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The effects of GSK2981710, a medium‐chain triglyceride, on cognitive function in healthy older participants: A randomised, placebo‐controlled study

  • Exploristics, Belfast, United Kingdom


Objective This double‐blind, randomised, placebo‐controlled, two‐part study assessed the impact of GSK2981710, a medium‐chain triglyceride (MCT) that liberates ketone bodies, on cognitive function, safety, and tolerability in healthy older adults. Methods Part 1 was a four‐period dose‐selection study (n = 8 complete). Part 2 was a two‐period crossover study (n = 80 complete) assessing the acute (Day 1) and prolonged (Day 15) effects of GSK2981710 on cognition and memory‐related neuronal activity. Safety and tolerability of MCT supplementation were monitored in both parts of the study. Results The most common adverse event was diarrhoea (100% and 75% of participants in Parts 1 and 2, respectively). Most adverse events were mild to moderate, and 11% participants were withdrawn due to one or more adverse events. Although GSK2981710 (30 g/day) resulted in increased peak plasma β‐hydroxybutyrate (BHB) concentrations, no significant improvements in cognitive function or memory‐related neuronal activity were observed. Conclusion Over a duration of 14 days, increasing plasma BHB levels with daily administration of GSK2981710 had no effects on neuronal activity or cognitive function. This result indicates that modulating plasma ketone levels with GSK2981710 may be ineffective in improving cognitive function in healthy older adults, or the lack of observed effect could be related to several factors including study population, plasma BHB concentrations, MCT composition, or treatment duration.
The effects of GSK2981710, a mediumchain triglyceride, on
cognitive function in healthy older participants: A randomised,
placebocontrolled study
Barry V. O'Neill
*|Chris M. Dodds
*|Sam R. Miller
*|Ashutosh Gupta
Philip Lawrence
*|Jonathan Bullman
|Chao Chen
|Odile Dewit
*|Subramanya Kumar
Mushi Dustagheer
*|Jeffrey Price
|Shaila Shabbir
|Pradeep J. Nathan
GSK Nutrition, GSK Consumer Healthcare,
Brentford, UK
Respiratory Health, GSK Consumer
Healthcare, Nyon, Switzerland
Department of Psychology, University of
Exeter, Exeter, UK
Department of Quantitative Sciences,
GlaxoSmithKline, Stevenage, UK
Department of Quantitative Sciences India,
GlaxoSmithKline, Bangalore, India
Clinical Unit, GlaxoSmithKline, Cambridge,
Clinical Pharmacology Modelling and
Simulation, GlaxoSmithKline, Stevenage, UK
Clinical Pharmacology Modelling and
Simulation, GlaxoSmithKline, London, UK
Clinical Pharmacology Study Sciences and
Operations, GlaxoSmithKline, Stevenage, UK
Sosei Heptares, Cambridge, UK
The School of Psychological Sciences,
Monash University, Clayton, Australia
Department of Psychiatry, University of
Cambridge, Cambridge, UK
Barry V. O'Neill, Respiratory Health, GSK
Consumer Healthcare, Site Nyon, Route de
l'Etraz 2, Case Postale 1279, CH1260, Nyon,
Funding information
GlaxoSmithKline, Grant/Award Number:
Objective: This doubleblind, randomised, placebocontrolled, twopart study
assessed the impact of GSK2981710, a mediumchain triglyceride (MCT) that
liberates ketone bodies, on cognitive function, safety, and tolerability in healthy older
Methods: Part 1 was a fourperiod doseselection study (n= 8 complete). Part 2
was a twoperiod crossover study (n= 80 complete) assessing the acute (Day 1)
and prolonged (Day 15) effects of GSK2981710 on cognition and memoryrelated
neuronal activity. Safety and tolerability of MCT supplementation were monitored
in both parts of the study.
Results: The most common adverse event was diarrhoea (100% and 75% of
participants in Parts 1 and 2, respectively). Most adverse events were mild to
moderate, and 11% participants were withdrawn due to one or more adverse
events. Although GSK2981710 (30 g/day) resulted in increased peak plasma
βhydroxybutyrate (BHB) concentrations, no significant improvements in cognitive
function or memoryrelated neuronal activity were observed.
Conclusion: Over a duration of 14 days, increasing plasma BHB levels with
daily administration of GSK2981710 had no effects on neuronal activity or
cognitive function. This result indicates that modulating plasma ketone levels with
GSK2981710 may be ineffective in improving cognitive function in healthy older
adults, or the lack of observed effect could be related to several factors including
study population, plasma BHB concentrations, MCT composition, or treatment
ageing, cognition, energy metabolism, ketone, mediumchain triglyceride
*Barry V. O'Neill, Chris M. Dodds, Sam R. Miller, Ashutosh Gupta, Philip Lawrence, Odile Dewit, and Mushi Dustagheer affiliation at time of study.
Received: 12 October 2018 Revised: 7 March 2019 Accepted: 13 March 2019
DOI: 10.1002/hup.2694
Hum Psychopharmacol Clin Exp. 2019;34:e2694.
© 2019 John Wiley & Sons, 1of14
Agerelated cognitive impairment describes cognitive decline occur-
ring in healthy individuals with advancing age. With increasing age,
capacity to acquire and retrieve new memories deteriorates, and pro-
cessing speeds slows (Salthouse, 1991; Small, Stern, Tang, & Mayeux,
1999). Although recognised as part of the normal ageing process,
some individuals display greater cognitive decline than would be
expected based on their age and educational background that may
be linked to early stages of Alzheimer's disease (AD), including preclin-
ical AD or mild cognitive impairment (MCI; Lim et al., 2013; Lim et al.,
2014; Lim et al., 2014). MCI can be classified as a transitional state
between normal cognitive function and the neuropathological condi-
tion of AD, which confers increased risk of developing AD (Petersen,
2004; Winblad et al., 2004). Cognitive function impairment is a
common feature of normal ageing, MCI and AD that encompasses
multiple domains, including episodic memory (Blackwell et al., 2004;
Doraiswamy et al., 2012; Egerhazi, Berecz, Bartok, & Degrell, 2007;
Fowler, Saling, Conway, Semple, & Louis, 2002; Lim et al., 2015;
Mormino et al., 2014; Spencer & Raz, 1995; Swainson et al., 2001).
There may also be overlap between mechanisms that cause abnormal
agerelated cognitive impairment, MCI and AD. For example, high
levels of amyloidβ(Aβ) are associated with greater decline in memory
and working memory in healthy older adults, as well as patients with
MCI and mildtomoderate AD (Doraiswamy et al., 2012; Lim et al.,
2015; Mormino et al., 2014).
The brain is highly metabolically active, relying primarily on glucose
as an energy source (Costantini, Barr, Vogel, & Henderson, 2008). Evi-
dence suggests that impaired glucose metabolism may lead to cogni-
tive impairment in healthy ageing, MCI and AD (Daulatazai, 2017).
For example, cerebral glucose metabolism has been shown to decline
with increasing age, which may predict MCI (Bentourkia et al., 2000;
de Leon et al., 2001). Decreased cerebral glucose metabolism has been
observed in patients with MCI and AD as well as healthy older individ-
uals in a network of areas including the hippocampus, parietal, poste-
rior cingulate, temporal, and frontal cortical regions (Herholz et al.,
2002; Mosconi et al., 2008). Decreased metabolism has also been
shown to correlate with cognitive impairment and cognitive decline
(de Leon et al., 2001; Haxby et al., 1990; Shokouhi et al., 2013;
Mosconi et al., 2008; Landau et al., 2011). The mechanism underlying
this hypometabolism is not yet fully characterised but may be
secondary to amyloid levels, calcium homeostasis dysregulation,
mitochondrial dysfunction, and oxidative damage leading to neurode-
generation (Gu, Huang, & Jiang, 2012; CabezasOpazo et al., 2015;
Angelova & Abramov, 2017). Consequently, it has been suggested
that therapies aimed at correcting impaired glucose metabolism may
be beneficial in treatment of agerelated cognitive impairment, MCI
and AD (Costantini et al., 2008; Cunnane et al., 2016).
One therapeutic approach is the induction of ketosis, causing the
liver to metabolise fatty acids to generate ketone bodies that can pro-
vide an alternative energy source for the brain (Henderson, 2008).
Indeed, ketone bodies have been established as a metabolic pheno-
type characteristic of the AD brain in clinical and preclinical studies
(Ding, Yao, Rettberg, Chen, & Brinton, 2013; Yao et al., 2009). The pri-
mary ketone body generated by the liver is βhydroxybutyrate (BHB),
which is taken up by neurones and converted in mitochondria to
acetoacetate, which is oxidised via the tricarboxylic acid cycle to liber-
ate energy (Henderson, 2008). In vitro evidence suggests that BHB
preserves neuronal integrity and stability during glucose deprivation
in rat hippocampal slices (Kashiwaya et al., 2000). A study in healthy
participants with insulininduced hypoglycaemia showed that BHB
infusion provides an alternative energy source for the brain and pro-
tects against cognitive dysfunction (Veneman, Mitrakou, Mokan,
Cryer, & Gerich, 1994).
Ketone bodies may be generated by administration of medium
chain triglycerides (MCTs), which liberate ketone bodies without die-
tary modification (Cunnane et al., 2016; Henderson, 2008). Indeed, a
robust dose response exists between singledose oral MCT administra-
tion and maximal BHB plasma levels with increasing oral MCT doses
(range 1070 g) resulting in increased plasma BHB (range 0.2
0.9 mM; see Figure 6 in Cunnane et al., 2016, for details). Alongside this
increase in ketones, cognitive improvements have also been reported
in response to MCT treatment in patients with MCI or AD following a
single dose (Henderson et al., 2009) and after 45 or 90 days of treat-
ment, with improvements primarily in apolipoprotein E4 (APOE4) non-
carriers (Henderson et al., 2009; Reger et al., 2004). Although these
findings are encouraging, there have also been contrasting findings
reported, with limited effects on cognitive function in patients with
AD (Ohnuma et al., 2016), though MCT supplementation was well tol-
erated. Further studies exploring different durations of MCT treatment
with larger sample sizes are warranted, to evaluate potential therapeu-
tic benefit of MCT treatment in patients with MCI or AD. In addition,
very little is known regarding potential cognitive benefits of MCT treat-
ment for individuals with cognitive impairment due to the normal age-
ing process. Given the data related to brain energy metabolism
discussed above, it is fair to assume that the healthy older brain may
present with decreased glucose metabolism (Herholz et al., 2002;
Mosconi et al., 2008). Indeed, recent studies have demonstrated this
to be the case where cognitively healthy older individuals presented
with reduced global brain glucose uptake when compared with a
younger control group (Nugent et al., 2014; Nugent et al., 2016).
Alongside this aberrant glucose metabolism, no differences in brain
ketone metabolism has been reported in older subjects (Croteau,
Castellano, Fortier, et al., 2018). Strikingly, brain ketone metabolism
demonstrated no significant differences between healthy young
adults, older adults, and those with MCI/AD (Nugent et al., 2014,
Castellano et al., 2015, Croteau, Castellano, Richard, et al., 2018).
This finding suggests that although glucose metabolism may be
compromised, ketone metabolism is preserved and the healthy ageing
brain may benefit from MCT supplementation.
This study evaluated potential procognitive effects of GSK2981710,
an MCT formulation comprising55% 1,2,3tricapyrloylglycerol (8carbon
chain [C8] fatty acid) and 45% 1,2,3tricaprinoylglycerol (10carbon
chain [C10] fatty acid) with trace amounts of C6 fatty acids, in older
adults. The primary objective of the study was to examine the effects
of GSK2981710 on cognition and brain function, and the secondary
2of14 O'NEILL ET AL.
objectives of the study was to examine the safety and tolerability of
GSK2981710 as well as its effects on plasma BHB levels. The study
was conducted in two parts. Part 1 was conducted to confirm previous
MCT dose related findings applied to the current study product and to
inform the dose level for use in Part 2, based on pharmacokinetic (PK)
analysis of plasma BHB concentrations. In Part 2, the acute (following a
single dose) and prolonged effects (examined at Day 15, 24 hr after the
final dose on Day 14) of GSK2981710 on BHB plasma concentrations,
cognition, and neural function were assessed. Safety and tolerability
were monitored throughout both parts of the study.
2.1 |Study design
This was a twopart Phase I singlecentre study (
identifier: NCT01702480, GSK ID: EMI116713) in older adults
(5580 years of age), conducted in the United Kingdom. Part 1 was
a randomised, placebocontrolled, doubleblind, fourperiod
doseescalation study. Part 2 was a randomised, placebocontrolled,
doubleblind, twoperiod crossover study to evaluate the efficacy of
GSK2981710 30 g following a single and repeat dosing (14 days of
treatment). Two participants participated in both study parts. Protocol
amendments are described in Supplementary Appendix B. The study
was approved by National Research Ethics Service Committee
(East of England, Cambridgeshire, and Hertfordshire) and conducted
in accordance with International Council for Harmonisation Good
Clinical Practice and the Declaration of Helsinki 2008.
2.2 |Participants
Males and nonpregnant females aged 5580 years were eligible for
inclusion in Part 1.
Exclusion criteria (Parts 1 and 2) included restricted or modified
intake of carbohydrates, proteins, fats, or a ketogenic diet; known
learning disability or learning disorder; history of neurological or
psychiatric disorder; history of drug dependence, as measured by the
Mini Neuropsychiatric Interview; and history of suicidal behaviour
or ideation, as measured by the Columbia Suicide Severity Rating
Scale (CSSRS). Additional inclusion criteria specific to Part 2 were
Wechsler logical memory test (Wechsler, 1987) score below the mean
level of performance of young healthy adults (cutoff: <24 on
immediate recall or <22 on delayed recall) and an otherwise normal
neuropsychological performance, as determined by a Mini Mental
State Examination Questionnaire score of 25 (Bravo & Hebert,
1997). A full list of inclusion and exclusion criteria is presented in
Supplementary Appendix C.
2.3 |Randomisation and blinding
In Part 1, participants were randomised to four sequences (1:1:1:1)
each including four of the following five treatments over a 2week
period: GSK2981710 10, 20, 30, 40 g, or placebo (Supplementary
Appendix A: Figure S1a). In Part 2, participants were randomised to
two groups (1:1) to receive daily oral dosing of either placebo or
GSK2981710 30 g for 14 days, starting on Day 1. After a minimum
7day washout (after Day 14) participants crossed over and received
the alternate treatment for a further 14 days (Supplementary
Appendix A: Figure S1b). A randomisation schedule was generated
by validated GSK software. Participants, investigators, and project
team staff were not made aware of treatment allocations.
2.4 |Procedures
2.4.1 |Interventions
Study treatment was supplied in powder sachets mixed with
125250 ml of water, administered in the morning with breakfast.
GSK2981710 and placebo (safflower oil base, with no/negligible
amounts of MCT) were identical in appearance.
2.4.2 |PK endpoints and assessments
In Part 1, the primary endpoint was the plasma BHB concentration
time course, including estimation of the area under the
concentrationtime curve to the last quantified concentration
[08 hours]
), the maximum observed concentration (C
), and the
first time after dosing at which C
was observed (t
). PK blood
sampling was completed at each dosing session. Plasma samples were
collected predose and at 30min intervals for 8 hr after dosing, except
for 5hr post dose, when lunch was served. BHB concentrations were
measured using a Stanbio Beta Hydroxybutyrate Liquicolour kit
(Texas, USA, distributed in the UK by Alere), modified to run in
Microtitre plate format with 10μl sample volume. In Part 2, trough
(predose) and postdose plasma samples were collected on Day 1,
and a single plasma sample was taken on Day 15, after breakfast.
Plasma samples during both treatment periods were taken immedi-
ately after pharmacodynamic (PD) assessments.
2.4.3 |PD endpoints and assessments (Part 2)
The primary PD endpoint was cognition function, measured using the
Cambridge Neuropsychological Test Automated Battery (CANTAB;
Swainson et al., 2001; Fowler et al., 2002; Egerhazi et al., 2007;
Nathan et al., 2017) and the Source Memory Task (Cooper, Greve, &
Henson, 2017). CANTAB cognitive assessments (adjusted for placebo)
included CANTAB paired associates learning (PAL) task, CANTAB ver-
bal recognition memory (VRM) task, CANTAB spatial working memory
(SWM) task, CANTAB rapid visual processing (RVP) task, and CANTAB
reaction time (RTI) task.
This task assesses visual memory and associative learning. Boxes are
displayed on the screen and are opened in a randomised order; one
or more of them will contain a pattern. The patterns are then
displayed in the middle of the screen, one at a time, and the partici-
pant must touch the box where the pattern was originally located. If
the participant makes a mistake, the boxes are reopened to remind
them of the patterns' locations; this is repeated until the participant
is correct. Primary outcome measure: total errors for six shapes and
eight shapes.
This task examines immediate and delayed memory of verbal informa-
tion under free recall and choice recognition conditions. Participants
are presented with a list of 12 words presented one at a time and
are asked to produce as many words as possible from the list immedi-
ately, recognise target words from a list of targets and distracters and
following a delay recognise target words from a list of targets and
distracters. Primary outcome measure: number of correct responses
(immediate and delayed recall).
This task examines ability to retain spatial information and to
manipulate remembered items in working memory. Participants are
presented with a number of squares on screen; participants perform
a search to find blue tokens. When a token is found, the participant
must perform a new search to find the next blue token; however,
the token will never be hidden twice in the same box. This is repeated
until all the blue tokens are found. Primary outcome measure:
between search errors.
This task measures sustained attention, whereby participants are
required to detect a series of individual digits from 2 to 9 presented
in a pseudorandom order in the centre of the screen and are
required to respond when a specific target sequence is displayed
(for example, 357). Primary outcome measure: A prime (A; i.e.
signal detection measure of sensitivity to the target, regardless of
response tendency).
This task assesses psychomotor speed, whereby participants must
select and hold a button at the bottom of the screen. Circles are
presented above (one for the simple mode, and five for the
fivechoice mode.) In each case, a yellow dot will appear in one of
the circles, and the participant must react as soon as possible,
releasing the button at the bottom of the screen, and selecting the
circle in which the dot appeared. Primary outcome measure: reaction
time (ms).
The outcome variables selected for each CANTAB test was based
on their sensitivity to detect changes in ageing and AD (Egerhazi
et al., 2007; Fowler et al., 2002; Nathan et al., 2017; Swainson et al.,
2001) and the demonstrated sensitivity of the tests and outcome
variables to pharmacological modulation (both acute and chronic
treatment) in both healthy young and older subjects (Elliott et al.,
1997; YurkoMauro et al., 2010) as well as patients with AD
(Kuzmickiene & Kaubrys, 2015).
For the source memory task (Cooper et al., 2017), participants
were asked to recognise previouslypresented items (item memory)
and recall their spatial location (source memory). This task was con-
ducted in two phases, a study phase and a test phase. During the
study phase participants were shown 40 objects, half appearing on
the top of the screen, half on the bottom. During the test phase par-
ticipants were reshown the same 40 objects and 20 unstudied objects.
Participants were asked to indicate whether they recognised the item
(item memory) and identify its original location (source memory);
response speed and accuracy were compared between participants.
Previous research has demonstrated a sensitivity of source memory
to age with different effects observed between younger and older
adults (Spencer & Raz, 1995), as well as healthy controls and amnesic
patients (Shimamura & Squire, 1987).
For the CANTAB VRM, CANTAB RVP, and source memory tasks,
higher values correspond to improved performance, with a positive
difference reflecting an improved performance with GSK2981710.
For the CANTAB PAL (6 and 8 shapes), CANTAB SWM (six and eight
boxes), and CANTAB RTI tasks, lower values correspond to improved
performance, with a negative difference reflecting poorer perfor-
mance with GSK2981710.
Secondary PD endpoints included neural activity measured by
electroencephalography (EEG) and eventrelated potential, which
included P300, EEG relative power (at various frequency bands) at
rest, and FN400 during the source memory task. P300 and FN400
are electrophysiological EEG markers relating to directed attention
(the contextual updating of working memory) and familiarity (source
memory), respectively. The P300 (P3a and P3b) was included due to
its correlation with age and changes in AD (Alperin, Mott, Holcomb,
& Daffner, 2014; Juckel et al., 2008; Polich, 1997; Polich, 2007). Rest-
ing state EEG has been associated with ageing and neuropsychological
performance in AD (Babiloni et al., 2007; Babiloni, Vecchio, Bultrini,
Luca Romani, & Rossini, 2006).
During EEG measurements, participants were seated upright with
their eyes open in a soundattenuated room and instructed to relax
and avoid facial muscle movements. EEG was recorded using tin
electrodes from 61 scalp sites according to the international 10/20
system. Nose and eye movement was recorded via an electrode
placed above, below, and to the left of the left eye ocular orbit and
the right of the right eye ocular orbit, using the point of the nose as
reference (mastoid electrodes were also fitted) and FZ and FPz as
ground. Data were recorded using Neuro Scan equipment with
SynAmps2TM amplifiers (Neuro Scan Inc., Charlotte, NC, USA).
P300 was assessed by comparing the AUC, amplitude, and latency
of P3a and P3b in response to auditory stimuli of varying frequencies
(1,000 Hz [standard], 2,000 Hz [target], white noise burst [novel]),
with a 100ms duration, and an intertrial interval of 1,0002,000 ms
in 100ms steps. Participants were instructed to press Yesto high
frequency tones and ignore standard and novel tones. Resting state
EEG was assessed by comparing relative power (%) of low (delta
[0.54 Hz]/theta [47 Hz]/alpha [813 Hz]) and high (beta [1835]/
gamma [3070 Hz]) frequencies from EEG recordings during 3 min
of having the eyes open and closed. Eventrelated potential activity
4of14 O'NEILL ET AL.
during the source memory task was assessed by measuring the FN400
AUC and latency from timelocked EEG recordings, to compare the
participant's speed of response and accuracy during the source mem-
ory task. A positive difference reflects an improvement with
CANTAB, resting EEG, and P300 measurements were carried out
at baseline of each study part (68 days before Day 1 of each treat-
ment period), on Day 1 (post dose) of each treatment period to assess
acute effects and on Day 15 (trough assessment approximately 1 day
after the last treatment in both treatment periods) to assess prolonged
effects. The source memory task was conducted at baseline and Day 1
(post dose) but not on Day 15. Participants were familiarised with the
use of the touch screen and cognitive tasks prior to cognitive testing
(at screening) to avoid familiarisation effects.
2.4.4 |PKPD
The correlation between systemic exposure of BHB and the CANTAB
domain and source memory assessments on Days 1 and 15 were eval-
uated graphically as a secondary objective in Part 2.
2.4.5 |Safety and tolerability
Key safety outcomes included adverse events (AEs), serious AEs,
diseaserelated AEs, clinical laboratory tests, vital signs, and electro-
cardiograms were monitored from the start of study treatment until
the end of followup. AEs were coded using the Medical Dictionary
for Regulatory Activities (MedDRA) coding system. Gastrointestinal
(GI) symptoms and stool quality were assessed using selfadministered
diaries, which were reviewed in the morning before each dose.
Participants rated GI symptoms as mild, moderate, or severe. Stool
consistency and quality were assessed by the Bristol Stool Form Scale
(Lewis & Heaton, 1997). A stool consistency that was 1 (watery) or 2
(loose), with a Bristol Stool Form that was 6 (fluffy pieces with jagged
edges) or 7 (watery, no solid pieces) was recorded as a diarrhoea AE.
2.5 |Statistical analysis
2.5.1 |Sample size
This was an exploratory study not specifically designed for hypothesis
testing. No samplesize calculation was performed for Part 1. Sample
size calculations for Part 2 showed that 80 participants completing
both periods would provide 80% power to detect an effectsize of
0.31 for any PD endpoint, with a 5% twosided type I error rate.
2.5.2 |Analysis populations
The intentiontotreat population included all participants randomised
and receiving at least one dose of GSK2981710 30 g and was used for
safety reporting. The perprotocol (PP) population included all partici-
pants who were randomised and received at least one dose of
GSK2981710 30 g, except the participants (or specific data points)
where the measurement was identified prior to unblinding as poten-
tially biased. The PP was the primary population for PD endpoints
because it was expected to have greater sensitivity to detect any sig-
nal in the data. The PK population included participants in the
intentiontotreat population for whom at least one PK sample was
obtained and analysed.
Individual and mean plasma BHB concentrationtime data were
plotted and analysed by noncompartmental methods using
WinNonlin® (Version 6.3), using actual sampling times recorded dur-
ing the study. C
and t
were determined from the plasma
concentrationtime curve. The AUC
[08 hours]
was determined using
the linear trapezoidal rule for increasing concentrations and the loga-
rithmic trapezoidal rule for decreasing concentrations. Treatment dif-
ferences were calculated by subtracting the values of C
[08 hours]
for placebo treatment from those for GSK2981710
treatment. PK parameters were summarised using summary statistics.
Taking into consideration the tolerability of GSK2981710, a plasma
BHB concentration of 0.4 mmol/L was used as the threshold for
dose selection from Part 1, based on a previous study using the
MCT AC1202 (Henderson et al., 2009). Duration of BHB level eleva-
tion was also considered to accommodate the time required to com-
plete PD assessments (approximately 2 hr) in Part 2. Changes from
baseline in PD endpoints for GSK2981710 were compared with pla-
cebo. A repeated measures analysis of variance mixedeffects model
was applied fitting the period, day, treatment, and day * treatment
interaction as fixed effects, with participant as a random effect and
day as a repeated effect. When measured, participantbaseline,
periodbaseline, and the interaction term for periodbaseline * day
were included as continuous covariates. Least squares means and
the mean treatment difference with corresponding 95% confidence
intervals and pvalues were calculated. Plasma BHB concentration ver-
sus CANTAB or source memory assessment scores were explored
In Part 1, 14 participants were screened for eligibility, nine were
randomised and eight completed the study (Figure 1a). In Part 2, 332
participants were screened, of whom 225 failed, 107 were
randomised, and 80 completed the study (Figure 1b). A summary of
participant disposition, including reasons for screen failure, is pre-
sented in Figure 1a,b. Participants were mostly male, >55 years or
age and White/Caucasian/European (Table 1).
In Part 1, BHB exposure and peak plasma concentration generally
increased with increasing GSK2981710 dose. Plasma BHB concentra-
tions peaked within 1 hr after dosing with 10 or 20 g GSK2981710 or
12 hr after dosing with 30 or 40 g GSK2981710 (Table 2), and gen-
erally returned to predose levels within 8 hr after dosing (Figure 2a).
GSK2981710 30 g was selected for use in Part 2, based on a mean
(placebocorrected) peak BHB plasma concentration of 0.452 mmol/
L at 1.26 hr after dosing (Table 2). In Part 2, mean plasma BHB con-
centrations for Periods 1 and 2, 1 hr after dosing with GSK2981710
30 g on Day 1, were 0.276 and 0.291 mmol/L, respectively, and 0.058
and 0.064 mmol/L for placebo, respectively (Table 3). On Day 15, for
Periods 1 and 2, the mean BHB plasma concentrations were 0.054 and
0.083 mmol/L for GSK2981710 30 g, respectively, compared with
0.054 and 0.055 mmol/L for placebo (similar to predose levels;
Table 3), respectively. Individual plasma BHB concentration time
profiles for Parts 1 and 2 are illustrated in Figure 2.
There was no significant difference between GSK2981710 30 g
and placebo for CANTAB cognitive tasks (Figure 3) or source memory
tasks (Figure 4).
In general, GSK2981710 was not associated with a significant treat-
ment difference in the AUC, latency and amplitude of P3a and P3b
compared with placebo, although statistical significance was observed
for some comparisons, including P3a AUC at Days 1 (central midline,
right Parietal, ParietoOccipital midline) and 15 (FrontoCentral;
Table S1). Compared with placebo, GSK2981710 30 g was not associ-
ated with any significant changes in the AUC or latency of the FN400
component of the EEG during the source memory task (Table S2).
Generally, GSK2981710 had no effect on low (delta [0.54 Hz]/
theta [47 Hz]/alpha [813 Hz]) and high (beta [1835]/gamma
[3070 Hz]) resting EEG activity, compared with placebo, although
some significant differences were observed for the theta frequency
band on Days 1 (ParietoOccipital and Temporal) and 15 (Temporal;
Table S3).
FIGURE 1 Participant disposition flow chart for Part 1 (a) and Part 2 (b). BP: blood pressure; CANTAB: Cambridge Neuropsychological Test
Automated Battery; EEG: electroencephalogram; ITT: intentiontotreat; PP: per protocol
6of14 O'NEILL ET AL.
PD assessments showed no significant correlation between plasma
BHB concentration and individual CANTAB tests and source memory
task assessment scores (Figure 5).
All participants in Part 1 and 96% of participants in Part 2 reported
at least one AE (listed in Table S4). Most AEs were mild to moderate
intensity, although nine participants reported a total of 24 AEs of
severe intensity. Most AEs were GIrelated, most commonly diarrhoea,
which was reported by all participants in Part 1 and 75% of participants
in Part 2. GIrelated AEs were the only AEs reported as drugrelated in
Part 1 and the AEs mostcommonly reported as drugrelated in Part 2
(Table S5). In Part 1, the proportions of participants who experienced
diarrhoea were 38%, 0%, 50%, 67%, and 83% in the period when they
received placebo, GSK2981710 10, 20, 30, and 40 g, respectively, sug-
gesting a doserelation between GSK2981710 and diarrhoea. The
number of participants with other GIrelated AEs or other AEs was
small in all periods, which does not allow to draw conclusions on a
doserelation between GSK2981710 and GIrelated AEs that are not
diarrhoea or nonGIrelated AEs. This information informed the deci-
sion to choose 30 g as the dose of GSK2981710 for Part 2.
No serious AEs, deaths, other significant AEs, or electrocardiogram
abnormalities were reported.
This study investigated effects of GSK2981710 on cognitive function
and neural activity in healthy older adults. In Part 1, GSK2981710 30 g
resulted in a mean peak plasma BHB concentration consistent with
previous work in the literature demonstrating efficacy of MCT on cog-
nitive function (Henderson et al., 2009). This, combined with tolerabil-
ity findings, led to the selection of a GSK2981710 30 g dose in Part 2.
In Part 2, GSK2981710 30 g treatment had no significant overall
effect on cognitive performance measures despite mean 1 hr postdose
BHB levels (following acute administration on Day 1) above those
required for cognitive improvement in the previous positive study of
AC1202 in patients with mildtomoderate AD (Henderson et al.,
2009). Although statistical significance was noted for some EEG mea-
surements at some time points (including P3a AUC), these analyses
were not corrected for multiple testing and were not consistent with
effects seen on amplitude, so these differences were deemed unlikely
related to a robust treatment effect. Almost all participants reported at
least one AE, most commonly diarrhoea. Most AEs were mild or mod-
erate in intensity and commonly reported in both GSK2981710 and
placebo groups, although more withdrawals due to GIrelated AEs
were reported in the GSK2981710 treatment group compared with
placebo. Overall these findings suggest that although GSK2981710
was well tolerated in healthy older adults, the current formulation
and dose tested (over a 14day period) were ineffective in improving
cognitive function. The findings imply that modulating plasma ketone
levels with MCTs may not be an effective treatment strategy to com-
pensate for reduced glucose metabolism and thus improve cognitive
function in older adult subjects.
Findings from this study contrast results from previous studies
demonstrating associations between MCT treatment, mild ketosis
(Henderson et al., 2009; Reger et al., 2004), BHB salt infusion (Vene-
man et al., 1994), and improved cognitive function. In patients with
mildtomoderate AD, treatment with the MCT AC1202 improved
TABLE 1 Participant demographics for Parts 1 and 2 (ITT
Part 1
Part 2
(N= 96)
Age in years, mean (SD) 61.0 (5.63) 65.4 (6.19)
Age range 5572 5579
Sex, n(%)
Female: 1 (13) 40 (42)
Male: 7 (88) 56 (58)
BMI, (kg/m
) mean (SD) 25.29
BMI range 22.329.0 18.630.2
Race, n(%)
8 (100) 94 (98)
AsianCentral/South Asian Heritage 1 (1)
AsianSouth East Asian Heritage 1 (1)
Note. BMI: body mass index; SD: standard deviation; ITT: intentionto
TABLE 2 Mean (CVb%) plasma BHB pharmacokinetic parameters from Part 1
Regimen Nt
Placebo corrected
Placebo corrected
(hr * mmol/L)
Placebo 8 3.02 (0.008.04)
GSK2981710 10 g 6 0.52 (0.512.50) 0.119 (36.5) 0.287 (43.6)
GSK2981710 20 g 6 0.52 (0.503.01) 0.451 (66.4) 1.110 (61.6)
GSK2981710 30 g 6 1.26 (0.503.51) 0.452 (184.5) 1.659 (64.8)
GSK2981710 40 g 6 2.26 (0.505.51) 0.588 (78.2) 2.277 (61.4)
Median (range); AUC
: area under the plasma concentrationtime curve to the last quantified concentration; BHB: βhydroxybutyrate; C
: maximum
observed plasma concentration; CVb: between participant coefficient of variation; t
: time to first observation of C
cognition, measured using the ADASCog, at plasma BHB levels similar
to those achieved in the current study (Henderson et al., 2009).
Another study in patients with AD or MCI showed a significant corre-
lation between elevated plasma BHB following MCT treatment and
improvements in paragraph recall compared with placebo (Reger
et al., 2004). A study of healthy adults with insulininduced
hypoglycaemia, showed infusion of BHB reversed the effects of
hypoglycaemiainduced cognitive dysfunction (Veneman et al., 1994).
However, in all these studies the effects were observed in a popula-
tion with diseaserelated pathology (i.e. amyloid; Reger et al., 2004)
and/or reduced glucose metabolism (Veneman et al., 1994). In this
study, although participants with memory impairment were selected
and hypothesised to have lower glucose metabolism, this was not con-
firmed using imaging techniques such as fluorodeoxyglucose positron
emission tomography. The lack of treatment effect in this study could
be due to participants already having sufficient neuronal metabolism
to perform cognitive tasks optimally.
There are, however, several important methodological consider-
ations. Firstly, previous studies that reported positive cognitive effects
with MCT following both acute (Reger et al., 2004) and chronic admin-
istration (Day 45 and Day 90; Henderson et al., 2009) only observed a
significant treatment effect in APOE4 noncarriers. However, a similar
openlabel study in Japanese patients with AD reported no effects in
APOE4 negative patients. Additionally, in the previous positive stud-
ies, when all genotypes were examined, MCT administration provided
no consistent and significant cognitive benefits (Henderson et al.,
2009; Reger et al., 2004), consistent with our observations. No geno-
type data were collected in our study, so APOE4specific effects could
not be examined. Secondly, negative findings in this study may also be
related to insufficient BHB plasma concentrations following
GSK2981710 administration, indicating that the 30 g dose may not
be optimal. Mean concentrations in the two treatment sessions were
0.276 and 0.291 mmol/L and were below the hypothesised effective
concentration of 0.4 mmol/L. In studies in patients with MCI and
AD, mean plasma levels ranged from 0.36 to 0.39 mmol/L (Henderson
et al., 2009) and 0.43 to 0.68 mmol/L (Reger et al., 2004), suggesting
that positive effects on cognition are more likely to be observed when
concentrations are >0.36 mmol/L. This is supported by findings that
cognitive performance is highly correlated with BHB concentrations,
irrespective of APOE4 genotype (Henderson et al., 2009; Reger
et al., 2004). Thirdly, these differences could relate to optimal concen-
trations of BHB (as discussed above) rather than treatment duration.
The positive effects of MCTs on cognition have been observed after
both acute (Reger et al., 2004) and chronic treatment over a 90day
period (Henderson et al., 2009). In the latter study however, the
effects on day 45 and 90 were observed and patients BHB levels were
high following dosing (i.e., testing performed 2hr postdose during the
rise in plasma BHB; Henderson et al., 2009). This raises the possibility
that the observed effect may be due to an acute effect following the
dose at day 45 and 90 rather than a chronic effect due to
FIGURE 2 Individual BHB concentrationtime profile, Part 1 (a) and Part 2 (b). In Part 1, plasma BHB concentrations peaked within 2 hr before
returning to predose levels within 8 hr. In Part 2, plasma BHB concentrations at 1hr postdose on Day 1 for GSK2981710 30 g were consistent
with Part 1. Plasma BHB concentrations on Day 15 were similar to predose levels on Day 1. Thicker line: median. BHB: βhydroxybutyrate.
TABLE 3 Mean (SD) BHB concentrations (mmol/L) in Part 2
Session 1 Session 2
Predose Day 1, 1hr postdose Day 15 Predose Day 1, 1hr postdose Day 15
Placebo 0.088 (0.055) 0.058 (0.019) 0.054 (0.023) 0.094 (0.078) 0.064 (0.031) 0.055 (0.023)
GSK2981710 30 g 0.087 (0.043) 0.291 (0.175) 0.083 (0.088) 0.080 (0.049) 0.276 (0.178) 0.054 (0.019)
Note. BHB: βhydroxybutyrate; SD: standard deviation.
8of14 O'NEILL ET AL.
accumulation of BHB concentrations, given that it would be unlikely
for BHB levels to accumulate as shown in the current study and the
prior study (Henderson et al., 2009). In the current study, participants
received GSK2981710 for only 14 days, and cognitive assessments
were carried out on Days 1 (immediately postdose to investigate acute
effects) and 15 (approximately 24hr post final dose [i.e. when BHB
levels have returned to baseline levels] to investigate effects of
prolonged treatment over 14 days). Our findings suggest that even
with 14 days of treatment, there were no prolonged effects when
BHB levels returned to baseline levels. This provide some evidence
to suggest that the positive effect reported in the Henderson et al.
(2009) study may indeed be related to the acute effect following the
Days 45 and 90 doses when BHB levels were rising postdose rather
than an accumulation of BHB levels over 90 days leading to chronic
effect. The latter would be unlikely due to BHB levels returning to
baseline levels within 8 hr.
FIGURE 3 Adjusted mean changes from baseline (95% CI) in CANTAB learning tasks: paired associates learning task* (a), verbal recognition
memory task(b), spatial working memory task* (c), rapid visual processing task(d), and reaction time* (e). There was no significant difference
between GSK2981710 30 g and placebo for CANTAB assessments on Days 1 and 15 (pvalues: 0.0980.983). *Lower values correspond to better
performance; higher values correspond to better performance. CANTAB: Cambridge Neuropsychological Test Automated Battery; CI: confidence
interval; PAL: paired associates learning; RTI: reaction time; RVP: rapid visual processing; SWM: spatial working memory; VRM: verbal recognition
Finally, MCT effects on cognitive function may be influenced by
C8 to C10 ratio. The MCT used in the AC1202 study was composed
mainly of glycerine and caprylic acid (C8:0), with 95% C8: 5%
C10/C6 (Henderson et al., 2009), whereas GSK2981710 contains
more C10:0 fatty acids (55% C8: 45% C10). These differences have
been shown to influence ketone body generation in a preclinical
rhesus monkey model (Tetrick, Greer, & Benevenga, 2010). However,
as the BHB levels observed with 30 g of GSK2981710 were similar
to those observed with AC1202, it is unlikely that differences in
the ability to generate ketone bodies between the two formulations
impacted efficacy.
There are numerous limitations, which may have impacted the
study. Firstly, the cognitive dysfunction of the study population may
have been too heterogeneous and/or mild at baseline to observe a
consistent treatment effect. Positive findings were reported in
patients with greater cognitive impairment at baseline (and potentially
greater abnormality in glucose metabolism), potentially contributing to
the procognitive benefit. Secondly, although we hypothesised that
healthy older adults enrolled in this study would have abnormal glu-
cose metabolism, this was not confirmed using fluorodeoxyglucose
positron emission tomography imaging. It is possible that not all partic-
ipants had abnormal glucose metabolism, would require an alternative
neuronal energy source, and would gain benefit from GSK2981710.
Although the previous MCT studies discussed (Henderson et al.,
2009; Reger et al., 2004) did not confirm reduced glucose metabolism
either, the inclusion of patients with MCI or AD with diseaserelated
pathology suggests that these patients had greater glucose metabo-
lism abnormalities compared with this study. In addition, the samples
administered in this study consisted of MCT and other excipient ingre-
dients including maltodextrin. Previous research has reported and
impaired ketogenesis with increased insulin (Elkeles, Wu, & Hambley,
1978). As such, maltodextrin levels in samples administered in the cur-
rent study may have led to increased insulin, an associated negative
impact on ketone production thereby influencing the reported results.
Finally, cognitive assessments on Day 1 were conducted after break-
fast, when MCT efficacy may have been blunted by subsequent glu-
cose surges. Previous studies that demonstrated efficacy
administered treatment either after an overnight fast, when blood glu-
cose levels were likely low (Reger et al., 2004), or during/after break-
fast, similar to the present study (Henderson et al., 2009). Therefore, it
is unclear whether the variations in efficacy are due to food intake.
Although meal components may have affected MCT absorption and
bioavailability (Bushra, Aslam, & Khan, 2011), this is unlikely as
postdose ketone levels were measured under similar conditions in
Parts 1 and 2.
In summary, this study examined the effects of an alternative
energy source on brain activity and cognitive function in a popula-
tion of healthy older adults with presumed abnormalities in glucose
metabolism. Over a duration of 14 days, increasing plasma BHB
levels with daily administration of GSK2981710 30 g had no effects
on any measure of neuronal activity or cognitive function. The lack
of effect on brain activity and cognitive function in this study sug-
gests that modulating plasma ketones with this particular type of
MCT formulation may not be effective in improving cognitive func-
tion in healthy older subjects. However, the observed results may
be related to the study population, plasma BHB concentrations,
MCT composition, and treatment duration. Further studies address-
ing these particular points are warranted to examine the potential
benefit of ketones as a therapeutic strategy for the treatment of
cognitive impairment.
This work was supported by GlaxoSmithKline (GSK study EMI11
FIGURE 4 Adjusted mean changes (95% CI)
from baseline in source memory task
assessment scores on Day 1*. There was no
significant difference between GSK2981710
30 g and placebo for item memory (p= 0.863)
and source memory (p= 0.805) tasks. *Higher
values correspond to better performance. CI:
confidence interval
10 of 14 O'NEILL ET AL.
The authors wish to thank the investigators and the subjects who
participated in this study, and Paul O'Regan, PhD, Fishawack Indicia
Ltd, UK, who provided editorial assistance with developing this
manuscript (in the form of writing assistance, including development
of the initial draft from the clinical study report, assembling tables
and figures, collating authors comments, grammatical editing, and
referencing). Editorial support was funded by GSK. The authors would
like to thank the recruitment coordinator Judy Gilbert and research
nurse Elizabeth Redman for all their help with identifying the
participants and collecting the clinical data for this study, respectively.
Anonymised individual participant data and study documents
can be requested for further research from www.clinicalstudydata
FIGURE 5 Pharmacokineticpharmacodynamic correlations. PD assessments showed no significant correlation between plasma BHB
concentration and CANTAB and source memory task assessment scores. *Lower values correspond to better performance; higher values
correspond to better performance. BHB: βhydroxybutyrate; CANTAB: Cambridge Neuropsychological Test Automated Battery; PAL: paired
associates learning; PD: postdose; RTI: reaction time; RVP: rapid visual processing; SWM: spatial working memory; VRM: verbal recognition
O'NEILL ET AL.11 of 14
SRM, JB, CC, SK, MD, SS, and JP are employees of GlaxoSmithKline
(GSK) and own their own GSK stock. BVO'N, AG, CMD, OD, PL, and
PJN are former employees of GSK. Their role included study concept
and design, funding of participating centres, analysis of data, develop-
ment, and funding of the final report and manuscript. OD and PJN are
current employees of Heptares Therapeutics Ltd.
The authors have declared that there is no conflict of interest.
Barry V. O'Neill
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How to cite this article: O'Neill BV, Dodds CM, Miller SR,
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... Of these, seven studies had ineligible study population and four had ineligible intervention. Six RCTs were included in the systematic review ( Fig. 1) [16,[18][19][20][21][22]. ...
... Four studies used MCT oils as a supplement [18][19][20]22], while two studies used MCT oils in a mixed meal [16,21]. MCT supplementation was given daily in four studies [18][19][20]22]and on separate days in two studies [16,21]. ...
... Four studies used MCT oils as a supplement [18][19][20]22], while two studies used MCT oils in a mixed meal [16,21]. MCT supplementation was given daily in four studies [18][19][20]22]and on separate days in two studies [16,21]. Treatment duration ranged from < 10 days [16,21], two weeks [19], to three months [18,20,22]. ...
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Background Ketosis has been exploited for its neuroprotective impact and treatment of neurological conditions via ketone production. Exogenous medium-chain triglyceride (MCT) supplementation may induce nutritional ketosis. The aim of this systematic review is to explore the effects of MCTs on memory function in older adults without cognitive impairment. Methods A systematic literature search of PubMed, Cochrane Library, Scopus, and Web of Science was employed from inception until April 2022 for randomized controlled trials (RCTs) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, investigating the impact of MCT oils on components of memory. Risk of bias (RoB2) tool was utilized for quality assessment. Results Six trials were included for qualitative synthesis, in which two studies examined the effect of MCTs through a ketogenic meal. MCT supplementation compared to controls was associated with improved indices of memory function in 4 out of 6 studies, particularly working memory. A meta-analysis was not employed due to the low number of studies, therefore, a true effect measure of MCT supplementation was not explored. Conclusions MCT supplementation may enhance working memory in non-demented older adults. These effects may be more prominent in individuals with lower baseline scores, from short and long-term supplementation. Further studies are warranted to confirm these findings in terms of optimal dose and MCTs composition, which may protect from memory decline during aging.
... Since 2019, we found ten studies, in humans, aiming at improving cognitive performance or biomarkers of AD (See Table 1) (13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Among them, seven used KS vs. placebo and three KD vs. control diet. ...
... On the other hand, in older adults with mild cognitive impairment (MCI) Fortier et al. showed that 30 g of MCT supplementation over a 6-month follow, significantly improved three major cognitive functions: episodic memory, executive function and language (19). Three studies in healthy participants used KS over very short intervention windows (0-5weeks) and reported improved cognitive functions and/or brain metabolism (14,16,22). ...
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Alzheimer's disease (AD) is the most frequent age-related neurodegenerative disorder, with no curative treatment available so far. Alongside the brain deposition of β-amyloid peptide and hyperphosphorylated tau, neuroinflammation triggered by the innate immune response in the central nervous system, plays a central role in the pathogenesis of AD. Glucose usually represents the main fuel for the brain. Glucose metabolism has been related to neuroinflammation, but also with AD lesions. Hyperglycemia promotes oxidative stress and neurodegeneration. Insulinoresistance (e.g., in type 2 diabetes) or low IGF-1 levels are associated with increased β-amyloid production. However, in the absence of glucose, the brain may use another fuel: ketone bodies (KB) produced by oxidation of fatty acids. Over the last decade, ketogenic interventions i.e., ketogenic diets (KD) with very low carbohydrate intake or ketogenic supplementation (KS) based on medium-chain triglycerides (MCT) consumption, have been studied in AD animal models, as well as in AD patients. These interventional studies reported interesting clinical improvements in animals and decrease in neuroinflammation, β-amyloid and tau accumulation. In clinical studies, KS and KD were associated with better cognition, but also improved brain metabolism and AD biomarkers. This review summarizes the available evidence regarding KS/KD as therapeutic options for individuals with AD. We also discuss the current issues and potential adverse effects associated with these nutritional interventions. Finally, we propose an overview of ongoing and future registered trials in this promising field.
... Among the eight studies, participants comprised healthy ageing subjects (N ¼ 2) [18,19] ], individuals with dementia based on clinical diagnostic criteria (N ¼ 1) [23], nursing home residents (N ¼ 1) [24] or healthy young students (N ¼ 1) [25]; mean age was 20-85 years old. These studies included limited numbers of participants , limited follow-up durations (2 weeks to 6 months for all studies but one examining the immediate effects of different MCT intakes), inconsistent sex ratios, various degrees of cognitive impairment, only two studies used cerebrospinal fluid (CSF) AD biomarkers [ ]. ...
... Overall, ketosis might be quickly and sustainably reached, irrespective of the kind of intervention but also of the age or cognitive status of participants. However, O'Neill et al. reported that after GSK2981710 administration (30 g/day), participants showed increased peak plasma BHB concentrations, but above the hypothesized effective concentration of 0.4 mmol/l [18]. ...
... This enzyme contributes to the homoeostatic control of plasma lipoprotein levels and to the prevention of cellular lipid overload in the liver, spleen, and their Mφs [197]. The Cer and TGs are involved in various cellular processes, which regulate lipid-protein interactions and the cell signaling events critical for the proper function of the organs [198][199][200][201]. However, LIPA/Lipa defect and resulting deficiency of LAL cause progressive lysosomal accumulation of CEs and TGs, which can affect multiple organs, such as the liver, spleen, adrenal gland, and intestine, as well as a variety of cells including neuronal stem cells, hepatocytes, MOs, and Mφs. ...
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Lysosomal storage diseases are a group of rare and ultra-rare genetic disorders caused by defects in specific genes that result in the accumulation of toxic substances in the lysosome. This excess accumulation of such cellular materials stimulates the activation of immune and neurological cells, leading to neuroinflammation and neurodegeneration in the central and peripheral nervous systems. Examples of lysosomal storage diseases include Gaucher, Fabry, Tay–Sachs, Sandhoff, and Wolman diseases. These diseases are characterized by the accumulation of various substrates, such as glucosylceramide, globotriaosylceramide, ganglioside GM2, sphingomyelin, ceramide, and triglycerides, in the affected cells. The resulting pro-inflammatory environment leads to the generation of pro-inflammatory cytokines, chemokines, growth factors, and several components of complement cascades, which contribute to the progressive neurodegeneration seen in these diseases. In this study, we provide an overview of the genetic defects associated with lysosomal storage diseases and their impact on the induction of neuro-immune inflammation. By understanding the underlying mechanisms behind these diseases, we aim to provide new insights into potential biomarkers and therapeutic targets for monitoring and managing the severity of these diseases. In conclusion, lysosomal storage diseases present a complex challenge for patients and clinicians, but this study offers a comprehensive overview of the impact of these diseases on the central and peripheral nervous systems and provides a foundation for further research into potential treatments.
... Decanoic acid is able to modulate astrocyte metabolism directly, leading to activation of the astrocyte-neuron lactate shuttle and providing fuel to neighboring neurons in the form of lactate (130,131). Healthy participants between 55 and 80 years had no effects on cognitive function with supplementation of 30 g MCT for a period of 2 weeks (132). ...
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Ketogenic diets and orally administered exogenous ketone supplements are strategies to increase serum ketone bodies serving as an alternative energy fuel for high energy demanding tissues, such as the brain, muscles, and the heart. The ketogenic diet is a low-carbohydrate and fat-rich diet, whereas ketone supplements are usually supplied as esters or salts. Nutritional ketosis, defined as serum ketone concentrations of ≥ 0.5 mmol/L, has a fasting-like effect and results in all sorts of metabolic shifts and thereby enhancing the health status. In this review, we thus discuss the different interventions to reach nutritional ketosis, and summarize the effects on heart diseases, epilepsy, mitochondrial diseases, and neurodegenerative disorders. Interest in the proposed therapeutic benefits of nutritional ketosis has been growing the past recent years. The implication of this nutritional intervention is becoming more evident and has shown interesting potential. Mechanistic insights explaining the overall health effects of the ketogenic state, will lead to precision nutrition for the latter diseases.
... O'Neill et al. conducted a randomized, double-blind crossover study of 80 subjects aged 55-80 years with MCI (94). They reported that when 30 g/day of MCTs (C8:C10 = 55:45) were ingested for 2 weeks, there was no significant difference in performance in cognitive function tests such as short-term memory, attention, and executive function from the comparison control, although there was a significant increase in beta hydroxybutyrate concentration. ...
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In the 1950s, the production of processed fats and oils from coconut oil was popular in the United States. It became necessary to find uses for the medium-chain fatty acids (MCFAs) that were byproducts of the process, and a production method for medium-chain triglycerides (MCTs) was established. At the time of this development, its use as a non-fattening fat was being studied. In the early days MCFAs included fatty acids ranging from hexanoic acid (C6:0) to dodecanoic acid (C12:0), but today their compositions vary among manufacturers and there seems to be no clear definition. MCFAs are more polar than long-chain fatty acids (LCFAs) because of their shorter chain length, and their hydrolysis and absorption properties differ greatly. These differences in physical properties have led, since the 1960s, to the use of MCTs to improve various lipid absorption disorders and malnutrition. More than half a century has passed since MCTs were first used in the medical field. It has been reported that they not only have properties as an energy source, but also have various physiological effects, such as effects on fat and protein metabolism. The enhancement of fat oxidation through ingestion of MCTs has led to interest in the study of body fat reduction and improvement of endurance during exercise. Recently, MCTs have also been shown to promote protein anabolism and inhibit catabolism, and applied research has been conducted into the prevention of frailty in the elderly. In addition, a relatively large ingestion of MCTs can be partially converted into ketone bodies, which can be used as a component of “ketone diets” in the dietary treatment of patients with intractable epilepsy, or in the nutritional support of terminally ill cancer patients. The possibility of improving cognitive function in dementia patients and mild cognitive impairment is also being studied. Obesity due to over-nutrition and lack of exercise, and frailty due to under-nutrition and aging, are major health issues in today's society. MCTs have been studied in relation to these concerns. In this paper we will introduce the results of applied research into the use of MCTs by healthy subjects.
... Following the 3-month intervention, MCT supplementation increased the MMSE score by 3.5 points from a mean baseline of 17.5, whereas LCT supplementation decreased MMSE score by − 0.7 points from a mean baseline of 17. In contrast, O'Neill et al. [79] assessed the impact of a 14-day trial of an MCT called GSK2981710 in a double-blind, randomized, placebo-controlled crossover study with 80 healthy older adults. Although 30 g/day resulted in peak β-OHB concentrations, there were no significant improvements in cognitive function or memory-related neuronal activity. ...
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Purpose of Review Increasing evidence points toward the importance of diet and its impact on cognitive decline. This review seeks to clarify the impact of four diets on cognition: the Mediterranean diet, the anti-inflammatory diet, the Seventh Day Adventist diet, and the Ketogenic diet. Recent Findings Of the diets reviewed, the Mediterranean diet provides the strongest evidence for efficacy. Studies regarding the anti-inflammatory diet and Seventh Day Adventist diet are sparse, heterogeneous in quality and outcome measurements, providing limited reliable data. There is also minimal research confirming the cognitive benefits of the Ketogenic diet. Summary Increasing evidence supports the use of the Mediterranean diet to reduce cognitive decline. The MIND-diet, a combination of the Mediterranean and DASH diets, seems especially promising, likely due to its anti-inflammatory properties. The Ketogenic diet may also have potential efficacy; however, adherence in older populations may be difficult given frequent adverse effects. Future research should focus on long-term, well-controlled studies confirming the impact of various diets, as well as the combination of diets and lifestyle modification.
... Dietary supplementation or restriction of a specific group of lipids could be an opportunity to modify the diet if it helps to improve the cognitive functions in T2DM (47,48). A recent randomized, placebo-controlled study evaluated the effects of supplementation of medium-chain triglycerides GSK2981710 in healthy older participants for improving cognitive functions in aging (49). In another study, inhibition of specific lipid was demonstrated in an animal model as a therapeutic target to prevent obesity and T2DM (48). ...
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The magnitude of type 2 diabetes mellitus (T2DM) is ever-increasing in India, and at present, ~77 million people live with diabetes. Studies have established that T2DM increases the risk of neurodegenerative disorders. This study aimed to determine the age-related prevalence of mild cognitive impairment (MCI) in T2DM patients in the Indian population and to identify link between cognitive dysfunction in T2DM patients and serum lipid composition through untargeted and targeted lipidomic studies. Using a cross-sectional study, we evaluated 1278 T2DM patients with Montreal cognitive assessment test (MoCA) and digit symbol substitution test (DSST) for cognitive functions. As per MoCA, the prevalences of MCI in T2DM patients in age groups below 40, 41-50, 51-60, 61-70, 71-80 and 81-90 years were 13.7, 20.5, 33.5, 43.7, 57.1 and 75% with DSST scores of 45.8, 41.7, 34.4, 30.5, 24.2 and 18.8% respectively. Binomial logistic regression analysis revealed serum HbA1c ≥ 7.51, duration of T2DM over 20 years, age above 41 years, and females were independent contributors for cognitive dysfunction in T2DM patients. Preliminary studies with untargeted lipidomics of the serum from 20 T2DM patients, including MCI and normal cognition (NC) group, identified a total of 646 lipids. Among the identified lipids, 33 lipids were significantly different between MCI and NC group, which comprised of triglycerides (TGs, 14), sphingolipids (SL, 11), and phosphatidylcholines (PC, 5). Importantly, 10 TGs and 3 PCs containing long-chain polyunsaturated fatty acids (PUFA) were lower, while 8 sphingolipids were increased in the MCI group. Since brain-derived sphingolipids are known to get enriched in the serum, we further quantified sphingolipids from the same 20 serum samples through targeted lipidomic analysis, which identified a total of 173 lipids. Quantitation revealed elevation of 3 species of ceramides, namely Cer (d18:1_24:1), Hex1Cer (d16:0_22:6), and Hex2Cer (d28:1) in the MCI group compared to the NC group of T2DM patients. Overall, this study demonstrated an age-related prevalence of MCI in T2DM patients and highlighted reduced levels of several species of PUFA containing TGs and PCs and increased levels of specific ceramides in T2DM patients exhibiting MCI. Large-scale lipidomic studies in future could help understand the cognitive dysfunction domain in T2DM patients, while studies with preclinical models are required to understand the functional significance of the identified lipids.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is mainly characterized by cognitive deficits. Although many studies have been devoted to developing disease-modifying therapies, there has been no effective therapy until now. However, dietary interventions may be a potential strategy to treat AD. The ketogenic diet (KD) is a high-fat and low-carbohydrate diet with adequate protein. KD increases the levels of ketone bodies, providing an alternative energy source when there is not sufficient energy supply because of impaired glucose metabolism. Accumulating preclinical and clinical studies have shown that a KD is beneficial to AD. The potential underlying mechanisms include improved mitochondrial function, optimization of gut microbiota composition, and reduced neuroinflammation and oxidative stress. The review provides an update on clinical and preclinical research on the effects of KD or medium-chain triglyceride supplementation on symptoms and pathophysiology in AD. We also detail the potential mechanisms of KD, involving amyloid and tau proteins, neuroinflammation, gut microbiota, oxidative stress, and brain metabolism. We aimed to determine the function of the KD in AD and outline important aspects of the mechanism, providing a reference for the implementation of the KD as a potential therapeutic strategy for AD.
Purpose of review: Ketogenic diets (KD) are validated treatments of pharmacoresistant epilepsy. Their interest in neurodegenerative diseases such as Alzheimer's disease (AD) has been suggested, because ketone bodies may reduce neuroinflammation, improve neurotransmitters transport pathway, synaptic maintenance, and reduce brain β-amyloid deposition. In this updated review, we aimed at critically examining the evidence of the past 2 years regarding KD or ketogenic supplements (KS) on cognitive and biological/neuropathological outcomes. We conducted our search in preclinical studies (animal models of AD) or in humans with or without cognitive impairment. Recent findings: Overall, 12 studies were included: four in animal models of AD and eight in humans. In preclinical studies, we found additional evidence for a decrease in cerebral inflammation as well as in specific features of AD: β-amyloid, aggregates of tau protein under KD/KS. Several AD mouse models experienced clinical improvements. Human studies reported significant cognitive benefits, improved brain metabolism and biomarkers change under KD/KS, despite rather short-term interventions. Adherence to KD or KS was acceptable with frequent, but minor gastrointestinal adverse effects. Summary: The present review gathered additional evidence for both pathophysiological and clinical benefits of KS/KD in AD. Further studies are warranted with a biomarker-based selection of AD participants and long-term follow-up.
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Source monitoring paradigms have been used to separate: 1) the probability of recognising an item (Item memory) and 2) the probability of remembering the context in which that item was previously encountered (Source memory), conditional on it being recognised. Multinomial Processing Tree (MPT) models are an effective way to estimate these conditional probabilities. Moreover, MPTs make explicit the assumptions behind different ways to parameterise Item and Source memory. Using data from six independent groups across two different paradigms, we show that one would draw different conclusions about the effects of age, age-related memory problems and hippocampal lesions on Item and Source memory, depending on the use of: 1) standard accuracy calculation vs MPT analysis, and 2) two different MPT models. The MPT results were more consistent than standard accuracy calculations, and furnished additional parameters that can be interpreted in terms of, for example, false recollection or missed encoding. Moreover, a new MPT structure that allowed for separate memory representations (one for item information and one for item-plus-source information; the Source-Item model) fit the data better, and provided a different pattern of significant differences in parameters, than the more conventional MPT structure in which source information is a subset of item information (the Item-Source model). Nonetheless, there is no theory-neutral way of scoring data, and thus proper examination of the assumptions underlying the scoring of source monitoring paradigms is necessary before theoretical conclusions can be drawn.
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We propose that brain energy deficit is an important pre-symptomatic feature of Alzheimer's disease (AD) that requires closer attention in the development of AD therapeutics. Our rationale is fourfold: (i) Glucose uptake is lower in the frontal cortex of people >65 years-old despite cognitive scores that are normal for age. (ii) The regional deficit in brain glucose uptake is present in adults <40 years-old who have genetic or lifestyle risk factors for AD but in whom cognitive decline has not yet started. Examples include young adult carriers of presenilin-1 or apolipoprotein E4, and young adults with mild insulin resistance or with a maternal family history of AD. (iii) Regional brain glucose uptake is impaired in AD and mild cognitive impairment (MCI), but brain uptake of ketones (beta-hydroxybutyrate and acetoacetate), remains the same in AD and MCI as in cognitively healthy age-matched controls. These observations point to a brain fuel deficit which appears to be specific to glucose, precedes cognitive decline associated with AD, and becomes more severe as MCI progresses toward AD. Since glucose is the brain's main fuel, we suggest that gradual brain glucose exhaustion is contributing significantly to the onset or progression of AD. (iv) Interventions that raise ketone availability to the brain improve cognitive outcomes in both MCI and AD as well as in acute experimental hypoglycemia. Ketones are the brain's main alternative fuel to glucose and brain ketone uptake is still normal in MCI and in early AD, which would help explain why ketogenic interventions improve some cognitive outcomes in MCI and AD. We suggest that the brain energy deficit needs to be overcome in order to successfully develop more effective therapeutics for AD. At present, oral ketogenic supplements are the most promising means of achieving this goal.
Background: The Cambridge Neuropsychological Test Automated Battery (CANTAB) was used to explore which tests and their measures are able to detect cognitive change after a single dose of donepezil in Alzheimer disease (AD) patients. The aim of this study was to establish the ability of CANTAB tests and their measures to detect cognitive change after a single 5-mg dose of donepezil in treatment-naïve AD patients. Material/Methods: We enrolled 62 treatment-naïve AD patients and 30 healthy controls in this prospective, randomized, rater- blinded study. AD patients were randomized to 2 groups: the AD+ group received donepezil after the first CANTAB testing and the AD– group remained treatment-naïve at second testing. The time period between repeated testing was 4 hours. Parallel versions of CRT, SOC, PAL, SWM, and PRM tests were used. Results: All groups did not differ according to age, education, gender, or depression (p>0.05). AD+ and AD– groups did not differ according to MMSE. SOC, PAL, PRM, and SWM tests distinguished AD from controls. Eight measures of PAL and PRM had a strong correlation with MMSE (r>0.7). Repeated-measures ANOVA with Bonferroni posthoc test showed the difference of change in AD+ and AD– groups between first and second CANTAB testing in 7 PAL measures. AD+ and AD– groups differed in the second testing by 7 PAL measures. Four PAL measures differed in first and second testing within the AD+ group. Conclusions: The CANTAB PAL test measures, able to detect cognitive change after a single dose of donepezil in AD patients, are: PAL mean trials to success, total errors (adjusted), total errors (6 shapes, adjusted), and total trials (adjusted).
Background: In Alzheimer's disease (AD), it is unknown whether the brain can utilize additional ketones as fuel when they are derived from a medium chain triglyceride (MCT) supplement. Objective: To assess whether brain ketone uptake in AD increases in response to MCT as it would in young healthy adults. Methods: Mild-moderate AD patients sequentially consumed 30 g/d of two different MCT supplements, both for one month: a mixture of caprylic (55%) and capric acids (35%) (n = 11), followed by a wash-out and then tricaprylin (95%; n = 6). Brain ketone (11C-acetoacetate) and glucose (FDG) uptake were quantified by PET before and after each MCT intervention. Results: Brain ketone consumption doubled on both types of MCT supplement. The slope of the relationship between plasma ketones and brain ketone uptake was the same as in healthy young adults. Both types of MCT increased total brain energy metabolism by increasing ketone supply without affecting brain glucose utilization. Conclusion: Ketones from MCT compensate for the brain glucose deficit in AD in direct proportion to the level of plasma ketones achieved.
Introduction: Deteriorating brain glucose metabolism precedes the clinical onset of Alzheimer's disease (AD) and appears to contribute to its etiology. Ketone bodies, mainly β-hydroxybutyrate and acetoacetate, are the primary alternative brain fuel to glucose. Some reports suggest that brain ketone metabolism is unchanged in AD but, to our knowledge, no such data are available for MCI. Objective: To compare brain energy metabolism (glucose and acetoacetate) and some brain morphological characteristics in cognitively healthy older adult controls (CTL), mild cognitive impairment (MCI) and early AD. Methods: 24 CTL, 20 MCI and 19CE of similar age and metabolic phenotype underwent a dual-tracer PET and MRI protocol. The uptake rate constants and cerebral metabolic rate of glucose (KGlu, CMRGlu) and acetoacetate (KAcAc, CMRAcAc) were evaluated with PET using [(18)F]-fluorodeoxyglucose ([(18)F]-FDG), a glucose analogue, and [(11)C]-acetoacetate ([(11)C]-AcAc), a ketone PET tracer. Regional brain volume segmentation and cortical thickness were evaluated by T1-weighted MRI RESULTS: In AD compared to CTL, CMRGlu was ~11% lower in the frontal, parietal, temporal lobes and in the cingulate gyrus (p<0.05). KGlu was ~15% lower in these same regions and also in subcortical regions. In MCI compared to CTL, ~7% glucose hypometabolism was present in the cingulate gyrus. Neither regional nor whole brain CMRAcAc or KAcAc were significantly different between CTL and MCI or AD. Reduced gray matter volume and cortical thinning were widespread in AD compared to CTL, whereas, in MCI compared to CTL, volumes were reduced only in the temporal cortex and cortical thinning was more apparent in temporal and cingulate regions. Discussion: This quantitative kinetic PET and MRI imaging protocol for brain glucose and acetoacetate metabolism confirms that the brain undergoes structural atrophy and lower brain energy metabolism in MCI and AD that demonstrates that the deterioration in brain energy metabolism is specific to glucose. These results suggest that a ketogenic intervention to increase energy availability for the brain is warranted in an attempt to delay further cognitive decline by compensating for the brain glucose deficit in MCI and AD.
The development of novel treatments for Alzheimer's disease (AD), aimed at ameliorating symptoms and modifying disease processes, increases the need for early diagnosis. Neuropsychological deficits such as poor episodic memory are a consistent feature of early-in-the-course AD, but they overlap with the cognitive impairments in other disorders such as depression, making differential diagnosis difficult. Computerised and traditional tests of memory, attention and executive function were given to four subject groups: mild AD (n = 26); questionable dementia (QD; n = 43); major depression (n = 37) and healthy controls (n = 39). A visuo-spatial associative learning test accurately distinguished AD from de-pressed/control subjects and revealed an apparent subgroup of QD patients who performed like AD patients. QD patients' performance correlated with the degree of subsequent global cognitive decline. Elements of con-textual and cued recall may account for the task's sensitivity and specificity for AD.
Few studies have examined the relationship between CSF and structural biomarkers, and cognitive function in MCI. We examined the relationship between cognitive function, hippocampal volume and cerebrospinal fluid (CSF) Aβ42 and tau in 145 patients with MCI. Patients were assessed on cognitive tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB), the Geriatric Depression Scale and the Functional Activities Questionnaire. Hippocampal volume was measured using magnetic resonance imaging (MRI), and CSF markers of Aβ42, tau and p-tau181 were also measured. Worse performance on a wide range of memory and sustained attention tasks were associated with reduced hippocampal volume, higher CSF tau and p-tau181 and increased tau/Aβ42 ratio. Memory tasks were also associated with lower ability to conduct functional activities of daily living, providing a link between AD biomarkers, memory performance and functional outcome. These results suggest that biomarkers of Aβ and tau are strongly related to cognitive performance as assessed by the CANTAB, and have implications for the early detection and characterization of incipient AD.
Two of the most devastating neurodegenerative diseases are consequences out of misfolding and aggregation of key proteins-alpha synuclein and beta-amyloid. Although the primary targets for the two proteins are different, they both share a common mechanism that involves formation of pore-like structure on the plasma membrane, consequent dysregulation of calcium homeostasis, mitochondrial dysfunction and oxidative damage. The combined effect of all this factors ultimately leads to neuronal cell death. Whereas beta amyloid acts on the astrocytic plasma membrane, exhibiting a tight dependence to the membrane cholesterol content, alpha-synuclein does not distinguish between type of membrane or cell. Additionally, oligomeric forms of both proteins produce reactive oxygen species through different mechanisms: beta-amyloid through activation of the NADPH oxidase and alpha-synuclein through non-enzymatic way. Finally, both peptides in oligomeric form induce mitochondrial depolarisation through calcium overload and free radical production that ultimately lead to opening of the mitochondrial permeability transition pore and trigger cell death.
Aging, hypertension, diabetes, hypoxia/obstructive sleep apnea (OSA), obesity, vitamin B12/folate deficiency, depression, and traumatic brain injury synergistically promote diverse pathological mechanisms including cerebral hypoperfusion and glucose hypometabolism. These risk factors trigger neuroinflammation and oxidative-nitrosative stress that in turn decrease nitric oxide and enhance endothelin, Amyloid-β deposition, cerebral amyloid angiopathy, and blood-brain barrier disruption. Proinflammatory cytokines, endothelin-1, and oxidative-nitrosative stress trigger several pathological feedforward and feedback loops. These upstream factors persist in the brain for decades, upregulating amyloid and tau, before the cognitive decline. These cascades lead to neuronal Ca(2+) increase, neurodegeneration, cognitive/memory decline, and Alzheimer's disease (AD). However, strategies are available to attenuate cerebral hypoperfusion and glucose hypometabolism and ameliorate cognitive decline. AD is the leading cause of dementia among the elderly. There is significant evidence that pathways involving inflammation and oxidative-nitrosative stress (ONS) play a key pathophysiological role in promoting cognitive dysfunction. Aging and several comorbid conditions mentioned above promote diverse pathologies. These include inflammation, ONS, hypoperfusion, and hypometabolism in the brain. In AD, chronic cerebral hypoperfusion and glucose hypometabolism precede decades before the cognitive decline. These comorbid disease conditions may share and synergistically activate these pathophysiological pathways. Inflammation upregulates cerebrovascular pathology through proinflammatory cytokines, endothelin-1, and nitric oxide (NO). Inflammation-triggered ONS promotes long-term damage involving fatty acids, proteins, DNA, and mitochondria; these amplify and perpetuate several feedforward and feedback pathological loops. The latter includes dysfunctional energy metabolism (compromised mitochondrial ATP production), amyloid-β generation, endothelial dysfunction, and blood-brain-barrier disruption. These lead to decreased cerebral blood flow and chronic cerebral hypoperfusion- that would modulate metabolic dysfunction and neurodegeneration. In essence, hypoperfusion deprives the brain from its two paramount trophic substances, viz., oxygen and nutrients. Consequently, the brain suffers from synaptic dysfunction and neuronal degeneration/loss, leading to both gray and white matter atrophy, cognitive dysfunction, and AD. This Review underscores the importance of treating the above-mentioned comorbid disease conditions to attenuate inflammation and ONS and ameliorate decreased cerebral blood flow and hypometabolism. Additionally, several strategies are described here to control chronic hypoperfusion of the brain and enhance cognition. © 2016 Wiley Periodicals, Inc.