P4-414

Poster P4:: Wednesday Posters P4-411

LONG-TERM EFFECTS OF CHOLINESTERASE INHIBITORS ON STRATEGIC PROCESSING USING VERBAL FLUENCY TESTS IN ALZHEIMER’S DISEASE

Pearl Behl, Donald T. Stuss, Krista Lanctot, David L. Streiner, Sandra E. Black, University of Toronto, Toronto, ON, Canada. Contact e-mail: [email protected] Background: Although executive dysfunction occurs early on in Alzheimer’s disease (AD), routine standardized tests have not been sensitive to these deficits. A few studies have assessed executive functioning and shown improvements in working memory in patients treated with cholinesterase inhibitors compared to untreated patients. Objective(s): To further assess executive dysfunction and treatment effects in AD, analyses were performed in tests of verbal fluency (phonemic and semantic). The active search and retrieval of information is primarily mediated by the frontal lobes and these tests can provide indices of strategic component processes such as speed of initiation and sustained production. A central hypothesis underlying our approach is that frontally mediated, strategic processes (phonemic fluency) may be particularly responsive to treatment and semantic fluency, considered less strategic in nature and dependent more on semantic memory (temporal lobes), may show less benefit. Methods: 130 patients meeting NINCDS-ADRDA criteria for probable AD underwent standardized assessments including verbal fluency at baseline, one and two years. Baseline assessment was within one month of treatment with CHEIs (N⫽65). Untreated patients were followed for one year or more prior to treatment (N⫽65). Results: Groups did not differ on detailed medical evaluations and demographics. Repeated measures MANOVA on phonemic fluency showed that treated patients produced more correct words at one year (p⫽ 0.031) and fewer errors at one (p⫽0.021) and two years (p⫽0.009) compared to untreated patients. Broken down by error types, treated patients produced fewer rule-breaks at one year (p⫽0.018) and a trend to fewer rule-breaks (p⫽ 0.089) and intrusions (p⫽0.054) at two years. There was no difference in speed of initiation and sustained production over one and two years. The overall GLM was not significant for semantic fluency at one and two years. Conclusions: As predicted, treated patients were more accurate on FAS fluency and made fewer errors on rule-breaks suggesting that they were able to remember and hold instructions in working memory. Executively loaded functions, rather than memory, may show the best response pragmatically to cholinesterase inhibitors since mnemonic functions may have been too severely compromised to benefit, whereas frontally mediated executive functions may allow for stabilization. P4-412

THE USE OF A REHABILITATION INVENTORY AND INTERDISCIPLINARY APPROACH IN THE TREATMENT OF PATIENTS WITH CORTICO BASAL DEGENERATION SYNDROME

Daniel Drubach, Mayo Clinic, Rochester, MN, USA. Contact e-mail: [email protected] Background: Cortico-basal degeneration syndrome is characterized by alteration in motor control (apraxia, alien limb syndrome, mirror movements), rigidity and movement disorders (rigidity, myoclonus, dystonia), sensorial abnormalities (alterations in proprioception, tactile defensiveness, dysesthesias), communication abnormalities (speech apraxia, aphasia) and neuropsychiatric abnormalities (depression, emotional incontinence and others), among others. While there is no specific treatment for the disorder, little is known regarding the benefit of rehabilitation interventions in this population. Objective: To identify areas of impaired function amenable to rehabilitation interventions delivered by an interdisciplinary team approach. Methods: We have devised a rehabilitation inventory specific to this disorder which helps us to identify specific functional abnormalities that may be amenable to treatment by a combination of rehabilitation and pharmacological interventions. Results: We have found that through means of this inventory we are able to identify areas for potential thera-

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peutic intervention that may not have been recognized otherwise. Conclusions: The utilization of a specific rehabilitation inventory may help to identify areas of compromised function which may not be identified otherwise. The treatment of these functional impairments by an experienced interdisciplinary team approach may help to improve the quality of life of patients with cortico basal degeneration disorders. P4-413

THE EVIDENCE-BASED ALTERNATIVE THERAPEUTIC INTERVENTION FOR DEMENTIA PATIENTS

Eun Ah Lee1, EunHyang Song1, Mee la Kim1, MeeSook Lee1, Taeyou Kim2, 1Seoul Metropolitan Seobuk Hospital, Seoul, Republic of Korea; 2Hansol Geriatric Hospital, Kimhae, Republic of Korea. Contact e-mail: [email protected] Background: Dementia is a longstanding progressive degenerative illness limited by the general pharmacotherapy. Even though several alternative therapeutic trials for Dementia patients have been attempted, systemic evidence-based clinical research is rare. Objective(s): Our aims were to assess the evidence-based effect of alternative therapeutic intervention such as music and art therapy, aromatherapy and reminiscent stimulation and were to investigate the validity of those as alternative therapeutic strategies of patients with dementia. Methods: We assessed 102 patients with Alzheimer’s and vascular dementia. Among them, forty patients received well designed Music therapy (MT) 4 times per week for 2 months, and 35 patients received Art therapy(AT) by same strategy. Each session was performed about 40 minutes. Twelve patients received aromatherapy using 2% lavender oil twice a day for 14 days. Twenty five patients received reminiscent film stimulation. We evaluated devised short-formed clinical assessment tools included several tests related to language and memory functions, visuospatial function for music and art therapy group. We also evaluated Pittsburg agitation scale (PAS) and NPI score for aromatherapy group and cerebral blood flow for reminiscent stimulation group. Results: In MT group, phonemic word fluency was significantly improved (p⬍0.005) without improvement in MMSE and semantic word fluency. In AT group, MMSE score, immediate and delayed visual recognition were significantly improved at 6 weeks after (p⬍0.05). In aroma therapy group, PAS and NPI score were significantly decreased at 7 days (p⬍0.05) but showed increasing tendency after then. In reminiscent stimulation group, the cerebral blood flow was significantly increased (p⬍0.05). Conclusions: Our results suggest that the various alternative therapeutic interventions can affect cognitive function and behavior of dementia patients in different ways by their specific characteristics. Music therapy improves phonemic fluency and executive functions, especially on frontal cognitive functions and art therapy improves visual recognition. Aromatherapy can be applicable as a transient BPSD control tool. Reminiscent stimulation can be applicable to nonpharmacologic therapy as a neuronal reactivation tool. P4-414

IMPACT OF ER␤-SELECTIVE PHYTOSERM FORMULATIONS ON NEURONAL SURVIVAL AND MORPHOGENESIS: PROMISE AS AN ESTROGEN ALTERNATIVE REPLACEMENT THERAPY FOR PREVENTION OF ALZHEIMER’S DISEASE AND RELATED NEUROLOGICAL DISORDERS

Liqin Zhao, Roberta Diaz Brinton, Department of Molecular Pharmacology & Toxicology, Norris Foundation Laboratory for Neuroscience Research, University of Southern California, Los Angeles, CA, USA. Contact e-mail: [email protected] Background: It is becoming increasingly apparent that in many contexts two estrogen receptor subtypes, ER␣ and ER␤, have a yin/yang relationship where activation of one ER subtype antagonizes the other, indicating that the lack of efficacy of a complex formulation of phytoestrogens (i.e. a soy protein supplement) to promote neurological function may partly

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Poster P4:: Wednesday Posters

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