[P‐001]: Cognitive ERPs as biomarkers and predictors of dementia in mild cognitive impairment (MCI)

not available. SUNDAY, JUNE 19, 2005 POSTER PRESENTATIONS BIOMARKERS P-001—P-024 P-001 COGNITIVE ERPS AS BIOMARKERS AND PREDICTORS OF DEMENTIA IN MILD COGNITIVE IMPAIRMENT (MCI) John M. Olichney, James Gatherwright, Jason R. Taylor, David P. Salmon, Marta Kutas, Vicente J. Iragui; University of California, San Diego, San Diego, CA, USA; VA San Diego Healthcare System, San Diego, CA, USA Background: Episodic and semantic memory both decline early in Alzheimer’s disease (AD). Two cognitive event-related potential (ERP) components, the P600 and N400, have demonstrated sensitivity to abnormal episodic/declarative memory and semantic processing, respectively. The main N400 generators are in the anterior fusiform gyri, a region implicated in conversion from MCI to AD. P600 generators in the hippocampus, entorhinal cortex, and cingulate gyrus are believed to play an important role in episodic/declarative memory. We have previously reported a decreased P600 word repetition effect in patients with well-circumscribed amnesia, but with relatively preserved N400 effects. In mild AD, we have found reduced word repetition effects on both the N400 and P600, suggesting a more wide-spread failure of synaptic plasticity. Objective: We sought cognitive ERP biomarkers of disease progression in MCI, particularly those that predict subsequent conversion to dementia. Methods: Individuals with MCI (n 32, mean age 74.8) were longitudinally studied annually with an ERP word repetition paradigm in which semantically congruous (50%) and incongruous (50%) target words were repeated 10-140 seconds after initial presentation. ERP data were analyzed to contrast MCI-to-AD “converters” (within 3 years; n 16, mean MMSE 27.3) vs. “non-converters” (follow-up 3 years; n 10, mean MMSE 28.0), using split-plot ANOVAs. Results: A small but significant (p 0.01) P600 congruous word repetition effect was found in non-converters, but not in converters (F 0.28, p 0.60), with a highly-significant intergroup difference (F 17.8, p 0.0005). Repetition of incongruous words produced a significant attenuation of N400 amplitude across righthemisphere sites (F 8.4, p 0.02) in non-converters, but this was absent in converters (F 1). The N400 congruity effect (for new words) was also highly significant in non-converters (p 0.0016), but only marginally significant in converters (p 0.057). The 11 Individuals with N400 and P600 word repetition effects both below the normal range had an 82% likelihood of dementia within 3 years, while those with normal N400 and P600 repetition effects had only a 25% likelihood. Conclusions: Absent ERP word repetition effects in MCI carry an increased risk of subsequent conversion to AD. N400 abnormalities occur early in the transition from MCI to AD, which may be a useful biomarker for distinguishing amnesia from incipient dementia. P-002 PROTON MAGNETIC RESONANCE SPECTROSCOPY IN ALZHEIMER MOUSE MODEL Malgorzata Marjanska, Geoffry L. Curran, Thomas M. Wengenack, Joseph F. Poduslo, Clifford R. Jack, Michael Garwood, Kamil Ugurbil; University of Minneapolis, Minneapolis, MN, USA; Mayo Clinic College of Medicine, Rochester, MN, USA Background: Proton magnetic resonance spectroscopy offers a noninvasive way to quantify many metabolites in vivo. Metabolite levels are sensitive to different in vivo pathologic processes; e.g. N-acetylaspartate (NAA) is a marker for neuronal number and health, and myoinositol (mIns) is thought to be a marker for osmotic stress. Transgenic mouse models have been developed for Alzheimer’s disease (AD). Recently spectroscopic analyses of single transgenic amyloid precursor protein (APP) mice brains showed altered neurochemical profiles. Mice that are doubly transgenic for human APP and presenilin mutations (APP-PS1) develop “human-like” plaques at a younger age than APP mice. Objectives: The purpose of this study was to characterize the neurochemical profile in APP-PS1 AD mice using high resolution single voxel H NMR compared to that of wild-type mice and to determine the changes in the neurochemical profile with age. Methods: In vivo H NMR spectra from twenty seven APP-PS1 and thirty B6SLJ wild type mice spanning the age from 66 to 904 days were obtained using a previously described LASER sequence at 9.4 T (31 cm horizontal bore magnet equipped with Varian INOVA console) from an 18 L voxel placed in the cortex and hippocampus. Conclusions: The age dependent neurochemical changes observed in doubly transgenic Alzheimer’s mice match expectations based on prior in vivo human MRS studies. Data averaged from all animals also demonstrated decreases in the concentration of both NAA and Glu for both wild-type and APPPS1 mice across age. The most consistent and profound finding observed was an increase in mIns across age in AD mice (reported as a ratio of concentration of mIns to cretaine/phosphocreatine (Cr/PCr in Figure). Activated microglia accumulate at the periphery of amyloid plaques both in human AD and in transgenic AD mice. It is believed that microglial activation may be responsible for at least some of the neuronal damage which characterizes AD. In theory, MRS could be used to measure the specific feature of AD pathology longitudinally and could serve as an in vivo biomarker of the efficacy of therapeutic measures designed to reduce neuronal damage mediated by microglial activation. S9 Abstracts: Biomarkers / 1 (Suppl 1) (2005)