Hot Topics e3

lateral ventricles in both PDCN and PDMCI. Hippocampal atrophy and lat-

eral ventricular enlargement show promise as sensitive biomarkers for track-

ing PD and PDD progression.

f

F2-02-05 FOUR SIBLINGS WITH VARIABLE CLINICAL AND

PATHOLOGICAL CHARACTERISTICS OF

ALZHEIMER’S AND LEWY BODY DISEASE

James B. Leverenz1,2, Cyrus Zabetian1,2, Ellen J. Steinbart1, Kate Nickel1,

Malia Rumbaugh1, Thomas J. Montine2, Thomas D. Bird1,2, 1VA-PSHCS,

Seattle, WA, USA; 2University of Washington, Seattle, WA, USA.

Contact e-mail: leverenz@u.washington.edu

Background: Lewy related pathology (LRP) is observed in number of

neurodegenerative diseases including Parkinson disease, dementia with

Lewy bodies, and Alzheimer’s disease (AD). Of interest, in some of these

diseases the presence and severity of LRP is quite variable, even within

dominantly inherited familial disease. The current report examines LRP

and related pathologic changes in 4 siblings with a familial neurodegen-

erative process. Methods: Clinical records were reviewed for 4 siblings

from a family with a history of late-onset dementia. In addition, detailed

neuropathologic evaluation was performed in all 4 siblings, including as-

sessment of LRP and pathologic changes associated with AD and fronto-

temporal dementia (neurofibrillary tangles, neuritic plaques, TDP-

43).Results: Family history was positive for dementia in the mother

and maternal uncle. Four of seven siblings were affected. Clinical char-

acteristics included dementia at onset in 3 of 4 siblings, while the re-

maining sibling was diagnosed with Parkinson disease. One sibling

with dementia at onset had motor parkinsonism and hallucinations. The

single sibling with parkinsonism at onset was responsive to dopaminergic

therapy and had evidence of cognitive impairment just prior to death (7

years after onset of motor parkinsonism). Mean age at onset was 80.5

years (range of 78 to 82 years). Neuropathologic examination revealed

AD in the three siblings with dementia at onset, however 2 of these

also had neocortical LRP. The sibling with clinical PD had neocortical

LRP, but Braak stage IV neurofibrillary tangles and CERAD stage A

neuritic plaques. APOE genotype was 3/3 for 2 siblings and 3/4 for

one. LRRK2 mutations were not found. Conclusions: We describe an in-

triguing family with a variable clinical picture within a single sibship.

One sibling fulfilled clinical criteria for Parkinson disease, while the 3

others had clinical histories consistent with AD or dementia with Lewy

bodies. Pathologic change generally correlated well with the clinical syn-

drome in each sibling. These findings, along with previous observations,

point to substantial variability of clinical syndrome and pathology in

many diseases with LRP. Further study of familial diseases characterized

by LRP may elucidate the genetic and environment factors that underlie

this variability.

F2-02-06 MIXED ALZHEIMER’S AND LEWY BODY DISEASE

PATHOLOGY PATTERNS

Melissa E. Murray, Brittany N. Dugger, Dennis W. Dickson,

Mayo Clinic College of Medicine, Jacksonville, FL, USA.

Contact e-mail: murray.melissa@mayo.edu

Background: The co-deposition of Alzheimer’s disease (AD) and Lewy

body disease (LBD) pathology in the elderly brain is commonly observed

at autopsy. Lewy bodies, the pathological hallmark in LBD, are cytoplasmic

neuronal inclusions consisting mainly of the pre-synaptic protein, alpha-

synuclein. Brainstem, transitional, and diffuse-LBD classifications reflect

pathologic burden of Lewy bodies in the brainstem nuclei, limbic areas,

and cortical regions, respectively. Neurofibrillary tangles (NFT) more so

than senile plaques (SPlq) are known to adversely affect neuronal popula-

tions in AD. We evaluated the hippocampal and cortical pattern of AD

and LBD pathology to determine whether differences existed among mixed

AD/LBD types. Methods: The Mayo Clinic Florida brain bank database

was queried for a concominant pathological diagnosis of AD and LBD. In-

cidental-LBD, amygdala only LBD and vascular disease cases were ex-

cluded. The cases were limited to a Braak NFT stage > 5 and ages 65-90

years at death. Our final cohort consisted of: 5 AD/BLBD (3 males), 92

AD/TLBD (45 males), and 113 AD/DLBD (56 males). Maximal NFT and

SPlq density was assessed with thioflavin-S fluorescent microscopy in

two sectors of hippocampus (CA1 and subiculum) and three association cor-

tices (superior temporal (ST), mid-frontal (MF), and inferior parietal (IP)).

Maximal LB density was assessed using alpha-synuclein immunoreactivity

in the same association cortices, the cingulate gyrus, and the parahippocam-

pal gyrus. Results: Mixed-AD diagnosis was more common in TLBD

(38%) and DLBD (31%), compared to BLBD (6%). There were no differ-

ences in age, sex, or Braak stage between groups. AD/TLBD cases had

more NFT in the CA1, MF, and IP (p<0.001), compared to both BLBD

and DLBD. There were no differences detected in the NFT density in the

subiculum or ST cortex. SPlq density did not differ amongst groups.

DLBD had greater LB density in all regions examined (p<0.001), compared

to both AD/BLBD and AD/TLBD.Conclusions:Differences were detected

in NFT and LB density amongst the three AD/LBD types. AD/DLBD con-

sistently had higher LB, while AD/TLBD had significantly higher NFT.

While both types of pathology can be observed in the same brain regions,

the apparent inverse relationship suggests the accumulation of NFT pathol-

ogy may interfere with LB formation, and vice versa.

F2-02-07 LOSS-OF-FUNCTION MUTATIONS IN THE

GLUCOCEREBROSIDASEGENEAREASSOCIATED

WITH LEWY BODY DEMENTIA

Debby Tsuang, University of Washington, Seattle, WA, USA.

Contact e-mail: dwt1@uw.edu

Background: Multiple investigators have recently demonstrated that loss-

of-function mutations in the glucocerebrosidase (GBA) gene convey an ap-

proximately 6-fold greater risk for developing Parkinson’s disease (PD).

However, the relationship between GBAvariants and cognitive dysfunction

in Lewy body dementias (LBDs) is not clear.Methods: GBA mutation fre-

quency was compared in a large sample of autopsied dementia cases and

controls from an NIH-funded multicenter clinicopathological study. Sub-

jects were classified by the following neuropathological subtypes: “pure”

Lewy body disease (n¼25), Lewy body-variant Alzheimer’s disease (AD;

n¼120), “pure” AD (lacking Lewy-related pathology; n¼169) and control

subjects (lacking either LB or AD pathology; n¼28). The entire GBA cod-

ing region was screened in study subjects. Results: The frequency of path-

ogenic GBA mutations was highest in the pure LBD group (4/25¼16%),

followed by the LB variant of AD group (5/120¼4.2%). Pathogenic GBA

mutations were rare in subjects with pure AD (1/169¼0.06%), and no mu-

tations were observed in controls (overall chi square¼19.8, df¼3,

p<0.0001). Of the three pathogenic mutations identified, the N370S muta-

tion was the most common (n¼8) Conclusions: The frequency of patho-

genic GBA mutations is highest in pure LBD groups, followed by LB

Hot Topicse4

variant of AD groups, whereas suchmutations are rare or nonexistent in pure

AD and control groups. Therefore, GBA appears to be a genetic risk factor

for LBD. To replicate these genetic associations, future studies will need to

include larger samples of subjects with pathologically confirmed LBD. If

these associations are replicated, investigations focused on cognitive im-

pairment and the loss-of-function of GBAwill be warranted.

SUNDAY JULY 11, 2010

P1-466 COGNITIVE EVENT-RELATED POTENTIALS AS

INDICATORS OF DONEPEZILTREATMENT

EFFECTS IN MILD ALZHEIMER’S DISEASE

Zoe Tieges1, Kerry W. Kilborn1, Jessica Price2, Bernard A. Conway2,

Alan Hughes3, Gillian McLean4, 1Glasgow University, Glasgow, United

Kingdom; 2Strathclyde University, Glasgow, United Kingdom; 3Greater

Glasgow NHS, Glasgow, United Kingdom; 4Forth Valley NHS, Falkirk,

United Kingdom. Contact e-mail: z.tieges@psy.gla.ac.uk

Background: In previous research we identified ERP and behavioural fea-

tures associated with memory that produced good discrimination between

mild AD and controls. Two prominent markers include a difference wave

around 600ms, and memory performance (d’ measures). In the current

study, we explore whether these markers of brain and cognitive function

are sensitive to treatment effects of donepezil. Methods: We examined

a range of ERP components and behavioral data based on a crossmodal ep-

isodic memory task designed to elicit activity in the hippocampus. The task

entails an old/new decision to simple visual images coupled with auditory

words. For example, the image of a train is presented with the word “tun-

nel.” Some pairs are presented a second or third time, at varying intervals.

Dense array (128 channel) EEG is acquired continuously during testing.

Patients newly diagnosed with probable AD participated in four successive

test sessions: pre-treatment Session 1, and post-treatment Session 2 (1

week), Session 3 (4 weeks) and Session 4 (12 weeks). All patients received

donepezil. We report here the findings for 8 patients who have completed

all test sessions in the ongoing study. Results: We observed significant ef-

fects between pre-treatment and post-treatment conditions, as measured by

both behaviorial (d’) and ERP variables. T-tests with the d’ measure show

significant differences between Session 1 and 3 (t ¼ -2.45, p < 0.045), and

between Session 3 and 4 (t ¼ -2.50, p<.042). These differences indicate an

improvement in memory task performance is associated with treatment.

We also observed memory-related ERP effects that vary according to treat-

ment condition. In the time interval 520-580ms post-stimulus, in healthy

controls we observe a left frontal negativity that is coupled with a right pa-

rietal positivity. Pre-treatment, this effect is greatly attenuated in AD pa-

tients. However, by Session 4 (12 weeks), we observe apparent recovery

of this functional ERP pattern (Memory x Session, F¼3.45, p<0.009; Ses-

sion 1 vs Session 4, F¼12.88, p<.013). Conclusions: The improvement in

memory performance, together with the recovery of brain function, indi-

cate that cognitive ERP methods are sensitive to treatment affects of done-

pezil in AD.

P1-467 ROLE OF POLYPHENOLS FROM GRAPE SEEDS IN

ATTENUATION OF TAU PATHOLOGY SPREADING

Giulio M. Pasinetti, Hanna Ksiezak-Reding, Jun Wang, Lap Ho,

Ismael Santa-Maria, Mount Sinai School of Medicine, New York, NY, USA.

Contact e-mail: giulio.pasinetti@mssm.edu

Background: Abnormal folding of protein tau leads to the generation of

paired helical filaments (PHFs), a key neuropathological feature in tauopa-

thies. There is evidence that anthraquinones, quinoxalines and polyphenols

are able to inhibit PHF formation in vitro and in cultured cells. Further-

more, we previously observed that naturally occurring polyphenols ex-

tracted from grape seeds (GSPE) suppressed neurodegeneration in vivo

in a Drosophila eye model of tau mutant R406W and in a mice model

of Alzheimer’s disease (Pasinetti et al. In press). Based on ongoing studies

in the lab, we hypothesize that GSPE may provide beneficial disease-mod-

ifying activities in tauopathies. Moreover, in a recently published work it

has been described the first evidence in vivo that tau aggregation can

spread between connected cells through the transmission of tau ‘seeds’.

This study confirms that, as previously demonstrated in vitro (in a cellular

model), tau aggregation can be transmitted from cell to cell in vivo. GSPE

may attenuate misfolding of tau protein that lead to the generation of fil-

amentous aggregates in different tauopathies including Alzheimer’s dis-

ease, promote their de-aggregation and improve susceptibility to

proteolytic clearance. The present studies are designed to explore this hy-

pothesis using these cellular models of tau pathology spreading. Methods:

As cellular model we utilized neuronal cell line SH-SY5Y cells transiently

transduced with lentivector of human tau. For seeding intracellular aggre-

gation we used PHFs from Alzheimer’s disease brain tissue. We explored

at biochemical and cellular level possible mechanisms of tau pathology

spreading induced by human PHFs and we explore the inhibitory effect

of GSPE in tau pathology spreading. Results: We report isolated human

PHFs from Post-mortem AD brain tissue can seed tau aggregation intrace-

lullary. In addition, we explored the effect of GSPE in tau pathology

spreading inhibition. We found that preincubation of cells with monomeric

fraction of GSE attennuates the seeding of tau aggregation induced by hu-

man PHFs. Conclusions: Our studies support an important role of PHFs in

tau pathology spreading from outside to the inside of a human tau express-

ing neuronal cell line. Moreover, we demostrated the beneficial role of

polyphenolic compounds for the treatment of tau mediated pathology in

Alzheimer’s disease and related tauopathies.

P1-468 HOW DO SYNAPTIC NUMERS AND SYNAPTIC

PROTEINS CORRELATE WITH AB42 IN

ASSOCIATION NEOCORTEX IN THE

PROGRESSION OFALZHEIMER’S DISEASE?

StephenW. Scheff1, Douglas A. Price1, Mubeen A. Ansari1, Paul Murphy1,

Elliott J. Mufson2, 1University of Kentucky, Lexington, KY, USA; 2Rush

University, Chicago, IL, USA. Contact e-mail: sscheff@email.uky.edu

Background: The progressive loss of synaptic connectivity in association

areas of the neocortex is believed to play a central role in cognitive impair-

ments observed in the early and late stages of Alzheimer’s disease (AD).

There is increasing evidence that amyloid beta peptide (Ab) may be funda-

mentally involved in the pathogenesis of AD. The most toxic form of Ab is

the small oligomeric species that is readily diffusible and known as soluble

Ab (sAb).The idea behind the sAb hypothesis is that small oligomeric spe-

cies of Ab42 accumulate at the synaptic cleft, disrupting the synaptic com-

plex leading loss of function and synaptic degeneration. This study

investigated the possible relationship between actual synaptic numbers, sev-

eral synaptic proteins, and sAb in the neocortex of individuals with mild

cognitive impairment (MCI), early AD (eAD), and moderate AD (mAD).

Methods:Tissuewas obtained at autopsy from the ADCenter at the Univer-

sity of Kentucky and the Religious Orders Study at Rush University. All in-

dividuals underwent detailed clinical evaluation within 12 months of death

and were categorized as no cognitive impairment (NCI), MCI, eAD, or

mAD based upon cognitive tests. Systematic random samples throughout

the inferior temporal gyrus were processed for standard transmission elec-

tron microscopy. Unbiased stereological techniques were used to estimate

total synaptic numbers. Adjacent tissue was processed for a bank of pre

and post synaptic proteins using Western blots, and assayed for the levels

of sAb. Results: Detailed analysis of total synaptic numbers revealed a sig-

nificant loss in synapses with the progression of the disease. Levels of var-

ious presynaptic proteins (Synapsin-1, Synaptophysin) and postsynaptic

proteins (PSD-95, Drebrin, SAP-97) showed a strong association with the

ultrastructural data. Both of these measures showed a strong association

with levels of sAb. As the levels of sAb increased the number of synapses

and levels of synaptic proteins declined.Conclusions: This is the first study

to associate total synaptic numbers and synaptic proteins with sAb during

the course of the disease. The results strongly implicate sAb in the loss of

synapses and suggest this as an avenue for therapy to slow the progression

of the disease.