Hot Topics e49

age¼69 6 6.1; MMSE¼27.8 6 1.9) and AD patients (n ¼ 7; age¼63 66.5; MMSE¼26.5 6 1.9). A modified reference-Patlak model, with cere-

bellar grey matter as reference, was chosen for kinetic analysis of the

DED data according to Johansson et al. (2007). Each participant’s imaging

data was analysed in native DED-PET space using a digital brain atlas;

Hammers et al. (2003), DED data from 20-60 minutes was analysed.

Mean regional glucose metabolism and PIB uptake ratios were calculated

for each patient with cerebellum grey matter as reference. Results: A slope

(DED-binding) and intercept (initial tracer distribution) ratio was calculated

for each region from the DED data. ANOVA on the regional DED ratios re-

vealed a significant group effect in the left temporal, left posterior cingulate,

bilateral frontal, left occipital, bilateral parietal and right putamen

(F2,19¼3.8-9.2 p ¼ 0.05). A trend for an increased DED ratio in MCI ex-

isted in cortical regions. All patients, except one MCI, were PIB+ (cortical

uptake ratios >1.41). There were no correlations between significant re-

gional DED ratios, FDG and PIB. There was no significant difference be-

tween FDG and PIB between MCI and AD patients. Conclusions: A

significant effect of DED ratios in several brain regions existed between

controls and patients. DED-PET did not correlate with FDG or PIB in the

brain regions investigated. These findings contrary to post-mortem data

support previous studies using PK11195 demonstrating a limited relation-

ship between PIB uptake and neuroinflammation (e.g. Wiley et al 2009).

The trend for increased DED ratios in the cortex of MCI patients might in-

dicate neuroinflammation is an early phenomenon in AD evolution. This

suggestion requires further investigation involving reliable in-vivo neuroin-

flammation markers.

P4-090 MULTIVARIATE PATTERNSOF BRAIN PERFUSION

AND DEFORMATION-BASED ATROPHIC

CHANGES IN NORMAL AGING

Michael Ewers1, Duygu Tosun1, Vince Calhoun2,3, Norbert Schuff1,

Michael Weiner1, 1University of California, San Francisco, San Francisco,

CA, USA; 2University of New Mexico, Albuquerque, NM, USA; 3The Mind

Research Network, Albuquerque, NM, USA. Contact e-mail: michael.

ewers@ucsf.edu.

Background: Brain aging is associated with regional tissue loss and di-

minished brain perfusion. However, to what extent tissue loss and hypo-

perfusion vary in aging independent of each other or together remains

unclear. In particular, a joint decline of both could be associated with

strong insults on the brain, potentially indicating increased vulnerability

toward AD. In this MRI study, we aimed to determine the pattern of joined

regional alterations of brain structure and perfusion in normal aging.

Methods: A total of 77 cognitively normal subjects within the age range

of 21 to 85 years (mean ¼ 56 yrs, SD ¼ 17.2 yrs) were assessed on a 4T

scanner. Continuous arterial spinal labeling (cASL) scans were used to as-

sess brain perfusion. Deformation based morphometry (DBM) was applied

to T1-weighted scans to assess tissue loss. The linear and quadratic asso-

ciation between age and either DBM or globally normalized brain perfu-

sion was computed by partial least squares analysis (PLS).To directly test

the multimodal association between DBM and perfusion changes, parallel

independent component analysis (pICA) was applied to those brain re-

gions that showed an association with age in the prior PLS analysis. Re-

sults: One significant latent variable of the bootstrapped PLS showed

a linear and quadratic association between age and reduced volume in

frontal, parietal and temporal brain regions but increased ventricular vol-

ume (p < 0.005). For perfusion, higher age was associated with lower tem-

poro-parietal, but higher medial temporal perfusion of the grey matter (p

< 0.005). Results of the multimodal pICA showed several correlated com-

ponents between DBM and perfusion. Most significantly, ventricular ex-

pansion and reduction in precuneus volume were associated with

increased perfusion of the hippocampus region (r ¼ -0.55, p < 0.001, fig-

ure 1), possibly as a compensatory response. Conclusions: The finding of

increased perfusion in the medial temporal lobe in association with re-

gional tissue loss is intriguing, because such perfusion changes may indi-

cate a compensatory response of the brain tissue loss in aging. Moreover,

as these changes are atypical for AD, the finding might improve the dif-

ferentiation between normal and pathological aging and ultimately provide

a sensitive index to identify incipient AD

P4-091 NOVEL ANTI-OLIGOMER COMPOUNDS STOP

MEMORY DEFICITS

Susan M. Catalano1, Jessica Ravesncroft1, Courtney Rehak1,

Raymond Yurko1, Nicholas Izzo1, Hank Safferstein1, Gilbert Rishton1,

Agnes Staniszewski2, Ottavio Arancio2, 1Cognition Therapeutics Inc.,

Pittsburgh, PA, USA; 2Columbia University, New York, NY, USA.

Contact e-mail: scatalano@cogrx.com.

Background: The memory loss that begins in Mild Cognitive Impairment

(MCI) and progresses as Alzheimer’s disease continues is likely caused by

accumulation of Abeta 1-42 oligomers in the patient’s brain (Georganopo-

lou et al.,’05, Shankar et al.,’08, Tomic et al.,’09, Fukumoto et al.,’10).

Oligomers bind to neuronal surface proteins at the synapse and inhibit syn-

aptic plasticity phenomenon such as LTP via effects on membrane traffick-

ing and induction of reversible spine loss in hippocampal neurons. This

results in reversible impairment of memory that culminates in anterograde

amnesia in the early stages of Alzheimer’s disease. Therapeutics directed

against these oligomers should rapidly block their effects on memory

and stop disease progress. Methods: We have screened a proprietary

CNS drug-like library and discovered three structurally distinct lead series

that block the synaptic toxicity of Abeta oligomers on primary hippocam-

pal neurons with low micromolar potency. These molecules appear to act

via partial antagonism of Abeta oligomer binding to the surface of the neu-

ron, or disruption of the Abeta oligomer ligand itself. These molecules are

plasma-stable (plasma t1/2 ¼ 3hr), non-toxic and highly brain penetrant

(brain/plasma ratio ¼ 8). Representative members of these compound se-

ries were tested in the fear conditioning behavioral task for their ability

to preserve normal associative memory. Compounds were injected bilater-

ally via intrahippocampal cannula (2 pmol) one hour prior to the injection

of Abeta 1-42 oligomers (200nM total Abeta) in wild-type C57Bl/6mice.

After an additional 20 minutes, animals received a mild electric foot shock.

Animals were tested for context-dependent learning 24 hours later. Re-

sults: Animals receiving Abeta oligomer injections exhibited significant

memory deficits as measured by decreased freezing behavior vs. vehicle

(13 +/- 2% vs. 27 +/- 1% respectively). Compounds administered prior

to Abeta oligomer completely blocked the effects of Abeta oligomers on

memory (CT0109 ¼30 +/- 2%, CT0093 ¼ 25 +/- 1%), and had no effect

on memory when administered without Abeta oligomers (CT0109 ¼28

+/- 1%, CT0093 ¼ 31 +/- 1%). Systemic administration of these com-

pounds does not induce motor deficits or abnormal behavior. Conclusions:

These compounds show promise as a disease-modifying Alzheimer’s ther-

apeutics.

P4-093 EMPIRICAL FACTORS AFFECTING

RECRUITMENT OF ETHNIC MINORITIES IN

ALZHEIMER’S DISEASE CLINICALTRIALS

Jacobo Mintzer1, Warachal Faison2, 1Medical University of South

Carolina, North Charleston, SC, USA; 2Pfizer Pharmaceuticals, New York,

NY, USA. Contact e-mail: mintzerj@musc.edu.

Background: Institutions such as the NIA and the Alzheimer’s Association

consider poor representation of ethnic minorities in AD clinical trials a ma-

jor obstacle in Alzheimer’s research. Although literature on this issue is ex-

tensive, the information is mostly anecdotal and experiential; a dearth of

information scientifically obtained from well-designed studies exists. We

present the early results of a qualitative study designed to understand the

African American decision-making process to participate in AD clinical tri-

als. Methods: Seven focus groups with 4-7 participants each were con-

ducted. Participants were African Americans � 55 years of age recruited

from churches, community associations, and word-of-mouth referrals. Par-

ticipants were caregivers of AD patients. All focus groups were facilitated