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derive from the antagonizing actions among different phytoestrogens through activation of both ER␣ and ER␤. Objective: The goal of this research is to investigate the impact of ER␣ or ER␤-selective phytoestrogens and select combinations on neuronal survival and morphogenesis, and ultimately, develop a formulation with efficacy to promote cognition and prevent age-related neurodegeneration associated with AD. Methods & Results: Using in silico molecular docking and physicochemical properties analyses followed by a competitive binding assay, we have identified a series of ER␣ or ER␤-selective plant-derived estrogenic molecules (so we called PhytoSERMs) from a natural source chemical database. Five candidate PhytoSERMs that have the greatest binding selectivity for ER␤ were assessed for their neuroprotective efficacy in primary cortical neurons. Dose-response analyses indicated that individually each of the 5 candidate PhytoSERMs was moderately protective against supraphysiological glutamate-induced neurotoxicity determined by LDH measurements, with the greatest neuronal response occurring at 100 nM ⬃ 1 ␮M. Western blot analyses demonstrated that 4 out of 5 candidate PhytoSERMs significantly increased the expression of the anti-apoptotic protein, Bcl-2, in neurons. Further analyses demonstrated that combined use of these candidate PhytoSERMs induced significantly increased neuroprotective efficacy compared to single components. Co-administration of all 4 candidate PhytoSERMs induced the maximal protection against glutamate-induced loss in neuron metabolic viability determined by Calcein AM assay, with an efficacy significantly greater than that induced by 17␤-estradiol. We are currently investigating the impact of these PhytoSERMs and combined formulations on neuronal morphogenesis, a marker of neuroplasticity associated with memory function. Conclusions: These results contribute to generating conclusive proof of principle that an ER␤-selective PhytoSERM formulation could serve as an effective alternative to estrogen therapy for sustaining neurological health, function and prevention of AD. This work is supported by a New Investigator Research Grant Award from the Alzheimer’s Association to LZ. P4-415

THE EFFECT OF MOXIBUSTION ON SPATIAL MEMORY OF AGING RATS AND THE UNDERLYING MECHANISMS

Yan-Jun Du1, Qing Tian2, Guo-Jie Sun1, Jian-Zhi Wang2, 1Hubei college of Traditonal Chinese Medicine, Wuhan, China; 2Department of Pathology and Pathophysiology, Key Laboratory for Neurological Disease of Hubei Province,Tongji Medical College, Huazhong University of Science and Technical, Wuhan, China. Contact e-mail: [email protected] Background: Moxibustion is one important clinical therapeutic method in the Traditional Chinese Medicine and has been widely used in the prevention of aging and related diseases, e.g. Alzheimer’s disease. The acupoints, Baihui (DU20) and Shenshu (BL23), have been proved to be the most effective acupoints in aging prevention with moxibustion by large clinical investigation. But the underlying mechanism is still unknown. Objective: To evaluate the effect of Baihui (DU20) and Shenshu (BL23) with moxibustion on the learning and memory of natural aging rats and the underlying mechenism. Methods: 30 aging SD rats (18-months old) were involved in this research and divided in 2 groups, control group (n⫽15) and the moxibustion group (n⫽15). The rats in the latter group have been treated with Baihui (DU20), Shenshu (BL23) by 10 minutes’ moxibustion each time for 40 days with an interval every five days. Then the spatial learning and memory of rats were detected by Morris water maze. The ratio of apoptosis, the mitochondrial membrance electro-bit (⌬⌿mt), the levels of Caspase-3, Bcl-2 and 14-3-3␰ protein and the ultrastructure of hippocampal neuron were also investigated. Results: It was observed that the aging rats with moxibustion showed significantly shorter latency to find the hidden platform in Morris water maze than the control rats. The significantly decreased number of apoptotic neuron and the caspase-3 level, the significantly increased levels of Bcl-2 and 14-3-3␰ and the obviously improved ultrastructure of hippocampal neuron and ⌬⌿mt were found in

moxibustion group. Conclusion: Moxibustion on Baihui (DU20) and Shenshu (BL23) could significantly improve the spatial learning and memory of aging rats. Improving the structure and function of mitochondria and anti-apoptosis may be the underlying mechanism. P4-416

EVIDENCE-BASED MEMORY PRESERVATION DIET™ ©2005 TO REDUCE RISK AND SLOW PROGRESSION OF ALZHEIMER’S DISEASE (AD)

Nancy B. Emerson Lombardo1,2, Antonio Martin3,4, Ladislav Volicer5, Michaelyn S. Holmes2, Xui Wen Zhang6, 1Boston University School of Medicine, Bedford, MA, USA; 2Edith Nourse Rogers Veterans Administration Med Center, Bedford, MA, USA; 3Vitazahar Company, Health and Aging, Granada, Spain; 4University of Granada and Tufts University in Boston, Granada, Spain; 5University of South Florida, Tampa, FL, USA; 6Greater Boston Chinese Golden Age Center, Boston, MA, USA. Contact e-mail: [email protected] Background & Methods: Persons with AD tend to have low B12 levels and are often deficient in B1, B2, B6, B12, E, C and Omega ‘3’s. The nutritionally rich Memory Preservation Diet (MPD) was developed by a multidisciplinary, multi-university team to reduce risk, delay onset, slow the progression of AD, and reduce conversion from progressive Mild Cognitive Impairment to AD. Evidence suggests that the proposed dietary program could produce stronger effects on cognition than current pharmacological treatments for early AD. MPD will reduce risk for stroke, heart disease, diabetes and insulin resistance, important risk factors in the pathogenesis of AD. Foods were chosen based on the evidence for both their individual contributions and synergistic interactions. Results: The MPD is an evidence-based comprehensive diet whose 6 primary objectives are to 1) increase intake of anti-oxidants including vitamins E & C; 2) achieve a higher ratio of Omega-3 polyunsaturated fatty acids (PUFA) to Omega-6 PUFAs to approach a 1: 4 ratio 3) achieve adequate amounts of folates, S-adenosyl methionine & B-vitamins, especially B-12; 4) increase insulin sensitivity 5) increase foods that are anti-inflammatory 6) reduce LDL cholesterol, saturated and trans fats, and substitute healthier fats. Conclusion: The MPD diet can be effective because it influences AD pathogenesis (A-beta and tau) and decreases the risk factors caused by other diseases. AD pathogenesis is multifactorial including both genetic and environmental factors. Approaches seeking a single pharmacological or nutritional agent may be insufficient to prevent, delay the onset, or slow its progression. Individual or groups of nutrients can modify several mechanisms thought to affect etiology of AD including oxidative stress, homocysteine levels, excess LDL cholesterol and other fat imbalances, impaired brain cell membrane repair and function, impaired synaptic function, microgliosis, excess C-Reactive protein and other aspects of inflammation, impaired insulin signaling, impaired blood flow or blood pressure, damage to mitochondria, disturbed metal ion homeostasis, Ca(2⫹) dysregulation. These mechanisms may affect, or be affected by, production, degradation, deposition and oligeramization of beta amyloid, amyloid plaques and/or affect phosphorylation of tau and development of neurofibrillary tangles characteristic of AD, and the rate of neurodegeneration and cell death. P4-417

COMBINATION TREATMENT OF GALANTAMINE AND MEMANTINE REVERSES BEHAVIOURAL DEFICITS IN THE ANTI-NGF MOUSE MODEL OF ALZHEIMER’S DISEASE

Simona Capsoni, Roberta De Rosa, Antonino Cattaneo, Lay Line Genomics S.p.A., Rome, Italy. Contact e-mail: [email protected] Background: Galantamine is a modest acetylcholinesterase inhibitor and an enhancer of acetylcholine action on nicotinic receptors, probably through binding to an allosteric receptor site; memantine is an uncompetitive NMDA receptor antagonist. Both are used to treat Alzheimer’s disease. Objective(s): Using the transgenic AD11 anti-NGF mouse model exhibiting a pathology mimicking “sporadic” AD, we explored potential

Poster P4:: Wednesday Posters actions of galantamine, memantine, and the combination. Methods: AD11 mice (4.5 months) were treated with IP galantamine 3.5 mg/kg/day or memantine 30 mg/kg/day in drinking water, or with both drugs for 2.5 months. Control groups consisted of WT and AD11 mice (all groups, n ⫽ 10), treated with vehicle. Due to deaths in the galantamine (n ⫽ 5), memantine (n ⫽1) and combination treated (n ⫽ 5) AD11 mice, doses were reduced (galantamine 3.5 mg/kg/alternate days or memantine 20 mg/kg/day) for an additional 4.5 months. AD11 mice were tested for object (OR) recognition and context (CTX), before and during treatment. Spatial deficits were determined after treatment using the Morris water maze test (MWM). Results: Intragroup and intergroup analysis was performed. Vehicle treated AD11 mice showed significant OR (P ⬍ 0.001), CTX (P ⫽ 0.045) and MWM deficits (P ⬍ 0.05). Despite reduced samples, drug efficacy could be tested. Galantamine (n ⫽ 6) and the combination (n ⫽ 4) rescued OR deficit (P ⫽ 0.009 and P ⫽ 0.007, respectively). Galantamine and the combination rescued CTX deficit during the initial phases of the treatment, with a reduced efficacy 5 months after treatment started (P ⫽ 0.06, P ⫽ 0.29, respectively). Memantine alone rescued OR deficit but did not ameliorate the late CTX deficit. All treatment regimens ameliorated the learning deficit during the acquisition phase of MWM, but only the combination improved the performance in the retention phase of MWM (P ⫽ 3.85 E-5). Conclusions: These data suggest that galantamine ameliorates OR and CTX deficits in AD11 mice and that the simultaneous administration of two drugs addressing AD at two different molecular levels reduces the spatial deficits in a mouse model for sporadic AD. Study sponsored by Janssen-Cilag Medical Affairs EMEA, a division of Janssen Pharmaceutica N.V. P4-418

DIAGNOSIS AND SEVERITY AS PREDICTORS OF RESPONSE TO CHOLINESTERASE INHIBITORS IN ROUTINE CLINICAL PRACTICE

Rupert McShane, Rohan Van Der Putt, Hugh Series, David Janes, Catherine Dineen, Oxfordshire Mental Healthcare Trust, Oxford, United Kingdom. Contact e-mail: [email protected] Background: The U.K. National Institute of Clinical Excellence (NICE, 2006) has recently recommended the use of cholinesterase inhibitors in moderate Alzheimer’s disease (AD) only. NICE’s pharmacoeconomic modelling, based in part on company efficacy data, suggested a differential cost-benefit ratio in the moderate compared to mild subgroup. Other evidence indicates that patients with dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) show better response than those with AD. Method: Data collected for the monitoring of cholinesterase inhibitor prescribing in clinics in Oxfordshire, U.K., over four years were supplemented with retrospective case notes inspection. ‘Clinical response’ was defined as improvement sufficient to merit continuation of therapy. ‘Cognitive response’ was defined as a mini-mental state examination (MMSE) improvement of 2 points or more. Results: Medication was prescribed for 1322 patients and outcome data were available in 1250. Subsequently, 939 patients were reassessed after a mean of 120 days (SD 64.1), and 311 discontinued medication early, mainly due to side effects. Of those who started treatment and for whom data were available 62% (771 of 1250) were clinical responders and 37% (352 of 939) were cognitive responders. Overall, MMSE scores improved by ⫹0.6 points (95% CI 0.3 to 0.9) and by ⫹1.0 points (95% CI 0.7 to 1.3) in clinical responders; and deteriorated -1.5 points (95% CI -0.9 to -2.1) in clinical non-responders. A greater probability of clinical response was seen for DLB/PDD compared with AD patients (OR⫽2.28, 95% CI 1.07 to 4.89), and in men (OR⫽1.51, 95% CI 1.02 to 2.23). A positive cognitive response was more likely in DLB/PDD compared to AD (OR⫽2.07, 95% CI 1.16 to 3.70), moderate dementia compared to mild dementia (OR⫽3.90, 95% CI 2.75 to 5.52), and in older patients (OR 1.03 for each incremental year, 95% CI 1.01 to 1.06). Conclusions: Those with DLB/PDD are more likely to respond to cholinesterase inhibitors than those with AD. There is a suggestion from these data that those with moderate AD may be more likely to respond than those

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with mild AD. Nevertheless, most patients with mild AD in this nonrandomised, non-blind study were clinical responders. P4-419

MEDICATION ERRORS ON OLDER PEOPLE’S MENTAL HEALTH IN-PATIENT UNITS

Ian Maidment1, Chris Fox2, Malaz Boustani3, Paul Lelliot4, Carol Paton5, 1University Kent, Canterbury, United Kingdom; 2 University Kent ⫹ Hull UK, Folkestone, United Kingdom; 3 Gerontology Regenstrief Institute, Indianapolis, IN, USA; 4Clinical Research Unit, Royal College of Psychiatrists, London, United Kingdom; 5Oxleas NHS Trust, London, United Kingdom. Contact e-mail: [email protected] Introduction: Medication error is the most frequent clinical error and causes over 7000 annual deaths in the US (1). The resulting economic burden is substantial; $2.8 million in a 700-bed hospital (2). In the NHS medication errors account for 10-20% of all adverse events with a direct cost of £200-400 million per year (3). Medication error may be a particular problem in older people; inappropriate prescribing occurred in 21% of 750,000 older people and 41% of the inappropriate scripts involved psychotropics (4). Older people with cognitive impairment may be less likely to query changes in their medication. Aims: To assess the literature relating to medication error on Older People’s Mental Health In-patient units and investigate possible risk factors. Method: Standard databases were searched. Results: One study that assessed prescribing against six quality measures during an admission was identified (5). In-patient medication drug charts were sampled over two years and a prescribing error found in 92 out of 112 records (82%; 5). Data are lacking on administration and dispensing incidents. Data from studies within mental health organizations that included older people’s in-patient units identified potential risk areas. Moderate or severe incidents occur disproportionately on older adult inpatient wards possibly due to common use of physical medication (P⫽0.014; 6). Errors are twice as frequent with non-psychotropics compared with psychotropics perhaps due to lack of familiarity (7). Conclusions: Medication errors are common on older people’s in-patient mental health units and present a particular risk due to the use of unfamiliar physical medicines. The training of clinicians working within older people’s mental health units should include aspects of physical medication. REFERENCES: 1. Phillips et al. Lancet 1998, 351, 643. 2. Bates et al. JAMA 1997, 277, 307-311. 3. Department of Health 2004. Building a safer NHS for patients: improving medication safety. 4. Curtis et al. Arch Int Med, 2004, 164, 1621-1625. 5. Nirodi et al. Aging Ment Health, 2002, 6, 191-196. 6. Maidment et al. Psych Bull, 2005, 29, 298-301. 7. Haw et al. Pharm Pract, 2003, 13, 64-66. P4-420

ANTI-INFLAMMATORY ACTIONS OF THE ENDOCANNABINOID SYSTEM IN A RODENT MODEL OF CHRONIC NEUROINFLAMMATION

Yannick Marchalant1, Susanna Rosi2, Gary L. Wenk1, 1Ohio State University, Columbus, OH, USA; 2University of Arizona, Tucson, AZ, USA. Contact e-mail: [email protected] Background: Neuroinflammation is associated with a variety of neurological diseases, including Alzheimer’s disease (AD), and is reliably detected by the presence of activated microglia. Recent evidence suggests that the activation of the endocannabinoid system may control inflammatory processes in the brain. Cannabinoids receptors are found associated with microglia in plaques; the activation of these receptors can reverse the beta-amyloid-induced activation of microglia, making them of potential