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genotype, 34/34 or 33/33, differed between pairs. Adjacent sections from

each pair were stained using two LCPs/LCOs: pentamer formyl thiophene

acetic acid (pFTAA) and polythiophene acetic acid (PTAA). Fluorescence

spectra from tissue sections were recorded with an LSM 510 META con-

focal laser scanning microscope, and spectral processing was achieved

with an LSM Image browser. Results: Using PTAA, we observed that

AD patients with 34/34 exhibited a different conformational spectrum

for core and cerebrovascular amyloid whereas their respective matched

33/33 pair exhibited indistinguishable conformational spectra between

the two amyloid structures. pFTAA, sensitive for different conformations

for Ab and NFTs, revealed NFT densities in 34/34 AD patients that were

apparently greater than those in 33/33 AD patients. Conclusions: The ob-

servation that PTAA core amyloid and cerebrovascular amyloid spectra

distinguish the amyloid deposits of APOE 34/34 from APOE 33/33 AD pa-

tients supports the hypothesis that APOE genotype modulates amyloid

structure. pFTAA holds promise as an especially sensitive reagent for vi-

sualizing NFTs. LCOs/LCPs show great potential as research tools for the

study of proteinopathies, including the pathogenesis of sporadic AD and

possibly the influence of APOE genotype.

O4-08-07 AMYLOID-b PLAQUES POP UP OR RATHER

GROW?

Jochen Herms1, Steffen Burgold1, Tobias Bittner1, Martin Fuhrmann1,

Daniel Kieser2, Boris Schmidt2, 1Ludwig Maximilian University of Munich,

Munich, Germany; 2Darmstadt Technical University, Darmstadt, Germany.

Background:The kinetics andmechanisms of amyloid-b plaque formation,

which is one of the characteristic hallmarks in Alzheimer’s disease (AD),

are a fundamental issue in AD research. A previous in vivo two-photon im-

aging study in transgenic AD mouse models, published 2008 in Nature, has

led to the unexpected conclusion that amyloid-b plaques do not grow after

they have appeared rapidly within 24 hours. Methods: We tried to repro-

duce these results in 12 month old Tg2576 mice and followed the growth

kinetics of new born plaques and already existing plaques over up to 6

weeks. Additionally, we examined already existing plaques at 18 months

of age, when amyloid plaque burden is in advanced stages. To label amy-

loid-b plaques in vivo the fluorescent dye methoxy-X04 was injected intra-

peritoneally one day before imaging. Results: New born plaques were

initially very small in size. Weekly imaging up to 6 weeks after their first

appearance, however, revealed a fast and highly significant growth. Also

pre-existing plaques clearly grew over 6 weeks, but with a slower kinetic.

Only in 18 month old Tg2576 mice, we did not observe any new born pla-

ques while pre-existing plaques did not grow anymore. Conclusions: Am-

yloid-b plaques do grow! The most likely explanation of the fundamental

discrepancies on new born plaque growth between the previous in vivo im-

aging study and ours will be presented.

O4-08-08 AMYLOID-BETA OLIGOMERS ARE EXCLUDED

FROM THE POST-SYNAPSES IN THE

HIPPOCAMPUS OF COGNITIVELY INTACT

INDIVIDUALS WITH SEVERE ALZHEIMER’S

DISEASE NUROPATHOLOGY

Nicole L. Bjorklund1, Lindsay C. Reese1, Randall Woltjier2,

Giulio Taglialatela1, 1University of Texas Medical Branch, Galveston, TX,

USA; 2Oregon Health Science University, Portland, OR, USA.

Background: Growing experimental evidence suggests that the early

symptoms of cognitive dysfunction in Alzheimer’s disease are likely due

to the effects of amyloid-b (Ab) oligomers on synapses. However, evidence

for oligomeric Ab association with the synapses in actual AD brains and its

relevance to cognitive decline in humans is still elusive.Methods: Here we

used sub-synaptic fractionations, immunoblots and immunohistochemistry

(IHC) to compare hippocampi from control, mild cognitive impaired (MCI)

and AD patients to hippocampi from a unique cohort of cognitively intact

individuals with severe AD neuropathology (plaques and tangles, Braak

stage: 6) which we termed Non-Demented AD (NDAD). Results: Immu-

noblots in synaptic protein fractions revealed the presence of Ab oligomers

in the post-synapses, but not pre-synapses, of MCI and AD, whereas Ab

oligomers were not detected in synaptic fractions of control or NDAD

cases. However, immunoblots on total protein extracts showed comparable

levels of Ab oligomers in both AD and NDAD cases. To test whether lack

of Ab oligomers within the synapse preserved neuronal functionality, we

used IHC to detect pCREB, a transcription factor essential for synaptic

plasticity and memory, in hippocampal neurons and found that pCREB

was significantly decreased in AD and, to a lesser extent, MCI, but not

in NDAD or controls, and that this decrease in pCREB correlated with

the degree of cognitive impairment. Conclusions: Collectively these re-

sults show selective postsynaptic localization of Ab oligomers in both

MCI and AD, suggesting that this is and early phenomenon in disease pro-

gression. More notably, our data show for the first time in humans that ex-

clusion of Ab oligomers from the post-synaptic density is sufficient to

prevent cognitive decline, even in the presence of soluble Ab oligomers

and advanced Tau pathology. The mechanism(s) responsible for preventing

Ab oligomers association with synapses in NDAD brains is currently under

investigation. Understanding such mechanism would obviously reveal an

exceptionally effective, novel pharmacological target to stop cognitive de-

cline in AD. Supported by Alzheimer Association IIRG-90755 and NINDS

1R01NS059901 to GT and by NIA P30AG008017 to RW (Pathology Core

Director).

P4-001 SUBTYPES OF MILD COGNITIVE IMPAIRMENT

DIFFERENTIATED BASED ON LIMBIC WHITE

MATTER INTEGRITYAND CORTICAL GLUCOSE

METABOLISM: A PILOT STUDY USING DTI AND

FDG-PET

Igor O. Korolev, Lori A. Hoisington, Kevin L. Berger, Andrea C. Bozoki,

Michigan State University, East Lansing, MI, USA.

Contact e-mail: korolevi@msu.edu.

Background:Mild cognitive impairment (MCI) is regarded as a pre-clinical

stage of dementia, particularly Alzheimer’s disease (AD). Several MCI sub-

types have been proposed based on distinct neuropsychological profiles, in-

cluding amnestic MCI (aMCI), non-amnestic MCI (naMCI), and multi-

domain MCI (mdMCI). Nevertheless, neuroimaging correlates of MCI re-

main controversial. We hypothesized that MCI brains can be differentiated

from brains of normal controls (NC) based on integrity of limbic tracts (for-

nix and cingulum) and cortical glucose metabolism, and that MCI subtypes

can be differentiated based on these markers of neuronal dysfunction.

Methods: We studied 16 NC and 20 MCI patients (11 mdMCI; 4 aMCI; 5

naMCI) with diffusion tensor imaging (DTI) and FDG-PET. DTI images

were acquired using these parameters: EPI, b ¼ 1000 with 6 directions, 4

NEX, 3 mm^2 in-plane resolution with 3 mm slices, interpolated to voxel

size of 1.5 mm^3. DTI tractography was used to map the fornix body, supe-

rior and descending cingulum, and posterior limb of internal capsule, and

both fractional anisotropy (FA) and volume measurements were obtained

for each structure. PET images were acquired following 10 mCi injection

of FDG and compared to an age-matched normal database. Pons-normalized

Z-scores were computed for posterior cingulate cortex (PCC), medial parie-

tal cortex (MPC), parietal association cortex (PAC), temporal association

cortex (TAC), and visual cortex using 3D-SSP technique. Results:MCI co-

hort exhibited decreased fornix FA (p < 0.001) and descending cingulum

volume (p¼ 0.001) relative toNC; neither FA nor volume of internal capsule

(control) differed between groups. Fornix volume differed among MCI sub-

types (p ¼ 0.008), with aMCI (p < 0.05) and mdMCI (p < 0.01) exhibiting

lower volumes than naMCI; however, fornix volume did not differ between