Poster Presentations e13

P4-283 PLASMA NORADRENALINE LEVEL IN

ALZHEIMER’S DISEASE AND MILD COGNITIVE

IMPAIRMENT (MCI)

Mizuki Oka, Sakuragaoka Memorial Hospital, Tokyo, Japan.Contact e-mail: papappapa29@hotmail.com

Background: Noradrenaline (NA) is synthesized from dopamine by dopa-

mine b-hydroxylase. It is released from the adrenal medulla, and is also a neu-

rotransmitter in the central nervous system and sympathetic nervous system

where it is released from noradrenergic neurons. NA released when a host of

physiological changes are activated by a stressful event. In the brain, this is

caused in part by activation of an area of the brain stem called the locus cer-

uleus (LC). This nucleus is the origin of norepinephrine pathways in the

brain, including the hippocampus, entorhinal cortex, and frontal cortex.

Physiologically, LC-derived NA plays an important role in selective atten-

tion, general arousal, and stress reactions to challenging environmental situ-

ations. Furthermore, NA has been implicated in a wide array of central

processes and diseases, including learning and memory, neuronal excitabil-

ity, drug addiction, pain, and affective disorders. And loss of LC neurons

does contribute significantly to both in Alzheimer’s disease (AD) neuropa-

thology and cognitive impairments. Although loss of noradrenergic neurons

in the LC has been consistently demonstrated postmortem AD, several stud-

ies suggest that indices of central noradrenergic activity increase with the se-

verity of AD in living patients. But the relationship between AD or mild

cognitive impairment (MCI) and noradrenergic activity is not fully under-

stood. Objective: To investigate the plasma NA level of AD and MCI.

Methods: We chose 54 outpatients with clinical diagnosis of MCI (n¼22

mean MMSE:26.4, mean age:76.3) and probable AD (n¼32 mean

MMSE:17.0, mean age:78.9) in the Memory Clinic, and check plasma NA

concentration (normal values:100-450pg/ml) in the sitting position. Conclu-

sion: Plasma NA level was significantly higher (p<0.01) in the patients with

probable AD (mean value ¼ 891.1 pg/ml, SD ¼ 464.1) than in those with

MCI (mean value ¼ 599.1 pg/ml, SD ¼ 154.1). Both plasma dopamine

and adrenaline level were almost all normal level in the all patients. This re-

sults suggest that NA activity increase as the disease progress. Plasma NA

levels may be a biomarker of the diagnosis of AD. And it might be a predic-

tive factor of some BPSD that can contribute to nursing loads and the medical

treatment economy.

P4-284 CURRENT ANTICHOLINERGIC MEDICATION USE

AND COGNITIVE IMPAIRMENT IN THE OLDER

POPULATION: THE MEDICAL RESEARCH

COUNCIL COGNITIVE FUNCTION AND AGEING

STUDY

Kathryn Richardson1, Chris Fox2,3, Ian Maidment2,3, David Smithard4,

Cornelius Katona2,5, Gill Livingston6,5, Malaz Boustani7,

George M. Savva1, Simon Coulton3, Fiona E. Matthews8, Carol Brayne1,1University of Cambridge, Cambridge, United Kingdom; 2Kent and MedwayNHS and Social Care Partnership Trust, West Malling, United Kingdom;3CHSS-University of Kent, Canterbury, United Kingdom; 4East Kent Hos-

pitals University Trust, Ashford, United Kingdom; 5University CollegeLondon, London, United Kingdom; 6Camden and Islington Mental Health

and Social Care Trust, London, United Kingdom; 7Indiana University, In-

dianapolis, IN, USA; 8Medical Research Council Biostatistics Unit, Cam-

bridge, United Kingdom. Contact e-mail: kjr43@medschl.cam.ac.uk

Background: The cholinergic system has been implicated in cognitive im-

pairment and is the target of Cholinesterase inhibitors, the primary pharma-

cotherapeutic treatment for Alzheimer’s disease. Cholinergic neurons

degenerate with age hence the elderly are more susceptible to cognitive ef-

fects of anticholinergics. Objective: Anticholinergic medication use has

been negatively associated with cognition in clinical settings and we sought

to examine this in a population-based study. Methods: The anticholinergic

burden scale which we have developed and validated previously was utilised

to code medications reported at baseline in the Medical Research Council

Cognitive Function and Ageing Study (MRC-CFAS). These were scored

as 0 (none), 1 (mild), 2 (moderate), or 3 (severe) according to their anticho-

linergic activity. Any discordance was resolved by discussion until a consen-

sus was obtained. Scores were summed for each participant to give a total

Anticholinergic Cognitive Burden (ACB) score. Incidence rate ratios for er-

rors in the Mini-Mental State Examination (MMSE) associated with cate-

gories of ACB score (0, 1, 2, 3, 4 or 5þ) were calculated using negative

binomial regression both unadjusted and adjusted for age, sex, education, so-

cial class, number of self-reported comorbidities, and number of other med-

ications. Results: Of the 11,994 participants, 59% were female and the mean

(SD) age was 75 (6.7) years. 26,759 prescription and over-the-counter med-

ications were reported by 9,530 participants and 47% of participants reported

taking medications with anticholinergic effects. A statistically significant

dose-response relation was observed between increasing ACB score and de-

creasing MMSE, e.g. those with an ACB score of 5 or greater were associated

with making 21% (95%CI 8%-35%) more errors on the MMSE than those

not taking anticholinergics. However, the relationship with cognitive impair-

ment was only seen for ACB conferred by Central Nervous System (CNS)

medications, in particular antipsychotics. The ACB of non-CNS medications

were not significantly associated with MMSE. Conclusion: Anticholinergic

medication use in the older population was common. An inverse relation ex-

isted between the anticholinergic burden of current medication use and cog-

nition, but the association was driven by the ACB of CNS medications.

Longitudinal analyses in population-based studies are required to further

examine the direction of causality.

P4-285 PROFILING OF MEMBRANE-ANCHORED

b-SECRETASE INHIBITORS IN CELL CULTURES

Heinke Schieb1, Hans-Joachim Knolker2, Sebastian Weidlich2,

Jens Wiltfang1, Hans W. Klafki1, 1Department of Psychiatry and Psycho-

therapy, University of Duisburg-Essen, LVR-Klinikum Essen, Essen,

Germany; 2Department of Chemistry, Technical University of Dresden,

Dresden, Germany. Contact e-mail: heinke.schieb@uni-due.de

Background: Recently, Rajendran and coworkers demonstrated that the po-

tency of a known b-secretase inhibitor can be substantially improved by tar-

geting the compound to membranes by coupling it to a sterol moiety

(Rajendran et al., Science 2008 Apr 25). The resulting ‘‘Tripartite Structure’’

- inhibitor is composed of three chemical modules, namely the pharmaco-

phor, the lipid anchor responsible for membrane targeting, and a linker region

to control the position of the pharmacophor relative to the lipid bilayer.

Objective: To study how modifications of each of the three modules affect

Aß generation in cell cultures. Methods: We have investigated the amount of

Ab peptides secreted by primary chicken telencephalon cultures and by a neu-

roblastoma cell line (SY5Y) overexpressing APP wildtype (wt) and mutant

APP (SWE), respectively. Results: Our findings indicate that the tripartite in-

hibitors carrying a peptide as pharmacophore potently reduce Abeta secre-

tion from primary neuronal cells as well as from SH-SY5Y cells

overexpressing wt and SWE APP. Importantly, BACE inhibition was ob-

served at inhibitor concentrations that were at least 2 orders of magnitude be-

low the concentrations that caused cell toxicity according to MTT and LDH

assays. The optimal linker length was determined to range from 35A and

89A. Replacing the cholesterol membrane anchor with oleyl or myristyl di-

minished the inhibition of Abeta secretion substantially. In contrast, a palmi-

tyl anchor resulted in only slighty reduced potency as compared to the

cholesterol anchors. Conclusion: Taken together, these findings may help

to optimize BACE inhibitor design and they may help to better understand

the molecular details of APP processing and the generation of Abeta peptides

and the involvement of cellular membranes.

P4-286 STATIN USE IS NOT ASSOCIATED WITH

COGNITIVE IMPAIRMENT IN A COHORT OF

OLDER WOMEN

Eric B. Schneider, Michelle M. Mielke, Sevil Yasar, Michelle C. Carlson,

Johns Hopkins University, Baltimore, MD, USA. Contact e-mail: eschneid@

jhsph.edu

Background: Studies examining statin use and cognition in older adults have

produced equivocal results. Objective: To determine whether statin use is