Correlation of white matter lesions with lacunar infarcts in patients with mixed Alzheimer's disease with subcortical vascular lesion

Additional Abstracts and non-protein thiols), mitochondrial enzymes activity and acetylcholinestrease level. Results: Chronic administration of D-galactose or six weeks significantly impaired behavioral (Morris water maze, elevated plus maze and locomotor activity), oxidative defense and impaired mitochondrial enzymes complex (I, II and III) activities as compared to sham group. Six weeks Centella asiatica treatment significantly improved behavioral alterations, oxidative damage and mitochondrial enzyme complex activities as compared to control (D-galactose). Centella asiatica also attenuated enhanced acetylcholine esterase enzyme level in D-galactose senescence mice. Conclusions: In conclusion, results of this study illustrate that Centella asiatica ameliorates memory dysfunction and biochemical, mitochondrial dysfunction in D-galactose induced senescence mice. P4-472

VASOGENIC EDEMA IN THE SETTING OF ß-AMYLOID LOWERING THERAPY, ADVERSE EVENT: WHAT IS IT AND HOW IS IT DETECTED?

Jerome Barakos1, Christopher Carlson2, Wahiba Estergard2, Joonmi Oh1, Joyce Suhy1, Clifford Jack3, Eric Siemers2, 1Synarc, San Francisco, California, United States; 2Eli Lilly and Company, Indianapolis, Indiana, United States; 3Mayo Clinic, Rochester, Minnesota, United States. Background: Vasogenic edema (VE) has been described as a potential adverse event associated with ß-amyloid lowering therapy. As part of ongoing Alzheimer’s disease (AD) clinical trials, we set out to describe the optimization of magnetic resonance imaging (MRI) safety scans to monitor for ß-amyloid lowering therapy-related VE. Aims of this presentation are to outline imaging features of VE and describe how ß-amyloid lowering therapy-related VE differs from that encountered in routine clinical practice. These described imaging factors relating to VE are important for the evaluation of patients enrolled in AD clinical trials to ensure adequate monitoring for potential adverse events. Methods: Baseline (pre-study treatment) MR images were obtained from patients entering 4 ongoing trials of ß-amyloid lowering agents for the treatment of AD. Two trials (H6L-MC-LFAN, IDENTITY and H6L-MC-LFBC, IDENTITY-2) were studying semagacestat, a gamma-secretase inhibitor. In these trials, the MRI exams were obtained from patients entered into an optional volumetric MRI addendum (n ¼ 625). Two additional trials (H8A-MC-LZAM, EXPEDITION and H8A-MC-LZAN, EXPEDITION-2) are studying the anti-Aß monoclonal antibody solanezumab. These MRI exams were obtained in 2134 of 2681 patients from baseline scans obtained as part of the protocol. Results: In the review of 2759 study enrollee pretreatment MR scans, we identified a series of cases with VE (n ¼ 4). We also found a series of cases which revealed artifactual VE (n ¼ 2). We describe the imaging features which allow differentiation of false positives from true positive cases of VE. Conclusions: In conclusion, ß-amyloid lowering therapy VE differs from that encountered in the routine clinical setting. As such, a specific understanding of the unique features of ß-amyloid lowering therapy-related VE is required in order to insure optimal imaging protocols allowing for accurate detection. Additionally, examples of artifactual VE are presented with a review of imaging features which allow characterization as artifact and differentiation from true VE. P4-473

FRONTOLIMBIC BRAIN REGIONS ASSOCIATED WITH AGITATION AND AGGRESSION SYMPTOMS IN MCI AND AD OVER A 2-YEAR PERIOD

Paula Trzepacz1, Peng Yu1, Phanikumar Bhamidipati1, Brian Willis1, Tammy Forrester1, Linda Tabas1, Adam Schwarz1, Andrew Saykin2, 1Eli Lilly and Company, Indianapolis, Indiana, United States; 2Indiana University School of Medicine, Indianapolis, Indiana, United States. Background: Atrophy of the hippocampus, other gray matter, and white matter disruptions are well-described in MCI and AD for cognition. However, there is very little reported on brain neuroanatomical relationships with behaviors in AD and MCI. We hypothesized that abnormalities of prefrontal and limbic regions would be more strongly associated with agitation and aggression (A/A) than posterior regions. Methods: We analyzed the public ADNI data released in September 2010 for AD, MCI-nonconverters, and MCI-converters (during the 2 years) at different time points (baseline

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6, 12, 18, and 24 months). A/A symptom severity was measured by a 4-item subscale of the Neuropsychiatric Inventory-Q (NPI-4) [ ¼ agitation/aggression, disinhibition, irritability/emotional lability, aberrant motor behavior; 0-3 points/item] and only cases with ¼ 1 point were included (n ¼ 535). NPI-4 scores were first evaluated using a longitudinal model. Measurements of preselected MRI ROIs (Freesurfer) from UCSF were correlated with NPI-4 raw scores in all subjects. ROIs with absolute (Spearman) r ¼ 0.09 to NPI-4 scores at 24 months were chosen to be included in an MMRM analysis (over 24 months) for each Dx group, with baseline age, sex, APOE- e4 status, education and MMSE as covariates. Results: NPI4 scores worsened over time in AD and MCI-converters (p <0.05), and trended for MCI (p ¼ .0518). MMRM revealed significant (p <0.05) relationships for atrophy of frontal, insula, amygdala and L hippocampus with greater A/A (see table). MMSE was significant only in MCI-converters. Demographics and APOE- e4 were not associated with A/A. Conclusions: A/A in AD may relate to decreased prefrontal regulation of impaired amygdala function with altered hippocampal inputs and insular processing of amygdala outflow for emotional information integration and autonomic stimulation. The interface of prefrontal regions with amgydalar networks may result in behavioral dyscontrol in a subset of patients with MCI and AD. L hippocampus was the only posterior ROI associated with A/A and has connectivity with amygdala and prefrontal cortex. Our findings are consistent with reports of A/A association with frontal and anterior/middle temporal hypoperfusion on SPECT and NFT burden on autopsy, insular pathology on autopsy, changes of white matter connectivity in fronto-limbic and late-myelinating regions, and impairments of insight and executive functioning. P4-474

CORRELATION OF WHITE MATTER LESIONS WITH LACUNAR INFARCTS IN PATIENTS WITH MIXED ALZHEIMER’S DISEASE WITH SUBCORTICAL VASCULAR LESION

Heeyoung Kim1, Jae-Hong Lee1, Rahyeong Juh1, Miseon Kwon1, Youngjoo No2, 1Asan Medical Center, Seoul, South Korea; 2Gangneung Asan Hospital, GangNeung, South Korea. Background: Cerebral white matter lesions (WMLs) and lacunar infarcts (LIs) are mostly caused by small vessel disease (SVD). Although mixed Alzheimer’s disease with subcortical vascular lesion (AD-SVL) or subcortical vascular dementia consequent to cerebral SVD is quite common among the elderly, there is a debate over the contribution of subcortical WMLs to cognitive decline and activities of daily living (ADL) in those conditions. Whereas the main pathomechanism behind LIs is SVD, a variety of etiologies could be implicated in WMLs. Furthermore, the issue as to which location of WML is more closely related to LIs and cognitive impairment has still not been settled. In this study, we subdivided WMLs into deep subcortical WMLs (DSWMLs) and periventricular WMLs (PWMLs) in patients with mixed AD-SVL. We attempted to investigate the relationship between WMLs and LIs and also to evaluate the contribution of WMLs and LIs to cognitive impairment and ADL. Methods: Data were drawn from the multicenter dementia study, the MR300 study. We counted the number of LIs and graded WMLs into mild, moderate and severe groups for each WMLs using a semiquantitative visual scale. Cognitive function, severity of dementia and daily functional impairment were assessed with Mini-Mental State Examination (MMSE), Global Deterioration Scale (GDS) and Seoul-Instrumental ADL (S-IADL) scale. Results: A total of 289 patients were enrolled into the MR300 study. Among them, 141 patients were classified into either AD (64.5%) with WMLs or SVaD (35.5%).Among the 3 groups of WMLs , there were no differences in terms of baseline characteristics (age, sex, duration of education, the presence of cardiovascular risk factors), MMSE, GDS and S-IADL. In univariate loglinear model, history of hypertension, history of stroke and DSWMLs were associated with LIs. In multivariate log linear model, increasing DSWMLs and history of hypertension were associated with LIs. There was no significantly associated with MMSE score, GDS, S-IADL scale and LIs. Conclusions: In patients with mixed AD-SVL, the severity of DSWMLs was associated with the number of LIs. These results suggest that the DSWMLs, may share the same vascular mechanism as

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Additional Abstracts

LIs. Further refined study employing quantitative measurement of WMLs is warranted to replicate this finding. P4-475

VASCULAR DEMENTIA WITH LEFT THALAMIC INFARCTION LINKED TO DECREASED WORD FLUENCY AND A DEPRESSIVE STATE THROUGH THE THALAMO-CORTICAL NETWORK: THE OSAKI-TAJIRI PROJECT

Kyoko Akanuma, Yoshitaka Ouchi, Mitsue Meguro, Kei Nakamura, Satoshi Yamaguchi, Tohoku University Graduate School of Medicine, Sendai, Japan. Background: Vascular dementia (VaD) is a condition in which decreased cerebral perfusion causes cognitive deterioration. The left thalamo-cortical network is thought to be associated with cognitive impairment. However, there has been little systematic research on VaD with thalamic infarction in relation to neuropsychological findings. Methods: The entry criteria for the study were evaluated in 120 consecutive outpatients with dementia. These criteria were 1) the presence of cerebrovascular disease (CVD) in the thalamus as shown by MRI, 2) meeting NINDIS-AIREN criteria for VaD, and 3) MMSE scores ¼ 9 to ensure verbal communication in neuropsychological tests. A total of 44 patients with VaD met all the study entry criteria, of whom 20 had bilateral thalamic infarctions, 18 had CVD only in the left thalamus, and 6 had CVD only in the right thalamus. Therefore, the effect of a left thalamic infarction was analyzed in 18 patients. 99mTc-ECD SPECT was used to assess cerebral blood flow (CBF). The original SPECT data were analyzed using the iSSP program (SSP; Nihon Mediphysics) modified with NEUROSTAT (Dr. Minoshima). The 3-Dimensional Stereotaxic Surface Projection (3D-SSP) programs were used to normalize the pixel values over the whole brain. The pixel values for each patient were compared with a normal database of elderly CDR 0 residents in the Osaki-Tajiri Project (n ¼ 18). Stereotaxic Extraction Estimation (SEE) software was used for region of interest (ROI) analysis. A word fluency test was used to evaluate frontal lobe function, and the Geriatric Depression Scale (GDS) was used to assess depressive state. Results: Both the left and right hemisphere showed decreased regional CBF (rCBF). MMSE scores showed no correlations with rCBF, but there were significant correlations between rCBF in the left anterior cingulate and word fluency scores, and between rCBF in the right rectal gyrus and GDS scores. Conclusions: VaD patients with left thalamic infarction showed decreased rCBF in the left anterior cingulate and right orbitofrontal cortex, and these changes were correlated with decreased verbal fluency and a depressive state. We suggest that these observations are due to a remote effect that occurs via the thalamo-cortical network. P4-476

AGING AND GENETICS IN THE LEMURIAN PRIMATE MICROCEBUS MURINUS: A USEFUL APPROACH FOR ALZHEIMER’S DISEASE STUDIES

Jean-Michel Verdier1, Nadine Mestre-Frances1, Gina Devau2, Stephanie Trouche1, Ronza Abdel-Rassoul1, Corinne Lautier2, Ayodeji Asuni3, Allal Boutajangout3, Einar Sigurdsson3, 1Ecole Pratique des Hautes Etudes, Montpellier, France; 2University of Montpellier 2, Montpellier, France; 3New York University School of Medicine, New York, New York, United States. Background: Studying Alzheimer’s disease (AD) necessitates animal models. A good model should show progressive pathology and associated cognitive deficits and should be robust enough. Most of used models are rodents but results cannot necessarily be extrapolated to humans. The use of nonhuman primates has been recommended. Mouse lemurs are small primates whose lifespan is around 13 years, are relatively easy to breed and maintain in captivity. Comparable to humans during aging, some, but not all, display the neuropathological signs of AD (AD-like animals). Methods: Immunohistochemical analysis was performed on mouse lemurs aged 1-13 years to detect Abeta deposition (n ¼ 150), and gliosis and phosphorylated Tau (n ¼ 50). We evaluated the safety and efficacy of immunization in young (n ¼ 25) and old (n ¼ 48) with an Abeta derivative. We analyzed the transcriptome of the temporal cortex using human chips. In some families, the

AD-like trait seemed inheritable. We selected and crossed them to develop an AD-like lineage. Results: Amyloid plaques were detected in 8-10% of animals, pre-tangles in few aged, and brain atrophy in some, but not all, aged. Immunotherapy in young have concluded that the Ab peptide derivative K6Abeta1-30 elicited a substantial antibody response, and importantly this effect was reversible. In old, vaccination led to a clearance of Abeta, a decrease of inflammation without T cell infiltration, and appeared to have some cognitive benefits. We identified 47 genes that discriminated young from healthy old and AD-like. Hierarchical clustering analysis indicated that each group had distinct expression profiles. Preliminary data of AD-like lineage showed a transmission over at least 3 generations of ADlike phenotype. Conclusions: Mouse lemurs display all pathognomonic lesions of AD: plaques, pre-tangles, cortical atrophy. They are a suitable model for assessing safety and efficiency of novel vaccines targeting Abeta pathology. Transcriptome analysis suggests the existence of compensatory mechanisms during healthy aging that disappear in AD-like. AD-like families will be part of a whole genome linkage analysis to identify chromosomic regions and candidate genes involved in the AD-like phenotype. Mouse lemurs provide a valuable natural primate model for aging and at least for some aspects of AD. P4-478

VALIDATION OF AN INTERNATIONALLY DEVELOPED PROTOCOL TO ASSESS THE DISTRIBUTION AND SEVERITY OF CEREBRAL AMYLOID ANGIOPATHY IN THE POST-MORTEM BRAIN

Seth Love1, Katy Chalmers1, Margaret Esiri2, Paul Ince3, Patrick Kehoe1, 1 University of Bristol, Bristol, United Kingdom; 2University of Oxford, Oxford, United Kingdom; 3Sheffield University, Sheffield, United Kingdom. Background: The commonest form of cerebral amyloid angiopathy (CAA) is that caused by the deposition of Aß peptide. The severity of the CAA and the likelihood of complications such as fibrinoid necrosis and haemorrhage have been reported to be influenced by APOE and other genetic factors. However, these findings have not been consistently demonstrated, probably because the cohort sizes have been small and the lack of consistency in methods used to assess CAA have precluded pooling or meaningful comparison of data between centres. Using the DELPHI questionnaire approach we devised a consensus protocol for assessing the distribution and severity of CAA and of concomitant pathologies such as fibrinoid necrosis and haemorrhage. Methods: 20 AD and 5 neurologically-normal control cases were selected from each of 3 UK centres (Bristol, Oxford and Sheffield) for evaluation. For each case sections from the frontal, temporal, inferior parietal and occipital cortex were cut and immune labelled for Aß (4G8) using standard avidin-biotin peroxidase immunohistochemistry. Sections were also stained with haematoxylin and eosin to assess vasculopathy. All sections were then assessed by a neuropathologist from each centre using criteria established previously. Briefly, CAA severity was graded in the parenchymal and meningeal vessels using a semi-quantitative scoring system and the presence or absence of capillary CAA and vasculopathy, such as thrombosis and fibrinoid necrosis, recorded. Inter-rater reliability was assessed using Cohen’s weighted Kappa statistics. Values between 0.61-0.80 were seen to have substantial and 0.81-1.00 as perfect agreement. Results: Inter-rater reliability was evaluated between the 3 assessors. Overall there was greatest consistency when scoring meningeal (0.711-0.894) and parenchymal (0.627-0.774) CAA. The ability to identify capillary CAA consistently was variable between assessors (0.242-0.694) as was the identification of vasculopathic changes (0.354-0.711). Conclusions: This validation study has shown that consensus criteria developed by several international researchers generate highly reproducible data when assessing the severity of meningeal and parenchymal CAA. However it is clear that criteria used to categorise capillary CAA and vasculopathy need to be further developed in order to achieve such consistency amongst assessors. The ability to score CAA severity consistently across centres will enable comparisons of data and promote collaboration. The biological relevance of the protocol with respect to the relationship of APOE genotype to CAA severity and vasculopathic complications is in progress.