Developing Topics e59

ES¼ 0.28; Total ES¼ 0.30) also showedmild to moderate efficacy trends at

Week 16 (Figure 1). No separation from placebo was observed on any other

secondary endpoint at Week 16. The adverse event (AE) incidence was

generally low, albeit slightly higher on GSK239512 (e.g. neuropsychiatric

AEs involving insomnia, sleep, dreams and mood) than placebo, generally

occurring early in titration and typically did not lead to study discontinua-

tion. The maintenance phase AE incidence was similar between

GSK239512 and placebo. The majority of AEs were mild to moderate in in-

tensity. One subject in each treatment group experienced non-fatal serious

adverse events on-therapy.Conclusions:GSK239512, at doses up to 80 mi-

crograms, demonstrated mild to moderate effects on some measures of the

computerised Cogstate battery. Other non-computerised measures showed

no separation at Week 16. No obvious treatment moderators associated

with effects were identified. In this study, GSK239512 appeared to be gen-

erally well tolerated with an AE profile consistent with its pharmacological

profile.

P4-419 PTEROCARPUS ERINACEUS EXTRACT

DECREASES b-AMYLOID PEPTIDE PRODUCTION

IN AN IN-VITRO MODEL

Salim Hage, Pascal Kienlen-Campard, Jean-No€el Octave, Jo€elle Quetin-

Leclercq, Catholic University of Louvain, Brussels, Belgium.

Background:We investigated the activity on ß-amyloid peptide production

of crude extracts of 9 plant species traditionally used in Benin or in Mada-

gascar for the treatment of cognitive disorders, in order to select candidates

for Alzheimer’s disease treatment, themain one being Pterocarpus erinaceus

stem-bark. Methods: For this species, several extracts were tested, at non-

toxic concentrations, on CHO cells overexpressing the human neuronal

ß-amyloid peptide precursor (APP695) to measure variations of APP

processing (by Western-blotting) and, for the most active, of Aß-amyloid

production (by ECLIA).Results:We observed, at non-toxic concentrations,

a significant increase in CTF/APP ratio Pterocarpus erinaceus aqueous ex-

tract. We also showed that this extract significantly decreased Aß produc-

tion, displaying effects similar to those of DAPT (g-secretase inhibitor)

on APP processing, but may act on another inhibition site. Conclusions:

This active extract is worth further studies to isolate the compounds respon-

sible for the observed activity, to analyze its mode of action and determine

its clinical potentials.

P4-420 LIRAGLUTIDE, A DRUG DEVELOPED TO TREAT

TYPE 2 DIABETES, HAS PROTECTIVE EFFECTS

IN MOUSE MODELS OFALZHEIMER’S DISEASE

Bettina Platt1, Christian Holscher2, 1Aberdeen University, Aberdeen,

United Kingdom; 2University of Ulster, Coleraine, United Kingdom.

Background:Recent research has shown that type 2 diabetes is a risk factor

for Alzheimer’s disease. In the brains of AD patients insulin signalling is im-

paired. The long-lasting incretin hormone Glucagon-like peptide-1 (GLP-1)

analogue liraglutide (Victoza�) is on the market as a treatment for diabetes.

We have previously shown that liraglutide injected ip. once-daily for 8

weeks protects memory formation and synaptic plasticity (LTP) in the

hippocampus of APP/PS1 DeltaE9 mice. Here we analyse plaque load

and soluble beta-amyloid oligomer and APP levels in the brain. The

inflammation response was tested, and the synaptic marker synaptophysin,

progenitor cell count and young neuron numbers in the dentate gyrus. In an

FDG-PET imaging study of PLB1-Triple mice, liraglutide was tested on the

age-dependent reduction of glucose uptake in the frontal brain. Methods:

Liraglutide was injected for 8 weeks at 25nmol/kg ip. once-daily in 9 month

old APP/PS1 or littermate control mice. Histological analysis of plaque

load, synaptophysin density, inflammation (IBA-1 stain), progenitor cell

proliferation (BrdU) and young neurons (double cortin). APP and amyloid

oligomers were analysed by ELISA. The FDG-PET study was conducted in

12 month old PLB1-triple mice. Results: Liraglutide reduced plaque load

(p <0.001), soluble oligomer (p <0.001) and APP levels (p <0.005). Neu-

ronal progenitor cells and young neuron count in the dentate gyrus was

greatly increased (p <0.001), synapses were protected as the reduction of

synaptophysin density was prevented in the hippocampus and cortex

(p<0.005). The FDG-PET study in 12months old PLB1-triple mice showed

an increase in metabolic activity in the frontal brain (p <0.01).

Conclusions: The results show that liraglutide has a range of neuroprotec-

tive properties when injected peripherally. They key hallmarks of AD are

much reduced, cognition and synaptic activity is protected, cortical activity

is preserved and neurogenesis is activated. Liraglutide is prescribed to dia-

betics and has been shown to be safe, and our results suggest that it may be

effective in preventing neurodegenerative processes in AD patients.

P4-421 DOES REPEATED DAILY TESTING IMPROVE

MEASUREMENT SENSITIVITY TO THE

COGNITIVE EFFECTS OF DONEPEZIL IN MILD

TO MODERATE ALZHEIMER’S DISEASE?

Judith Jaeger1, Hans-Goran Hardemark2, Annika Zettergren2,

Niclas Sj€ogren2, Kristin Hannesdottir2, 1Astrazeneca, Wilmington,

Delaware, United States; 2Astrazeneca, Sodertalje, Sweden.

Background: Normal daily fluctuation in cognitive test performance is

likely exaggerated in clinical populations including AD, degrading signal

sensitivity and possibly contributing to the need for long (3-6 month) PoP

trials. Takingmultiple baseline and follow upmeasurements should improve

accuracy and permit shorter trials. Neither ADAS-Cog nor NTB were de-

signed for short interval repeated assessments. In contrast, several measures

from the CogState battery were specifically designed for this purpose. The

aim of this study was to determine whether a brief battery of CogState tests,

using repeated measures methodology, is sensitive to the effect of donepezil

after onemonth.Methods:Mild-Moderate AD patients (N¼ 124) were ran-

domized to either placebo or donepezil titrated from 5mg daily for 2 weeks

to 10mg for the remainder of the 12 week treatment period. Prior to random-

ization, patients were given practice trials of the ADAS-Cog and NTB fol-

lowed by 10 daily administrations of the 15 minute CogState battery within

a two week period (at home or clinic) at the end of which baseline ADAS-

Cog and NTB tests were administered. Each month ADAS-Cog and NTB

were re-administered (on separate days) and CogState was administered 5

times within a 7-day timewindow.Results: The composite score averaging,

for each timepoint, all administrations of all four CogState tasks did not did

not differentiate donepezil from placebo at 4 weeks. Donepezil was superior

to placebo on one of the two computerized memory tasks (OCL) at 8 and 12

weeks and in 3 out of 6 NTB memory subtests at 12 weeks. There were no

effects on ADAS-Cog, ADCS-CGIC, MMSE, non-memory tests in NTB or

in ADAS-Cog or on CogState’s CPAL. Sensitivity of OCL was improved if

the first two baseline measurements were excluded and not appreciably de-

graded if the last two follow up measures were also excluded.Conclusions:

The donepezil effect was small and could not be detected after 4 weeks. A

memory signal could be detected with one of two CogState memory tests

and several NTB subtests, but not ADAS-Cog at 8 and 12 weeks. Repeated

testing may improve signal sensitivity for symptomatic treatment trials in

AD.

P4-422 MANIPULATION ENDOGENOUS NEUROTROPHIC

FACTORS: A PROMISING THERAPY IN

ALZHEIMER’S DISEASE (HYPOTHETIC STUDY)

Mohammad Karimipour1, Ebrahim Esfandyari1, Mohammad Mardani1,

Shirin Babri2, Hojjatollah Allaei3, Abolghasem Esmaeilli4, 1Department of

Anatomical Sciences and Molecular Biology, Isfahan University of Medical

Sciences, Isfahan, Iran; 2Department of Physiology, Tabriz University of

Medical Sciences, Tabriz, Iran; 3Department of Physiology, University of

Isfahan, Isfahan, Iran; 4Department of Molecular and Cellular

Neurobiology, University of Isfahan, Isfahan, Iran.

Background: Neurodegenerative diseases, such as Alzheimer’s disease

(AD), accompanied by a shifting balance between neurogenesis and neuro-

degeneration, are suitable for stimulation of neurogenesis for the benefit of

diseased patients. One of the most important strategies to promote