- Email: [email protected]
S4-03-02: Physical activity and cognitive function
T180 S4-02-06
Symposia S4-03: Epidemiology and Risk Factors INTEGRATIVE APPROACH TARGETING NEUROINFLAMMATION
Linda J. Van Eldik, Northwestern University, Chicago, IL, USA. Contact e-mail: [email protected] Background: Neuroinflammation as a component of CNS disease is a complex process that involves a diversity of changes in products produced by glia. One change is the increased production of proinflammatory cytokines in response to diverse stressors. Clinical observations and preclinical animal studies identify increased cytokine production as a potential contributor to disease progression, requiring that it be tested as a potential drug discovery target for CNS disorders such as Alzheimer’s disease (AD). Because restoration of homeostasis is the goal, candidate therapies must be selective in their action (i.e., NOT pan-suppressors of glia function). Current FDA-approved drugs that modulate cytokine function are macromolecules, which have disadvantages for chronic CNS disorders. Therefore, there is a critical unmet need for small molecule, orally active, brain-penetrant compounds that can reduce excessive proinflammatory cytokine production by glia back towards basal levels with resultant improvement in neurologic outcomes. To address this need, we are using a de novo synthetic chemistry platform integrated with hierarchal biology screening to develop candidate compounds that attenuate excessive proinflammatory cytokine production and modify disease progression in animal models. Methods: We refer to the approach as use of “smart chemistry” integrated with “smart biology”. An inactive core scaffold was subjected to focused chemical diversification based on chemoinformatics and pharmacoinformatics to generative novel compounds that were prioritized based on screening their promise for metabolic stability, oral bioavailability, brain uptake, and lack of toxicity. Qualified compounds were subjected to efficacy testing in animal models. Results: Novel candidate compounds emerged within an accelerated timeline and limited budget. The unbiased, function-driven approach yielded one group of analogs referred to as the Minozac family, whereas the single molecular target approach that was focused on a protein kinase candidate yielded the Minokine family of compounds. Both Minozac and Minokine are efficacious in an AD-relevant animal model. Conclusions: The integrative approach, being increasingly adopted in academia and industry, allows for rapid and efficient discovery of novel small molecules that are candidates for therapeutic development campaigns focused on modification of disease progression. WEDNESDAY, JULY 30, 2008 SYMPOSIA S4-03 EPIDEMIOLOGY AND RISK FACTORS S4-03-01
PERSONALITY AND RISK OF COGNITIVE IMPAIRMENT IN OLD AGE
Robert S. Wilson, Rush University Medical Center, Chicago, IL, USA. Contact e-mail: [email protected] Background: Recent epidemiologic research suggests that selected dimensions of personality may affect risk of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) in old age. This presentation will consider two triats: neuroticism, which refers to the tendency to experience psychological distress, and conscientiousness, which refers to the tendency to control impulses and be goal-directed. Methods: Review of recent data from epidemiologic and clinical-pathologic studies. Results: High neuroticism/distress predicts loss of cognition in the form of increased incidence of MCI and AD and more rapid cognitive decline. Level of distress does not appear to increase during the prodromal phase of AD, however, or to be correlated with the neuropathologic lesions most commonly seen in persons with AD and other forms of dementia (ie, amyloid plaques, neurofibrillary tangles, Lewy bodies, cerebral infarctions). The applicability of animal models of chronic stress to these observations will be discussed. In addition, data will be presented showing lower level of conscientiousness to be associated with increased loss of cognition, even
after controlling for neuroticism, despite a lack of association with common age-related neuropathologic lesions. Conclusions: Personality contributes to risk of MCI and dementia in old age but does not appear to be related to the neuropathologic lesions traditionally associated with these conditions. Understanding the neurobiologic mechanisms through which personality affects cognition in late life may suggest novel strategies for delaying the onset of dementia in old age. S4-03-02
PHYSICAL ACTIVITY AND COGNITIVE FUNCTION
Laura Fratiglioni, Karolinska Institute, Stockholm, Sweden. Contact e-mail: [email protected] Background: A substantial number of studies have explored the association between physical activities and risk of dementia or Alzheimer’s disease (AD). Methods: The majority of the studies are longitudinal with a follow-up time ranging from 2 to 16 years. Physical activity is studied as a part of leisure activities, usually grouped according to the nature of activities such as physical, mental, and social. Results: Among leisure activities, physical activity is the most studied. Of the 14 studies (only two of them are case-control studies), 11 reported a relation between participation in physical activities and lower risk of dementia or AD. Another study found that physical activity was related to decreased risk of dementia but the study power was too small to detect a statistically significant association. Two studies have reported a decreased risk of AD in subjects with high physical activity during midlife. Conclusions: Physical exercise may reduce the risk of brain damage from atherosclerosis, or increase the cognitive reserve. However, the relevance of physical activity itself remains in debate, as most physical activities include also social and mental components. Complex leisure activities with all three components seem to have the most beneficial effect. Finally, we have few data to help disentangle whether early-life conditions and adult-life work related physical activity can decrease the lifetime risk of disease or merely postpone the onset of dementia. S4-03-03
ADIPOSITY AND DEMENTIA
Deborah Gustafson, Go¨teborg University, Go¨teborg, Sweden. Contact e-mail: [email protected] Background: Adiposity, commonly measured as body weight or body mass index (BMI), may influence or be influenced by brain structures and functions involved in dementia processes. Adipose tissue changes in degree and intensity over the lifespan, and has been shown to influence brain development in relationship to early and late measures of cognitive function and disorders of cognition such as dementia. Methods: Epidemiology, complemented by experimental studies, provide the basis for a link between adiposity and dementia. Results: A lower BMI is associated with prevalent dementia, potentially due to underlying brain pathologies and correspondingly greater rates of BMI or weight decline observed during the years immediately preceding clinical dementia onset. However, high BMI during midlife or at least approximately 5-10 years preceding clinical dementia onset may increase risk. Conclusions: The interplay of adiposity and the brain occurring over the course of the lifespan will be discussed in relationship to late life changes in cognition and dementia. Characterizing the life course of adiposity among those who do and do not become demented enhances understanding of biological underpinnings relevant for understanding the etiologies of both dementia and obesity and their coexistence. S4-03-04
PROGNOSTIC MODELS FOR COGNITIVE IMPAIRMENT AND MIDLIFE RISK
Miia Kivipelto, Karolinska Institutet, Stockholm, Sweden. Contact e-mail: [email protected] Background: Identifying individuals with an elevated dementia risk is important for targeting interventions. This could be done based on cogni-
Symposia S4-03: Epidemiology and Risk Factors INTEGRATIVE APPROACH TARGETING NEUROINFLAMMATION
Linda J. Van Eldik, Northwestern University, Chicago, IL, USA. Contact e-mail: [email protected] Background: Neuroinflammation as a component of CNS disease is a complex process that involves a diversity of changes in products produced by glia. One change is the increased production of proinflammatory cytokines in response to diverse stressors. Clinical observations and preclinical animal studies identify increased cytokine production as a potential contributor to disease progression, requiring that it be tested as a potential drug discovery target for CNS disorders such as Alzheimer’s disease (AD). Because restoration of homeostasis is the goal, candidate therapies must be selective in their action (i.e., NOT pan-suppressors of glia function). Current FDA-approved drugs that modulate cytokine function are macromolecules, which have disadvantages for chronic CNS disorders. Therefore, there is a critical unmet need for small molecule, orally active, brain-penetrant compounds that can reduce excessive proinflammatory cytokine production by glia back towards basal levels with resultant improvement in neurologic outcomes. To address this need, we are using a de novo synthetic chemistry platform integrated with hierarchal biology screening to develop candidate compounds that attenuate excessive proinflammatory cytokine production and modify disease progression in animal models. Methods: We refer to the approach as use of “smart chemistry” integrated with “smart biology”. An inactive core scaffold was subjected to focused chemical diversification based on chemoinformatics and pharmacoinformatics to generative novel compounds that were prioritized based on screening their promise for metabolic stability, oral bioavailability, brain uptake, and lack of toxicity. Qualified compounds were subjected to efficacy testing in animal models. Results: Novel candidate compounds emerged within an accelerated timeline and limited budget. The unbiased, function-driven approach yielded one group of analogs referred to as the Minozac family, whereas the single molecular target approach that was focused on a protein kinase candidate yielded the Minokine family of compounds. Both Minozac and Minokine are efficacious in an AD-relevant animal model. Conclusions: The integrative approach, being increasingly adopted in academia and industry, allows for rapid and efficient discovery of novel small molecules that are candidates for therapeutic development campaigns focused on modification of disease progression. WEDNESDAY, JULY 30, 2008 SYMPOSIA S4-03 EPIDEMIOLOGY AND RISK FACTORS S4-03-01
PERSONALITY AND RISK OF COGNITIVE IMPAIRMENT IN OLD AGE
Robert S. Wilson, Rush University Medical Center, Chicago, IL, USA. Contact e-mail: [email protected] Background: Recent epidemiologic research suggests that selected dimensions of personality may affect risk of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) in old age. This presentation will consider two triats: neuroticism, which refers to the tendency to experience psychological distress, and conscientiousness, which refers to the tendency to control impulses and be goal-directed. Methods: Review of recent data from epidemiologic and clinical-pathologic studies. Results: High neuroticism/distress predicts loss of cognition in the form of increased incidence of MCI and AD and more rapid cognitive decline. Level of distress does not appear to increase during the prodromal phase of AD, however, or to be correlated with the neuropathologic lesions most commonly seen in persons with AD and other forms of dementia (ie, amyloid plaques, neurofibrillary tangles, Lewy bodies, cerebral infarctions). The applicability of animal models of chronic stress to these observations will be discussed. In addition, data will be presented showing lower level of conscientiousness to be associated with increased loss of cognition, even
after controlling for neuroticism, despite a lack of association with common age-related neuropathologic lesions. Conclusions: Personality contributes to risk of MCI and dementia in old age but does not appear to be related to the neuropathologic lesions traditionally associated with these conditions. Understanding the neurobiologic mechanisms through which personality affects cognition in late life may suggest novel strategies for delaying the onset of dementia in old age. S4-03-02
PHYSICAL ACTIVITY AND COGNITIVE FUNCTION
Laura Fratiglioni, Karolinska Institute, Stockholm, Sweden. Contact e-mail: [email protected] Background: A substantial number of studies have explored the association between physical activities and risk of dementia or Alzheimer’s disease (AD). Methods: The majority of the studies are longitudinal with a follow-up time ranging from 2 to 16 years. Physical activity is studied as a part of leisure activities, usually grouped according to the nature of activities such as physical, mental, and social. Results: Among leisure activities, physical activity is the most studied. Of the 14 studies (only two of them are case-control studies), 11 reported a relation between participation in physical activities and lower risk of dementia or AD. Another study found that physical activity was related to decreased risk of dementia but the study power was too small to detect a statistically significant association. Two studies have reported a decreased risk of AD in subjects with high physical activity during midlife. Conclusions: Physical exercise may reduce the risk of brain damage from atherosclerosis, or increase the cognitive reserve. However, the relevance of physical activity itself remains in debate, as most physical activities include also social and mental components. Complex leisure activities with all three components seem to have the most beneficial effect. Finally, we have few data to help disentangle whether early-life conditions and adult-life work related physical activity can decrease the lifetime risk of disease or merely postpone the onset of dementia. S4-03-03
ADIPOSITY AND DEMENTIA
Deborah Gustafson, Go¨teborg University, Go¨teborg, Sweden. Contact e-mail: [email protected] Background: Adiposity, commonly measured as body weight or body mass index (BMI), may influence or be influenced by brain structures and functions involved in dementia processes. Adipose tissue changes in degree and intensity over the lifespan, and has been shown to influence brain development in relationship to early and late measures of cognitive function and disorders of cognition such as dementia. Methods: Epidemiology, complemented by experimental studies, provide the basis for a link between adiposity and dementia. Results: A lower BMI is associated with prevalent dementia, potentially due to underlying brain pathologies and correspondingly greater rates of BMI or weight decline observed during the years immediately preceding clinical dementia onset. However, high BMI during midlife or at least approximately 5-10 years preceding clinical dementia onset may increase risk. Conclusions: The interplay of adiposity and the brain occurring over the course of the lifespan will be discussed in relationship to late life changes in cognition and dementia. Characterizing the life course of adiposity among those who do and do not become demented enhances understanding of biological underpinnings relevant for understanding the etiologies of both dementia and obesity and their coexistence. S4-03-04
PROGNOSTIC MODELS FOR COGNITIVE IMPAIRMENT AND MIDLIFE RISK
Miia Kivipelto, Karolinska Institutet, Stockholm, Sweden. Contact e-mail: [email protected] Background: Identifying individuals with an elevated dementia risk is important for targeting interventions. This could be done based on cogni-