P3-199

S434

Poster P3:: Tuesday Posters

microscopic examination apart from neuronal loss and minimal spongiform change the most striking feature was presence of abundant eosinophylic, round, plaques with distinct borders-cotton wool plaques. These plaques were observed in the cerebral cortex, more frequently in the occipital and temporal than frontal lobes. The classic amyloid plaques were also sporadically seen in the cerebral cortex. In cerebellar cortex the cotton wool plaques were also abundant, the classic plaques were sparse in the pyramidal layer. In Congo staining the cotton wool plaques didn’t show green birefringence in polarized light. The immunohistochemistry with antibodies for Ab40 and Ab42/43 showed immunoreactivity for the Ab42/43 but not for Ab40 antibody within the cotton wool plaques. The classic plaques showed classical pattern of immunoreactivity by bounding Ab40 and Ab42 in the central core and Ab42/43 in the surrounding. There was also a robust Ab42 and Ab40 immunoreactivity within the cerebral vessel walls especially in cerebellum. There was also a robust Ab42/43 and Ab40 immunoreactivity within the cortical and meningeal vessel walls especially in cerebellum. The immunochemistry shows reactivity for the pathological form of PrP. The most striking ultrastructural feature was presence of dystrophic neuritis with robust autophagic vacuoles. The autophagic vacuoles were also observed in the cell bodies. Conclusions: The clinical history with myoclonus, rapidly progressive dementia in a young man suggested Creutzfeldt Jakob disease. After re-estimation of the whole case the CJD can be excluded and Alzheimer disease with cotton wool plaques must be diagnosed. P3-199

THE GLUTAMATE TRANSPORTER, EAAT3 (EAAC1), IS ABERRANTLY EXPRESSED IN HIPPOCAMPUS OF INDIVIDUALS WITH ALZHEIMER’S DISEASE

David G. Cook1, Kevin Deurson1, James Leverenz1, Thomas Bird1, Thomas Montine2, David Pow3, 1VA Medical Center, Univ. Washington, Seattle, WA, USA; 2Univ. Washington, Seattle, WA, USA; 3University of Newcastle, Newcastle, Australia. Contact e-mail: [email protected] Background: Disturbed glutamate homeostasis may contribute to some of the pathological processes associated with Alzheimer’s disease (AD) including synaptic dysfunction, synapse loss, and neuron loss. A family of five glutamate uptake transporters (EAAT1 through EAAT5) are essential for maintaining normal glutamate levels in the brain. Previous studies have reported that some glutamate transporters are reduced in AD brains. In this regard very little is known about EAAT3, which in the brain, is expressed primarily by neurons. Unlike other glutamate transporters, a relatively large proportion of EAAT3 is localized in regulated intracellular pools that can be mobilized to function in response to specific cellular signals. EAAT3 is also distinct because it more readily transports cysteine, which is used by mature neurons to synthesize glutathione. Objective(s): We asked whether EAAT3 expression is altered in AD. Methods: We performed immunohistochemistry in the hippocampus and frontal cortex of AD and normal control subjects matched for age and gender. Results: As expected, in AD cortex the number of EAAT3 immuno-positive neurons was lower than in control cortex, presumably due to AD-related neuron loss. In contrast to this, AD hippocampal pyramidal neurons of the CA2 and CA3 displayed a marked increase in EAAT3 immunoreactivity compared to controls. Interestingly, EAAT3 immunoreactivity in dentate gyrus neurons, which tend to be spared in AD, was moderately lower in AD compared to controls. Finally, we observed no obvious association between senile plaques immunostained for A␤ and those neurons with elevated EAAT3. However, we did observe numerous EAAT3-positive pyramidal neurons with granulovacuolar lesions. Conclusions: EAAT3, which plays important roles in glutamate clearance, GABA synthesis, and protecting against oxidative stress, is aberrantly expressed in AD. The higher EAAT3 levels in CA2/3 pyramidal neurons is especially interesting because it hints at the possibility that EAAT3 may be upregulated by some neurons as a means to compensate for specific ongoing neurological insults associated with AD. These data also lend further support to the idea that glutamate or

cysteine dyshomeostasis may be an important feature of the Alzheimer’s disease process. These studies are supported by a VA Merit Award to DGC. P3-200

RELATIONSHIP BETWEEN NEUROFIBRILLARY PATHOLOGY AND A␤ DEPOSITION IN ALZHEIMER DISEASE

Chiara Cupidi1,2, Giorgio Giaccone2, Raffaella Capobianco2, Bernardino Ghetti3, Orso Bugiani2, Fabrizio Tagliavini2, 1Department of Neurology and Psychiatry, University of Palermo, Palermo, Italy; 2 Istituto Nazionale Neurologico Carlo Besta, Milan, Italy; 3Department of Pathology and Laboratory Medicine, Division of Neuropathology, Indiana University School of Medicine, Indianapolis, IN, USA. Contact e-mail: [email protected] Background: The relationship between development of A␤-deposition and neurofibrillary pathology is a key issue in the pathogenesis of Alzheimer disease (AD). Objective: To investigate the relative extent and topographical distribution of tau- and A␤-related pathology in neocortical areas and their correlation with disease duration in a homogeneous sample of patients with advanced stages of AD. Methods: Silver impregnations (Gallyas, Bodian), amyloid staining (thioflavine S) and immunohistochemistry for hyperphosphorylated tau (AT8-Innogenetics) and A␤ (pan␤-Biosource) was performed in 44 AD patients at Braak stage IV-VI. Morphometric analysis of A␤-load was conducted on 18 patients (3 patients at Braak stage IV, 10 patients at Braak stage V, 5 patients at Braak stage VI) in 6 neocortical areas. Data were submitted to statistical analysis using ANOVA and multiple linear regression. Results: Analysis of AT8-stained sections identified three different patterns of distribution of neurofibrillary pathology, corresponding to Braak stage VI in 18 patients, Braak stage V in 23 patients and Braak stage IV in 3 patients. Duration of disease was longer in patients at stage VI than in those at stage V and IV (p⬍0.01). A␤-load values showed a great variability among individuals (mean⫾SD: 5.2⫾ 2.5%; coefficient of variation 48%). Further, A␤-load was not uniform throughout the neocortex even in the same individual. The difference in A␤-load among neocortical areas (p⬍0.001) allowed us to define a distinct pattern of extent of A␤-pathology, marked by decreasing severity from inferior temporal, anterior cingulate and insular cortex to superior temporal and premotor cortex, and finally to primary motor cortex. The A␤-load did not have significant different averages in the three groups of AD patients identified by Braak stage and did not correlate with disease duration, except for primary motor cortex where A␤-load was higher in Braak stage VI than in stage IV (p⬍0.05) and correlated positively with disease duration (p⬍0.05). Conclusions: Our findings suggest the existence of a marked heterogeneity in morphology, extent and topographical distribution of A␤ deposits even in AD brains that are homogeneous for neurofibrillary pathology. This heterogeneity cannot be completely explained by a simple and regular build-up of lesions during the progression of disease. P3-201

STUDIES ON THE EFFECT OF THE APOLIPOPROTEIN E GENOTYPE ON THE LIPID PROFILE IN ALZHEIMER’S DISEASE

Marwan N. Sabbagh1, Shawn Sandhu2, Heather Kolody2, Tyson Lahti2, Nina B. Silverberg2, D. Larry Sparks2, 1Sun Health Research Institute, Sun City, AZ, USA; 2Sun Health Research Institute, Sun City, USA. Contact e-mail: [email protected] Background: Links between hypercholesterolemia and AD development continue to grow. Presently, limited information exists about the influence of the Apo E genotype on the lipid profile characteristics in AD. Objective(s): To determine whether Apolipoprotein E4 (Apo E4) gene status or ApoE gene dose affect the lipid profile in AD. Methods: We examined the lipid profiles (total cholesterol (TC), high-density lipoprotein (HDL), lower-density lipoprotein (LDL), TC/HDL ratio, and triglyceride (TG) levels) of 142 subjects with probable or possible AD (mean age 76.5 ⫾ 8.9 years),