- Email: [email protected]
P-195
S160
Posters: P-194
three months of memantine treatment. There were 49 patients with diagnosis of VD & 112 patients who met the diagnosis of possible AD. All patients were treated previously with one of the Ach-E inhibitors (donepezil, rivastigmine or galantamine). Average age of patients was 83.4 years old. Only one reported case of increased confusion during the second week of treatment. In both centers, no patients stopped treatment due to adverse event. An impressive cognitive improvement was reported by caregivers of 26 patients with VD. No noticeable cognitive improvement was reported by any of AD caregivers during the initial three months of treatment. Conclusions: This preliminary report demonstrates that during the three initial months of treatment, memantine slowly titrated (monthly) to a maximum dose of 20 mg/day in two divided doses was reported to show noticeable cognitive improvement by caregivers of patients with VD. No such improvement was reported with AD patients. P-194
MODIFICATION OF THE STAGGERED START AND RANDOMIZED WITHDRAWAL CLINICAL TRIAL DESIGNS: TOWARD A PRACTICAL DEMONSTRATION OF DISEASE MODIFICATION IN ALZHEIMER’S DISEASE (AD)
Suzanne Hendrix, Alexander Gutin, Kenton Zavitz, Graham Carron, Mark Laughlin, Scott Horton, Myriad Pharmaceuticals, Salt Lake City, UT, USA. Contact e-mail: [email protected] Background: Demonstration of Disease Modification in AD is a complicated topic that has been approached in many ways. Among the strategies proposed are two approaches based on measuring clinical outcomes in a cross-over type study: 1. the staggered start design and 2. the randomized withdrawal design. These two study designs are complicated by the long duration of the studies, leading to high dropout rates which introduce bias. A suggested alternative is a parallel groups design comparing slopes and severity of disease at baseline. Objective(s): The objective is to demonstrate that a more practical, parallel group design is equivalent to either a randomized withdrawal or staggered start clinical trial design in demonstrating disease modification based on identifying relevant patterns of clinical disease progression. Methods: A randomized withdrawal design can be used to distinguish between a disease modifying and a symptomatic drug. A disease modifying drug will maintain a clinical benefit even when the drug is withdrawn. The staggered start design can be mathematically proven to be equivalent to the randomized withdrawal design. The connections between the clinical outcomes used in these designs and the underlying disease progression are investigated and described. A proposed “natural history staggered start” design based on parallel groups is compared to the staggered start and randomized withdrawal designs to see whether it is also capable of distinguishing between a disease modifying and a symptomatic drug. Results: A “natural history staggered start” design is described in which an analysis of slope divergence is combined with an analysis assessing difference in treatment effect depending on severity of disease at baseline. This design is shown to be mathematically equivalent to a staggered start or randomized withdrawal design. Conclusions: The staggered start and randomized withdrawal designs are impractical because of the long duration of treatment required, the bias introduced by the associated high dropout rates, and ethical concerns. A novel and practical parallel groups design allows measurement of the same underlying patterns of drug effect and differentiation of symptomatic and disease modification drug effects without the complications of these cross-over approaches. P-195
INHIBITORY EFFECT OF EGCG ON BETAAMYLOID AND LIPOPOLYSACCHARIDE INDUCED-COGNITIVE DYSFUNCTION AND SECRETASE ACTIVITY
Jin Tae Hong, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is characterized by the extracellular deposition of beta-amyloid peptide (A) in cerebral plaques. A is
derived from the -amyloid precursor protein (APP) by the enzymes,  and ␥-secretase. Recently, secretase is an attractive drug target for AD. Compounds that alter the proteolytic cleavage of APP, including those that inhibit - or ␥-secretase activity, can reduce the production of A peptides and may have therapeutic potential in the treatment of AD. Objective(s): We investigated possible effects of (-)-epigallocatechin3-gallate (EGCG) on memory dysfunction caused by lipopolysaccharide (LPS) and A1-42 through inhibition of secretase activities and A1-42 aggregation. Methods: In vitro study To determine whether EGCG affects A fibrillogenesis, we measured in vitro aggregation of A in the absence and presence of EGCG by the thioflavin T method. The inhibitory effect of EGCG on the A aggregation was also found by the observation of A aggregation under electronic microscope. In vivo study EGCG (1 and 2%; 1.5 and 3 mg/kg) was added into the drinking water and were accessed by mouse (25⬃30 g) for 3 weeks ad libitum before the induction of memory impairment mice model. The inducers (A1-42 of 0.23 ng/mouse and 1 g/mouse of LPS) and vehicle (saline) were administrated intracerebroventricularly, and the behavioral tests were started 1 day after injection. Leaning and memory capacity was determined by passive avoidance and water maze tests. Activities of - and ␥-secretase were assessed by using commercially available assay kit. Results: EGCG reversed the LPS and A1-42induced memory dysfunction in dose dependent manner (Figure 1A and B). EGCG also dose-dependently attenuated LPS and A-induced  and ␥-secretase activities in cortex and hippocampus of the mice brain. These inhibitory effects are accorded well with the inhibitory effect of EGCG on the A aggregation in vitro (ID50: 6.18 g/ml) (Figure 2). Conclusions: Our current study shows that EGCG has recovery effect against LPS and A1-42-induced memory dysfunction through inhibition of secretase activity and A aggregation in addition to anti-oxidant mechanism. This study therefore suggests that EGCG may be useful agent for prevention of development or progression of AD.
Posters: P-194
three months of memantine treatment. There were 49 patients with diagnosis of VD & 112 patients who met the diagnosis of possible AD. All patients were treated previously with one of the Ach-E inhibitors (donepezil, rivastigmine or galantamine). Average age of patients was 83.4 years old. Only one reported case of increased confusion during the second week of treatment. In both centers, no patients stopped treatment due to adverse event. An impressive cognitive improvement was reported by caregivers of 26 patients with VD. No noticeable cognitive improvement was reported by any of AD caregivers during the initial three months of treatment. Conclusions: This preliminary report demonstrates that during the three initial months of treatment, memantine slowly titrated (monthly) to a maximum dose of 20 mg/day in two divided doses was reported to show noticeable cognitive improvement by caregivers of patients with VD. No such improvement was reported with AD patients. P-194
MODIFICATION OF THE STAGGERED START AND RANDOMIZED WITHDRAWAL CLINICAL TRIAL DESIGNS: TOWARD A PRACTICAL DEMONSTRATION OF DISEASE MODIFICATION IN ALZHEIMER’S DISEASE (AD)
Suzanne Hendrix, Alexander Gutin, Kenton Zavitz, Graham Carron, Mark Laughlin, Scott Horton, Myriad Pharmaceuticals, Salt Lake City, UT, USA. Contact e-mail: [email protected] Background: Demonstration of Disease Modification in AD is a complicated topic that has been approached in many ways. Among the strategies proposed are two approaches based on measuring clinical outcomes in a cross-over type study: 1. the staggered start design and 2. the randomized withdrawal design. These two study designs are complicated by the long duration of the studies, leading to high dropout rates which introduce bias. A suggested alternative is a parallel groups design comparing slopes and severity of disease at baseline. Objective(s): The objective is to demonstrate that a more practical, parallel group design is equivalent to either a randomized withdrawal or staggered start clinical trial design in demonstrating disease modification based on identifying relevant patterns of clinical disease progression. Methods: A randomized withdrawal design can be used to distinguish between a disease modifying and a symptomatic drug. A disease modifying drug will maintain a clinical benefit even when the drug is withdrawn. The staggered start design can be mathematically proven to be equivalent to the randomized withdrawal design. The connections between the clinical outcomes used in these designs and the underlying disease progression are investigated and described. A proposed “natural history staggered start” design based on parallel groups is compared to the staggered start and randomized withdrawal designs to see whether it is also capable of distinguishing between a disease modifying and a symptomatic drug. Results: A “natural history staggered start” design is described in which an analysis of slope divergence is combined with an analysis assessing difference in treatment effect depending on severity of disease at baseline. This design is shown to be mathematically equivalent to a staggered start or randomized withdrawal design. Conclusions: The staggered start and randomized withdrawal designs are impractical because of the long duration of treatment required, the bias introduced by the associated high dropout rates, and ethical concerns. A novel and practical parallel groups design allows measurement of the same underlying patterns of drug effect and differentiation of symptomatic and disease modification drug effects without the complications of these cross-over approaches. P-195
INHIBITORY EFFECT OF EGCG ON BETAAMYLOID AND LIPOPOLYSACCHARIDE INDUCED-COGNITIVE DYSFUNCTION AND SECRETASE ACTIVITY
Jin Tae Hong, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is characterized by the extracellular deposition of beta-amyloid peptide (A) in cerebral plaques. A is
derived from the -amyloid precursor protein (APP) by the enzymes,  and ␥-secretase. Recently, secretase is an attractive drug target for AD. Compounds that alter the proteolytic cleavage of APP, including those that inhibit - or ␥-secretase activity, can reduce the production of A peptides and may have therapeutic potential in the treatment of AD. Objective(s): We investigated possible effects of (-)-epigallocatechin3-gallate (EGCG) on memory dysfunction caused by lipopolysaccharide (LPS) and A1-42 through inhibition of secretase activities and A1-42 aggregation. Methods: In vitro study To determine whether EGCG affects A fibrillogenesis, we measured in vitro aggregation of A in the absence and presence of EGCG by the thioflavin T method. The inhibitory effect of EGCG on the A aggregation was also found by the observation of A aggregation under electronic microscope. In vivo study EGCG (1 and 2%; 1.5 and 3 mg/kg) was added into the drinking water and were accessed by mouse (25⬃30 g) for 3 weeks ad libitum before the induction of memory impairment mice model. The inducers (A1-42 of 0.23 ng/mouse and 1 g/mouse of LPS) and vehicle (saline) were administrated intracerebroventricularly, and the behavioral tests were started 1 day after injection. Leaning and memory capacity was determined by passive avoidance and water maze tests. Activities of - and ␥-secretase were assessed by using commercially available assay kit. Results: EGCG reversed the LPS and A1-42induced memory dysfunction in dose dependent manner (Figure 1A and B). EGCG also dose-dependently attenuated LPS and A-induced  and ␥-secretase activities in cortex and hippocampus of the mice brain. These inhibitory effects are accorded well with the inhibitory effect of EGCG on the A aggregation in vitro (ID50: 6.18 g/ml) (Figure 2). Conclusions: Our current study shows that EGCG has recovery effect against LPS and A1-42-induced memory dysfunction through inhibition of secretase activity and A aggregation in addition to anti-oxidant mechanism. This study therefore suggests that EGCG may be useful agent for prevention of development or progression of AD.