- Email: [email protected]
S3-01-01
S198
Symposium S3-01-01: Lifestyles and Technology
ious membrane-bound and soluble isoforms - have roles in systemic, neurovascular, and brain inflammation through the activity of the autonomic nervous system and modulation of brain parenchymal ACh. They may relieve ACh blockade of proinflammatory responses in regions distal from synaptic sites. Non-catalytic functions of cholinesterases (ChEs) include BuChE antagonism of AChE-S, and likely other pathological chaperone-mediated A fibrilization in a concentration-dependent manner. BuChE and AChE are also implicated in the metabolic syndrome, acute phase and neuro-immune responses, neuroepithelial and glial cell proliferation and activation, glutamate and oxidative homeostasis, and may have roles in preserving the integrity of myelin, perhaps via modulation of oligodendrocyte function. Objective(s): Elucidate the influence of ChEs and their inhibitors (ChE-Is) in neurodegeneration. Methods: Determine the effects of common polymorphisms of ChEs on risk, type and progression of dementia, and the effects of different ChE-Is that inhibit AChE and/or BuChE, and that markedly up-regulate AChE-R and/or AChE-S splice variants. Results: In Mild Cognitive Impairment (MCI) subjects, the BuChE K-variant may interact with risk factors for A deposition such as APOE e4 to accelerate A pathology. BuChE wt/wt may interact with risk factors for white matter demyelination such as APOE e4 and hyperhomocysteinemia to accelerate age-related loss of cognitive processing speed. In retrospective analyses of MCI trials, slowed progression of MCI to AD in APOE e4 carriers with less hippocampal volume loss has been seen for one ChE-I, and slowed progression of MCI to AD in wild-type BuChE (wt/wt) with less ventricular expansion was seen with another. Differential response to two ChE-Is by BuChE genotype was evidenced in a comparative 2-year study in younger (⬍75 years) moderate AD patients. Conclusions: Polymorphisms, splice variant expression, and quantity of AChE and BuChE may effect risk of developing and progression of neurodegenerative disorders. More targeted interventions to modulate function and expression of ChEs may achieve improved symptomatic and disease modifying results that contrast with the generally modest overall treatment effects of currenty applied ChE-I therapy. TUESDAY, JUNE 12, 2007 SYMPOSIUM S3-01 LIFESTYLES AND TECHNOLOGY S3-01-01
FROM DIET AND LIFSTYLE FACTORS TO ALZHEIMER’S MECHANISM AND TREATMENT
Huntington Potter1,2, 1Johnnie B. Byrd Sr. Alzheimer’s Center and Research Institute, Tampa, FL, USA; 2University of South Florida College of Medicine, Tampa, FL, USA. Contact e-mail: [email protected] Background: Alzheimer’s disease is probably close to 70% heritable. However, the remaining 30% and up to ten years difference in age of onset in identical twins indicate that environment, particularly diet and lifestyle, is as important as genetics in increasing or decreasing Alzheimer’s risk and could lead to new insights into Alzheimer’s mechanisms and to new, effective treatment and prevention. The striking success of this approach in the other major diseases of aging— cancer and cardiovascular disease— suggests that it will also work for AD. Indeed all three diseases share overlapping mechanisms. Objectives: Epidemiological studies in humans suggest that diet and lifestyle affect an individual’s risk for AD, but unraveling cause and effect in what could be a near-lifelong disease is hard. Experiments in transgenic animals have been designed to test whether diet and environment/lifestyle play an important causal role in AD and may provide insights into mechanism. Methods: We and others have used epidemiology or transgenic mouse models of AD to determine what diet and lifestyle factors are associated with AD risk in humans and which affect amyloid formation and/or cognitive decline in mice. Intervention trials in humans are being designed to test the efficacy of some of these factors. Results: Cognitive stimulation, cholesterol reduction, exercise, folate, antioxidants, omega three fatty acids, green tea, and most recently
caffeine have been shown to correlate with or actually cause improved cognition in either humans or animal models or both. That some of these treatments can reverse cognitive decline an Alzheimer transgenic mice is particularly encouraging. Biochemical and microarray analysis of the “protected” brains of transgenic mice and of cells in culture identify mechanisms by which diet and lifestyle influence the Alzheimer Pathogenic Pathway. Conclusions: Diet and lifestyle factors strongly influence amyloid formation and cognitive decline in animals and likely in humans, suggesting that a public health/education approach to combating AD should complement drug development. However, experience has shown us that lifestyle changes, no matter how effective, are hard to adopt. Therefore, diet and lifestyle experiments in AD should also be used to identify new therapeutic targets and develop new biochemical interventions. S3-01-02
LIFESTYLE FACTORS AND ALZHEIMER’S DISEASE: EXPERIMENTAL APPROACHES AND CLINICAL IMPLICATIONS
Giulio M. Pasinetti, Mount Sinai School of Medicine, New York, NY, USA. Contact e-mail: [email protected] Background and Objective: Alzheimer’s disease (AD) is a rapidly growing public health concern with potentially devastating effects. Presently, there are no known cures or effective preventive strategies for this disease. While genetic factors are relevant in early-onset cases, they appear to play less of a role in late-onset-sporadic cases, the most common form of AD. Due to the fact that the disease typically strikes later in life, delaying symptoms could be of great benefit to many people. It is now widely accepted that if the onset of the disease is delayed by even five years, the risk of developing AD could be halved. Methods: Both clinical and epidemiological evidence suggest that modification of lifestyle factors such as nutrition may prove crucial to managing AD. Recent experimental evidence using mouse models of AD suggest that brain cells are remarkably responsive to lifestyle modifications, including diet and physical activity. Results: In our lab we found that high caloric intake based on saturated fat promotes AD-type -amyloid (A) related cognitive deterioration (Ho et al., 2005). Conversely, we also found that reduction of total caloric intake consisting primarily of carbohydrates is able to significantly prevent AD-type cognitive deterioration in Tg2576 mice (Wang et al., 2006) through mechanisms that involve increased expression of genes that promote longevity in the brain (e.g. SIRT1) (Qin et. al., 2006). In addition, we found that moderate consumption of red wine in a form such as Cabernet Sauvignon may also significantly attenuate AD-type cognitive deterioration in a Tg2576 mouse model of AD through mechanisms involving the prevention of A oligomerization into high molecular weight soluble extracellular species in the brain. (Wang et al., 2007). Conclusion: Clarifying the mechanisms through which certain dietary lifestyles may influence AD neuropathology will help in the development of preventative “lifestyle therapeutic strategies” for AD that may translate toward preventing other neurodegenerative disorders. Supported by Dana Foundation for Brain Research Initiatives, The Robert Atkins Foundation and AG02219 to GMP. S3-01-03
TECHNOLOGY IN MANAGING DEMENTIA
Jeffrey A. Kaye, Oregon Health & Science University, Portland, OR, USA. Contact e-mail: [email protected] Background: Current approaches to assessing and managing Alzheimer’s disease and the dementias have a number of limitations. Many of these limitations may be overcome by application of existing and emerging technologies especially deployed in the home or community environment. Objective: This symposium presentation will focus on reviewing new approaches employing technologies to help assess and manage people with Alzheimer’s disease with an emphasis on two aspects: early detection for future prevention and technologies to help maintain community independence. Results and Conclusion: At the end of this presentation attendees
Symposium S3-01-01: Lifestyles and Technology
ious membrane-bound and soluble isoforms - have roles in systemic, neurovascular, and brain inflammation through the activity of the autonomic nervous system and modulation of brain parenchymal ACh. They may relieve ACh blockade of proinflammatory responses in regions distal from synaptic sites. Non-catalytic functions of cholinesterases (ChEs) include BuChE antagonism of AChE-S, and likely other pathological chaperone-mediated A fibrilization in a concentration-dependent manner. BuChE and AChE are also implicated in the metabolic syndrome, acute phase and neuro-immune responses, neuroepithelial and glial cell proliferation and activation, glutamate and oxidative homeostasis, and may have roles in preserving the integrity of myelin, perhaps via modulation of oligodendrocyte function. Objective(s): Elucidate the influence of ChEs and their inhibitors (ChE-Is) in neurodegeneration. Methods: Determine the effects of common polymorphisms of ChEs on risk, type and progression of dementia, and the effects of different ChE-Is that inhibit AChE and/or BuChE, and that markedly up-regulate AChE-R and/or AChE-S splice variants. Results: In Mild Cognitive Impairment (MCI) subjects, the BuChE K-variant may interact with risk factors for A deposition such as APOE e4 to accelerate A pathology. BuChE wt/wt may interact with risk factors for white matter demyelination such as APOE e4 and hyperhomocysteinemia to accelerate age-related loss of cognitive processing speed. In retrospective analyses of MCI trials, slowed progression of MCI to AD in APOE e4 carriers with less hippocampal volume loss has been seen for one ChE-I, and slowed progression of MCI to AD in wild-type BuChE (wt/wt) with less ventricular expansion was seen with another. Differential response to two ChE-Is by BuChE genotype was evidenced in a comparative 2-year study in younger (⬍75 years) moderate AD patients. Conclusions: Polymorphisms, splice variant expression, and quantity of AChE and BuChE may effect risk of developing and progression of neurodegenerative disorders. More targeted interventions to modulate function and expression of ChEs may achieve improved symptomatic and disease modifying results that contrast with the generally modest overall treatment effects of currenty applied ChE-I therapy. TUESDAY, JUNE 12, 2007 SYMPOSIUM S3-01 LIFESTYLES AND TECHNOLOGY S3-01-01
FROM DIET AND LIFSTYLE FACTORS TO ALZHEIMER’S MECHANISM AND TREATMENT
Huntington Potter1,2, 1Johnnie B. Byrd Sr. Alzheimer’s Center and Research Institute, Tampa, FL, USA; 2University of South Florida College of Medicine, Tampa, FL, USA. Contact e-mail: [email protected] Background: Alzheimer’s disease is probably close to 70% heritable. However, the remaining 30% and up to ten years difference in age of onset in identical twins indicate that environment, particularly diet and lifestyle, is as important as genetics in increasing or decreasing Alzheimer’s risk and could lead to new insights into Alzheimer’s mechanisms and to new, effective treatment and prevention. The striking success of this approach in the other major diseases of aging— cancer and cardiovascular disease— suggests that it will also work for AD. Indeed all three diseases share overlapping mechanisms. Objectives: Epidemiological studies in humans suggest that diet and lifestyle affect an individual’s risk for AD, but unraveling cause and effect in what could be a near-lifelong disease is hard. Experiments in transgenic animals have been designed to test whether diet and environment/lifestyle play an important causal role in AD and may provide insights into mechanism. Methods: We and others have used epidemiology or transgenic mouse models of AD to determine what diet and lifestyle factors are associated with AD risk in humans and which affect amyloid formation and/or cognitive decline in mice. Intervention trials in humans are being designed to test the efficacy of some of these factors. Results: Cognitive stimulation, cholesterol reduction, exercise, folate, antioxidants, omega three fatty acids, green tea, and most recently
caffeine have been shown to correlate with or actually cause improved cognition in either humans or animal models or both. That some of these treatments can reverse cognitive decline an Alzheimer transgenic mice is particularly encouraging. Biochemical and microarray analysis of the “protected” brains of transgenic mice and of cells in culture identify mechanisms by which diet and lifestyle influence the Alzheimer Pathogenic Pathway. Conclusions: Diet and lifestyle factors strongly influence amyloid formation and cognitive decline in animals and likely in humans, suggesting that a public health/education approach to combating AD should complement drug development. However, experience has shown us that lifestyle changes, no matter how effective, are hard to adopt. Therefore, diet and lifestyle experiments in AD should also be used to identify new therapeutic targets and develop new biochemical interventions. S3-01-02
LIFESTYLE FACTORS AND ALZHEIMER’S DISEASE: EXPERIMENTAL APPROACHES AND CLINICAL IMPLICATIONS
Giulio M. Pasinetti, Mount Sinai School of Medicine, New York, NY, USA. Contact e-mail: [email protected] Background and Objective: Alzheimer’s disease (AD) is a rapidly growing public health concern with potentially devastating effects. Presently, there are no known cures or effective preventive strategies for this disease. While genetic factors are relevant in early-onset cases, they appear to play less of a role in late-onset-sporadic cases, the most common form of AD. Due to the fact that the disease typically strikes later in life, delaying symptoms could be of great benefit to many people. It is now widely accepted that if the onset of the disease is delayed by even five years, the risk of developing AD could be halved. Methods: Both clinical and epidemiological evidence suggest that modification of lifestyle factors such as nutrition may prove crucial to managing AD. Recent experimental evidence using mouse models of AD suggest that brain cells are remarkably responsive to lifestyle modifications, including diet and physical activity. Results: In our lab we found that high caloric intake based on saturated fat promotes AD-type -amyloid (A) related cognitive deterioration (Ho et al., 2005). Conversely, we also found that reduction of total caloric intake consisting primarily of carbohydrates is able to significantly prevent AD-type cognitive deterioration in Tg2576 mice (Wang et al., 2006) through mechanisms that involve increased expression of genes that promote longevity in the brain (e.g. SIRT1) (Qin et. al., 2006). In addition, we found that moderate consumption of red wine in a form such as Cabernet Sauvignon may also significantly attenuate AD-type cognitive deterioration in a Tg2576 mouse model of AD through mechanisms involving the prevention of A oligomerization into high molecular weight soluble extracellular species in the brain. (Wang et al., 2007). Conclusion: Clarifying the mechanisms through which certain dietary lifestyles may influence AD neuropathology will help in the development of preventative “lifestyle therapeutic strategies” for AD that may translate toward preventing other neurodegenerative disorders. Supported by Dana Foundation for Brain Research Initiatives, The Robert Atkins Foundation and AG02219 to GMP. S3-01-03
TECHNOLOGY IN MANAGING DEMENTIA
Jeffrey A. Kaye, Oregon Health & Science University, Portland, OR, USA. Contact e-mail: [email protected] Background: Current approaches to assessing and managing Alzheimer’s disease and the dementias have a number of limitations. Many of these limitations may be overcome by application of existing and emerging technologies especially deployed in the home or community environment. Objective: This symposium presentation will focus on reviewing new approaches employing technologies to help assess and manage people with Alzheimer’s disease with an emphasis on two aspects: early detection for future prevention and technologies to help maintain community independence. Results and Conclusion: At the end of this presentation attendees