchi et al.  reported improve-
ments to memory and learning following 300 mg PS/day
for 6 months.
In elderly populations with mild cognitive impairment
and age-associated memory impairment (AAMI), PS has
also been found to be effective in ameliorating cognitive
declines. Crook et al.  administered 300 mg/day PS
to 149 elderly patients (aged 50 to 75 years) with age-
associated memory impairment for 12 weeks, and ob-
served significant improvements in performance tests of
learning and recall abilities such as name-face matching.
In a multi-centre trial by Villardita et al. , 300 mg/day
PS versus placebo was administered to 170 elderly patients
for 90 days. Significant improvements in attention, con-
centration and short-term memory were found in those
receiving PS. These earlier trials were conducted using
PS derived from bovine cortex, but more recently trials
have also been conducted using soybean (SB)-derived PS
due to concerns over bovine spongiform encephalop-
athy. The results in relation to SB-PS have been more
mixed, with Jorissen et al.  reporting no significant
effects on learning and memory, whereas more recently
Vakhaporva et al.  and Kato-Kataoka et al.  re-
ported significant improvements to verbal learning follow-
ing ≥3 months supplementation. An intriguing study by
Hellhammer et al.  using the same milk-derived phos-
pholipids as the current study (PL-20) also reported
improvements to working memory function following
3 weeks supplementation in healthy adults aged 30 to
Choline is an essential nutrient critically needed for syn-
thesis of the neurotransmitter acetylcholine; important
in brain functions, such as memory and mood, but also
important in skeletal-muscle control, heart rate and
breathing. Numerous animal studies demonstrate that
choline is necessary for normal development of the
memory function and sub-optimal dietary intake of cho-
line by the pregnant mother and later by the infant and
child directly affects brain development and results
in permanent changes in brain function (Zeisel et al.
1991). Choline or its metabolites, are also needed for
the structural integrity and signaling functions of cell
membranes; it is the major source of methyl-groups in
the diet (one of choline’s metabolites, betaine, partici-
pates in the methylation of homocysteine (HCy) to form
methionine), and it directly affects cholinergic neuro-
transmission, transmembrane signaling and lipid trans-
port/metabolism [44,45]. Nagata et al.  documented
recently that dietary supplements of PhosChol compounds
(1,2-dilinoleoyl-sn-glycero-3-phosphocholine; DL-PC and
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; PO-PC) )
enhanced the memory and learning ability in the elderly
in the Mini Mental State Examination (MMSE). In an-
other placebo-controlled clinical trial, Ladd et al. 
found that the supplementation of SB-PC in normal col-
lege students lead to an improvement in explicit memory
function due to increased choline supply and improved
A poor folate status is associated with cognitive de-
cline and dementia in older adults . Although im-
paired brain methylation activity and HCy toxicity are
widely thought to account for this association, how fol-
ate deficiency impairs cognition is still uncertain. Troen
et al.  found a correspondence of cognitive outcomes
to changes in brain membrane PC content (in rats),
which suggests that altered PC and possibly choline me-
tabolism might contribute to the manifestation of folate
deficiency-related cognitive dysfunction. Up to 50% of
older people have been reported to have folate deficiency,
with higher levels in those institutionalized . For this
reason, there is a sound theoretical reasoning to speculate
on a positive beneficial outcome in relation to cognition
and boosting memory with choline and choline-containing
Elevated total homocysteine (tHcy), a risk factor for
many chronic diseases including cognitive decline, can
be remethylated to methionine by folate . Alternatively,
tHcy can be metabolized by other 1-carbon nutrients, that
is, betaine and its precursor, choline. Elias et al.  re-
ported that tHcy levels are inversely associated with visual-
spatial organization, working memory, scanning-tracking,
and abstract reasoning. Chiuve et al.  assessed the asso-
ciation between the dietary intakes of betaine and choline
and the concentration of tHcy. They found the total cho-
line+betaine intake to be inversely associated with tHcy.
In a double-blind, placebo-controlled clinical trial Olthof
et al.  investigated the supplementation with soybean
PC (PhosChol) on homocysteine plasma concentrations
in men with mildly elevated levels. They found that PC
was able to reduce homocysteine levels, thus supporting
the link between dietary intake of PC and homocysteine
Scholey et al. Trials 2013, 14:404
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Brain content of specific gangliosides (for example, GM1)
has been documented to decrease with age, and a low
GM1 content has been observed in the brains of patients
with AD . Exogenously administered gangliosides have
been shown to exhibit neurotrophic action, and to in-
crease the release of brain-derived neurotrophic factor
(BDNF) in vitro . Experimental data have shown that
gangliosides, and in particular, GM1, exhibit properties
similar to the neurotrophins. The neurotrophins promote
neurogenesis, which is essential for specific cognitive func-
tions that decline in some neurological disorders and in
ageing . A systemic administration of GM1 in rats
ameliorated the age-related decreased activity of choline
acetyl transferase and choline uptake in the brain of aged
rats as well as improved spatial learning and memory tasks
in the aged rats . Dietary gangliosides increase total
brain-ganglioside content in rats .
The myelin content of the brain decreases with age and
the age-related slowing in cognitive processing speed is
associated with myelin integrity in a very healthy elderly
population . Dietary bovine SM contributes to cen-
tral nervous system (CNS) myelination . Sphingo-
myelin is also a source of choline. Clinical trials are yet
to be conducted in order to assess the in vivo neurocog-
nitive effects of SM in humans.
Phospholipid intervention for cognitive ageing rever-
sal (PLICAR) is a randomized, double-blind, placebo-
controlled, three-arm, stratified parallel-groups clinical
trial with participants randomized to receive a minimum
daily dosage of 2.7 g phospholipids (and minimum daily
dose of 300 mg/day PS) from Lacprodan® PL-20 or one of
two placebos (milk protein concentration or rice starch)
over a 180-day (6-month) period. The maximum daily
dose of Lacprodan® PL-20 will be 16 g/day. Participants
will be stratified according to age, IQ using Raven’s
Progressive Matrices (RPM)  and baseline score on
the Wechlser Memory Scale-Revised (WMS-R) .
Aims and study hypotheses
The primary objective of the current study is to evaluate
the chronic effects of daily Lacprodan® PL-20 supple-
mentation on cognitive performance in a healthy elderly
population with age-associated memory impairment
(AAMI). The secondary objectives of the study are to in-
vestigate mood and CV effects of Lacprodan® PL-20 as well
as the in vivo mechanisms of action by which Lacprodan®
PL-20 may improve cognitive function. To this end, a
range of measurement modalities will be employed in-
cluding assessments of CV function, blood biomarkers,
gastrointestinal (GI) microbiota, pharmacogenomics and
brain activity assessed by functional magnetic resonance
imaging (fMRI), magnetoencephalography (MEG) and dif-
fusion tensor imaging (DTI).
Performance on the various outcome measures for par-
ticipants receiving Lacprodan® PL-20 will be compared
to the performance of participants receiving (i) an inert
placebo powder made of rice starch, and (ii) a milk-
protein concentrate without phospholipids that has been
matched for protein content and total calories. The rea-
son/rationale for including two comparator treatments
(rather than one) is the opportunity to address separ-
ate research questions. The first comparison (to inert
placebo) addresses the research question of whether
Lacprodan® PL-20 as a whole has benefits for cognitive
function and other secondary outcomes. The second
comparison to a milk-protein concentrate without phos-
pholipids addresses a more specific research question re-
garding whether benefits to cognition and other outcomes
associated with Lacprodan® PL-20 can be attributed specif-
ically to the phospholipid content in the formula. In con-
sideration of previous research demonstrating cognitive
benefits associated with dairy components other than
phospholipids , the inclusion of a third treatment arm
was deemed necessary in order to properly delineate the
effects of phospholipids versus other dairy components
present in Lacprodan® PL-20.
On the basis of previous human clinical studies with
bovine and plant-derived phospholipids, it is hypothesised
that in comparison to the inert placebo, Lacprodan® PL-20
supplementation over 180 days will result in significant
improvements on our primary variable, namely a com-
posite memory score computed from the Rey’s Verbal
Learning Test (RVLT). We are also exploring the pos-
sibly that the treatment may benefit other elements of
cognitive performance (including processing speed and
global functioning). A second hypothesis is that cogni-
tive benefits of a lesser magnitude will be observed when
comparing supplementation with Lacprodan® PL-20 with
milk protein concentrate (MPC) without phospholipids
placebo over 180 days. Additionally we are exploring
the effects of Lacprodan® PL-20 on a number of central,
CVand GI biomarkers.
PLICAR will be conducted at the Centre for Human
Psychopharmacology, Swinburne University of Technology,
A total of 150 healthy elderly participants (≥55 years)
with AAMI will take part in the study. AAMI is defined
on the basis of criteria first outlined by Crook et al.
[63,64]: (i) a score >25 on the Memory Complaint
Scholey et al. Trials 2013, 14:404
Page 4 of 15
Questionnaire (MAC-Q ) and (ii) a score ≤1 stand-
ard deviation below the mean for healthy young adults
on the paired associates test from the WMS-R . Par-
ticipants will be excluded from participation if they are
currently diagnosed with dementia and/or score <24 on
the MMSE ; have a neurological, cardiac, endocrine,
GI or bleeding disorder; have a psychiatric illness, in-
cluding moderate-to-severe depression, as defined as a
score ≥20 on the Beck Depression Inventory II (BDI-II)
; have a current or previous history of alcoholism
and/or substance abuse; have a known or suspected al-
lergy to cow’s milk and/or lactose intolerance; are a
current smoker, or are not fluent in the English language.
To be eligible, participants also cannot be currently taking
any medications or herbal/dietary supplements with
known cognitive effects. The study is jointly funded by
Arla Foods (Denmark) and Swinburne University of
Technology. It was ethically approved by the Swinburne
University Human Research Ethics Committee (pro-
ject number 2012/294) and all participants will provide
written informed consent. The trial has been registered
with the Australian and New Zealand Clinical Trials
Eligible participants are required to attend four testing
sessions. An overview of the testing sessions is provided
in the clinical trial flow chart (Figure 1).
Visit 1 (screening/practice)
During the first visit, voluntary written informed consent
is obtained from all participants. Then the participants
are further screened for eligibility and administered
the MMSE, MAC-Q, WMS-R and BDI-II. A detailed
medical history is also taken, a dietary questionnaire is
administered [67,68] and demographic information is
collected, which includes body mass index (BMI), age,
educational background and general intelligence (as
measured by RPM). All eligible participants are then
required to complete practice versions of all the cognitive
outcome measures to be used in the study.
Visit 2 (Baseline)
The second visit will be scheduled for one week follow-
ing the screening/practice visit. In preparation for the
baseline visit, all participants will be required to collect
and store their faecal sample (as per the procedure pro-
vided in the faecal sample collection kit) a day before
the actual visit. The faecal sample for GI microbiota ana-
lysis will be deposited at the Centre for Human Psycho-
pharmacology, Swinburne University, when the participant
comes for the baseline visit. The faecal samples will be
stored at -80°C until further analysis. Also in preparation,
participants will be required to fast from 10 pm the night
before. A fasting blood sample will then be taken in order
to assess the baseline biochemical measures, together with
a separate blood sample, which will be used for Apolipo-
protein E (APOE) and Methylenetetrahydrofolate reductase
(MTHFR) genotyping. Following the blood samples, partic-
ipants will eat a light breakfast. Half an hour after break-
fast, participants will be required to complete all pre-dose
cognitive, mood and CV measures. Participants will then
be randomized to their treatment group (Lacprodan
PL-20® or MPC or rice starch) and consume their first sa-
chet of study treatment dissolved in water. A lunch break
of 90 minutes will then follow, before post dose testing
on all cognitive, mood and cardiovascular measures. At
the conclusion of the baseline study visit, participants will
be provided with enough study treatment for the next
Visits 3 and 4 (90 and 180 days)
The schedule of events for the 90-day and 180-day visits
is identical to that for the baseline visit. On the day of
each study visit participants will be required to wait until
the completion of pre-dose assessments before consum-
ing their daily study treatment.
Participants involved in the neuroimaging sub-study will
be required to attend two additional sessions, the first in
the week preceding their baseline visit and the second in
the week preceding their 180-day visit (see Figure 1).
In the second visit they will be required to consume
their study treatment as usual in the morning before the
scans. This is due to the fact that the neuroimaging
sub-study is only concerned with the chronic effects of
PL-20 on brain function.
Based on the reviewed literature, we predict a small-
medium effect size (f = 0.14) on the primary variable.
The sample size for this study is 150 participants, with
50 participants in each treatment group (Lacprodan®
PL-20, MPC or rice starch). Allowing for a 20% drop-out
rate over the course of the 180-day testing period, this
will give 80% power to detect significant treatment ×
time interactions from baseline to 180 days for the
primary outcome (calculated using G*Power 3.1, with
α=0.05 and r=0.5 for the correlation between repeated
Lacprodan® PL-20, a powdered MPC rich in phos-
pholipids, is manufactured by Arla Foods Ingredients
Group P/S, Viby J, Denmark. The content of individ-
ual phospholipids in Lacprodan® PL-20 is displayed
in Table 1.
Scholey et al. Trials 2013, 14:404
Page 5 of 15
Lacprodan® PL-20 will be administered orally at a max-
imum dose of 16 g/day, providing minimum daily dosages of
2.7 g PL and 300 mg PS. The powder is dissolved in 150 to
200 mL water and drunk once per day with breakfast. Two
placebo treatments will also be administered: (i) an inert
placebo consisting of rice starch (20 g/day), and (ii) an MPC
without phospholipids (Arla Foods); (12 g/day). Both placebo
treatments are also administered orally as powders dissolved
in ≤250 mL water and matched to Lacprodan® PL-20 for
colour and taste in order to ensure treatment blinding.
Figure 1 Phospholipid intervention for cognitive ageing reversal (PLICAR) protocol flow diagram. AAMI, age-associated memory
impairment; MAC-Q, Memory Complaint Questionnaire; MMSE, Mini Mental State Examination; BDI-II, Beck Depression Inventory II; BMI,
body mass index; RPM, Raven’s Progressive Matrices; APOE, Apoliprotein E; MTHFR, Methylenetetrahydrofolate reductase; MRI, magnetic
resonance imaging; MEG, magnetoencephalography; MPC, milk protein concentrate; TICS-M telephone interview for cognitive
Scholey et al. Trials 2013, 14:404
Page 6 of 15
Randomization and safety
Randomization of participants to treatment groups will
be determined by random allocation. For the neuroim-
aging sub-study 60 randomization numbers will be set
aside, which correspond to 10 female participants
receiving Lacprodan® PL-20, 10 receiving MPC and
10 receiving rice starch placebo, and 10 male partici-
pants receiving Lacprodan® PL-20, 10 receiving MPC
and 10 receiving rice starch placebo. Blinding for
both the main study as well as the neuroimaging
sub-study will be conducted by an independent staff
member at the Centre for Human Psychopharma-
cology, who is outside of the project, to code the
treatments, and maintain the key to this code until
data collection is completed. All potential adverse
events will be monitored throughout the trial, with
oversight from the Swinburne University of Technology
Human Research Ethics committee.
The primary study outcome is the effect of Lacprodan®
PL-20 supplementation on memory as measured using a
compound score from the RVLT [69,70], similar to that
used previously . The memory score will be derived
using the formula:
?Z15‐Word Learning test ‘total immediate recall’
þZ15‐Word Learning Test ‘maximum immediate recall’
þZ15‐Word Learning Test ‘delayed recall’Þ=3:
The RVLT is a test of verbal learning and memory that
has a long history of use both in the assessment of
clinical memory disturbances as well as cognitive decline
associated with normal ageing . Verbal learning, as
measured by the RVLT and similar tests, has previously
been found to be sensitive to the effects of phospholipid
interventions in AAMI populations [39,41]. Similarly,
verbal memory has also been found to be sensitive to
other nutraceutical interventions such as Bacopa monnieri
 and folic acid  in elderly populations. For these
reasons, the inclusion of the RVLT will enable direct com-
parison of the efficacy of the milk-derived phospholipids
present in Lacprodan® PL-20 to previous cognitive inter-
vention studies in the elderly.
A range of secondary outcomes will be used, encompass-
ing cognitive performance, mood, CV, GI microbiota, bio-
chemical, genetic and brain imaging modalities. Secondary
outcomes will include other elements of cognitive per-
formance as measured by a battery of well-validated and
highly sensitive cognitive tests. Traditional paper-and-
pencil neuropsychological tests as well as computerized
tasks have been included. These tests will be implemented
at baseline, 90 days and 180 days (pre-dose) in order to
capture chronic effects. This battery will consist of the
MMSE , the Prospective and Retrospective Memory
Questionnaire (PRMQ) , RVLT [69,70], Spatial Work-
ing memory and Contextual Memory tasks from the
Swinburne University Computerized Cognitive Ageing
Battery (SUCCAB ), rapid visual information process-
ing (RVIP), serial 3 s and 7 s subtraction and the Hick’s re-
action time paradigm. In order to capture potential acute
cognitive effects associated with Lacprodan® PL-20 supple-
mentation, the SUCCAB tests, RVIP, serial 3 s and 7 s sub-
traction and Hick’s reaction time will also be administered
90 minutes post dose.
The MMSE  is a global measure of cognitive func-
tion that has been used extensively both as a diagnostic
tool for dementia screening as well as a cognitive out-
come measure for gauging the efficacy of chronic nutra-
ceutical interventions in elderly participants, for example
[71,75,76]. The MMSE was included in the current study
due to its widespread use in previous research; however
problems with ceiling effects and insensitivity to change
amongst high-functioning individuals have been previ-
ously well-documented .
The PRMQ  is a self-report instrument which pro-
vides a measure of retrospective as well as prospective
memory slips in everyday life. The PRMQ was included
in the current study in order to provide an ecologically
valid measure of typical memory complaints that may be
of concern to elderly individuals. Although most memory
complaint questionnaires focus exclusively on failures to
remember previous information (retrospective memory),
the PRMQ is unique in that it additionally provides a
measure of prospective memory failures, which are failures
relating to tasks that need to be completed at a certain
time (for example, remembering to turn up to an appoint-
ment on time) [73,78].
In addition to the use of traditional psychometric tests,
the importance of including computerized tests that may
accurately gauge the speed of well-differentiated cogni-
tive functions has emerged in recent years . In the
Table 1 Phospholipid composition of Lacprodan® PL-20
by percentage and daily dose
Percentage (%) Minimum dose
Sphingomyelin4.3 688 mg
Phosphatidyl choline (PC)4.3 688 mg
Phosphatidyl serine (PS) 1.9304 mg
Phosphatidyl ethanolamine (PE)3.5 560 mg
Phosphatidyl inositol (PI)1.3 208 mg
Ganglioside and others0.7 112 mg
Scholey et al. Trials 2013, 14:404
Page 7 of 15
current study the spatial working memory and context-
ual memory tasks from the SUCCAB have been included
due to high degrees of sensitivity to the effects of ageing,
as measured using response times . Similarly, signifi-
cant reductions in response times on both of these tasks
have previously been reported in older participants fol-
lowing chronic nutraceutical interventions [80,81]. For
the assessment of processing speed, the highly sensitive
Hick reaction time paradigm  will be used. For the
assessment of cognitive function during increased de-
mand, serial 3 s and serial 7 s subtraction will be assessed
together with the RVIP computerized measure of sus-
tained attention. Previous research from our laboratory
has found the serial subtraction and RVIP tasks to be
particularly sensitive to the acute effects of nutraceutical
There is evidence to suggest that phospholipid supple-
mentation may have a positive effect on chronic stress
as well as mood. Mood improvements have been previ-
ously reported in a double-blind trial of PS in depressed
patients . A number of studies have also demon-
strated that phospholipids may have anti-stress effects,
as demonstrated by lowered levels of adrenocorticotro-
pic hormone (ACTH), reduction in perceived stress rat-
ings in response to acute stress  and reduced cortisol
release in response to acute stress [89,90]. In relation to
milk-based phospholipids, it was recently demonstrated
that chronic supplementation may lead to increased
morning cortisol availability in chronically stressed men
 as well as a blunting of self-report stress ratings in
response to an acute stressor .
Chronic changes in mood over the course of the trial
will be assessed using the Depression, Anxiety and Stress
Scale (DASS) , the Profile of Mood States (POMS)
 and Bond-Lader visual analogue mood scales .
These measures will be administered at baseline, 90 and
180 days pre-dose. The Bond-Lader scales will addition-
ally be administered post dose at each study visit in
order to capture potential acute mood effects associated
with Lacprodan® PL-20 treatment. The Bond-Lader
scales have previously been used by our group in a
wide range of acute and chronic intervention studies,
and have been found to display excellent sensitivity to
subtle affective changes.
There is evidence to suggest that increases in arterial
stiffness with ageing, which are reflected in measures of
blood flow velocity, may be a contributing factor in cogni-
tive decline [95,96]. Previous research suggests that milk
proteins may increase insulin secretion, as well as help to
reduce blood pressure and plasma cholesterol levels [3,97].
Further, high levels of B12 present in milk may also help to
lower HCy levels, which are a contributing factor to CV
disease . In light of the fact that Lacprodan® PL-20 is
an MPC, it could be argued that chronic supplementation
may have a positive influence on CV function. By this
reasoning, the inclusion of CV parameters in the current
study will enable exploration of whether improvements to
CV function are a mechanism by which with Lacprodan®
PL-20 may achieve cognitive benefits.
CV function will be assessed using brachial blood pres-
sure, aortic blood pressure, carotid-femoral pulse wave
velocity (PWV) as well as blood flow velocity in the medial
carotid artery and the common carotid artery (CCA). Bra-
chial blood pressure will be calculated with the participant
seated and following a five-minute rest period using a
clinically validated automated sphygmomanometer. Aortic
blood pressure, pulse pressure and PWV (all aspects of
arterial stiffness and CV pressures) will be measured non-
invasively using the SphygmoCor device. Applanation
tonometry of the radial artery will be used to estimate aor-
tic pressures and wave reflections, and applanation of the
carotid and femoral arteries will be used to measure PWV.
A non-invasive transcranial Doppler system will be used
to record middle cerebral artery (MCA) blood velocity by
placing a sensor close to the participant’s ear and common
carotid artery (CCA) blood velocity will be recorded by
placing a hand-held sensor at the base of the participant’s
neck. All CV measures will be assessed pre- and post dose
at the baseline, 90-day and 180-day study visits in order to
capture both acute and chronic effects associated with
Lacprodan® PL-20 supplementation.
In recent years research in the field of GI microbiota
has caught major interest. Research is suggesting that
modifications in the composition of the GI microbiota
influence normal physiological functions and contribute
to diseases ranging from inflammation to diabetes. Col-
lectively studies now indicate that the gut microbiota also
communicates with the CNS possibly through immune,
neural and endocrine pathways, and by these means
influences gut-brain communication, brain function and
even behaviour [99-101]. Studies on germ-free animals
and animals exposed to pathogenic bacterial infections,
probiotic bacteria or antibiotics, suggest a role of GI
microbiota in the regulation of cognition, anxiety and
mood [101-103]. Moreover GI microbiota perform many
important functions like protection, immune develop-
ment and metabolism, which together have an enormous
effect on host nutrition and health condition [104-106].
Previous studies suggest that human and bovine milk
proteins prevent the adhesion and colonisation of patho-
genic bacteria in the GI tract [107-109] and promote the
growth of beneficial bacteria . As knowing that GI
Scholey et al. Trials 2013, 14:404
Page 8 of 15
microbiota have several physiological functions in the hu-
man health condition, it can be influenced by Lacprodan®
PL-20 milk protein supplementation. Therefore, it will be
valuable to study the GI microbiota at different time
points across the clinical trial to identify the effect of
Lacprodan® PL-20 on indigenes microbial community.
Faecal samples will be collected for the GI microbiota
analysis at baseline, 90 days and 180 days to explore the
possible effect of Lacprodan® PL-20 on the microbial
composition. The microbiota analysis will be carried out
by utilising deep next-generation shotgun sequencing
 of DNA extracted from collected faecal samples.
This analysis will provide insight into GI microbiota of
the ageing population and also functional character-
isation will provide understanding of the potential mechan-
ism by which Lacprodan® PL-20 may influence age-related
cognitive decline (ARCD).
Haematological testing will be conducted at baseline,
90 days and 180 days in order to further investigate pos-
sible mechanisms by which Lacprodan® PL-20 may influ-
ence cognitive decline. These measures have been chosen
on the basis of current aetiological understanding of brain
ageing as well as proposed in vivo actions of Lacprodan®
Previous research has demonstrated that administration
of PC, a major phospholipid component of Lacprodan®
PL-20, can increase the plasma choline as well as brain
acetylcholine (Ach) supply [112,113]. Further, elevated
levels of the neurotoxic substance HCy have been found
to be a risk factor for cognitive decline [48,114-116].
Improved HCy levels have been found to result from
increased intake of PC and choline [52,53]. Vitamin B12,
which is present in high quantities in dairy products ,
has also been found to be effective in reducing HCy in eld-
erly populations . For these reasons plasma choline
as well as B Vitamins and HCy levels will be monitored
throughout the study.
Other major contributors to brain ageing are oxidative
stress [119,120] and inflammation . The phos-
pholipids PC and PS have both been found to display
anti-inflammatory and antioxidant properties, inhibiting
microglial activation as well as superoxide and nitric
oxide production . Endogenous antioxidant glutathi-
one (GSH) is the most abundant antioxidant in human
cells, which plays a central role in defence from oxidative
stress . Under normal physiological conditions the
ratio of reduced GSH to oxidized glutathione (glutathione
disulphide, GSSG) is as high as 100:1. However, in cases
of increased oxidative stress the ratio changes due to
increased levels of GSSG or decreased levels of reduced
GSH. For this reason peripheral blood levels of GSH as
well as the ratio of GSH/GSSG in the blood are good
measures of oxidative stress, and have been found to be al-
tered in patients with mild cognitive impairment and AD
. Another widely-used biomarker of oxidative
stress is F2-isoprostane, which is an excellent in vivo
measure of lipid peroxidation . Peripheral blood
plasma levels of F2 isoprostane have been found to be
significantly elevated in mild cognitive impairment
. A previous study from our laboratory in elderly
participants found plasma F2 isoprostane levels to
significantly decline following a 3-month intervention
with the antioxidant Pycnogenol . In addition to
these measures of oxidative stress, serum measures of in-
flammation will be provided using the following inflam-
matory biomarkers: TNF-α, IL-1β, IL-6 and C-reactive
protein (CRP). Peripheral levels of these inflammatory
biomarkers have previously been found to be elevated in
cases of mild cognitive impairment and AD in compari-
son to healthy age-matched controls [128,129].
A separate blood sample will be collected pre-
randomization for the analysis of single nucleotide poly-
morphisms (SNP) in the APOE and the MTHFR genes.
The APOE-ε4 allele has been found to be associated with
an increased risk of developing AD as well as cognitive
decline in normal elderly [130,131]. Testing for allelic dif-
ferences in the APOE gene was included in the current
study in order to determine whether these genetic differ-
ences may affect the efficacy of Lacprodan® PL-20 as a
treatment for AAMI. MTHR is an important enzyme
involved in the metabolism of HCy. The MTHFR 677 T
allele is associated with reduced enzymatic activity, which
results in decreased serum and plasma levels of folate as
well as increased plasma levels of HCy . In consider-
ation of the relationship between levels of phospholipids,
vitamin B12 and HCy [53,118], genetic testing for allelic
differences in the MTHFR gene was included in the
current study in order to assess whether this may also
affect the efficacy of Lacprodan® PL-20 as an AAMI
Neuroimaging with fMRI and MEG will be conducted in
a subset of 60 participants in order to further explore
the in vivo mechanisms of action of Lacprodan® PL-20
in the brain. Previous neuroimaging studies using PS
supplementation in AD have been conducted using elec-
troencephalography (EEG) as well as positron emission
tomography (PET) [133-135]. PET results revealed that
for the PS group there was increased glucose metabol-
ism during a visual recognition task across a number of
brain regions, most notably the temperoparietal regions
. However, to date no further neuroimaging studies
Scholey et al. Trials 2013, 14:404
Page 9 of 15
have been conducted using phospholipid interventions,
and to the best of our knowledge none have been
conducted using MRI or MEG.
In the current study structural and functional MRI
scans will be acquired using a Siemens 3 Tesla Tim Trio
MRI scanner (Erlangen, Germany), located at the Centre
Table 2 Summary of PLICAR outcome measures by visit
MeasuresV1 V2V3 V4
Screening Written informed consentX
Cognitive Memory Complaint Questionnaire (MAC-Q)X
Wechsler Memory Scale Revised (WMS-R)X
Raven’s Progressive Matrices (RPM)X
Mini Mental State Exam (MMSE)XXXX
Rey Verbal Learning Test (RVLT)XXXX
SUCCAB Spatial Working MemoryXXXX
SUCCAB Contextual MemoryXXXX
Prospective and Retrospective Memory (PRMQ)XXXX
Rapid visual information processing (RVIP)XXXX
Serial 3 s and 7 s subtractionXXXX
Jensen box taskXXXX
Mood Beck Depression Inventory (BDI-II)X
Depression, Anxiety and Stress Scale (DASS)XXXX
Profile of Mood States (POMS)XXXX
Bond-Lader visual analogue mood scalesXXXX
Cardiovascular Brachial blood pressureXXX
SphygmoCor (Aortic blood pressure, pulse pressure, PWV)XXX
Blood velocity (MCA and CCA)XXX
GI microbiota Intestinal bacteriaXXX
Biochemical Oxidative stress (Glutathione and F2 isoprostanes)XXX
Inflammation (TNF-α, IL-1β, IL-6 and CRP)XXX
B Vitamins (B6, B9 and B12)XXX
GeneticApolipoprotein E and MTHFRX
Brain imagingStructural magnetic resonance imaging (MRI)XX
Diffusion tensor imaging (MRI)XX
Default mode network activation (MEG and MRI)XX
Episodic Memory task (functional MRI and MEG)XX
N-Back working memory task (functional MRI and MEG)XX
V1, screening/practice session; V2, baseline visit; V3, 9-day visit; V4, 180-day visit; GI, gastrointestinal; SUCCAB, Spatial Working memory and Contextual Memory
tasks from the Swinburne University Computerized Cognitive Ageing Battery; PWV, pulse wave velocity; MCA, medial carotid artery; CCA, common carotid artery;
CRP, C-reactive protein; MTHFR, Methyltetrahydrofolate reductase; MEG, magnetoencephalography.
Scholey et al. Trials 2013, 14:404
Page 10 of 15
for Human Psychopharmacology, Swinburne University
of Technology. During the initial scan, a structural
image will be obtained for each participant and used
as a reference point for further functional scans. Scan-
ning for DTI analysis, a measure of white matter integ-
rity, will also be conducted. Following DTI there will be
scanning in a resting state in order to assess activity
in the default mode network (DMN) for approximately
6 minutes. Additional analysis of cell membrane fluid-
ity will also be conducted by using the T2 signal tim-
ing information (relaxometry) while in a resting state.
Changes in the blood oxygenation-level dependent (BOLD)
signal will also be analysed while participants complete
in-scanner versions of verbal episodic memory (approxi-
mately 20 minutes) and N-Back working memory tasks
(approximately 20 minutes).
MEG scanning will be conducted using an Elekta
Neuromag® TRIUX 306-Channel Magnetometer system
(Helsinki, Finland) MEG system, also located at the
Centre for Human Psychopharmacology, Swinburne
University of Technology. Initial scanning while in a rest-
ing state will be conducted in order to collect informa-
tion as to activity in the DMN. Following this scanning
will be conducted whilst participants complete the same
in-scanner tasks as used in the fMRI task: verbal episodic
memory and N-Back working memory. The two tasks are
kept the same across both fMRI and MEG in order for
information from the two imaging modalities to be com-
bined into a single comprehensive analysis. MEG scan-
ning provides important complementary information,
which is additional to that provided by fMRI. The tem-
poral resolution of MEG is far superior to fMRI; MEG is
capable of recording neural oscillations from delta right
through to the gamma range (>40 Hz). Although the
spatial resolution of MEG is less than that of fMRI, the
high number of sensors (approximately 300), together
with modern source reconstruction algorithms (for ex-
ample, beam forming) means that the spatial resolution
of MEG is far superior to conventional scalp-recorded
EEG . The combination of the two imaging modal-
ities is state-of-the-art and will provide an unparalleled
level of analysis of the effects of Lacprodan® PL-20 on
All primary and secondary outcome measures are
displayed in Table 2.
The primary analysis will investigate the effect of
treatment on all cognitive outcomes from baseline to
180 days, using the groups as randomized (intention to
treat). Statistical analyses will be conducted using linear
mixed modelling, whereby subject-specific random in-
tercepts and slopes will be fitted to subject data and
fixed effects will be fitted to treatment group, time and
the treatment × time interaction. On the basis of APOE
and MTHFR genotyping, subgroup analysis will also be
conducted in order to investigate the effect of allelic
differences on treatment response. Secondary outcome
variables will be analysed using similar statistical tech-
niques. Results will be considered statistically signifi-
cant at an alpha level of P <0.05 corrected for multiple
Although stratification according to age, intelligence
and baseline WMS-R scores may help to explain some
of the residual between-group variance unrelated to the
treatment effect, further exploration of possible covari-
ates will also be investigated. Baseline correlations be-
tween the primary cognitive outcome measures and
other baseline variables, including BMI, educational
background, diet, CV function, GI microbiota and bio-
chemical parameters, will also be investigated in order
to investigate other important covariates. In the event
that significant correlations at the P <0.05 level are
found at baseline then these additional variables will
also be controlled for in the primary analysis of cogni-
Analysis of functional neuroimaging data (both MEG
and fMRI) during episodic memory and N-Back working
memory tasks will be conducted using a region of inter-
est (ROI) approach. Using this method, between-group
(Lacprodan® PL-20 versus MPC and inert placebo) func-
tional differences in predefined brain regions will be
statistically analysed. The ROIs for the episodic memory
task will include the medial temporal lobes, the lateral
prefrontal cortices, the associative temporal and paretial
regions, the cingulate gyrus and the cerebellum. The
ROIs that will be analysed in the N-Back working memory
task will include the dorsolateral, ventrolateral and medial
prefrontal cortex, anterior cingulate, parietal cortex and
sensorimotor cortex .
The trial is currently recruiting.
AAMI: Age-associated memory impairment; AD: Alzheimer’s disease;
APOE: Apolipoprotein E; ARCD: Age-related cognitive decline; BDI-II: Beck
depression inventory II; BMI: Body mass index; CCA: Common carotid artery;
CNS: Central nervous system; CRP: C-reactive protein; V: Cardiovascular;
DASS: Depression anxiety and stress scale; DNM: Default mode network;
DTI: Diffusion tensor imaging; EEG: Electroencephalography; fMRI: Functional
magnetic resonance imaging; GI: Gastrointestinal; GSH: Glutathione;
GSSG: Glutathione disulphide; HCy: Homocysteine; L: Interleukin;
MAC-Q: Memory complaint questionnaire; MCA: Middle cerebral artery;
MEG: Magnetoencephalography; MPC: Milk protein concentrate;
MTHFR: Methylenetetrahydrofolate reductase; MSE: Mini mental state
Examination; PC: Phosphatidylcholine; PET: Positron emission tomography;
PL: Phospholipid; PLICAR: Phospholipid intervention for cognitive ageing
reversal; POMS: Profile of mood states; PRMQ: Prospective and retrospective
memory questionnaire; PS: Phosphatidylserine; PWV: Pulse wave velocity;
ROI: Region of interest; RPM: Raven’s progressive matrices; RVIP: Rapid visual
information processing; RVLT: Rey’s verbal learning test; SB: Soybean;
SUCCAB: Spatial working memory and contextual memory tasks from the
Scholey et al. Trials 2013, 14:404
Page 11 of 15
Swinburne university computerized cognitive ageing battery; tHcy: Total
homocysteine; TICS-M: Telephone interview for cognitive status – modified;
TNF: Tumour necrosis factor; WMS-R: Wechlser memory scale-revised.
AS and CS receive research funding from the food industry, PF is an
employee of Arla Foods. The other authors declare that they have no
AS conceived the study, participated in its design and contributed to
drafting the manuscript, DC developed the study design and drafted the
manuscript, MH conceived and has responsibility for the fMRI component of
the study, WW conceived and has responsibility for the MEG component of
the study, CS participated in the study design and contributed to the
manuscript, DW participated in the study design and contributed to the
manuscript, SG developed the protocol and has responsibility for the
microbiota component of the study, PF participated in the study design and
contributed to the manuscript. All authors read and approved the final
This study is funded by Arla Foods, Denmark. Author PF is an employee of
Arla Foods and contributed to the study design and to the manuscript.
1Centre for Human Psychopharmacology, Swinburne University of
Technology, Melbourne 3122, Victoria, Australia.2Brain & Psychological
Sciences Research Centre, Swinburne University of Technology, Melbourne,
Australia.3Arla Food Ingredients, P/S Sønderhøj 14, 8260, Viby J, Denmark.
Received: 17 July 2013 Accepted: 11 November 2013
Published: 26 November 2013
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Cite this article as: Scholey et al.: A randomized controlled trial
investigating the neurocognitive effects of Lacprodan® PL-20, a
phospholipid-rich milk protein concentrate, in elderly participants with
age-associated memory impairment: the Phospholipid Intervention for
Cognitive Ageing Reversal (PLICAR): study protocol for a randomized
controlled trial. Trials 2013 14:404.
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