- Email: [email protected]
Conformationally directed immunomodulation for multiple pathological conformers
Poster Presentations P3
S582
rivastigmine treatment of degenerating primary neurons promoted survival (Bailey and Lahiri, 2010). Both drugs increased neuronal and synaptic markers, and immunocytochemistry showed preservation of neuronal morphology with both drugs. Memantine reduced levels of Ab42 secretion in primary cells, and reduced soluble Ab42 levels in the cortices of transgenic mice. These drugs are now being tested in primary lymphocyte cultures from human subjects, and other mechanistic studies are ongoing. Conclusions: The responses to memantine and rivastigmine treatment observed in these different models are not identical, though there are important similarities with potentially important implications for current and future therapeutic interventions for AD. Both drugs increased or preserved cellular viability, neuronal morphology and possibly synaptic transmission in degenerating primary neurons, in addition to preserving synaptic markers that are reduced in AD. These drugs were shown to alter APP processing in cell culture and animal models, though the response varied between models. APP and Ab are associated with neurite and synapse regulation, so taken together, these results imply common or synergistic modes of action that could be further explored for the development of improved therapeutic agents.
P3-439
DONEPEZIL PROMOTES THE PROLIFERATION OF NEURAL STEM CELLS IN THE DENTATE GYRUS OF AGED MICE
Tatsuhiro Hisatsune, University of Tokyo, Kashiwa, Japan. Contact e-mail: [email protected] Background: Donepezil is a leading medication for Alzheimer disease, but its mechanism for treating Alzheimer disease has not been fully clarified yet. To know roles of donepezil in maintaining and/or enhancing hippocampal plasticity, we assessed the effect of donepezil on regulation of adult hippocampal neurogenesis. New neurons are generated in the dentate gyrus of the hippocampal formation from neural stem cells and contribute to the maintenance of hippocampal plasticity throughout life. The number of new neurons decreases as age progresses, but neural stem cells are reserved even in aged animals. There is a hypothesis that donepezil can maintain hippocampal plasticity through the promotion of new neuron generation. Methods: In order to evaluate whether donepezil promote the proliferation of neural stem cells in aged animals, we utilized aged nestin-GFP mice (> 2 years old) and counted the number of proliferating neural stem cells after the administration of donepezil hydrochloride (2 mg/kg/day for 3 days; kindly provided from Eisai Co., Tokyo, Japan) in combination with the injection of BrdU, a marker for cell division. We can identify neural stem cells by nestin-promoter driven GFP and GFAP expressions in aged nestin-GFP transgenic mice. Mice were killed 24 hr after the BrdU injection, and hippocampal slices were processed with the triple immunostaining: anti-GFP, anti-GFAP, and anti-BrdU. Results: We found the clear increase in the number of proliferating neural stem cells by the administration of donepezil. The number of BrdU-labelled neural stem cells in the donepezil group (n ¼ 5) was 556 6 47; whereas, that in the control group (n ¼ 6) was 156 6 50. These data has been reported previously (Itou et al., Hippocampus, DOI 10.1002/hipo.20761 (2010) online). Conclusions: We can propose a new scheme that the effect of donepezil would be, in part, through the promotion of adult hippocampal neurogenesis, which contribute to the maintenance and/or the enhancement of hippocampal plasticity in Alzheimer’s patients.
P3-440
OXIDATIVE STRESS-INDUCED MITOCHONDRIAL FAILURE AND BRAIN HYPOMETABOLISM UNDERLAY THE PATHOPHYSIOLOGY OF ALZHEIMER’S DISEASE AND OFFER TARGET FOR TREATMENT: ASTONISHING EFFECT OF MELANIN AND MITOCHONDRIAL ANTIOXIDANTS
Gjumrakch Aliev1,2, Hector H. Palacios3, Eldar Gasimov4, Dmitry Gokhman5, Jerzy Leszek6, Ludis Morales1, Mark E. Obrenovich7,
Valentin Bragin2, Arturo Solı´s Herrera8, 1Pontificia Universidad Javeriana, Bogota´, Colombia; 2Stress Relief Center, Brooklyn, New York, NY, USA; 3 Department of Biology, University of Texas at San Antonio, San Antonio, TX, USA; 4Department of Cytology, Histology and Embryology, Azerbaijan Medical University, Baku, Azerbaijan; 5Department of Mathematics, University of Texas at San Antonio, San Antonio, TX, USA; 6Department of Psychiatry, Wroclaw Medical University, Wroclaw, Poland; 7Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; 8Centro de Estudios de la Fotosı´ntesis Humana. S.C., Aguascalientes, Mexico. Contact e-mail: [email protected] Background: It is widely accepted that neuronal energy crisis, cerebral hypometabolism and vascular hypoperfusion are major and potentially treatable contributors to the loss of functioning in patients with Alzheimer disease (AD). In addition, recently we have found an unexpected capacity for melanin to dissociate water and aid in deriving energy in the process. We hypothesize that melanin can be used as a new and more effective therapeutic approach in the treatment of AD patients. The goal of our work is to potentially target melanin’s dissociation properties for therapy of the disease by using a combination of selective mitochondrial antioxidant plus the Melanin analogue (QIAPI-1) both in combination with our recently developed brain exercising program. Methods: This study applies the brain hypometabolism paradigm to AD patients in order to analyze cognitive function in the patients who receive Alpha-Lipoic Acid, Acetyl-L-Carnitine, Omega3-6-9 from Fish, Flax, Borage oil as well as Coenzyme Q-10 and Melanin analogue (QIAPI-1, developed by Dr. Solis), along with diet changes in combination with and our recently developed brain activation program (a home-based protocol involving mild physical exercise and cognitive training. The average age of patients were 73.5. These patients were evaluated at baseline and in one and two years post treatment. Results: Our clinical results showed that patients who received the combination of mitochondrial antioxidants and QIAPI-1 presented the maximum significant cognitive improvement at the end of 24 months of treatment. The maximum significant cognitive improvement was seen with the combined treatment in MMSE, attention, memory, naming, construction, clock drawing, verbal fluency, and Ruff Frontal Fluency tests. By the end of 24 months of the treatment, significant improvement was especially observed in attention, construction and clock drawing when patients received combined treatment. In addition, this group also showed that rest of the tests no signs of decreases and/or decline below base line for the entire period of the treatment. Conclusions: Further examination of the potential pharmacologic modulation of brain hypometabolism by using human photosynthesis compounds such as selective mitochondrial antioxidants and Melanin analogue represents a completely new and more effective strategies to treat Alzheimer and/or other dementia types. P3-441
CONFORMATIONALLY DIRECTED IMMUNOMODULATION FOR MULTIPLE PATHOLOGICAL CONFORMERS
Thomas Wisniewski, Yong Ji, Yanjie Sun, Henrieta Scholtzova, Frances Prelli, Fernando Goni, NYU School of Medicine, New York, NY, USA. Contact e-mail: [email protected] Background: Alzheimer’s disease is the most common of the conformational neurodegenerative disorders, where the pathogenesis is linked to a normal protein undergoing a shape change into a pathological conformer with a high b-sheet content. In the case of AD this involves both amyloid b and abnormally phosphorylated tau forming toxic oligomeric structures, as well as neuritic plaques, congophilic angiopathy and neurofibrillary tangles. In the case of another conformational disorder, the prion diseases, the pathogenesis is linked to a change in the cellular prion protein (PrPC) into the disease associated PrPSc . Despite their biochemical heterogeneity the pathological conformers underlying the pathogenesis of the various conformational disorders show pathological conformation mimicry. We sought to develop a novel immunomodulation method which would specifically target this abnormal conformation
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,
S582
rivastigmine treatment of degenerating primary neurons promoted survival (Bailey and Lahiri, 2010). Both drugs increased neuronal and synaptic markers, and immunocytochemistry showed preservation of neuronal morphology with both drugs. Memantine reduced levels of Ab42 secretion in primary cells, and reduced soluble Ab42 levels in the cortices of transgenic mice. These drugs are now being tested in primary lymphocyte cultures from human subjects, and other mechanistic studies are ongoing. Conclusions: The responses to memantine and rivastigmine treatment observed in these different models are not identical, though there are important similarities with potentially important implications for current and future therapeutic interventions for AD. Both drugs increased or preserved cellular viability, neuronal morphology and possibly synaptic transmission in degenerating primary neurons, in addition to preserving synaptic markers that are reduced in AD. These drugs were shown to alter APP processing in cell culture and animal models, though the response varied between models. APP and Ab are associated with neurite and synapse regulation, so taken together, these results imply common or synergistic modes of action that could be further explored for the development of improved therapeutic agents.
P3-439
DONEPEZIL PROMOTES THE PROLIFERATION OF NEURAL STEM CELLS IN THE DENTATE GYRUS OF AGED MICE
Tatsuhiro Hisatsune, University of Tokyo, Kashiwa, Japan. Contact e-mail: [email protected] Background: Donepezil is a leading medication for Alzheimer disease, but its mechanism for treating Alzheimer disease has not been fully clarified yet. To know roles of donepezil in maintaining and/or enhancing hippocampal plasticity, we assessed the effect of donepezil on regulation of adult hippocampal neurogenesis. New neurons are generated in the dentate gyrus of the hippocampal formation from neural stem cells and contribute to the maintenance of hippocampal plasticity throughout life. The number of new neurons decreases as age progresses, but neural stem cells are reserved even in aged animals. There is a hypothesis that donepezil can maintain hippocampal plasticity through the promotion of new neuron generation. Methods: In order to evaluate whether donepezil promote the proliferation of neural stem cells in aged animals, we utilized aged nestin-GFP mice (> 2 years old) and counted the number of proliferating neural stem cells after the administration of donepezil hydrochloride (2 mg/kg/day for 3 days; kindly provided from Eisai Co., Tokyo, Japan) in combination with the injection of BrdU, a marker for cell division. We can identify neural stem cells by nestin-promoter driven GFP and GFAP expressions in aged nestin-GFP transgenic mice. Mice were killed 24 hr after the BrdU injection, and hippocampal slices were processed with the triple immunostaining: anti-GFP, anti-GFAP, and anti-BrdU. Results: We found the clear increase in the number of proliferating neural stem cells by the administration of donepezil. The number of BrdU-labelled neural stem cells in the donepezil group (n ¼ 5) was 556 6 47; whereas, that in the control group (n ¼ 6) was 156 6 50. These data has been reported previously (Itou et al., Hippocampus, DOI 10.1002/hipo.20761 (2010) online). Conclusions: We can propose a new scheme that the effect of donepezil would be, in part, through the promotion of adult hippocampal neurogenesis, which contribute to the maintenance and/or the enhancement of hippocampal plasticity in Alzheimer’s patients.
P3-440
OXIDATIVE STRESS-INDUCED MITOCHONDRIAL FAILURE AND BRAIN HYPOMETABOLISM UNDERLAY THE PATHOPHYSIOLOGY OF ALZHEIMER’S DISEASE AND OFFER TARGET FOR TREATMENT: ASTONISHING EFFECT OF MELANIN AND MITOCHONDRIAL ANTIOXIDANTS
Gjumrakch Aliev1,2, Hector H. Palacios3, Eldar Gasimov4, Dmitry Gokhman5, Jerzy Leszek6, Ludis Morales1, Mark E. Obrenovich7,
Valentin Bragin2, Arturo Solı´s Herrera8, 1Pontificia Universidad Javeriana, Bogota´, Colombia; 2Stress Relief Center, Brooklyn, New York, NY, USA; 3 Department of Biology, University of Texas at San Antonio, San Antonio, TX, USA; 4Department of Cytology, Histology and Embryology, Azerbaijan Medical University, Baku, Azerbaijan; 5Department of Mathematics, University of Texas at San Antonio, San Antonio, TX, USA; 6Department of Psychiatry, Wroclaw Medical University, Wroclaw, Poland; 7Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; 8Centro de Estudios de la Fotosı´ntesis Humana. S.C., Aguascalientes, Mexico. Contact e-mail: [email protected] Background: It is widely accepted that neuronal energy crisis, cerebral hypometabolism and vascular hypoperfusion are major and potentially treatable contributors to the loss of functioning in patients with Alzheimer disease (AD). In addition, recently we have found an unexpected capacity for melanin to dissociate water and aid in deriving energy in the process. We hypothesize that melanin can be used as a new and more effective therapeutic approach in the treatment of AD patients. The goal of our work is to potentially target melanin’s dissociation properties for therapy of the disease by using a combination of selective mitochondrial antioxidant plus the Melanin analogue (QIAPI-1) both in combination with our recently developed brain exercising program. Methods: This study applies the brain hypometabolism paradigm to AD patients in order to analyze cognitive function in the patients who receive Alpha-Lipoic Acid, Acetyl-L-Carnitine, Omega3-6-9 from Fish, Flax, Borage oil as well as Coenzyme Q-10 and Melanin analogue (QIAPI-1, developed by Dr. Solis), along with diet changes in combination with and our recently developed brain activation program (a home-based protocol involving mild physical exercise and cognitive training. The average age of patients were 73.5. These patients were evaluated at baseline and in one and two years post treatment. Results: Our clinical results showed that patients who received the combination of mitochondrial antioxidants and QIAPI-1 presented the maximum significant cognitive improvement at the end of 24 months of treatment. The maximum significant cognitive improvement was seen with the combined treatment in MMSE, attention, memory, naming, construction, clock drawing, verbal fluency, and Ruff Frontal Fluency tests. By the end of 24 months of the treatment, significant improvement was especially observed in attention, construction and clock drawing when patients received combined treatment. In addition, this group also showed that rest of the tests no signs of decreases and/or decline below base line for the entire period of the treatment. Conclusions: Further examination of the potential pharmacologic modulation of brain hypometabolism by using human photosynthesis compounds such as selective mitochondrial antioxidants and Melanin analogue represents a completely new and more effective strategies to treat Alzheimer and/or other dementia types. P3-441
CONFORMATIONALLY DIRECTED IMMUNOMODULATION FOR MULTIPLE PATHOLOGICAL CONFORMERS
Thomas Wisniewski, Yong Ji, Yanjie Sun, Henrieta Scholtzova, Frances Prelli, Fernando Goni, NYU School of Medicine, New York, NY, USA. Contact e-mail: [email protected] Background: Alzheimer’s disease is the most common of the conformational neurodegenerative disorders, where the pathogenesis is linked to a normal protein undergoing a shape change into a pathological conformer with a high b-sheet content. In the case of AD this involves both amyloid b and abnormally phosphorylated tau forming toxic oligomeric structures, as well as neuritic plaques, congophilic angiopathy and neurofibrillary tangles. In the case of another conformational disorder, the prion diseases, the pathogenesis is linked to a change in the cellular prion protein (PrPC) into the disease associated PrPSc . Despite their biochemical heterogeneity the pathological conformers underlying the pathogenesis of the various conformational disorders show pathological conformation mimicry. We sought to develop a novel immunomodulation method which would specifically target this abnormal conformation
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,