Hot Topics e35

fuel to glucose. Nothing is yet known about whether brain ketones uptake is

decreased in AD or during healthy aging. Using positron emission tomogra-

phy (PET), we observed that rats in mild experimental ketonemia have a 2-3

fold increase in brain uptake of both 11-carbon acetoacetate (11-C-AcAc)

and 18-fluorodeoxyglucose (18-F-FDG). Short term controlled human trials

show that ketogenic supplement modestly improves cognition in AD. The

objective of our study was to assess whether changes in human brain metab-

olism occurring with age concern glucose only or ketones as well, the other

key brain fuel.Methods: All participants underwent detailed screening, in-

cluding extensive medical histories, blood chemistry and MMSE test. Two

age groups were studied: 18-30 y old and 65+ y old (n ¼ 10/gp). The PET

protocol involved a positioning CT scan, injection of 11-C-AcAc and 30

min scan, 30 min wash out, second CT scan, injection of 18-F-FDG and

42 min scan. Tracer uptake was assessed in 18 brain regions with and with-

out normalization for the uptake in the cerebellum. For the moment, data are

expressed as standardized uptake values (SUV) but cerebral metabolic rates

of glucose and acetoacetate are being calculated. Results: Referenced

against the cerebellum and expressed as SUV, 18-F-FDG uptake averaged

across all brain regions was 17% lower in the elderly group as compared

to the young group. Expressed the same way, 11-C-AcAc uptake was 9%

lower in the elderly. Relative to the cerebellum, the striatum was notable

in having higher 11-C-AcAc uptake in the elderly as compared to the young.

Conclusions: This double tracer PETmethod permits a comparison of brain

glucose and ketones uptake in both humans and animal models. It may lead

to a better understanding of how brain metabolism changes with age and in

AD on a cerebral regional basis.

P4-050 TOMM40 VARIABLE LENGTH POLYMORPHISM IS

ASSOCIATEDWITH MEMORY FUNCTION IN

ASYMPTOMATIC MIDDLE-AGED PERSONS

Mark A. Sager1, Asenath La Rue1, Sterling C. Johnson1,

Ann M. Saunders2, Allen D. Roses2, Rebecca Koscik1, Erin Jonaitis1,

Michael W. Lutz2, Sanjay Asthana1, Robert C. Green3, Bruce P. Hermann1,1UW Medical School-Madison, Madison, WI, USA; 2Duke University,

Durham, NC, USA; 3Boston University, Boston, MA, USA.

Contact e-mail: masager@wisc.edu.

Background:ATOMM40 polymorphism, a variable length intronic poly T

repeat (rs10524523), has been shown to influence age of Alzheimer’s dis-

ease (AD) onset. In this study, we tested the hypothesis that subjects homo-

zygous for TOMM40 short poly T sequences<21 (SPT) would show better

performance on measures of learning and memory than those who were ho-

mozygous for longer poly T sequences �21 (LPT) in middle-aged subjects

with a family history of AD. Methods: The study population includes 726

middle-aged asymptomatic persons enrolled in the Wisconsin Registry for

Alzheimer’s Prevention (WRAP) who had been genotyped for APOE and

TOMM40. A total of 129 were homozygous for SPT sequences <21 (low

risk) and 229 were homozygous for LPT sequences �21 (high risk). Study

groups were defined by TOMM40 genotyping based on the length of the

poly T sequences regardless of APOE genotype. Serial position profiles

and total learning on the Rey Auditory Verbal Learning Test (AVLT) were

compared between groups controlling for age, gender and education. Re-

sults: The mean age of the study population was 54 and 69% were female.

There were no significant age, gender or education differences between SPT

and LPT groups. The two TOMM40 groups differed significantly in total

words learned on the AVLT (p ¼ .012) with the LPT TOMM40 group re-

membering fewer words. There were significant differences in the serial po-

sition curve with significantly poorer recall from the primacy region on the

AVLT (p¼ .001). Nineteen percent of the SPT group had an APOE 34 com-

pared with 55% of the LPT group. When APOE genotype (34 carrier vs.

non-carrier) was added to the model, TOMM40 remained significant on

both measures. Conclusions: Longer TOMM40 poly T sequence length

was associated with differences in memory and learning that are seen in

early AD. These changes were seen in middle-aged asymptomatic persons,

suggesting that TOMM40 genotyping may prove useful in stratifying per-

sons at different levels of AD risk in studies of pre-symptomatic AD. The

role that TOMM40 plays in AD pathogenesis and its relationship to

APOE genotype as a genetic risk factor for AD remain to be determined.

P4-051 EFFECTOFANALOG P165 OFAPP 5-MER PEPTIDE

ON INSULIN SIGNALING PROTEIN IN TYPE 3

DIABETES RATS

Rong Wang, Xiang Hong Meng, Zhi Wei Zhao, Zhi Juan Ji, Shu Li Sheng,

Beijing Xuanwu Hospital, Capital University of Medical Sciences, Beijing,

China. Contact e-mail: rong_wang72@yahoo.com.cn.

Background: To investigate the effect of Analog P165 of APP5-mer pep-

tide on the change of learning and memory ability, and insulin signaling

pathway in type 3 diabetes rats. Methods: SD rats were randomly divided

into 3 groups: Control group; type 3 diabetes (T3DM) group; T3DM admin-

istrated P165 group. T3DM group and treatment groups were induced by in-

tracerebroventricular injection of STZ, 3mg/kg, bilaterally. Repeat the

process on the thrid day. The control group was replaced with saline. The

treatment groups were administrated with P165, intragastric dose of P165

was 335mg/kg/day. The other groups were treated with saline. Record

body weight every two weeks, before making models and before sacrifice,

blood glucose was measured. Learning and memory ability was detected

by Morris water maze test 4 weeks later. The rats serum insulin, gluocagon,

insulin-like growth factor-1 (IFG-1) was detected by ELISA method. After

sacrifice, insulin signaling proteins, such as IR-b, IRS-1, AKT,p-CREB,-

were observed by immunohistochemistry and western blot. Results: In

Morris water maze tests, compared with control group, the escape latency

of model rats were significantly prolonged (p< 0.01); compared with model

group, the escape latency of P165 treated rats shortened significantly(p <

0.05). Compared with control group, serum IGF-1 level of model rats de-

creased significantly (p<0.05); compared with model group, serum IGF-1

level of P165 treated rats significantly increased(p<0.01); There was no sig-

nificant difference in serum insulin and glucagon among groups. Compared

with control group, IR and IRS-1 expression increased significantly in hip-

pocampus of model rats (p < 0.01); compared with model group, IR and

IRS-1 expression decreased significantly in P165 treated rats (p < 0.01);

There was no significant difference both in AKT and p-CREB among

groups. Western blotting:the band of AKT,p-CREB showed no significant

difference among groups.Conclusions: 1. Intracerebroventricular injection

of STZ could damage rats learning and memory ability, reduce peripheral

blood serum IGF-1 level, IR,IRS-1 expression increased, insulin signaling

pathway impaired. 2. P165 could ameliorate model rats learing and memory

ability, the expression of IR,IRS-1 recovered to nomal. In addition, P165

could raise model rats blood serum IGF-1 level, play an important role on

the neuroprotective effect aspect.

P4-052 REGIONAL CEREBRAL BLOOD FLOW PATTERNS

DETECTED BY SPECT WITH EASY Z-SCORE

IMAGING SYSTEM ANALYSIS IN EARLY-STAGE

ALZHEIMER’S DISEASE

Chigusa Watanabe, Sadao Katayama, Takako Makino, Masahiro Higaki,

Hiroshimanishi Medical Center, Ootake, Japan. Contact e-mail: chigusa@

hiroshimanishi-nh.hosp.go.jp.

Background: The objective of this study is to investigate the characteristic

patterns of regional cerebral blood flow reduction in early Alzheimer’s dis-

ease (AD). Methods: Twenty patients were recruited in this study. We per-

formed MRI(Siemens, MAGNETOM Harmony 1.0T,) and single-photon

emission computed tomography (SPECT) technetium-99m cysteinate dim-

mer (99m Tc-ECD) (Toshiba, 7200A�DI), simultaneously, and corrected

using voxel-based morphometry as to reduce the atrophic influence. We

evaluated regional cerebral blood flow patterns using easy Z-score imaging

system (eZIS) analysis, and we calculated the extent of each regions using

voxel-based Stereotactic Extraction Estimation (vb SEE)(Level 3 classifica-

tion). In 8 subjects, MRI and SPECTwere reevaluated one or two years after

and the comparative study was performed. Results: There was prominent

decrease in the bilateral posterior cingulated gyrus, parietal cortex, temporal

cortex, and frontal cortex. Conclusions: The eZIS analysis with vb SEE is