Behavioral performance of aged wild type and APPSWE2576 mice fed with LMN diet

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PHARMACOLOGICAL AND BEHAVIORAL PROFILE OF EVP-5141, A NOVEL a7 NICOTINIC ACETYLCHOLINE RECEPTOR AGONIST

Frank Boess1,2, Jean de Vry2, Christina Erb2, Timo Flessner2, Martin Hendrix2, Joachim Luithle2, Christoph Methfessel2, Katrin Schnizler2, F. Josef van der Staay2, Marja van Kampen2, WelfBurkhard Wiese2, Gerhard Koenig3, 1Current address Lilly Deutschland, Bad Homburg, Germany; 2Bayer Healthcare AG, Wuppertal, Germany; 3 EnVivo Pharmaceuticals, Watertown, MA, USA. Contact e-mail: gkoenig@ envivopharma.com Background: Agonists at a7 nicotinic acetylcholine receptors (nAChRs) may have therapeutic potential for the treatment of cognitive deficits. Methods: The effect of the novel a7 nAChR agonist EVP-5141 on a4b2 and a7 nAChR in rat brain membranes was determined using [3H]cytisine and [3H]methyllycaconitine binding assays. Affinity at recombinant human 5-HT3 receptor expressed in HEK293 cells was measured in [3H]GR65630 binding assays. The functional potency and selectivity of EVP-5141 was determined in electrophysiological assays using recombinant a7, a3b4, a4b2 and muscle nAChRs and 5HT3 receptors expressed in Xenopus oocytes. Subsequently the effects of EVP5141 in drug discrimination and several tests of learning and memory were determined. Results: EVP-5141 bound to a7 nAChR in rat brain membranes (Ki ¼ 270 nM) and to recombinant human 5-HT3 receptors (Ki ¼ 880 nM), but had low affinity for a4b2 nAChRs (Ki > 100 mM). EVP-5141 was a potent agonist at the recombinant rat and human a7 nAChR, but did not show agonist activity at the 5-HT3 receptor and no or weak agonist activity at the other nAChR subtypes tested. EVP-5141 acted as an antagonist of the 5HT3 receptor but did not block a3b4, a4b2 and muscle nAChR. Rats trained to discriminate nicotine (0.4 mg/kg, s.c.) from vehicle did not generalize to EVP-5141 (0.3-30 mg/kg, p.o.) suggesting that the nicotine cue is not mediated by the a7 nAChR and that selective a7 nAChR agonists may not share the abuse liability of nicotine. Performance in the rat social recognition test was improved after administration of 0.3-3 mg/kg EVP-5141. EVP-5141 (0.3 mg/kg p.o.) antagonized scopolamine-induced retention deficits in the passive avoidance task in rats. EVP-5141 (1 mg/kg, i.p.) improved spatial working memory of aged rats in a water maze repeated acquisition task. In addition, EVP-5141 improved both object (0.3 mg/kg p.o.) and social recognition memory in mice (0.001 - 3 mg/kg). Conclusions: EVP-5141 improved performance in several learning and memory tests in both rats and mice supporting the hypothesis that a7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits in Schizophrenia and Alzheimer’s Disease. P1-235

EFFECTS OF THE NOVEL HISTAMINE H3 RECEPTOR ANTAGONIST S 38093 IN A NON-HUMAN PRIMATE MODEL OF COGNITIVE DYSFUNCTION

Jay S. Schneider1, Emmanuel Decamp1, Michael Hill2, Erwan Bezard1, Alan Crossman2, Brian Murphy1, Elisabeth Mocaer3, Nitza ThomassonPerret3, 1Motac Cognition Inc., Cherry Hill, NJ, USA; 2Motac Cognition Inc., Manchester, United Kingdom; 3IRIS Servier, Courbevoie, France. Contact e-mail: [email protected] Background: Chronic low dose administration of the dopaminergic neurotoxin MPTP (CLD MPTP) induces a fronto-striatal dysfunction characterized by attention and executive function deficits without inducing parkinsonianlike motor symptoms. S 38093, a novel histamine H3 type receptor antagonist, has cognitive enhancing effects in rats, aged mice, and aged monkeys and is intended for the treatment of Alzheimer’s disease. The aim of this study was to explore effects of S 38093 on attention and executive functioning in CLD MPTP-treated monkeys. Methods: Five adult male cynomolgus monkeys performed the following tasks: Variable Delayed Response (VDR, a spatial memory task with a strong attention component at short duration delays and a memory component at long duration delays); Continuous Performance Task (CPT, test of sustained/selective visual attention); and Discrimination Reversal Task (DisR, a test of cognitive flexibility). Animals were administered low doses of MPTP until stable cognitive deficits were produced. S

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38093 was then tested at doses of 0.10, 0.30 and 1.00 mg/kg, p.o. Results: Significant improvements in VDR task performance were observed only at the two shortest duration delays at all doses of S 38093 (i.e., mean percent correct responses of 90% and 85% respectively vs. 64% and 71% after MPTP alone). Significant improvements in CPT performance (i.e., increased positive hits (mean of 52 vs. 41 after MPTP alone), decreased omission errors (i.e., 8 vs. 20 after MPTP alone) were also observed at all doses following S 38093 administration, suggesting an effect on sustained/selective visual attention. There was also significant improvement in DisR performance (i.e., significant decrease in the number of trials to reach criterion (36 vs. 156 under MPTP alone) after S 38093 (0.3 mg/kg p.o), suggesting a beneficial effect on cognitive flexibility. Conclusions: These data demonstrate that S 38093 has positive effects on attention, as evidenced on performance of the attentional component of the VDR task and the CPT task, as well as a positive effect on at least one aspect of executive functioning (i.e., cognitive flexibility) in CLD MPTP-treated monkeys. These results indicate that S 38093 may be useful to enhance attention and cognitive flexibility. P1-236

AGITATION AND NURSING HOME STRUCTUREHOW ARE THEY RELATED?: A THREE COUNTRY STUDY

Ingelin Testad1, Stefanie Auer2, Mary Mittelman3, Clive Ballard4, Dag Aarsland1, 1Stavanger University Hospital, Stavanger, Norway; 2 M.A.S. Alzheimerhilfe, Bad Ischl, Austria; 3NYU School of Medicine, NY, NY, USA; 4Kings College, London, United Kingdom. Contact e-mail: tesi@ sus.no Background: Agitation and other behavioral problems are commonly observed phenomena in persons with dementia, particularly in nursing homes. Agitation is frequently treated with neuroleptic medications with questionable efficacy and poor tolerability. The role of environmental factors such as nursing home culture and structure in the development of agitation is poorly understood. In the present exploratory study we compared different care environments in different countries with respect to levels of agitation, usage of psychotropic medication and patient/staff ratio. Methods: Baseline data for three different intervention studies in Austria (n¼38), England (n¼302) and Norway (n¼163) were combined posthoc. The nursing facilities selected for comparison differed substantially in their care conceptionalization and the nursing homes selected for comparison were not randomly selected homes and not considered typical for each country’s care concept. Patients were grouped according to their dementia severity using the GDS, FAST and CDR scales. For the measurement of agitation, the Cohen-Mansfield Agitation Inventory (CMAI) was used. The usage of psychotropic medications was assessed by reviewing medical charts. Data analysis was performed using one-way ANOVA, multivariate and linear regression analysis. Results: From the nursing facility population of 590 subjects, 503 subjects met the study inclusion criteria of having dementia (about 15% of screened subjects had no dementia). The level of agitation differed between countries, with higher mean score in Austrian compared to UK and Norwegian nursing homes. In the regression analysis, after adjustment for age, sex, and dementia severity, country still had a significant effect (beta ¼ -2.5, p¼0.012) on agitation as reflected by the CMAI. Similarly, the use of psychotropic drugs differed significantly, with a higher proportion on neuroleptics in UK and Austria compared to Norwegian nursing homes. This remained significant even after adjusting for age, gender, dementia severity and CMAI score. The mean number of patients and staff/resident ratio differed also, with the Norwegian nursing homes having lower number of patients per ward and higher staff/resident ratio compared to homes in Austria and UK. Conclusions: These results suggest that higher specialization of the institution and higher patient/staff ratio are associated with lower agitation levels and less usage of neuroleptic medications. P1-237

BEHAVIORAL PERFORMANCE OF AGED WILD TYPE AND APPSWE2576 MICE FED WITH LMN DIET

Rosa M. Escorihuela1, Je´ssica Ruiz1, Irene Bolea2, Gemma Comes3, Juan Hidalgo3, Bartolome´ Ramı´rez4, M. Neus Angle´s4,

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Poster Presentations P1

Jose´ Ramo´n Morello´4, Jordi Reguant4, Merce` Boada5, Mercedes Unzeta2, 1 Dept. Psiquiatria i Medicina Legal. Institut de Neurocie`ncies. UAB, Barcelona, Spain; 2Dept. Bioquimica i Biologia Molecular. Institut de Neurocie`ncies. UAB, Barcelona, Spain; 3Dept. Biologia Cel.lular, Fisiologia i Immunologia. Institut de Neurocie`ncies. UAB, Barcelona, Spain; 4La Morella Nuts SA, Reus (Tarragona), Spain; 5Servei de Neurologia, Hospital G.U. Vall d’Hebron. Fundacio´ ACE, Institut Catala` de Neurocie`ncies Aplicades., Barcelona, Spain. Contact e-mail: rosamaria. [email protected] Background: There is evidence indicating that some nutrients of the diet can affect the progression of cognitive decline in Alzheimer´s disease (AD). Objectives: We studied whether the *LMN diet, rich in cocoa, nuts and other compounds affected behavioural performance of aged transgenic APPSWE2576 mice, a mouse model of AD. Methods: Beginning at 13 months of age, control and transgenic male mice were feed with the standard Harlan 2014 control diet, or the diet containing 9,27% of *LMN. The animals were tested after 4 months on the diets and they were maintained over testing. Two young groups of wild type and transgenic mice fed with the control diet were also included in the experiments in order to study the behavioural changes produced by aging. Sensorimotor reflexes, exploration, emotionality, motor activity and spatial learning were evaluated. Results: Equilibrium, prehensile reflex and forelimb strength were reduced in aged and/or APP mice. Head-dipping behaviour in the hole-board was reduced by age, and increased by LMN diet in aged mice. No significant effects of age, genotype or diet were observed in the number of entries and the time spent into the open arms of the elevated plus-maze. APP mice showed reduced ambulation in the open field, no other significant effect appeared in this test. Aged animals swam slower than young adults in the Morris water maze and, APP mice performed longer distances than wild type. An almost significant genotype x diet interaction was found on latencies and distances over the 8 sessions of spatial learning. In the probe test, aged animals spent less time, travelled shorter distances and decreased annulus crossings in the target quadrant as compared with young mice. LMN diet increased the distance travelled in the target quadrant and the number of annulus crossings with respect to the control diet. Conclusions: The results indicated that APP mice showed sensorimotor deficits, decreased ambulation, and impaired spatial learning. Aging also decreased sensorimotor reflexes, exploratory behaviour and spatial learning, whereas LMN diet showed beneficial effects over the spatial learning and the probe test. Thus, LMN diet could be a promising nutrient for reducing the cognitive decline associated with aging and AD. P1-238

CONSISTENCY OF BEHAVIORAL AND NEURAL CHANGES AFTER FOCUSED COGNITIVE REHABILITATION IN PATIENTS WITH MILD COGNITIVE IMPAIRMENT

Benjamin M. Hampstead1,2, Anthony Y. Stringer1, Randall F. Stilla1, K. Sathian1,2, 1Emory University, Atlanta, GA, USA; 2Atlanta VAMC RR&D, Decatur, GA, USA. Contact e-mail: [email protected] Background: Memory deficits are characteristic of mild cognitive impairment (MCI), which is often a precursor to Alzheimer’s disease (AD), and are a major cause of functional decline and disability. Relatively little work has investigated the efficacy of cognitive rehabilitation (CR) in this population. Moreover, while a number of structural and functional neuroimaging studies have provided substantial insight into the nature of brain changes in MCI and AD, there has been no systematic study of the neural underpinnings of CR in patients with MCI or AD. Objectives: We have undertaken a program of research with the intention of developing empirically validated and neuroscientifically driven CR strategies. We have developed CR paradigms targeting the explicit memory system because it is affected early in the course of MCI. Methods: Two distinct training paradigms (face-name and object-location associations), requiring patients to associate various aspects of information, were used. These paradigms were modified from the EON-MEM training program (Stringer, 2007). In both paradigms, patients underwent pre- and post-training functional magnetic resonance imaging (fMRI) scans as they encoded the associa-

tions, with subsequent tests of memory. Between these scanning sessions, patients received three 1-hour training sessions during which they were taught CR strategies to facilitate learning and memory. Long-term retention was assessed 1 month later. Results: To date, these focused interventions have significantly improved the accuracy of memory and reaction time for the trained associations, with the benefits persisting for at least 1 month. Analysis of the fMRI data has consistently revealed increased encoding-related activation within a widespread cerebral cortical network primarily involving medial frontoparietal and lateral tempoparietal areas (i.e. portions of the default network). Additionally, training has resulted in increased effective connectivity between many of these regions. Conclusions: Our findings suggest that focused CR can be effective in patients with MCI. These benefits seem to be driven through recruitment of default network areas that are critical for internally driven processes, including episodic memory. Future work will seek to further capitalize on these changes in order to develop the most effective CR strategies for this growing population. P1-239

AN INVESTIGATION OF BEHAVIORAL EFFECTS OF HUPRINE X, A NEW POTENT ANTICHOLINESTERASIC, COMPARED WITH HUPERZINE-A IN 3XTGAD MICE

Lydia Gimenez Llort1, Miriam Ratia2, Pelayo Camps3, Diego Mua˜ ˆ Victoria Clos2, Albert Badia2, 1Dept. ’Oz-Torrero3, Frank M. Laferla4, MA Psychiatry and Forensic Medicine Aˆ$ Institute of Neuroscience Aˆ$ Autonomous University of Barcelona, Bellaterra Aˆ$ Barcelona, Spain; 2 Dept. Pharmacology, Therapeutics and Toxicology Aˆ$ Institute of Neuroscience Aˆ$ Autonomous University of Barcelona, Bellaterra Aˆ$ Barcelona, Spain; 3Lab of Pharmaceutical Chemistry Aˆ$ Faculty of Pharmacy Aˆ$ University of Barcelona, Barcelona, Spain; 4Dept. Neurobiology and Behavior Aˆ$ University of California Irvine, Irvine, CA, USA. Contact e-mail: [email protected] Background: Huprine X is a tacrine and huperzine A hybrid that shows high selectivity and potent inhibitory action on acetylcholinesterase in both in vitro and ex vivo studies. In addition huprine X has an agonistic action on muscarinic M1 and nicotinic receptors. The behavioral effects of huprine X remain to be established, particularly with regards to its cognitive enhancing properties. Therefore, we have studied the behavioral effects of chronic administration of huprine X comparatively to those of huperzine A in a triple-transgenic model of AlzheimeraˆVÔs disease (3xTg-AD) mice. Methods: Previous tests were performed in order to homogenize the different groups according with animalaˆVÔs inborn skills. Afterwards 7-month-old 3xTg mice received chronic i.p. treatment with either saline, ˆ mmols.kg-1) or huperzine A (0.8 A ˆ mmols.kg-1) for 21 huprine X (0.12A days. The assessment of spatial reference learning and memory in the Morris water maze, emotionality and motor activity in the open-field test, and anxiety-like behavior in the white-black box test were performed in the 3xTg-AD mice. Results: The results show that both huprine X and huperzine A improve learning and memory, with a better day by day performance resulting in a faster acquisition of the place task. Only 3 days were required in huprine X group and as compared to 6 days in the huperzine A group while the saline group were unable to reach that acquisition level. No changes on motor activity nor anxiety-like behaviours, as measured in the open-field, dark-light box and corner test were observed for the two compounds. Conclusions: Our results suggest that huprine X is able to improve cognition at lower doses than huperzine A and it could be a promising therapeutic agent for the treatment of dementias caused by cholinergic disfunction. Supported by DGICYT (SAF2006-13642 and SAF2006-04339). MR was supported by UAB fellowship. P1-240

ITEM ANALYSIS OF ADAS-COG AND CDR SYSTEM COGNITIVE MEASURES IN AD PATIENTS ON STABLE TREATMENT WITH ANTICHOLINESTERASES

Chris Edgar1, Keith A. Wesnes2, Niels Andreasen3, Hans Basun4, Lars Lannfelt4, Henrik Zetterberg5, Kaj Blennow5, Lennart Minthon6,