CVD only frontal GM was determined by %WML, the other lobes andhippocampal volume were determined by lobar volume alone. In AD,temporal and occipital GM were determined by lobar volume (p�0.05) butnot frontal, parietal and hippocampal GM. Conclusion: The finding thatlobar WML determined frontal and occipital GM and hippocampal volumein controls suggests that WML can be associated with localized GMatrophy. In CVD, frontal WML determined frontal GM but not GM inother lobes. This suggests that similar to AD, GM atrophy in CVD isdetermined by cortical pathology, e.g. microinfarcts, rather than remoteeffects of WML.

P2-377 CSF BIOMARKERS CORRELATE WITHREGIONAL BRAIN VOLUME AND FMRIACTIVATION PATTERNS IN MIDDLE-AGEDADULTS AT RISK FOR ALZHEIMER’S DISEASE

Cynthia M. Carlsson1,2, Mehul A. Trivedi1, Kimberly Arnold1,Hanna M. Blazel1, Zachary J. Clark1, Taylor W. Schmitz1,Britta M. Torgerson1, Carey E. Gleason1,2, Mark A. Sager1,Bruce P. Hermann1, Sanjay Asthana1,2, Sterling C. Johnson1,2,1University of Wisconsin School of Medicine and Public Health,Madison, WI, USA; 2Madison VA Geriatric Research, Education andClinical Center (GRECC), Madison, WI, USA. Contact e-mail:cmc@medicine.wisc.edu

Background: CSF and neuroimaging biomarkers are promising tools forthe preclinical diagnosis of Alzheimer’s disease (AD), but little is knownabout their interaction in middle-aged persons at risk for AD. Objective:To investigate the relationship between CSF A�42, tau, regional brainvolume, and fMRI activation patterns in adults at risk for AD. Methods:This is a cross-sectional pilot study analyzing data from subjects withoverlapping participation in two independent clinical trials evaluating CSFand fMRI biomarkers for AD. Subjects (n�14) were presymptomatic adultchildren (ages 40-65 y) of persons with AD. Baseline CSF A�42 and taulevels were analyzed using ELISA. A General Electric 3.0 Tesla SIGNAMRI system was used to obtain fast gradient T1-weighted 3D volumes andecho-planar BOLD fMRI. During fMRI scanning, subjects were presentedwith new and previously learned items in a pseudorandom order and madea forced choice response with a two-button device in the right hand.Voxel-based morphometric (VBM) analyses of gray and white matter andbrain activation ensued. Results: Subject characteristics are shown inTable 1. CSF A�42 levels correlated positively with white matter volumein the right posterior cingulate (PC) isthmus (r�0.611, p�0.01), an areainvolved in memory and retrieval (Figure 1). CSF A�42 did not correlatesignificantly with fMRI activation patterns. CSF total tau correlated in-versely with gray matter volume in the right PC isthmus (r� -0.698,p�0.01) (Figure 2) and positively with fMRI signal activation to previ-ously learned items in the retrosplenal and PC areas (r� 0.685, p�0.01).In addition, the ratio of CSF total tau/A�42 correlated with increased signalactivation to previously learned items in the precuneus and right PC areas(r� 0.670, p�0.01). Conclusions: In this pilot study of middle-aged adultsat risk for AD, lower CSF A�42 and higher CSF total tau levels, potentialmarkers of preclinical disease progression, were associated with greatercerebral atrophy in areas related to memory and retrieval. Higher CSF totaltau and total tau/A�42 ratios were associated with increased fMRI activa-tion to previously learned items, consistent with studies showing greatercognitive work in those at risk for disease progression.

Table 1Subject Characteristics

Characteristic (n14) Value (mean SD)

Age (yrs) 50.6 � 6.6Women (n, %) 10 (71%)Education (yrs) 16.6 � 3.3APOE4 Positive (n, %) 8 (57%)CSF A�42 (pg/mL) 774.9 � 251.2CSF Total Tau (pg/mL) 436.8 � 224.3

P2-378 AUTOMATIC SEGMENTATION OF AGE-RELATED WHITE-MATTER CHANGES IN AMULTI-CENTER STUDY

Charlotte Ryberg1, Tim Dyrby2, Egill Rostrup2, E.C.W. van Straaten3,Frederik Barkhof4, Stefan Ropele5, Lars Kaj Hansen6,Domenico Inzitari7, Leonardo Pantoni7, Gunhild Waldemar1, 1MemoryDisorders Research Group, Copenhagen Ø, Denmark; 2Danish ResearchCenter for Magnetic Resonance, Copenhagen University Hospital,Hvidovre, Denmark; 3Department of Neurology, VU Medical Center,Amsterdam, The Netherlands; 4Department of Radiology and ImageAnalysis Center, VU Medical Center, Amsterdam, Denmark;5Department of Neurology, Medical University, Graz, Austria;6Informatics and Mathematical Modelling, Technical University ofDenmark;, Kgs. Lyngby, Denmark; 7Department of Neurological andPsychiatric Sciences, University of Florence, Florence, Italy. Contacte-mail: ryberg@drcmr.dk

Introduction: The Leukoraiosis And Disability (LADIS) study investi-gates the impact of ARWMC on the transition to disability in an elderlycohort of subjects. Objectives: Automatic segmentation of Age-RelatedWhite Matter Changes (ARWMC) using an artificial neural network(ANN) model was tested on ARWMC ROIs, hand-drawn by a single experton a cohort of elderly subjects. Method: MR scans were collected on 639

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non-demented subjects (65 - 84 years) at 11 different centers. In order toachieve a uniform quality level for this study, the dataset was reduced to224 subjects from 6 centers. A supervised fully connected ANN wasimplemented with a single layer of hidden units and 30 inputs (3 modal-ities, each with their respective 3x3 neighborhood and spatial information).The output comprised of four probability maps - GM, WM, CSF andARWMC, but only the ARWMC output is assessed here. Before segmen-tation all data were pre-processed for head motion and intensity variations.The ANN was trained with an ROI dataset drawn on 6 subjects from 4centers. For segmentation, the optimal threshold of the ARWMC proba-bility map was determined using the Index of Similarity describing theoverlap between ANN and manual ROI’s. Here a threshold of 90% wasfound to be optimal. Results: From each of the 6 center the correlationcoefficient between ANN and manually determined were generally high:0.97, 0.97, 0.87, 0.88, 0.73 and 0.98. The correlation of the combined setwas 0.89. The two first centers, with a correlation coefficient of 0.97, hadtwo subjects in the training set which may explain their better performance.Deviating quality in the FLAIR image contributes to the lowest correlationin a center. In other cases a systematic bias was present in some anatomicalregions (e.g. septum pellucidum, where lesion were not drawn manually) orregarding lacunar infarcts. Conclusion: In this multi-center investigationof ARWMC segmentation a high average correlation of 0.89 was found.Improvements may be gained from representing more centres in the train-ing set. The results demonstrate the generalizability of ANN methods, andunderline the importance of rigorous standardization of MRI quality inmulti-center studies.

P2-379 MEMORY FUNCTION TESTS CORRELATEDIFFERENTLY TO REGIONAL CEREBRALBLOOD FLOW IN MILD COGNITIVEIMPAIRMENT AND ALZHEIMER’S DISEASE. A123I-IMP SPECT STUDY WITH STATISTICALPARAMETRIC MAPPING

Md. Ashik B. Ansar, Hiroaki Kazui, Naohiko Oku, Yasuyuki Kimura,Nobuyo Kimura, Hiroaki Kato, Begum N. Nessa, Yashitaka Ikejiri,Masatoshi Takeda, Jun Hatazawa, Osaka University, Suita, Japan.Contact e-mail: ashik@tracer.med.osaka-u.ac.jp

Background and Objectives: Neuronal circuits critical for learning andmemory are particularly vulnerable to dysfunction and degeneration in thecourse of Alzheimer’s disease (AD). To investigate the brain function andmemory function in patients with mild cognitive impairment (MCI) andAD, we examined the correlation between the scores of Wechsler MemoryScale-Revised (WMS-R) and the brain perfusion by single photon emissioncomputed tomography (SPECT). Methods: Twelve MCI (70.0 � 5.8 y,MMSE 27.3 � 1.9, CDR, 0.5, Petersen’s criteria) and nine AD (68.5 �1.0 y, MMSE 21.3 � 1.5, CDR, 0.5 (n�2) or 1.0 (n�7), NINCDS-ADRDA) patients were consecutively recruited in this study. Patient’smemory functions were evaluated by the neuropsychiatric assessmenttool-WMS-R and then they underwent routine 123I-IMP brain SPECT. 111MBq of tracer was injected and SPECT was performed by four-headrotating gamma camera. Butterworth filter and Chang’s attenuation cor-rection were applied to reconstruct the images (64 X 64 matrix, 4 X 4 mmper pixel, 4 mm thickness) for each subject. The images were anatomicallystandardized and smoothed by means of SPM99. The weighted sum scoresof general memory of the WMS-R were employed for SPM analysis tosearch for the underlying correlation with rCBF abnormality in MCI andAD patients (MCI group vs. MCI plus AD combined groups). Results:General memory scores, that showed significant correlation with brainperfusion at right hippocampus (BA 28), and middle temporal gyrus (BA21) (clusters, P �0.05, corrected) in MCI patients group, whereas thatscores significantly correlated to the right parietal (BA 40) and left poste-rior cingulate (BA 31) (clusters, P �0.001, corrected) in MCI and ADcombined groups (Figure 1). Conclusions: Current study indicates that themedial temporal cortex is one of the important locations for the memoryfunction in the patients with mild cognitive impairment whereas left pos-

terior cingulate and right parietal cortex might play an important role in thememory processing in the patients with Alzheimer’s disease.

P2-380 NOVEL RECOMBINANT ANTIBODIES AGAINSTAD BIOMARKERS LINKED TO NEUROTROPHINSIGNALLING AS POTENTIAL DIAGNOSTICTOOLS

Gabriele Ugolini1, Sonia Covaceuszach1, Francesca Paoletti2,Michela Visintin3, Doriano Lamba4, Antonino Cattaneo5, 1Lay LineGenomics S.p.A., Roma, Italy; 2International School for Advanced,Trieste, Italy; 3Lay Line Genomics S.p.A., Trieste, Italy; 4InternationalCentre for Genetic Engineering and Biotechnology, Trieste, Italy;5European Brain Research Institute, Roma, Italy. Contact e-mail:g.ugolini@laylinegenomics.com

Background: Nerve growth factor (NGF) is important for regulation,differentiation, and survival of peripheral and central nervous systemneurons, including basal forebrain cholinergic neurons (BFCNs), that arestrongly and precociously affected by Alzheimer’s disease (AD). MatureNGF protein is processed from a larger precursor, proNGF, which accu-mulates in AD brain, starting from the preclinical stage of the disease. Theaccumulation of proNGF is correlated with the loss of cognitive function,identifying proNGF as an early biological marker for the onset of AD. Thehigh affinity receptor for NGF, the TrkA tyrosine kinase is another excel-lent molecular marker for early diagnosis of AD. In fact, TrkA receptorsare expressed by BFCNs. Remarkably, the number reduction of TrkA-expressing BFCNs represents an extremely early event in AD neuropatho-logical staging. TrkA-positive projections of BFCNs are particularly abun-dant in cortical areas. Remarkably, TrkA expression decrease in the cortexof patients parallels cognitive decline, confirming TrkA as an ideal markermolecule to monitor AD progression. Objective(s): LLG aim is to developantibodies to both the TrkA receptor and the proNGF ligand as ADdiagnostic tools. Methods: A panel of monoclonal antibodies directedagainst the two antigens pro-NGF and TrkA were respectively generatedby means of LLG proprietray technology (SPLINT) and classical hybrid-oma techniques. After selection, the anti-TrkA antibody was humanized bymeans of a novel proprietary method, based on structural characterizationof the antibody. Results: A super-stable recombinant antibody directedagainst pro-NGF was isolated from proprietary SPLINT libraries and LLGresearchers started to characterize it. Several anti-TrkA antibodies werealso generated, one of which was fully characterized as for its in vitro andin vivo TrkA binding features. Its humanized variant (huMNAC13) ispresently available in several recombinant molecular formats (includingmonovalent Fab). Conclusions: Some of the molecular components of theNGF pathway represent excellent markers to identify AD neurodegenera-tion in its incipient phase, to monitor the progression of the disease itselfand to evaluate the efficacy of therapeutic agents while being employed inpatients. On this basis, both anti-TrkA and anti-proNGF antibodies can bedeveloped into AD diagnostic tools for in vivo imaging.

P2-381 FAILURE OF HIPPOCAMPAL HABITUATION INMILD COGNITIVE IMPAIRMENT ANDALZHEIMER’S DISEASE

Kristina M. DePeau1,2, Maija Pihlajamaki1,3, Eli L. Diamond1,4,Saul M. Miller1,2, Elizabeth F. Chua1,5, Brad C. Dickerson1,2,Marilyn S. Albert6, Deborah Blacker2, Reisa A. Sperling1,2, 1Departmentof Neurology, Brigham & Women’s Hospital, Harvard Medical School,Boston, MA, USA; 2Departments of Neurology and Psychiatry,Massachusetts General Hospital, Boston, MA, USA; 3Departments ofNeuroscience and Neurology, University of Kuopio, Kuopio, Finland;4Albert Einstein College of Medicine, Bronx, NY, USA; 5Department ofPsychology, Harvard University, Boston, MA, USA; 6Department ofNeurology, Johns Hopkins University School of Medicine, Baltimore,MD, USA. Contact e-mail: kdepeau@partners.org

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