P2-275

Poster P2:: Monday Posters Background: The neuropathological hallmarks of Alzheimer’s disease, amyloid senile plaques and tau neurofibrillary tangles, also accumulate in cortical brain regions in patients with mild cognitive impairment (MCI) who are at risk for Alzheimer’s disease. A non-invasive method to determine regional cerebral patterns of these abnormal protein aggregates would facilitate early diagnosis and monitoring of novel treatments to prevent and eliminate their accumulation. Methods: We performed positron emission tomography (PET) scans on 60 subjects (20 cognitively intact controls, 20 with MCI, 20 with Alzheimer’s disease) after intravenous injections of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl) amino]-2-naphthyl} ethylidene)malononitrile (FDDNP), a molecule that binds to plaques and tangles in vitro. Subject groups were age-matched, and clinical assessments and FDDNPPET scans were repeated for 9 subjects (5 controls, 4 MCI subjects) after approximately two years (mean ⫾ SD ⫽ 24 ⫾ 5 months). Autopsy follow-up was available on 1 patient with Alzheimer’s disease. Results: Global FDDNP-PET binding (temporal, parietal, posterior cingulate, and frontal average) was lower for the control group compared with the MCI group (P⬍0.001), which showed lower binding compared with the Alzheimer’s disease group (P⬍0.001). Higher cognitive test scores correlated inversely with lower FDDNP binding values (P⬍0.001). At follow-up, subjects who converted from normal cognitive status to MCI or from MCI to Alzheimer’s disease showed regional FDDNP binding increases ranging from 5 to 11 percent, and autopsy follow-up demonstrated high concentrations of plaques and tangles in brain regions with high FDDNP binding. Conclusions: Although previous PET studies have found differences in cerebral amyloid measures when small groups of dementia patients and controls are compared, the present study is the first to describe in vivo cerebral imaging of amyloid and tau deposits in larger subject groups, including patients with MCI, as well as longitudinal clinical and autopsy follow-up. FDDNP-PET differentiates MCI from Alzheimer’s disease and controls and demonstrates increased binding as clinical neurodegeneration progresses. These results point to the potential utility of FDDNP-PET in early, “preclinical” diagnosis, as well as in monitoring interventions designed to prevent or reduce brain amyloid or tau accumulation. P2-275

A CLUE TO THE LACK OF SUCCESS OF AMYLOID IMAGING AGENTS IN TRANSGENIC MOUSE MODELS OF ALZHEIMER’S DISEASE

Liang Ye, Jennifer Morgenstern, Paul Thompson, Sharon Baker, Jonathan R. Lamb, Andrew Lockhart, GlaxoSmithKline, Cambridge, United Kingdom. Contact e-mail: [email protected] Despite the emerging successful application of amyloid PET imaging agents including PIB and FDDNP in Alzheimer’s disease (AD) patients, the successful use of these agents in transgenic mouse models of AD has not been reported to date. To understand the behavior of these ligands in transgenic models, we set up in vitro binding assays to investigate the interaction of PET ligands including PIB and FDDNP with rodent A␤(1-40) fibrils. These data indicate that the pattern of ligand binding to rodent A␤ fibrils is broadly similar in terms of binding affinities and compound specificity to our previous report using human A␤(1-40) fibrils (Table 1). Immunohistochemical studies suggest that endogenous mouse A␤ is deposited alongside the human A␤ peptides in the plaques of the transgenic mice and that this might potentially be in the form of co-polymers. Based on this observation, we further characterized the number of high affinity [3H]Me-BTA-1 binding sites in human A␤ fibrils formed in the presence of increasing amounts of rodent A␤ (1, 5, 10% w/w). Our results demonstrate a dose dependent reduction in the number of high affinity sites with a 95% decrease at the highest amount of rodent A␤. In the light of these studies, we hypothesise that the weak binding signal observed in vivo in the transgenic models may, in part, be due to the decreased number of high affinity binding sites.

P2-276

S319

MAPPING OF PROGRESSIVE LOSS OF ACETYLCHOLINESTERASE ACTIVITIES IN EARLY- AND LATE-ONSET ALZHEIMER’S DISEASE

Hitoshi Shinotoh1,2, Kiyoshi Fukushi1, Noriko Tanaka1, Tsuneyoshi Ota1, Shigeki Hirano1, Koichi Sato1, Hitoshi Shimada1, Shuji Tanada1, Toshiaki Irie1, 1National Institute of Radiological Sciences, Chiba, Japan; 2Asahi Hospital for Neurological Disorders, Matsudo, Japan. Contact e-mail: [email protected] Background: Recent studies of postmortem brains with early stage of Alzheimer’s disease (AD) suggest that there is not any or only mild cholinergic deficits in mild AD. N-[11C]methylpiperidin-4-yl acetate (MP4A) has been shown to be a useful radiotracer for quantitative measurement of AChE activity in the cerebral cortex and thalamus in vivo. Objective(s): To elucidate how cholinergic deficits progress in early(EOAD) and late-onset AD (LOAD). Methods: Nineteen healthy subjects (12M and 7F, 64⫾12 y.o.), 27 patients with EOAD (12M and 15F, 62⫾5 y.o.), and 23 patients with LOAD (7M and 14F, 74⫾5 y.o.) took part in this study. AD patients were divided into subgroups according to MMSE scores; mildly (MMSE score 20-23, n⫽7 in EOAD and LOAD), moderately I (MMSE 16-19, n⫽7 in EOAD and LOAD), moderately II (MMSE 11-15, n⫽6 in EOAD and 7 in LOAD), and severely demented groups (MMSE 0-10, n⫽7 in EOAD and 0 in LOAD). [11C]MP4A-PET acquisition was a dynamic sequence of 14 PET scans over a 40-minute period. A three-compartment model was employed to yield voxel-by-voxel estimates of K1, k2, and k3 in the whole brain using the arterial input function. Group comparisons of k3 values (indices of AChE activity) in normal controls and each patient group were performed using two-sample t-test in SPM2 (uncorrected p⬍0.0001, cluster extent K⬎ 50 voxels). Results: The results suggest that k3 values were significantly reduced in the temporo-parietal cortices including the posterior cingulate cortex and precunei in the mild EOAD group, and more extensively reduced in the whole cerebral cortex in the moderate I, II and severe EOAD groups. In the mild LOAD group, k3 values were not significantly reduced in the brain. The k3 values were modestly reduced in the temporal cortex in the moderate LOAD I group, and moderately reduced in the fronto-temporal and cingulate cortices in the moderate LOAD II group. Conclusions: Our results of LOAD groups are in accord with recent studies of postmortem brains with early stage of AD. However, our results of EOAD groups suggest that there are significant cholinergic deficits even in the early stage of EOAD. P2-277

CLINICAL USEFULNESS OF 99MTC-ECD SPECT: COMPARISON BETWEEN ALZHEIMER DISEASE AND RELATED DISORDERS BY SPM

Makoto Tanaka, Rieko Suzuki, Koichi Okamoto, Gunma University Graduate School of Medicine, Maebashi, Japan. Contact e-mail: [email protected]