Poster Presentations P3 S525

P3-251 MAGNETIC RESONANCE BIOMARKERS OF

De

Volume

(mm3)

low

FA low

ADC

(mm2/s

x 10L3)

hig

T1r (ms) hig

T2r (ms) hig

NEURODEGENERATION IN A TRANSGENIC

MOUSE MODEL OF ALZHEIMER’S DISEASE

Malgorzata Marjanska1, R. Chamberlain1, G. Preboske2, A. Polk1,

L. Kotilinek1, T. M. Wengenack2, J. F. Poduslo2, S. A. Youdas2,

K. H. Ashe1, M. Garwood1, C. R. Jack, Jr.,2, 1University of Minneapolis,Minneapolis, MN, USA; 2Mayo Clinic, Rochester, MN, USA.

Contact e-mail: gosia@cmrr.umn.edu

Background: The histological abnormalities that characterize Alzheimer’s

disease (AD) are commonly divided into four major classes: amyloid pla-

ques, neurofibrillary tangles, inflammation, and neurodegeneration (NDG).

In this work we compare the ability of various MR techniques (volume,

T1r, T2r, ADC, FA) to detect the NDG in the rTg4510 mouse model (1) com-

pared to wild-type (WT) mice. Methods: In vivo experiments were per-

formed using a 9.4-T/31-cm horizontal bore magnet equipped with

a Varian INOVA spectrometer. rTg4510 mice over express mutant human

tau leading to an induced tauopathy and extensive neurodegeneration by 9

months of age. Four Tg4510 mice were imaged at 13 months of age and

four WT mice were imaged at 12 months of age. All images were acquired

using a quadrature surface coil. The volume image was acquired with a 3D

multi-asymmetric spin-echo pulse sequence (2) with resolution 120 mm x

120 mm x 400 mm. The apparent diffusion coefficient (ADC) and fractional

anisotropy (FA) and the rotating frame relaxation times, T1r and T2r, were

measured with a 2D single slice with in-plane resolution of 80 mm x 80

mm, slice thickness of 1 mm. Results: All MR techniques detected the ex-

pected differences between WT and rTg4510 mice as shown in the table.

Hippocampus Corpus Callosum

tecting WT Tg4510 WT Tg4510

er - neuronal

loss

28.9 6 0.9 23 6 1 – –

er - loss of

white matter

tract integrity

– – 0.73 6 0.01 0.63 6 0.01

her - neuronal

loss

1.44 6 0.01 1.66 6

0.03

– –

her - decrease

in protein-water

interaction

95.3 6 0.8 105 6 2 83.3 6 0.4 89.8 6 0.5

her - decrease

in protein-water

interaction

42.9 6 0.1 46.6 6

0.6

39.5 6 0.2 41.5 6 0.3

Conclusions: These results show that NDG can be detected with various

measurements in transgenic mice over expressing mutant human tau. These

techniques are all in theory candidate biomarkers for human AD and could

enhance diagnostic sensitivity and aid in early diagnosis of AD in humans.

References

[1] SantaCruz K, et al, Science 309: 476 (1998), [2] Chamberlain R, et al,

MRM 61: 1158 (2009).

P3-252 NOVEL CSF BIOMARKERS FOR ALZHEIMER’S

DISEASE AND MILD COGNITIVE IMPAIRMENT

William T. Hu1,2, Alice Chen-Plotkin1, Steven E. Arnold1,

Murray Grossman1, Christopher M. Clark1, Leslie M. Shaw1, Virginia M.-

Y. Lee1, Holly D. Soares3, John Q. Trojanowski1, 1University of Pennsyl-

vania, Philadelphia, PA, USA; 2Emory University, Atlanta, GA, USA; 3Pfizer

Global Research and Development, Groton, CT, USA.

Contact e-mail: mustard.clinic@gmail.com

Background: The accuracy of biomarkers for Alzheimer’s disease (AD) can

be best determined in well-characterized patients longitudinally followed to

autopsy confirmation. Levels of CSF biomarkers may also track cognitive

decline during disease progression, and their levels may be considered sec-

ondary endpoints in future therapeutic trials. Objective: To identify antemor-

tem cerebrospinal fluid (CSF) diagnostic biomarkers that distinguish

pathologically confirmed AD from cognitively normal (NL) subjects and pa-

tients with other neurodegenerative disorders such as frontotemporal lobar

degeneration and dementia with Lewy bodies, and CSF biomarkers that cor-

relate with cognition in AD and mild cognitive impairment (MCI). Methods:

CSF samples were collected antemortem from 66 AD patients with AD and

25 patients with other neurodegenerative dementias followed longitudinally

to neuropathologic confirmation, 42 longitudinally followed MCI patients,

and 33 NL. Levels of 151 novel analytes were measured via a targeted mul-

tiplex panel enriched in cytokines, chemokines, and growth factors as well as

established AD biomarkers (ApoE4 allele, and levels of Ab42, tau, and p-

tau181). Results: AD is best distinguished from NL by a combination of tra-

ditional AD biomarkers that confer sensitivity, and multiplex biomarkers that

confer specificity relative to NL. Two categories of biomarkers were identi-

fied: 1) analytes that specifically distinguish AD (especially CSF Ab42

levels) from NL and other neurodegenerative disorders; and 2) analytes al-

tered in multiple neurodegenerative diseases, but not in NL subjects. Six an-

alytes were correlated with severity of cognitive impairment at CSF

collection, and two were associated with subsequent cognitive decline in

MCI. Conclusions: Our targeted proteomic screen revealed novel CSF bio-

markers that distinguished AD from NL and other neurodegenerative disor-

ders, and subsets of biomarkers that correlated with cognition and subsequent

cognitive decline. A multiplex panel of CSF biomarkers can improve the an-

temortem diagnostic and prognostic classification of AD and MCI.

P3-253 CHANGES IN AB42 LEVELS ARE ASSOCIATED

WITH THE FUNCTIONAL OUTCOME IN

ALZHEIMER’S DISEASE

Anton Alvarez1, Carolina Sampedro1, Veronica Couceiro1,

Ramon Cacabelos1, Manuel Aleixandre2, Carlos Linares3, Elias Granizo3,

Herbert Moessler4, Manfred Windisch5, Markus Mandler6, Frank Mattner6,1Euroespes Biomedical Research Centre, A Coruna, Spain; 2Faculty of

Psychology, Granada University, Granada, Spain; 3Memory Clinic, Ma-

laga, Spain; 4Ever Neuro Pharma, Unterach, Austria; 5JSW Life Sciences,Grambach, Austria; 6Affiris AG, Vienna, Austria.

Contact e-mail: xantonal@yahoo.es

Background: Amyloid-beta (AB) is the main pathogenic factor in Alzheim-

er’s disease (AD). Reductions of the AB42 fragment in the cerebrospinal

fluid (CSF) are of diagnostic value and correlate with AD severity. However,

there are no clear clues for the interpretation of changes in plasma and CSF

AB42 levels after therapeutic interventions. Methods: We evaluated AB42

levels in two different sets of AD patients completing per protocol two ran-

domized clinical trials: (1) 158 patients treated during 28 weeks with Cere-

brolysin 10mL, Donepezil-10mg or a combination of both; and (2) 54

patients receiving either placebo, 20mg or 30mg of Phenserine tartrate for

24 weeks. Samples of plasma (both studies) and CSF (second trial only)

were obtained at baseline and after treatment. Changes in cognition (ADAS-

cog+ scores), functioning in activities of daily living (ADCS-ADL scores)

and neuropsychiatric symptoms (NPI scores) were compared between pa-

tients showing reductions and those undergoing increases in AB42 levels

from baseline. Results: Independently of the treatment received, patients

with decreases in plasma AB42 showed a significant improvement of func-

tioning (p < 0.01) as compared to those with AB42 elevations. On the con-

trary, increases in CSF AB42 levels were associated with a better functional

outcome (p < 0.01) in AD patients. No significant differences were found

between the two AB42-response groups for changes in cognitive performace

or behavior in any study. Conclusions: These results indicate that reductions

in plasma AB42 and/or increases in CSF AB42 levels are associated with

a better functioning in activities of daily living after treatment with neurotro-

phic and/or cholinergic drugs in AD patients. If there is a direct link between

changes in plasma/CSF AB42 and functional improvement, or if both facts

are merely a reflect of an improved general condition of the patients merits

further investigation.