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Funds Awarded for 2009 Funding Cycle

Published: June 20th, 2009

Category: News

With joint support from the McKnight Brain Research Foundation and the National Institute on Aging, this initiative funds cognitive aging research through a program of peer reviewed grants in the following areas:

  1. Interventions to remediate age-related cognitive decline, and
  2. Neural and behavioral profiles of cognitive function in aging.

In 2009, grants will be awarded to six applicants in the first category, and 11 in the second category, for a total of 17 funded grant awards.

Grants Funded Through the Research Partnership in Cognitive Aging Fall 2009

With joint support from the McKnight Brain Research Foundation and the National Institute on Aging, this initiative funds cognitive aging research through a program of peer reviewed grants in the following areas:

  1. Interventions to remediate age-related cognitive decline, and
  2. Neural and behavioral profiles of cognitive function in aging.

In 2009, grants will be awarded to six applicants in the first category, and 11 in the second category, for a total of 17 funded grant awards.

Grant Category:  Interventions to Remediate Age-Related Cognitive Decline

Project Title:  Combining Exercise and Cognitive Training to Improve Everyday Function
Principal Investigator:  Ellen F. Binder, Mark A. McDaniel (Washington University)

Description (provided by applicant):  The possibility that lifestyle activities may benefit cognitive health in late life is of major importance for our increasingly aging population. Although many studies of physical and cognitive training activities in older adults have attempted to demonstrate such benefits, transfer and maintenance of these benefits have been minimal. In this proposal, we introduce and evaluate two novel, theoretically motivated advances to optimize the effects of training, including transfer to daily, real world activities. Recognizing that real world activities, unlike laboratory tasks, rarely rely upon a single cognitive process, one advance is the incorporation of training that interleaves practice involving three cognitive control processes (task-coordination, prospective and retrospective memory). A second advance rests on the observation that few studies to date have carefully assessed the possibility that aerobic exercise and cognitive training together may be additive or synergistic in yielding cognitive benefits. Accordingly, an important objective is to evaluate the benefits of combining aerobic exercise with cognitive training for optimizing training and transfer of cognitive function, particularly for daily activities. We propose to conduct a randomized, controlled prospective study with residents of a Naturally Occurring Retirement Community (NORC). Ninety-six men and women, age 55-75 years who are in stable health and without contraindications to exercise or evidence of dementia or cognitive impairment, will be enrolled. Individuals will be randomly assigned to one of four groups for six months: Exercise, Cognitive training, Combined exercise and cognitive training, and Control. This design will allow us to evaluate the unique benefits of each intervention for improving performance from baseline to post-training on measures of cognitive control, including training specific, laboratory and everyday transfer tasks; everyday subjective memory performance; self-reported activities of daily living (ADLs) and quality of life; and objective physical performance. We also plan to compare 6-month maintenance of transfer, ADL, and subjective memory performance gains for individuals in the Cognitive, Exercise, and Combined groups following the 6-month intervention period (12 months after baseline).

Public Health Relevance:  The possibility that lifestyle activities may benefit cognitive health in late life is of major importance for our increasingly aging population. Although many studies of physical and cognitive training in older adults have attempted to demonstrate such benefits, transfer and maintenance of these benefits have been minimal. If cognitive training combined with aerobic exercise training is proven to have effects that transfer to everyday activities and are sustained, the results of this study could eventually be directly applied to a variety of community settings to reduce or delay age-related cognitive decline.

Project Title:  Dose-Response Study of Exercise in Older Adults
Principal Investigator:  Jeffrey Murray Burns (University of Kansas Medical Center)

Description (provided by applicant):  The unprecedented growth of the elderly population and subsequent increase in age-related disorders requires effective strategies for promoting healthy brain aging. Accumulating evidence suggests that aerobic exercise may protect against cognitive decline and dementia. Although there is consensus that current recommendations (~ 30 minutes of exercise most days of the week) provides general health benefits to older adults, there is a need for rigorous clinical trial data to guide exercise prescription specific to the older adult population. For instance, unlike with prescription drugs, the minimum and maximum effective exercise doses are not well defined for general health effects. Moreover, the dose-response relationship between exercise and cognition has not been examined in randomized trials. Thus, there remains a need for rigorous, well- designed clinical trials to define the long-term benefits of exercise in promoting healthy brain aging and preventing cognitive and functional decline. We will examine the benefits of three doses of aerobic exercise (representing 50%, 100%, and 150% of the recommended dose) on aerobic fitness, physical function, and cognition. Sedentary, older adults with cognitive complaints aged 75 and over (n = 100) will be randomized into a non-exercise control group or one of three exercise dose groups for 26 weeks. Exercise dose will be manipulated by duration of exercise (as opposed to intensity). Supervised exercise will occur within the network of Greater Kansas City YMCAs, building on our group’s history of NIH-funded collaborations with the community. Our objective is to establish feasibility of a long-term exercise intervention to remediate age-related cognitive decline. We hypothesize that increasing exercise doses will provide greater cognitive, aerobic fitness and physical function benefits. Our primary goal is to determine the optimal exercise dose for maximizing exercise-related gains in 1) cognition, 2) aerobic fitness and 3) adherence in this vulnerable population for planning a more definitive study. Aim 1 will examine the dose-response of aerobic exercise on cognitive function and provide expected cognitive effect sizes for each dose to inform the design of a large, definitive trial. Aims 2 and 3 will assess physiologic adaptations including aerobic fitness and measures of physical function. The current project is a natural extension of a programmatic line of investigation developed by the KU Alzheimer and Memory Program. The pilot study will generate important data regarding the magnitude of exercise-related effect sizes and dose-response trends for cognitive, aerobic fitness and physical function changes. This data will inform the choice of the most effective and feasible exercise dose in older adults for a more definitive trial.

Public Health Relevance:  The unprecedented growth of the elderly population and subsequent increase in age-related disorders requires effective strategies for promoting healthy brain aging. Accumulating evidence suggests that aerobic exercise may protect against cognitive decline and dementia, yet there remains a need for rigorous, well-designed clinical trials to define the long-term benefits of exercise for promoting healthy brain aging. A primary goal of the current study is to define an optimal dose of exercise in older adults 75 years and older. The current study will provide important public health information regarding fundamental questions about exercise in delaying age-related cognitive and functional decline.

Project Title:  A Brain-Based-Approach to Enhancing Executive Control Functions in Healthy Aging
Principal Investigator:  Mark D’Esposito (University of California, Berkeley)

Description (provided by applicant): Poor goal direction, or loss of ability to concentrate and ‘stay on task’ in a distracting environment, is a common complaint in advanced age. Such subjective reports are consistent with an emerging consensus in the cognitive aging research literature suggesting that the executive control processes necessary for maintaining goal direction are particularly susceptible to decline with advancing age. Unfortunately, there have been few efficacious treatments for executive control deficits reported in the literature despite their significant impact on daily life functions and the maintenance of functional independence into later life. Here we argue that the efficacy of such treatments is hindered by our poor understanding of the neural mechanisms subserving executive control processing in the brain. The first aim of the proposal is to develop robust biomarkers of executive control processes to complement neurocognitive and functional outcome measures of treatment efficacy. These biomarkers will serve to identify neural processes that are most responsive to treatment and predictive of neurocognitive and functional gain, thus informing the design of more targeted and efficacious brain-based treatments. A second aim of the proposal is to test this brain-based approach explicitly using an integrated strategy-based and targeted process training protocol to enhance executive control processing in healthy aging. Through this combined treatment approach we intend to leverage gains realized from targeted training by reinforcing and contextualizing them in a therapist-guided, strategy-based goal management program. This program is standardized for the process of interest (executive control), but guides strategy application to individually-salient, self-generated goals and personally-relevant real-life situations. Outcomes will be assessed at the neural, neurocognitive and functional outcome levels. Such a scaffolded approach, building from the level of brain to behavior to lasting functional change, ensures that cognitive remediation efforts benefit older adults directly, and society more generally, by delaying the need for home care, nursing home or hospital services while preserving the functional independence and dignity of an aging population.

Public Health Relevance:  Cognitive decline associated with normal aging can have a broad impact on an individual’s productivity, physical health and general sense of well-being. Especially with the expected increase in the aging population in the next few decades, age-related cognitive decline is a major public health issue. The aim of this project is to investigate the neural mechanisms underlying age-related cognitive decline and to develop interventions and biomarkers to evaluate the efficacy of these interventions.

Project Title: Tai Chi and Guided Autobiography for Remediation of Age-Related Cognitive Decline
Principal Investigator:  Victor W. Henderson (Stanford University)

Description (provided by applicant): A widely-held distinction between ‘usual aging’ and ‘successful aging’ implies that a variety of extrinsic factors influence how we age, including how cognitive abilities change with age. There is convincing evidence that physical activity, mental activity, and social engagement have great potential to ameliorate age-related cognitive decline, and that these factors contribute independently and additively to reducing the impact of usual cognitive aging. Using a parallel groups design, we will conduct a pilot randomized controlled trial among healthy older adults aged 70 and above, to assess behavioral interventions predicted to remediate age-related cognitive decline. Prior behavioral interventions in older adults that improved cognitive skills usually failed to show transfer to untrained activities, perhaps reflecting the narrowness of such interventions, a lack of complexity, or both. For these reasons, we have selected experimental interventions that engage multiple pathways linked to cognitive aging. These were also chosen to be easy to implement, appeal to older adults, have intrinsic value, and have the potential for long-term sustainability. The selected interventions are (1) Tai Chi, a moderate-intensity low-impact Eastern exercise program that combines physical activity and intense mental concentration, (2) Guided Autobiography, a complex mental activity performed in a setting that promotes a high level of social engagement, (3) a combined intervention that thus incorporates physical activity, two distinct forms of mental activity, and social engagement, and (4) a general health education control group. We hypothesize that structured programs in Tai Chi, Guided Autobiography, and Tai Chi and Guided Autobiography combined are feasible to implement and maintain in an older population, and – in comparison to a health education control program – will improve neuropsychological measures of executive function and episodic memory. Our research goals are to establish the feasibility of the two experimental interventions alone and combined in healthy older adults, assess which of the experimental interventions is most likely to be successful in a full- scale randomized controlled trial, and to estimate immediate (3 month) and short-term (12 month) parameters needed to guide the design of such a larger trial.

Public Health Relevance:  Thirty-seven million Americans are aged 65 and older, and their numbers will nearly double by 2030. Cognitive aging is an important, widespread concern in this age group. We will conduct a pilot randomized controlled trail among healthy older adults to assess whether innovative programs in Tai Chi exercise, guided autobiographical writing, or a combination of both are feasible interventions for remediation of age- related cognitive decline.

Project Title:  Omega-3 and Blueberry Supplementation in Age-Related Cognitive Decline
Principal Investigator:  Robert Krikorian (University of Cincinnati)

Description (provided by applicant):  Older adults with age-related cognitive decline experience at least modest inefficiency in everyday functioning and have increased risk of developing dementia, in particular Alzheimer’s disease (AD). With the expansion of the elderly population there is concern that the prevalence of AD may increase substantially beyond previous projections that ranged from 11 to 16 million affected individuals by the year 2050. Current pharmaceutical therapies provide only partial and transient symptomatic improvement and produce adverse responses in some individuals. At this time, early intervention represents the optimal approach for slowing or preventing further cognitive decline. Omega-3 fatty acid deficiency represents a plausible pathoetiological mechanism for neuropathology associated with cognitive aging and dementia, and omega-3 fatty acid treatment has positive effects on a number of putative mechanisms of age-related decline. In addition, basic animal research during the last decade and very recent human preliminary data indicate that blueberry supplementation produces substantial neurobiological benefit and has the potential to ameliorate age-related cognitive decline. Further, there are indications that the combined effects of these nutraceutical approaches may offer more potent additive as well as complementary benefits aimed specifically at neurodegenerative mechanisms. Our long-term objective is to develop a nutraceutical intervention strategy that can be effective when applied with older adults experiencing age-related decline. In this investigation, we will evaluate the efficacy of combined omega-3 fatty acid and blueberry supplementation in improving memory function in elderly individuals with early memory changes. We propose a 6-month randomized, double-blind, placebo-controlled trial involving daily supplementation with these nutraceutical products and longitudinal assessment up to one year after baseline. Our primary outcomes will be assessment of change in aspects of memory function and daily functioning in response to the intervention. We plan to use the findings of this study to support future, more comprehensive research examining mechanisms of action, dosage, and duration of effects in older adults. This proposal was generated in response to the NIA request for proposals to investigate novel, combined non-pharmaceutical interventions designed to improve cognitive function in older adults.

Public Health Relevance:  Evidence-based treatments are urgently needed for elderly individuals with or at risk for age-related cognitive decline. As an initial step to establish early intervention and prevention strategies, this application proposes a double-bind placebo-controlled treatment trial to evaluate the neurocognitive benefits of combined omega-3 fatty acid and blueberries in elderly subjects at risk for age-related cognitive decline.

Project Title:  Combined Exercise and Cognitive Training Intervention in Normal Aging
Principal Investigator:  Yaakov Stern (Columbia University Health Sciences)

Description (provided by applicant): This is a pilot study to test a candidate intervention for age-related cognitive decline in healthy older individuals. Epidemiologic evidence suggests that cognitive training and physical exercise have positive effects on cognition and healthy elderly individuals. Evidence from animal studies indicate that enriched environment and aerobic exercise can induce changes that increase neural plasticity. We propose to test a combination of a cognitive intervention and aerobic exercise. There has been some success with previous cognitive interventions in elderly individuals, but effect sizes have been relatively small. We hypothesize that the effects of aerobic exercise on the brain can potentiate the benefit of our proposed cognitive intervention, resulting in larger effect sizes and previously seen in intervention studies. A common problem in cognitive intervention studies to date is the failure of the training to generalize to other tasks. Our proposed cognitive intervention uses emphasis change training in the context of the space fortress game, a complex and demanding video game that was specifically developed for research purposes. The emphasis change training approach has been shown to enhance attentional control and executive functions in younger individuals. Because normal aging is associated with declines in control processes and executive function, we hypothesize that enhancing these functions will result in generalized improvement across many tasks and day-to-day activities. Also, previous studies in both young and old individuals have found that the emphasis change training approach is associated with transfer of training to other tasks. Ninety elders will be randomized into three study arms: control, space fortress training alone, and space fortress training within the exercise. The formal intervention period, conducted in the laboratory and fitness center, will be three months, with pre- and post-testing. In order to test the feasibility of maintenance of treatment over long periods of time, participants completing this additional training period will continue their respective training program at home for one year. Compliance will be monitored and the efficacy of this long- term training will be assessed. PUBLIC HEALTH RELEVANCE: Evidence from animal and human studies strongly suggests that aerobic exercise and cognitive stimulation have a beneficial effect on cognition, but intervention studies in healthy elders have not shown large improvements, and these improvements have not transferred to day-to-day activities. The goal of the proposed study is to evaluate the benefit of a combination of aerobic exercise and a cognitive intervention designed to enhance executive control processes. This combined intervention may provide enhanced benefits, and the targeted cognitive functions may enable generalization of training to many other tasks and activities. The possibility that this intervention may markedly improve day-to-day function in healthy elders has enormous potential significance for public health.

Grant Category:  Neural and Behavioral Profiles of Cognitive Aging

Project Title:  Characterizing the Behavior Profile of Healthy Cognitive Aging
Principal Investigator:  Patricia A. Boyle (Rush University Medical Center)

Description (provided by applicant): Cognitive decline is nearly universal in older persons and its prevention is one of the most important public health challenges of the 21st century. Despite considerable progress in identifying the causes of cognitive decline in older persons, surprisingly little is known about the profile of healthy cognitive aging. Most of the available studies of healthy cognitive aging have examined cognitive change in persons without clinical dementia. However, the vast majority of persons without dementia who come to autopsy have extensive neuropathologic evidence of the diseases commonly known to cause cognitive impairment in old age, particularly Alzheimer’s disease, cerebral infarcts, and Lewy bodies, and the exclusion of persons without clinical dementia does not account for the effect of accumulating neuropathology on the trajectory of cognitive aging. Moreover, most older persons exhibit a precipitous decline in cognition in the years just prior to death, a phenomenon referred to as terminal decline, and this also contributes to cognitive aging. Thus, a substantial portion of the cognitive decline currently attributed to healthy cognitive aging likely is due to the influence of accumulating neuropathology and terminal decline. We propose to use innovative statistical approaches to characterize the profile of healthy cognitive aging defined as age-related cognitive change not accounted for by the presence of common neuropathologies (i.e., Alzheimer’s disease, cerebral infarcts, and the Lewy body diseases) or terminal decline. The proposed study will capitalize on the unique longitudinal cognitive and neuropathologic data available from two ongoing epidemiologic studies, the Religious Orders Study (P30AG10161), which will serve as the exploratory cohort, and the Rush Memory and Aging Project (R01AG17917), which will serve as the confirmatory cohort. These studies perform comparable and detailed annual cognitive evaluations on more than 2,300 persons in total, all of whom have agreed to brain donation. By the end of the funding period of the proposed study, more than 23,000 cognitive data points will be available from more than 2,500 persons with up to 20 years of annual follow-up. In addition, detailed post-mortem data will be available from more than 1,200 persons. Data from these studies will be used to model the trajectory of cognitive change as a function of accumulating neuropathology and terminal decline in order to elucidate the trajectory of healthy cognitive aging (i.e., age-related cognitive change not accounted for by common neuropathologies or terminal decline). The proposed study offers a novel, timely, and potentially powerful approach to identify the profile of healthy cognitive aging. Knowledge of the trajectory of healthy cognitive aging is essential for the identification of persons who might benefit from interventions to prevent age-related cognitive decline and, ultimately, for the identification of factors associated with successful aging.

Public Health Relevance:  Cognitive decline is nearly universal in older persons and its prevention is one of the most important public health challenges of the 21st century. First, knowledge of the profile of healthy cognitive aging will allow for identification of persons exhibiting the earliest signs of pathologic cognitive aging who are most likely to benefit from the available therapies and disease modifying agents as they become available. Second, the proposed study will elucidate the extent to which common neuropathologies underlie age-related cognitive change and will directly inform on the public health burden associated with the diseases commonly known to cause cognitive impairment in old age; if common neuropathologies account for most of cognitive change seen in older persons, then these data would suggest that the public health burden posed by these diseases is greater than currently recognized and that a much larger group of persons, including those without overt dementia, ultimately may benefit from effective treatment and prevention strategies developed for cognitive impairment and dementia.

Project Title:  Neural Processes Underlying Cognitive Aging
Principal Investigator:  Randy L. Buckner (Massachusetts General Hospital)

Description (provided by applicant): The present proposal seeks to characterize neural processes that affect cognition in normal aging distinct from early-stages of pathological change. Multiple brain changes are present in clinically normal aging including white-matter disruption, depletion of neurotransmitter systems, and preclinical Alzheimer’s disease (AD) pathology. While it is common for all of these brain changes to be present in the same individuals, dissociations raise the possibility that certain components may reflect normal aging independent of the progression to clinical dementia. For example, we recently observed that white-matter integrity in normal aging was linked to executive dysfunction in the absence of amyloid deposition. Advanced aging is also associated with increased (often bilateral) recruitment of cortical systems, similar to that observed in other situations where brain systems are stressed. Activity increases are prominent in older adults who, as a group, display the brain changes noted above raising the possibility that they reflect a compensatory response. Testing hypotheses associated with cognitive aging is challenging because it is extremely difficult to identify a pure cohort of normal older adults that is sparred the preclinical stages of AD pathology. As a novel approach to the study of cognitive aging, we will explore the link between brain aging and executive dysfunction in a group of older adults screened for the presence of amyloid deposition using PET molecular markers. Specifically, we aim to (1) explore whether disruption of large-scale brain networks (via DTI and fcMRI) accounts for cognitive variation in the absence of amyloid deposition, (2) explore whether there is MTL-linked memory variance in normal aging that is independent of preclinical AD, and (3) explore whether activity increases are present in normal aging and mitigate cognitive decline. We hypothesize that there exists a prominent cascade affecting executive function during normal aging that is independent of amyloid plaque pathology and that activity increases are a response to mitigate the effects of this cascade. The cascade is proposed to arise from white-matter disruption and impaired coordination of large-scale brain systems. By completing this project, in addition to testing our specific hypotheses, we will generate and openly share a normative data set on aging that includes structural, functional, and cognitive data that is stratified by high or low amyloid deposition.

Public Health Relevance: An increasing percentage of the population is living well beyond retirement age. Here we seek to understand the brain factors in normal aging that impair cognition as well as compensate to mitigate cognitive decline. By understanding these factors we hope to promote healthy, graceful aging

Project Title:  Gene Expression, Compensation, Mechanisms, and Successful Cognitive Aging
Principal Investigator:  Carl W. Cotman (University of California, Irvine)

Description (provided by applicant): What are the neural and behavioral profiles that serve successful cognitive aging? Because gene activity provides the fundamental building blocks for cellular function and dysfunction, gene expression patterns must be the cornerstone of successful cognitive aging. One mechanism underlying preservation or maintenance of cognitive function in aging may involve engagement of compensation, a concept that is emerging from human brain imaging data. We propose to identify possible compensatory mechanisms in aging, based on a multidisciplinary approach using microarray analyses to profile gene expression patterns in clinically well-characterized human brain tissues, complemented by animal models to test mechanisms by which physical activity prevents cognitive decline, followed by a translation of the animal data to humans. In Aim 1, a set of clinically and pathologically well-defined human tissues will be used. We hypothesize that in the presence of pathology, compensatory gene expression will be mobilized to help preserve cognitive function. To address this, cases will be divided into cognitive quintiles, from which we will select the top 20th cognitive percentile, representing successful cognitive aging. To identify possible compensatory gene mobilization, we will assess gene expression profiles in the successful aging cohort, comparing gene those with low vs. moderate levels of pathology. In addition, maintaining pathology constant at a moderate level, we will assess gene expression profiles across the top 4 cognitive quintiles to identify how gene expression patterns change with declining cognition. We hypothesize that declines in cognition will be reflected in a downregulation of select gene classes and genes, particularly genes linked to synaptic integrity, plasticity and energy metabolism. Various lifestyle factors are emerging as key for successful cognitive aging, in particular, increased physical activity. Thus, in Aim 2, using both human and animal tissue, we will evaluate the hypothesis that physical activity helps maintain successful cognitive aging by engaging compensatory gene mechanisms, particularly in vulnerable populations. In aged animals showing cognitive impairment, we hypothesize that exercise will reverse the impairment and mobilize a gene profile supportive of cognition/plasticity. In transgenic mouse models carrying the ApoE4 gene, a major risk factor for cognitive decline in humans, we test the hypothesis that exercise may be paradoxically more effective in E4 than E3 animals, in improving cognitive function and mobilizing plasticity-related gene expression. Finally, we seek to translate the animal research to a set of human cases where physical activity and cognition have been monitored, using post-mortem brain tissue to analyze brain gene expression patterns in high- active vs. relatively inactive people. Taken together, our project will provide new insight into gene expression profiles in the human that underlie successful cognitive aging, which are currently unknown.

Public Health Relevance: The human population is aging and thus there is a great need to promote successful cognitive aging. Our studies will define the gene expression profiles in the human brain of those who have achieved successful cognitive aging, and determine if exercise will build and strengthen the aging brain through action on gene expression. Accordingly, these studies will help provide a rational for including exercise as a formula to promote successful cognitive health during aging.

Project Title:  Neural and Biochemical Mechanisms of Cognitive Aging
Principal Investigator:  William J. Jagust (University of California, Lawrence Berkeley Lab)

Description (provided by applicant): The cognitive aging field has long debated whether presymptomatic brain disease accounts for a proportion of what is considered to be normal age-related cognitive decline. This is most notable in relation to Alzheimer’s disease (AD) not only because it is a highly prevalent age-associated condition, but also because several features of AD are seen in normal aging. In particular, decline in episodic memory, deposition of ¿- amyloid plaques, and neurofibrillary tangle-related hippocampal atrophy are all aspects of AD that are also common in cognitively intact older people. However, the effects of AD pathology are not straightforward and are likely to be mediated by intervening factors that can be characterized as vulnerability and reserve. Within the past several years, scientific advances have allowed the measurement of the multiple processes that may be involved in this model of age-related memory loss. Thus, it is possible to measure ¿-amyloid with positron emission tomography (PET) and the amyloid imaging agent [11C] Pittsburgh Compound B (PIB), to assess neurofibrillary tangle burden and hippocampal atrophy with magnetic resonance imaging (MRI), and to assess reserve processes with PET measures of glucose metabolism (using [18F]-Flurodeoxyglucose, or FDG) and with functional MRI (fMRI). In this project, a group of 125 older cognitively intact individuals will be recruited over 5 years, carefully characterized in terms of overall cognition and episodic memory, and studied with PIB- and FDG-PET imaging and structural MRI. A subgroup of 50 of these subjects, along with 50 healthy young subjects will be studied with fMRI and an event-related behavioral paradigm that contrasts brain activity during successfully remembered and forgotten items. A major question is whether, and how, older people without evidence of ¿- amyloid deposition or hippocampal atrophy differ from older people with these characteristics, and from younger people. In addition key hypotheses will be tested in continuous multivariate models in which PET measures of ¿-amyloid and MR measures of hippocampal atrophy are expected to be related to poorer episodic memory function, while resting prefrontal glucose metabolism will attenuate this relationship. Similar findings are expected during cognitive activity using fMRI, in which diminished brain activity in the medial temporal lobes may be related to ¿-amyloid deposition, and better performance may be related to increased prefrontal cortical activation. Finally, a subgroup of subjects will be re-evaluated at a 2-year interval to see whether these measures predict change over time in cognition. In total, this project will both provide a description of optimal cognitive aging independent of brain amyloid deposition, and will begin to unravel the mechanisms associated with the loss and preservation of memory function in aging.

Public Health Relevance: This project will assess whether and how Alzheimer’s disease may account for the memory loss experienced by healthy normal older people. This is important both for understanding relationships between AD and normal aging, and for developing ways of optimizing brain function in aging.

Project Title:  Synaptic Function and Plasticity in CA3 Circuits in the Aging Hippocampus
Principal Investigator:  Alfredo Kirkwood (Johns Hopkins University)

Description (provided by applicant):  Aging has a profound impact on learning and encoding new memories. Advances in the field of aging suggest that changes at the cellular level rather than structural alterations are more relevant for understanding cognitive deficits associated with aging. In this regard, electrophysiological analysis of synaptic function in the CA1 region of the hippocampus has provided the important insights that age disrupts the mechanisms by which the synaptic connectivity is modified to encode new memories. These changes in synaptic plasticity provide a conceptual basis to understand learning deficits in aged individuals. Although focusing on alterations in CA1 associated with learning deficits has been fruitful, recently it has become clear the need to expand the research scope. First is the realization that other circuits in the hippocampus participate differently during memory encoding, and that aging affects them differently, and even more prominently, in the case of CA3. In addition, although on average cognitive abilities decline with age, a recognizable subpopulation of aged individuals maintains mental abilities. Thus, while an ultimate goal could be to preserve the integrity of the cellular processes normally affected by age, a complementary approach is to focus on adaptative changes occurring naturally in response to lost functions. We approach these issues ex vivo, by studying synaptic plasticity in hippocampal slices from aged rats characterized in a hippocampal- dependent learning task. The goals of this project are to 1) understand how aging affects the synaptic functions that support learning in CA3, 2) identify mechanisms that allow some aged individuals to maintain cognitive abilities and 3) understand how intervention treatments that improve learning in aged individuals affect synaptic plasticity. Our research suggests that some mechanisms of synaptic plasticity are irreversibly lost in aged rats. However, those aged individuals that maintained cognitive performance manage to compensate for the lost by boosting other mechanisms. These adaptatively enhanced plasticity mechanisms are an obvious target for therapeutical strategies aimed at restoring learning in aged individuals.

Public Health Relevance: Aging can have a pronounced impact on mental abilities, particularly on learning and memory. Although such decline is widespread enough to be often considered a normal aspect of aging, some older individuals retain strong cognitive abilities. This proposal will investigate the type of neural adaptive changes that are required to maintain cognitive performance at old age.

Project Title:  Hippocampal Electrophysiology and Myelinogenesis in Healthy Cognitive Aging
Principal Investigator:  Philip W. Landfield (University of Kentucky)

Description (provided by applicant): This application proposes to address a fundamental unresolved question in the field of cognitive aging, the nature of the neurobiological factors that distinguish individuals with healthy cognitive aging (HCA) from those with unhealthy cognitive aging (UCA). The focus of the studies will be on biomarkers developing near the age of divergence of unhealthy from healthy cognitive aging, as these appear particularly likely to provide important insights into causal mechanisms. A major emphasis of the project will also be testing the hypothesis that midlife activation of myelinogenic programs in the hippocampus is an important factor in converting HCA to UCA. This view derives from our recent work with both microarray and immunohistochemical techniques showing that myelinogenesis is increased around midlife in rats, the same age range in which unhealthy cognitive aging begins to appear. The proposed studies will comprise a large multidisciplinary project aimed at obtaining a unique integrated perspective on neurobiological correlates of cognitive aging in an established rat model of aging. It will involve state-of-the-art intracellular electrophysiology in hippocampal slices, concomitant Ca2+ imaging in recorded neurons, extensive immunohistochemistry with a battery of stains, diffusion tensor imaging (MRI/DTI), separate microarray analysis of each individual rat, and substantial behavioral testing of each animal. Multiple techniques will be applied in each animal. These studies will pursue the aims of correlating electrophysiological and genomic markers of cognitive aging in the same animals and will relate cognitive function to myelin structure and density in cross-sectional and longitudinal analyses. Further, the course of myelinogenesis will be altered in long-term studies that manipulate dietary iron and/or treat with cuprizone. Animals subjected to altered myelinogenesis will be tested on a battery of behavioral, electrophysiological, microarray and immunohistochemical analyses, to test the proposition that conversion to UCA has been slowed and, if it has, to determine through which hippocampal pathways this occurred. Overall, these studies should substantially elucidate neurobiological markers distinguishing UCA from HCA, and should importantly determine the role of myelinogenic programs in cognitive aging. Further, the proposed longitudinal studies should have direct translational relevance.

Public Health Relevance:  This proposed research will be conducted in an established rat model of aging, which shows demonstrated relevance to human aging. These studies will elucidate neurobiological markers of and processes influencing the divergence of healthy and unhealthy cognitive aging. Therefore, the proposed studies should have both predictive and therapeutic value in determining the course of human cognitive aging.

Project Title:  Molecular Mechanisms Regulating Age-Related Cognitive Decline in C Elegans
Principal Investigator:  Coleen Tara Murphy (Princeton University)

Description (provided by applicant): C. elegans, like humans, experience cognitive functional declines with age, but the cause of these declines are not yet known. We propose to identify age-related changes in neuronal function, and to distinguish those changes that are functionally deleterious from those that may be an adaptive response to aging. In our first Aim, we will identify the genes required for long-term associative memory (LTAM) that change with age and with decreased function, and rescue function with age through manipulation of candidate genes. Our second Aim focuses on the identification of the cells involved in LTAM, and the characterization of their roles in the LTAM process. Furthermore, we will assess changes in cellular function with age. Finally, we will compare changes during normal aging to pathological changes in two C. elegans models of dementia. Comparisons with models of dementia will distinguish healthy from pathological age-dependent changes. Through these studies, the contributions of specific components to functional cognition will be used to identify the best targets of therapeutic intervention to treat cognitive decline with age.

Public Health Relevance:  In our work, we propose to use the model organism C. elegans to discover genes whose changes in function are correlated with decline in cognitive ability with age. We have designed a test of long-term memory in this organism, and observe that the animals lose their ability to remember with age. Using this test and various molecular tools, we can study the genes and cells responsible for loss of memory with age and in neurodegenerative disease.

Project Title:  Health Behaviors Over the Adult Lifecourse and Cognitive Aging
Principal Investigator: Mika J. Kivimaki, Archana Singh-Manoux (University College London)

Description (provided by applicant): There is increasing evidence of an association between health behaviors and cognitive aging. Smoking, alcohol, physical activity and nutrition have all been found to be associated with poor cognitive function and dementia. The extent to which health behaviors can explain cognitive aging trajectories is of substantial public health relevance, particularly as they may be ‘the’ key modifiable risk factors for dementia. The overarching aim of this proposal is to examine the combined impact of health behaviors over the adult lifecourse in determining cognitive aging trajectories starting from midlife. The specific aims are: 1. To examine the combined impact of smoking, alcohol consumption, physical activity and diet on cognitive decline in order to assess whether the impact of health behaviors in early, mid and late midlife is most important and whether this effect accumulates over time. 2. To examine the extent to which change in one behavior leads to changes in others and the extent to which these changes influence cognitive aging. 3. To examine bidirectional associations between health behaviors and cognitive aging starting in midlife: 4. To examine the extent to which biological changes, such as those in vascular risk factors and diseases, explain the association between health behaviors and cognitive aging. We will also examine the role played by two potential effect modifiers of the association between health behaviors and cognitive aging: socioeconomic status (SES) and the apolipoprotein E (APOE) e4 allele. In addition, our work will focus on issues to do measurement of health behaviors: Detailed attention will be paid to the categorization of the health behaviors in order to understand the shape of the association between each measure of behavior and cognitive aging, whether different measures diet have similar associations with cognitive aging and whether there are discrepancies between the objective and subjective measures of physical activity. We will also examine the impact of health behaviors on specific domains of cognitive aging, with memory and executive function as two major aspects. The Whitehall II test battery was introduced to the full Whitehall II cohort at phase 5 when participants were on average 55 years old and had already been assessed for behaviors over the previous 10 years. A third wave of cognitive data is currently being collected, and will be available late 2009, allowing us look at trajectories of cognitive change. Although the proposal is based primarily on the British Whitehall, the research team is composed of scientists based in France as well as the UK, providing us with the opportunity to validate some of our results in data from the French GAZEL study.

Public Health Relevance:  Continuing increases in life expectancy come in tandem with knowledge that the prevalence of dementia rises with age, doubling every 4-5 years after the age of 60. By age 80 over one third of the population is likely to be living with dementia; for industrialized countries an unprecedented challenge in terms of care provision. Although dementia generally occurs late in life, it is increasingly recognized that there is a long preclinical phase, making the evaluation of risk factors prior to and during this phase a crucial next step in the battle to prevent or delay the onset of dementia. Driven by this ‘long’ view of dementia our research focuses on the determinants of heterogeneity in cognitive aging starting from early midlife. Existing research suggests an association between health behaviors and cognitive aging; smoking, alcohol, physical activity and nutrition have all been found to be associated with poor cognitive function and dementia. What remains unknown is the extent to which these behaviors, acting in combination, determine cognitive aging trajectories. In public health terms, why is this knowledge so important? Because these behaviors are likely to be ‘the’ key risk factors for dementia that are both modifiable and amenable to low-cost intervention at the national level. In research terms, the unique feature of this proposal is three repeat assessments of cognitive function using a comprehensive test battery with a first assessment carried out in early midlife allowing an examination of the inflection point in changes in cognitive functioning.

Project Title:  Neural and Behavioral Profiles of Cognitive Aging
Principal Investigator:  Scott A. Small (Columbia University Health Sciences)

Description (provided by applicant): With increasing longevity, decreasing morbidity, and as older individuals expect to live intellectually challenging lives, cognitive aging has emerged as a major societal problem. Aging does not cause diffuse brain dysfunction but rather targets select brain areas, in particular the frontal lobes and the hippocampal formation. The hippocampal formation itself is made up of separate but interconnected subregions. A wide range of studies have established that hippocampal subregions are differentially vulnerable to mechanisms of dysfunction. Each subregion houses a molecularly-distinct population of neurons, providing a molecular basis for the observed differential vulnerability. A range of in vivo functional imaging and post-mortem studies suggest that: A) In contrast to early stages of Alzheimer’s disease, normal aging differentially targets the dentate gyrus; B) the dentate gyrus is differentially vulnerable to elevations in blood glucose; and, C) the dentate gyrus differentially benefits from physical exercise. Additionally, preliminary data suggest that, D) age-related dentate gyrus dysfunction is linked to changes in the expression of molecules related to histone modification. In this proposal we link these observations into a general top-down model, suggesting etiologies, molecular mechanisms, and ways to ameliorate age-related hippocampal dysfunction. The general goal of this proposal is to test hypothesized elements of the model. The general approach is to use a high-resolution variant of functional magnetic resonance imaging that can assess the mouse hippocampal formation longitudinally over time. By mapping the effects various manipulations have on the living dentate gyrus, this approach will allow us to test specific hypotheses of the model. By confirming or modifying the top-down model, this proposal is potentially significant as it will expand our mechanistic understanding, but more importantly, it will directly lead to ways to ameliorate age-related hippocampal dysfunction.

Public Health Relevance: With increasing longevity and decreasing morbidity, cognitive aging has emerged as a major societal problem. The short term goal of this proposal is to rely on previous findings to test hypotheses about etiologies and molecular mechanisms that contribute to cognitive aging. The general approach is to use a high-resolution variant of functional imaging that can assess the mouse brain longitudinally over time. More than just understanding mechanisms of dysfunction, the ultimate goal of this proposal is learn how to ameliorate cognitive aging.

Project Title:  High Resolution Structural and Functional Brain Imaging of the Medial Temporal Lobe
Principal Investigator:  Craig E. Stark (University of California, Irvine)

Description (provided by applicant): Cognitive decline with aging, especially in the memory domain, has been documented as an important risk factor for Alzheimer’s disease (AD). Examining neurocognitive aging will help us better characterize pathological and non-pathological changes in the brain throughout the lifespan and identify preclinical markers for cognitive decline. It will also help us pinpoint cognitive processes and mechanisms that can be altered to delay onset or reverse pathology altogether. With the population over 60 rising rapidly, discoveries in this domain will likely have dramatic impact on public health and substantially reduce the burden on families as well as government and social programs. There is a clear need for targeted investigations of memory and the brain that cover the entire spectrum of aging throughout the adult lifespan. The goal of this proposal is to collect a comprehensive set of behavioral and high-resolution neuroimaging data to test several key predictions of a neurocognitive model of age-related memory impairment. This work is based on converging insights from computational models as well as behavioral, electrophysiological, and neuroanatomical findings in rodent models of aging. The approach is based on the premise that the hippocampal dentate gyrus is critically involved in episodic memory by virtue of its exceptional capacity for performing pattern separation, or the ability to isolate similar memories from each other. Pattern separation is a key computational component of many forms of memory often attributed to the hippocampus (e.g., episodic memory, recollection, etc). The model posits that degraded input to the dentate gyrus and CA3 region from layer II entorhinal cortex neurons with aging leaves the system with an impaired ability to perform pattern separation. We propose to test predictions of this model using behavioral experiments and a combination of cutting-edge neuroimaging techniques (functional and structural MRI, DTI, and PIB PET). We predict that aging will result in behavioral impairments consistent with a reduction in pattern separation abilities, and that there will be neural changes in CA3/DG activity consistent with this reduction. We also predict that aging will result in changes in the connectivity within the hippocampus and between the hippocampus and surrounding cortices (e.g. entorhinal cortex). Finally, we predict that individual differences in memory performance, imaging data, and ApoE4 genetic susceptibility will differentiate healthy from pathological aging and that these differences will be key to predicting subsequent decline. Critically, this rich dataset will have uses beyond our questions and hypotheses. We will provide and share all components of this extensive dataset for other researchers to study using the robust Biomedical Informatics Research Network (BIRN) infrastructure.

Public Health Relevance:  The population over 65 is projected to increase to 86.7 million by 2050 (U.S. Census Bureau, Population Estimates and Projections, 2004) and the impact of aging and aging-related disorders e.g. Alzheimer’s disease (AD) on the health care system will rise dramatically as the rate of AD doubles for every five year period beyond the age of 65. Even outside of AD, one of the primary complaints and deficits observed with aging is a decline in learning and memory function, leading to decreased quality of life and a greater burden on families and social services. Understanding the neural mechanisms that underlie these age-related deficits is crucial to understanding the effect of aging on dementia, and paving the way to improving treatments for both normal and pathological changes in memory and for early prevention.

Project Title:  Hippocampal Network Profiles of Memory Aging
Principal Investigator:  Joe Z. Tsien (Medical College of Georgia)
(Supported by Recovery Act Funds)

Description (provided by applicant): One of the major obstacles in our understanding of memory ageing is lack of an effective tool to address the fundamental questions such as: what are memory traces? What are the major alterations in the network-level dynamics and memory-encoding patterns during aging? How can we identify network characteristics that give rise to superior memory function in the aged brain? In this application, we propose to apply large-scale ensemble recording method to identify, visualize, and characterize memory traces in CA1 region throughout all major stage of the memory process, namely, acquisition, consolidation, and retrieval in both young adult and aging brains. In our application, we hypothesize that unique activation and reactivation patterns by CA1 cell assemblies form the network-level basis for predicting behavioral performances in memory tests. We will test this key hypothesis by examining four specific questions: 1) what are the ensemble patterns of CA1 activity during memory acquisition, consolidation, and retrieval? 2) What are the fundamental network-level characteristics that are correlated with behavioral memory performances? 3) How does the aging process affect those characteristics? 4) What is the role of the NR2B in the regulation of network-level features underling the enhanced memory during aging? It is conceivable that identification and visualization of CA1 memory traces should enable us to manipulate and discover the neural processes underlying memory decline in the old brain. Such a new capacity and knowledge should lead to new strategies for potential therapeutic interventions for memory ageing.

Public Health Relevance:  Both people and animals exhibit deterioration of cognitive function as they age. The neural bases for the gradual decline in attention and memory are poorly understood. Based on our recent success in applying large-scale in vivo recording techniques and computational algorithms for monitoring and analyzing activity patterns of over hundreds of individual neurons in the CA1 region of freely behaving mice, we propose to identify and characterize network-level memory traces in both young and old animals. Moreover, we will investigate the neural network basis underlying enhanced memory function in young and aged NR2B transgenic mice. We will compare the similarity and differences between wild-type aged mice and transgenic aged mice. It is conceivable that the identification and biophysical description of network-level memory traces should provide crucial insights into the question of what memory is, and how memory is altered by aging.