S1-01-04 ADVANCED MRI Alan Koretsky; National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA Background: MRI continues to have a large impact. The past five years have seen new developments in MRI technology that are leading to sig- nificantly higher resolution. In addition, new molecular imaging agents are being tested in animal models that will increase the range of information available from MRI. Objectives: The goal of this talk is to illustrate recent developments of MRI that demonstrate the potential impact of increased resolution and the potential of two imaging agents. Results of MRI of mouse models of neurological disorders are clearly demonstrating the benefits of very high resolution analysis of the brain. The potential for increasing resolution in the human brain for measurements of both anat- omy and regional blood flow will be illustrated. Work with two agents that are increasing information from MRI in animal models will be reviewed. Manganese Enhanced MRI is leading to contrast that can report on neural activity, neural connectivity, as well as give novel anatomical contrast. Iron oxide based contrast is enabling MRI detection of migration of cells in vivo, with the potential to detect single cells. Methods: MRI of rodent brain was obtained on a 11.7T, 31 cm magnet (Magnex, UK) interfaced to an Avance imaging console (Bruker Inc, MA), with specially designed gradients and shims (Resonance Research, MA). MRI of the human brain was obtained on 3T and 7T MRI (General Electric, WI) utilizing specially designed multi-channel detectors (Nova Biomedical, MA). Conclusions: Developments in MRI is leading to increases in sensitivity of almost ten fold thanks to new array detectors and higher magnetic fields. This is leading to increases in resolution for all MRI techniques in human and animal brain. The rapid growth in interest in molecular imaging is leading to new agents that will greatly expand the information from MRI. All of these developments are occurring in animal models or on specialized equipment. While there are many hurdles to be overcome before they can be applied routinely to study diseases of the human brain, it is clear that the range of information from MRI will continue to grow rapidly. SUNDAY, JUNE 19, 2005 SYMPOSIA S1-02 BIOMARKERS S1-02-01 BIOMARKERS 101 John Growdon; Massachusetts General Hospital, Boston, MA, USA A biomarker is a laboratory measurement that reflects the activity of a disease process. A biomarker is valuable in direct proportion to its ability to capture an important and even unique feature of a disease with high sensitivity and specificity. There are 3 different areas where biomarkers have potential importance: as markers of disease trait, state and rate. A measure of trait implies the ability to predict susceptibility to a disease. Such a marker may be especially useful in screening large populations for people at risk. When used in this way, the marker should have a sensitivity approaching 100% but specificity is less important and will likely be lower. For individuals at risk to develop MCI or sporadic late onset AD, prom- ising predictor markers include the e4/e4 genotype and atrophic hippocam- pal regions on MRI brain scans. A measure of state is in fact a diagnostic marker that can be used to complement the clinical examination. To be maximally useful, sensitivity and specificity should be 85%. Examples of promising diagnostic biomarkers include decreased A and increased tau levels in CSF, and bilateral posterior parietal and temporal lobe hypome- tabolism on PET brain scans. The third biomarker category -rate- is in essence a surrogate marker, which denotes that the marker in so tightly linked to the disease process that it changes in parallel with the natural course of illness or in response to a therapeutic intervention. Surrogate outcomes have the most stringent demands for specificity (100%) but do not require high sensitivity. There are no surrogates that are accepted for AD, although rates of atrophy on brain MRI scans show promise. Regard- less of the category, biomarkers need to be embedded in clinical assess- ments and judgment. S1-02-02 CSF BIOMARKERS Henrik Zetterberg 1,2 , Kaj Blennow 2 ; 1 Laboratory Medicine, Gothenburg, Sweden; 2 Clinical Neuroscience, Mo¨lndal, Sweden Background: Early and accurate diagnosis of Alzheimer’s disease (AD) is important to initiate symptomatic treatment against AD, and will be of even greater significance if treatments aimed at slowing down the degenerative process, such as vaccination regimes and - and -secretase inhibitors, prove to have clinical effect. Objective(s): The presentation will review the diagnostic performance of established and novel cerebrospinal fluid (CSF) biomarkers for AD. Methods: Litera- ture review, ELISA and SELDI-TOF. Conclusions: In the right clinical context, the CSF biomarkers total tau (T-tau), phospho tau (P-tau) and A42, which all reflect central disease processes in AD, have high diagnostic accuracy to identify AD and to differentiate AD from normal aging and several important differential diagnoses. However, the spec- ificity against other dementias is not optimal. A higher discriminative power may be achieved using a larger panel of biomarkers for different pathogenic processes. We have developed multi-immunoassays using the Luminex xMAP technology. The first assay for simultaneous mea- surement of T-tau, P-tau, and A42 shows high analytical precision and diagnostic performance. In the search for a specific AD biomarker pattern, we have used the protein chip technology SELDI-TOF. In our first study, we found an increase in 36 and a decrease in 16 peptides/ proteins in AD. After data processing, five peaks showed a sensitivity of 100% for AD at a specificity level of 91%. The SELDI-TOF tech- nique can also be used to characterize changes in the isoform pattern of specific proteins and peptides, such as truncated -amyloid variants. CSF biomarkers may also turn out to be valuable tools to identify and monitor biochemical effects of new treatments in living patients. The CSF level of AChE changes dose-dependently during treatment with AChE inhibitors and this change correlates to clinical outcome. Possi- bly this may be the case for CSF T-tau, P-tau and A42; a hypothesis that will be tested in future studies of disease-modifying treatments. S1-02-03 PLASMA BIOMARKERS IN ALZHEIMER’S DISEASE DIAGNOSTIC Domenico Pratico; University of Pennsylvania, Philadelphia, PA, USA Background: The diagnosis of Alzheimer’s disease (AD) is currently based on clinical and neuropsychological examination. Because these procedures are time-consuming and costly, there is a need to identify biological tests that can circumvent aspects of this workup and point the physician to the correct diagnosis. It is highly desirable to measure a substance or substances in urine or plasma or cerebrospinal fluid that would lead to a positive diagnosis of AD. Objective(s): In the present paper, an overview of the current state of knowledge on biologic markers in plasma (serum) is presented. Methods: In general, plasma biomarkers are always preferable in large-scale clinical trials and pop- ulation-screening test. However, one of the major issues with this kind of marker is to what extent changes in blood composition reflect pathological changes in the brain. In line with the heterogeneous pa- thology of AD, several plasma markers related to different pathophys- iological mechanisms have been considered so far. Among them, mark- ers related to beta-amyloid, inflammation, oxidative stress, brain specific structural alteration, and cholesterol metabolism have been used. To date no one of these tests can discriminate AD patients from healthy individuals. Nonetheless, some of them have the potential of S8 Abstracts: Biomarkers / 1 (Suppl 1) (2005)