Antioxidant supplementation and the course of dementia in down syndrome

Poster Presentations P3 to reduce the potential toxicity of an immune response to a normal self protein. Methods: We used active immunization with aggregated British amyloid (ABri) related peptides in a predominantly b-sheet conformation alone or in combination with related immunogens. ABri is a rare form of familial human amyloidosis associated with a mis-sense mutation in a stop codon resulting in the production of a highly amyloidogenic protein with no sequence homology to other native human proteins. This immunization was done in APP/PS1 Tg mice, vascular amyloid model Tg SwDI mice and in 3x Tg mice with both tau and amyloid pathology Results: Our preliminary data indicates that mice immunized with aggregated/oligomerized preparations of ABri recognized heterologous amyloid structures including oligomeric Ab and PrPSc. ABri has no sequence homology with Ab, tau or PrP; hence, this immune response is not amino acid sequence specific but represents a preferential targeting of the pathological protein/peptide conformations shared by Ab, tau and PrPSc. Immunization of APP/PS1 AD Tg and the TgSwDI mice with ABri produces significant cognitive benefits in association with marked reductions in the parenchymal and vascular amyloid burdens, as well as reduced Ab oligomer levels, in the absence of any evident toxicity. Conclusions: Our results suggest that conformationally based immunomodulation targeting the pathological conformational mimicry of multiple disease associated proteins is feasible and effective.

P3-442

PRECLINICAL AND EARLY CLINICAL STUDIES OF AVN-101, A NOVEL BALANCED MOLECULE FOR THE TREATMENT OF ALZHEIMER’S DISEASE

Yan Lavrovsky1, Alexander V. Ivachtchenko1, M. Morozova2, R. M. Salimov3, V. Kasey3, 1Avineuro Pharmaceuticals, Inc., San Diego, CA, USA; 2The Mental Health Research Center of RAMS, Moscow, Russian Federation; 3Chemical Diversity Research Institute, Moscow, Russian Federation. Contact e-mail: [email protected] Background: Cognitive decline and anxiety are clinical symptoms of Alzheimer’s disease. Dimebon, developed by Medivation, Inc. and Pfizer, is in Phase III trials to treat Alzheimer’s disease. However, it has multiple liabilities, especially regarding DMPK, and very limited pre-clinical data. Methods: More than 10,000 compounds from the ChemDiv, Inc. proprietary library were screened on a panel of GPCRs reportedly involved in the pathophysiology of Alzheimer’s disease. Several hits were tested in in vitro and in vivo models and optimized on a smaller panel of GPCRs, including the serotonin receptor 5-HT6. Radioligand binding and cell-based functional assays were used to determine the selectivity and specificity of lead candidates. Preclinical ADME and behavioral studies comparing our lead compounds with Dimebon and other cognitive-enhancing compounds were performed in mice and rats. Additional safety studies were performed in rabbits, guinea pigs, dogs and monkeys. A dose-escalation Phase I study in healthy volunteers was completed. A Phase II study has been initiated. Results: Optimization of lead compounds resulted in drug candidate AVN-101. Its chemical synthesis, physico-chemical properties, metabolism, molecular pharmacology, pharmacokinetics, in vivo efficacy in behavioral models and safety profile will be presented. Both the molecular pharmacological properties and in vivo efficacy of AVN-101 are similar to those of Dimebon. Scopolamine- and MK-801-induced cognitive dysfunction was restored by AVN-101 in all behavioral tests. Additionally, AVN-101 had similar or better efficacy compared to clinically used anxiolytics in animal models. AVN-101 showed superior efficacy over Dimebon in most behavioral tests. In Phase I studies AVN-101 was very well tolerated in 32 healthy volunteers. The harmonic mean half life reached 14 hours with a linear increase of Cmax and AUC in the dose range from 2 to 20 mg given orally. Phase II studies of once-a-day oral dosing of AVN-101 are ongoing for anxiety and in planning for Alzheimer’s disease. The PK profile of AVN-101 has a clear superiority over that of Dimebon. Conclusions: Overall, AVN-101 is a promising, new drug candidate to treat Alzheimer’s Disease.

P3-443

S583 LONG-TERM LITHIUM TREATMENT FOR PATIENTS WITH MILD COGNITIVE IMPAIRMENT: BENEFITS ON COGNITION AND EVIDENCE OF DISEASE MODIFICATION

Orestes V. Forlenza, Breno S. Diniz, Franklin S. Santos, Marcia Radanovic, Ivan Aprahamian, Aaron O. Barbosa, Maria F. Castanheira, Wagner F. Gattaz, Department and Institute of Psychiatry, Faculty of Medicine, University of Sao Paulo, Sa˜o Paulo-S.P., Brazil. Contact e-mail: [email protected] Background: Two recent clinical studies in patients with Alzheimer’s disease (AD) support the feasibility of trials to evaluate disease-modifying properties of lithium in older adults with dementia. This study aims to evaluate the efficacy and tolerability of long-term, low dose, lithium treatment on cognitive and biological outcomes in sample of patients at risk of dementia. Methods: 77 older adults with amnestic mild cognitive impairment (MCI) were recruited for a 12-month, randomized, placebo-controlled trial; 51 signed informed consent (6 excluded through baseline assessment); 45 subjects were randomized to receive lithium (0.25-0.5 mmol/L) (n ¼ 24) or placebo (n ¼ 21), and 41 reached endpoint after one year of double-blind treatment. Primary outcomes: modification of cognitive and functional scores, and/or concentrations of CSF biomarkers (Ab42, total Tau, phosphorylated Tau). Safety and tolerability of lithium treatment, and the conversion rate from MCI to AD were secondary outcomes. Results: Patients in both groups displayed a mild progression of functional deficits as shown by the Clinical Dementia Rating Scale (Sum-of-Boxes scores). Lithiumtreated patients had a better performance on tests addressing global cognitive function (ADAS-Cog) and attention tasks, as compared to controls. Lithium treatment was associated with a significant reduction in CSF concentrations of phospho-Tau (p ¼ 0.03). Seven patients in the placebo group and 4 in the lithium group progressed from MCI to AD after one year (N.S.). Overall tolerability of lithium was good, and compliance to this study was 91%. Conclusions: The present data support the hypothesis that lithium has diseasemodifying properties with potential clinical implications in the MCI-AD continuum. P3-444

ANTIOXIDANT SUPPLEMENTATION AND THE COURSE OF DEMENTIA IN DOWN SYNDROME

Ira T. Lott1, Eric Doran2, Anne E. Tournay2, Elizabeth Head3, 1University of California, Irvine, Departments of Pediatrics and Neurology, Orange, CA, USA; 2University of California, Irvine, Department of Pediatrics, Orange, CA, USA; 3University of Kentucky, Sanders-Brown Center on Aging, Lexington, KY, USA. Contact e-mail: [email protected] Background: Alzheimer disease (AD) occurs with increased frequency and with a younger age of onset in adults with Down Syndrome (DS) compared to the general population. Seizures frequently occur in the course of the dementia in DS. DS is characterized by a life-long oxidative defect leading to high levels of oxidative damage to proteins, lipids and DNA/RNA. Thus, reducing oxidative stress may lead to clinical improvements in adults with DS and AD. Canine and human data support the therapeutic use of antioxidant supplementation (AOX) in AD. Oxidative stress is considered to be a precursor of AD in DS but little information is available regarding the response to AOX. Methods: Fifty-eight subjects were randomized to receive placebo or AOX supplement consisting of vitamin E, (900 IU), vitamin C (200 mg), and alpha-lipoic acid (300 mg) daily for 24 months. Outcome measures consisted of 6 standardized tests that measured cognition, adaptive skills and behavior (Dementia Questionnaire for Mentally Retarded Persons; Vineland Adaptive Behavior Scales; Bristol Activities of Daily Living; Severe Impairment Battery; Brief Praxis Test; Modified FULD Object Memory Test; Rapid Assessment for Developmental Disabilities). Results: Vitamin E levels in the treated group rose 91% above values for the placebo group suggesting good compliance. No treatment effect was observed in the clinical outcome measures and these showed a strong linear decline over the study epochs in both groups (p 0.03-0.001). In those subjects who had seizures at baseline,

S584

Poster Presentations P3

cognitive decline was precipitous to the point where floor effects precluded cognitive testing by 12 months. The safety and tolerability profile of the trial was favorable. Conclusions: 1) AOX supplementation to treat dementia in DS is ineffective at the dosages employed in the study; 2) Compliance utilizing the oral AOX supplementation was excellent; 3) The outcome measures utilized were highly sensitive to cognitive decline over the course of the study; and 4) Seizures associated with dementia in DS have a poor prognosis for cognitive functioning.

P3-445

FITNESS FOR THE AGING BRAIN STUDY II: A MULTISITE RANDOMIZED CONTROLLED TRIAL TO DETERMINE THE CLINICAL BENEFITS OF PHYSICAL ACTIVITY FOR PATIENTS WITH MILDTO-MODERATE ALZHEIMER’S DISEASE

Elizabeth V. Cyarto1, Muireann Irish1, Kay Cox2, Osvaldo P. Almeida2, Leon Flicker2, David Ames1, Keith Hill1,3, Gerard J. Byrne4, Kana Appadurai4, Christopher Beer2, Dina LoGiudice5, Emma Renehan1, Fran Waddell2, Katherine Hughes2, Nicola T. Lautenschlager6,2, 1National Ageing Research Institute, Melbourne, Australia; 2University of Western Australia, Perth, Australia; 3La Trobe University and Northern Health, Melbourne, Australia; 4The University of Queensland, Brisbane, Australia; 5 Royal Melbourne Hospital, Melbourne, Australia; 6The University of Melbourne, Melbourne, Australia. Contact e-mail: [email protected]. edu.au Background: Existing observational data suggest that people who are physically active are less likely than their sedentary peers to experience cognitive decline and dementia in later life. There is a lack of randomized controlled trials (RCT) investigating the benefits of physical activity (PA) for patients with mild to moderate Alzheimer’s Disease (AD). The Fitness for the Ageing Brain Study II (FABS II) study is a multi-site RCT designed to investigate the clinical benefits of a physical activity program for patients with mild to moderate AD living in the community. This paper offers an overview of the trial design, details about the physical activity intervention and recruitment strategies. Methods: A total of 230 people with AD and a ‘support coach’ (friend or family member) are being recruited from three metropolitan areas in Australia. The PA intervention is a modification of the intervention previously trialed in older adults with subjective memory complaints and mild cognitive impairment (FABS I). It comprises 24 weeks of moderate, home-based PA (150 minutes per week) and a behavioral intervention package. Cognitive decline, as measured by the ADAS-cog, is the primary outcome measure. Quality of life, activities of daily living, behavioral and psychological symptoms, carer burden, functional fitness, physical performance tasks and level of physical activity comprise secondary measures. Results: The PA intervention previously used in FABS I had to be adapted for patients with more severe cognitive impairment by training a friend or family member to work as a ‘support coach’. The presentation will describe details about the physical activity intervention as well as strategies used to recruit and retain participants in the study. Conclusions: Preliminary results suggest that patients with AD can participate in a tailored PA intervention. If successful, such a program could be become an essential part of clinical treatment for AD.

P3-446

EFFECT OF LIST WORD PRESENTATION ORDER ON NOISE LEVEL IN VERBAL MEMORY TASKS

William R. Shankle1,2, Adam Fleisher3,4, Mike Rafii3, Steven H. Ferris5, Ron Petersen6, Paul Aisen7, 1Medical Care Corporation, Irvine, CA, USA; 2 Dept. of Cognitive Science, University of California at Irvine, Irvine, CA, USA; 3Dept. of Neurology, University of California at San Diego, San Diego, CA, USA; 4Banner Alzheimer’s Institute, Phoenix, AZ, USA; 5Dept. of Psychiatry, New York University, New York, NY, USA; 6Mayo Clinic, Rochester, MN, USA; 7Dept. of Neurosciences, University of California at San Diego, San Diego, CA, USA. Contact e-mail: [email protected]

Background: The order of word presentation during list learning may affect verbal memory performance. We compared memory performance using the ADAS-Cog wordlist memory (WLM) task_presenting list words in a different order on each of three learning trials (shuffled order)_with that using the MCI Screen (MCIS)_presenting list words in the same order on each of three learning trials (fixed order). These two WLM tasks are otherwise very similar. We adjusted for differences in the samples used for these two WLM tasks. Methods: ADAS-Cog WLM data came from the Alzheimer’s Disease Cooperative Study (ADCS) trial of donepezil and vitamin E (N ¼ 724). MCIS data came from three sources_a memory clinic (N ¼ 70), a primary care clinic (N ¼ 262), and an insurance applicant sample (N ¼ 46,667). Conditional logistic regression was used to estimate the effect of the fixed vs. shuffled order method on number of words per trial after adjusting for potential sample differences. For each word order method, bootstrap sampling was used to generate 200 data sets to which logistic regression was applied to predict diagnosis based on delayed recall or total recall scores after adjusting for potential sample differences. Results: The ratio of the fixed/shuffled order sample variances for age and education combined was 1.95:1, indicating that the fixed order sample should show greater variability in memory performance. After covariate adjustment, the ratios of words recalled per trial for the fixed/shuffled order methods were 0.59, 0.60, and 0.71 for trials 2-4, indicating that the shuffled order method increases the number of words recalled on each trial. After covariate adjustment, the variance explained by delayed or total recall scores was two times greater for the fixed order method, and diagnostic classification accuracy was also higher. Conclusions: Because these findings were extensively controlled for sample differences, it appears that the fixed order method of the MCIS is superior to the shuffled order method of the ADAS-Cog WLM tasks for reducing error variance, detecting change, and classification.

P3-447

DEVELOPMENT OF AFFITOPE VACCINES FOR ALZHEIMER’S DISEASE

Achim Schneeberger1, Markus Mandler1, Wolfgang Zauner1, Peter DalBianco2, Margot Schmitz3, Alexandra Kutzelnigg4, Siegfried Kasper4, Martin Brunner5, Markus Mueller5, Frank Mattner1, Walter Schmidt1, 1 Affiris AG, Vienna, Austria; 2Medical University of Vienna, Department of Neurology, Vienna, Austria; 3Institute of Psychosomatic Medicine, Vienna, Austria; 4Medical University of Vienna, Department of Psychiatry, Vienna, Austria; 5Medical University of Vienna, Department of Clinical Pharmacology, Vienna, Austria. Contact e-mail: [email protected] Background: Based on the notion that cerebral accumulation of certain Ab species (unprocessed and N-terminally truncated/modified molecules) is central to the pathogenesis of Alzheimer’s disease (AD) and endowed with the knowledge emerging during clinical testing of the first Alzheimer vaccine, AN1792, AFFiRiS designed a new type of AD vaccines. Methods: Rather than relying on full-length Ab or fragments thereof, AFFITOPE vaccines use short peptides mimicking neoepitopes of Ab as their antigenic component. The technology created to identify these peptides, termed AFFITOME-technology, concomitantly provides the basis for the multicomponent safety concept realized in AFFITOPE vaccines. First, as they are non-self, AFFITOPES don’t need to break tolerance typically established against self proteins. This allows the use of aluminium, the first immunological adjuvant approved for human use and, thus, exhibiting an excellent safety profile. Second, AFFITOPES applied in AD vaccines are only 6 amino acids in length, which precludes the activation of Ab-specific autoreactive T cells. Third, the AFFITOME technology allows for controlling the specificity of the vaccine-induced antibody response focusing it on Ab and preventing crossreactivity with APP. Results: In a program based on two AFFITOPES, AD01 and AD02, both targeting the N-terminus of Ab, this approach was taken all the way from concept to clinical application. Clinical phase I data on both vaccines support the safety concept inherent to the new generation of AFFITOPE AD vaccines. Conclusions: Further clinical testing, done by AFFiRiS, will focus on the vaccines’ effects on the pathology underlying