Poster Presentations: P1P300

reversed Ab oligomer-damaged long-term potentiation (LTP) at concentra-

tions that did not interfere normal high frequency stimulation-induced LTP.

Moreover, bis(heptyl)-cognitin prevented Ab oligomer-induced reduction

of neurite length and synaptic quantity in mature hippocampal neurons. In

contrast, tacrine could not reverse synaptic impairments in these models.

Under oligomerization condition, bis(heptyl)-cognitin reduced the amount

of Ab oligomer as evidenced by dot blot assay and immunoblot analysis. Fi-

nally, bis(heptyl)-cognitin was shown to alter Ab self-assembling as demon-

strated by circular dichroism spectroscopy and transmission electron

microscopy. Conclusions: All these results not only offer a modality as to

how dimeric agents protect against Ab oligomer-induced synaptic impair-

ments, but also offers a strong support for the beneficial therapeutic effects

of bis(heptyl)-cognitin in the treatment of AD.

P1-386 CROSS-SPECIES ANALYSIS OF CEREBROSPINAL

FLUID (CSF) BETA-AMYLOID REDUCTIONS BY

THE BACE1 INHIBITOR PF-05297909 INDICATES

SPECIES DIFFERENCES IN PK/PD

RELATIONSHIPS: RELEVANCE TO CLINICAL

TRANSLATION

Table 1

Results for LADIS subjects who did not progress to MCI or dementia

Baseline data 3-year follow-up data

Beta 95 % CI P value Beta 95 % CI

P

value

Memory

composite

–0.49 –0.93- –0.06 0.03 .0006 –0.16 - 0.16 0.99

Executive

composite

0.39 0.07 - 0.74 0.04 0.24 0.10 - 0.38 0.001

Processing speed

composite

0.56 0.26 - 0.86 <0.0001 0.15 0.02 - 0.29 0.02

The table displays results from the regression analysis in subjects who did

not progress to MCI or dementia during the 3-year follow-up

Adjusted model. Covariates: diabetes, history of stroke, MMSE score at

baseline, years of education, gender and WMH score at baseline

Eva Hajos-Korcsok1, Charles Nolan2, Ashley Robshaw3,

Curt Christoffersen4, JinHua Liu5, Yasong Lu6, Cheng Chang6,

Sridhar Duvvuri6, Michael Brodney1, Brian O’Neill6, Timothy Nicholas7,

Joanne Bell8, David Riddell1, 1Pfizer Inc., Cambridge, Massachusetts,

United States; 2Pfizer Inc., Cambridge, Massachusetts, United States;3Pfizer Inc., Cambridge, Massachusetts, United States; 4Pfizer Inc.,

Cambridge, Massachusetts, United States; 5Pfizer Inc., Groton,

Connecticut, United States; 6Pfizer Inc., Groton, Connecticut, United

States; 7Pfizer Inc., Groton, Connecticut, United States; 8Pfizer Inc.,

Cambridge, Massachusetts, United States. Contact e-mail: eva.

hajos-korcsok@pfizer.com

Background: PF-05297909 is a novel, brain-penetrable, small molecule in-

hibitor of BACE1, the enzyme involved in the formation of toxic species of

amyloid-b (Ab) in the brain. Since Ab peptides can also be measured in the

CSF in both animals and humans, changes in CSF Ab represent mechanis-

tically-relevant, translatable pharmacodynamic endpoints. In the present

study, we have evaluated acute brain Ab-lowering efficacy of PF-

05297909 in rats, and compared the pharmacokinetic/pharmacodynamic

(PK/PD) relationship for reduction of CSF Ab across multiple species

(rat, dog, non-human primate, human).Methods: PF-05297909 (cell based

IC50¼32 nM) or vehicle was administered acutely to rats, dogs and non-hu-

man primates at doses ranging up to 100 mg/kg. In separate cohorts of rats,

brain and CSFwere harvested at multiple time points post-dose for measure-

ment of Ab40, Ab42 and total Ab by ELISA. In dogs and non-human pri-

mates, serial CSF samples were collected over a 72-hour period via an

indwelling cisterna magna cannula. Human PK/PD data was obtained, as

described by Bell et al. (AAIC, 2013). Results: The efficacy of PF-

05297909 to decrease amyloidogenic peptides was demonstrated in rats,

with maximum reductions of brain and CSFAb40 by 49% and 87%, respec-

tively. Acute administration of PF-05297909 in dogs (25 mg/kg) and non-

human primates (30 mg/kg), reduced CSF concentrations of all Ab analytes

measured, with reduction of Ab40 by 25% and 62% at Tmax, compared to

baseline levels. Exposure-response analysis revealed that the compound’s

potency to inhibit CSF Ab40 varied about 5-fold between species, with

IC50¼97, 80 and 20 nM (expressed as unbound drug concentration) for

non-human primate, rat and dog, respectively. Conclusions: Present studies

demonstrate robust CSF Ab reductions in multiple preclinical species fol-

lowing acute BACE1 inhibitor treatment. Cross-species comparison of the

PK/PD relationships indicate that the dog is the most sensitive species in

CSF Ab modulation, however predictions based on dog PK/PD failed to

translate to the clinic. Present results provide a greater understanding of

how preclinical models of efficacy may be correlated to a clinical effect.

These data also indicate that using dog as a preclinical model may overes-

timate the clinical Ab-lowering efficacy of BACE1 inhibitors.

P1-387 PHYSICAL ACTIVITY IS ASSOCIATEDWITH

IMPROVED EXECUTIVE FUNCTION AND

PROCESSING SPEED: THE LADIS STUDY

Kristian Steen Frederiksen1, Ana Verdelho2, Sofia Madureira3,

Hansj€org B€azner4, John O’Brien5, Franz Fazekas6, Philip scheltens7,

Reinhold Schmidt8, Anders Wallin9, Lars-Olaf Wahlund10,

Erkinjuntt Timo11, Anna Poggesi12, Leonardo Pantoni12,

Domenico Inzitari13, Gunhild Waldemar14, 1Rigshospitalet, Copenhagen,

Denmark; 2Department of Neurosciences, Lisbon, Portugal; 3Centro de

Estudos EgasMoniz, Hospital de SantaMaria, University of Lisbon, Lisbon,

Portugal; 4Department of Neurology, University of Heidelberg, Klinikum

Mannheim, Mannheim, Germany; 5Newcastle University, Newcastle upon

Tyne, United Kingdom; 6Karl Franzens University Graz, Graz, Austria; 7VU

University Medical Center, Amsterdam, Netherlands; 8Medical University

of Graz, Graz, Austria; 9University of Gothenburg, M€olndal, Sweden;10Karolinska Institutet, Stockholm, Sweden; 11University of Helsinki,

Helsinki, Finland; 12Department of Neurological and Psychiatric Sciences,

University of Florence, Florence, Italy; 13University of Florence, Florence,

Italy; 14Rigshospitalet - Copenhagen University Hospital, Copenhagen,

Denmark. Contact e-mail: Kristian.Steen.Frederiksen@regionh.dk

Background: Physical activity in mid- and late-life has been associated

with a reduced risk of dementia, and may also benefit cognitive function

in subjects who do not have dementia. Elderly subjects with unspecific ce-

rebrovascular changes, such as white matter hyperintensities and lacunes

may benefit more from physical activity since any cognitive deficits may

be due to vascular changes, which are modifiable by physical activity. In

the present study, we therefore explored the relationship between physical

exercise and executive function, memory and processing speed. Methods:

For the present study, data from the LADIS study was used. All subjects in-

cluded in the LADIS study were free of dementia at baseline. For the present

study, only subjects who did not progress to MCI or dementia at or before 3-

year follow-up, were included. At baseline, subjects were asked whether

they were physically active more than 30 minutes a day (yes/no). Composite

scores on executive function, processing speed and memory were used as

cognitive outcomes at baseline and 3-year follow-up. Multivariable linear

regression with relevante covariates (diabetes (yes/no), history of stroke

(yes/no), MMSE score at baseline, years of education, gender and WMH

score at baseline) were used for the analysis. Results: Of the 639 subjects

included in the LADIS study, 635 subjects had data available on one or

more cognitive domains as well as data on physical activity at baseline.

Ninety subjects had progressed to dementia and 147 subjects to MCI by

the 3-year follow-up, leaving 402 subjects who did not progress. For sub-

jects who did not progress to neither MCI nor dementia, being physically

activity was associated with a worse memory score at baseline, but there

was no association at 3-year follow-up. For executive functions and process-

ing speed, being physically activity was significantly associatedwith a better

score at baseline and 3-year follow-up (Table 1). Conclusions: Being

Poster Presentations: P1 P301

physically activity benefits executive function and processing speed, but not

memory functions in elderly subjects with unspecific cerebrovascular

changes who did not progress to dementia or MCI.

P1-388 BEXAROTENE FOR THE TREATMENT OF

Table

Scale

MOCA

ADAS-Cog

CDR-SOBl

CDR global

COGNITIVE DECLINE IN AN INDIVIDUALWITH

ALZHEIMER’S DEMENTIA

Babak Tousi1, 1Cleveland Clinic, Cleveland, Ohio, United States.

Contact e-mail: babak.tousi@ccf.org

Background: To educate the professional community regarding the effects

of Bexarotene in a patient with Alzheimer’s disease . Bexarotene is a com-

pound currently used to treat cutaneous T-cell lymphomas, has shown prom-

ise in mouse models of Alzheimer’s Dementia.Methods: Case report; This

is a 79 year old female with history of memory loss for 10 years, diagnosed

with Alzheimer’s dementia 7 years ago. She has history of breast cancer

andhypertension. She had occasional vague headaches with negative work

up which resolved by progression of disease over pastyears. Amyvid imag-

ing showed cortical uptake consistent with amyloid accumulation in both

hemispheres. She has been treated with Aricept and Namenda which were

discontinued over last year per request of her husband and she was taking

valsartan and vitamin D. Her husband showed special interest in Bexarote-

ne.He had thoroughly studied the pertaining literature includingthe ones not

supporting the use of Bexarotene for treatment of Alzheimer’s . The limited

data for efficacy was discussed. The decision was made for compassionate

use of this medication. Shewas started on Bexarotene 150mg daily and con-

tinued for 3months. The blood tests including liver function test, lipid panel,

Blood cell count and thyroid function tests were done at baseline and re-

peated at week 2, week 6, week 8 and after 3 month treatment. Results:

There was no noticeable change inlabs exceptthe gradual increase in choles-

terol level. She was started on Omega-3-acid as preventive measure for hy-

pertriglyceridemia at week 2. Atorvastatin 10 mg was added at Week 6 to

treat hypercholestrolemia.Shewas more interactive on week 6 visit, as no-

ticed by her husband too. H erMOCA and ADAS-Cog score did not show

any significant change during this period. S he gradually developedmore be-

havioral symptoms such as sundowning. Bexarotene was stopped after 3

months. Conclusions: Bexarotene was well tolerated, but did not improve

cognition of our patient in moderately severe stage of Alzheimer’s dementia.

The patient only developed hypercholesterolemia which responded well to

statin therapy. There was worsening of behavioral symptoms which contin-

ued after discontinuation of drug, whichmay be related to the progression of

dementia.

Baseline Week 2 Week 6 Month 3

4/30 - 4/30 6/30

33 32 33 33

15 - - 16

2 - - 3

P1-389 EFFECTS OF TREATMENT WITH MEMANTINE

ON TWO PATIENTS DIAGNOSEDWITH

PRECLINICAL DEMENTIAWITH LEWY BODIES

Masahiko Takaya1, Eiji Kirime1, Noa Tsujii1, Hidenori Matsunaga2,

Osamu Shirakawa1, 1Kinki University School of Medicine,

Osakasayama-shi, Osaka, Japan; 2Osaka General Medical Center, Osaka,

Japan. Contact e-mail: takaya@med.kindai.ac.jp

Background:Memantine has been reported to have positive effects on neu-

ropsychiatric symptoms and cognitive impairment in patients with Demen-

tia with Lewy bodies (DLB) as well as those with Alzheimer’s disease. We

hypothesized that memantine also would have similar effects on symptoms

of two patients with preclinical DLB. Methods: Firstly, before treatment,

we evaluated cognitive abilities of the patients with MMSE, ADAS, some

parts of WMS-R, and so on. Based on these results, we decided whether

the patients could be diagnosed to Dementia or not. In the second, we

checked whether parkinsonism was observed or not. In the third, magnetic

resonance (MR) imaging was performed. In the fourth, we performed

MIBG-scintigraphy for the patients. In the fifth, we evaluated neuropsychi-

atric symptoms, for example, visual hallucinations, delusion, etc. of the pa-

tients, using neuropsychiatric inventory (NPI) with the help of their

caregivers. We started treatment with memantine after written informed

consent for the patient. We evaluated particularly the effects of memantine

on neuropsychiatric symptoms using NPI scores, both at baseline and after

the treatment.Results:Both the patient were not diagnosed to dementia, but

to mild cognitive impairment MCI). They did not show parkinsonism and

nothing particular was observed in MR images. According to MIBG-myo-

cardial scintigraphy, the heart/mediastinum (H/M) ratio showed low uptake

in both early and delayed images, in both patients. H/M ratio of early and

delayed images were 1.60 and 1.28, respectively, in one patient, and 1.30

and 1.00, respectively, in the other patient. These results suggested detected

early stage of DLB in both the patients with MCI. Treatment of one patient

with memantine resulted in the disappearance of visual hallucinations, but it

could not stop the progression to dementia. That of the other patient them

resulted in the improvement of neuropsychiatric symptoms. Conclusions:

Our results suggested that memantine had positive effects on neuropsychi-

atric symptoms of patients having preclinical DLB to some degree.

P1-390 EFFECTS OF VARIOUS ANTIDEMENTIA DRUGS

FOR ALZHEIMER‘S DISEASE AS EXAMINED BY

SPECT IMAGING USING SPM8

Kiyoshi Kanaya1, Shine Abe1, Minoru Sakai1, Hiroko Fujii1,

Kiyoshi Koizumi1, Toshihio Iwamoto2, 1Tokyo Medical University Hachioji

Medical Center, Tokyo, Japan; 2Tokyo Medical University, Tokyo, Japan.

Contact e-mail: kitikiti@hi-ho.ne.jp

Background:Although four anti-dementia drugs have been authorized

for use in Japan starting in 2011, each has a different mechanism of

action while also having different therapeutic effects and adverse side

effects. We therefore decided to conduct a comparative study of the

effects of each of these drugs on cerebral blood flow. Methods:

The study subjects consisted of 126 patients diagnosed with Alzheimer’s

disease (AD) according to the NINCDS-ADRDA criteria (55 men,

71women, average age: 78.9 years). The subjects were randomly assigned

to single administration groups, consisting of 45 subjects administered

donepezil at 5 mg/day (Group D), 12 subjects administered memantine

at 20 mg/day (Group M), 10 subjects administered galantamine at 16

mg/day (Group G) and 20 subjects administered rivastigmine at 18 mg/

day (Group R), and concomitant administration groups, consisting of

26 subjects administered donepezil + memantine (Group DM) and 13 sub-

jects administered galantamine + memantine (Group GM). Each subject

underwent SPECT with 99m Tc-ECD before administration and at 4 to

6 months after administration to conduct a comparative study of changes

in cerebral blood flow using SPM8. Results: 1. Single administration

groups: Significant increases in cerebral blood flow were observed in

a portion of the left parietal lobe (supramarginal gyrus) in Group D, bilat-

erally in the angular gyrus, temporal lobe and hippocampus in Group M,

bilaterally in the outer surface of the frontal lobe in Group G, and in the

inner surface of the frontal lobe in Group R. 2. Concomitant administra-

tion groups: Significant increases in cerebral blood flow were observed

over a wide area from the orbital gyri bilaterally to the anterior cingulate

gyrus, bilaterally in a portion of the parietal lobe, from the left angular gy-

rus to the middle/inferior temporal gyri, and in the lower pons in Group

DM. Increases in cerebral blood flow were observed over a wide range

centering primarily in the occipital lobe in Group GM. Conclusions:

Changes in cerebral blood were observed that differed for each drug. It

is interesting to note that the wide-ranging increases in blood flow ob-

served in Group DM were thought to constitute synergistic effects of do-

nepezil and memantine.