Scott A. Small, Md - US grants

The candidate's background in cognitive neuroscience and clinical neurology has recently culminated with a fellowship in aging and dementia. It was in this setting that he developed an interest on the effect of aging on memory, and has committed himself to a career studying the presentation, clinical course, and causes of age-related memory decline. Following the memory performance of a single cohort prospectively is a powerful approach in addressing lingering questions about memory and aging. With some exceptions, however, longitudinal studies have had difficulty in documenting age-related memory decline, either because of the learning effect associated with repeated testing or because of selective subject attrition. In a series of preliminary studies the candidate has recently identified an experimental design that demonstrates age-related memory decline using longitudinal data. The first objective of this proposal is for the candidate to receive formal training in longitudinal analysis of neuropsychological and other data. The first research goal of this proposal is for the candidate to apply this knowledge to community- based elderly individuals followed prospectively, in an attempt to better document age-related memory decline. The causes of age-related memory decline remain unknown but likely include early Alzheimer's disease (AD) as well as other physiological processes that change in an age-dependant manner. The candidate has recently developed a method using functional magnetic resonance imaging (fMRI) to study elderly individuals with memory decline. Preliminary findings suggest that this method can dissociate individuals into those with an AD-like pattern of brain dysfunction and those with a separate pattern of dysfunction. The second training objective of this proposal is for the candidate to continue his training in functional imaging. The second research goal is to validate-that the fMRI method can dissociate different etiologies by following the clinical course of individuals with memory decline prospectively.

Clinical criteria can identify elderly individuals with mild cognitive impairment (MCI). Although MCI is enriched with subjects who have pre-dementia Alzheimer's disease (AD), MCI is clinically heterogeneous. Alzheimer's disease begins in the entorhinal cortex, and imaging entorhinal integrity enhances our ability to detect AD among MCI subjects. MRI can assess entorhinal integrity using two approaches: The first approach relies on structural images to measure entorhinal volume; while the second MRI approach relies on hemodynamic images to estimate entorhinal metabolism. Among different hemodynamic variables, MRI measures of cerebral blood volume (CBV) have proven capable to detect AD-related metabolic dysfunction, including entorhinal dysfunction. The primary goal of this proposal is to determine which MRI measure of entorhinal integrity best detects pre-dementia AD?entorhinal volume, entorhinal metabolism, or perhaps both in combination. In order to achieve this goal we will measure entorhinal volume and entorhinal CBV in a single group of individuals with MCI. We will follow subjects until progression to dementia, and identify which measure of entorhinal integrity best predicts progression to AD. An ancillary goal of this proposal is to follow subjects until autopsy.

DESCRIPTION (provided by applicant): A range of studies suggests that Alzheimer's disease (AD) begins by impairing synaptic function in select subregions of the hippocampal formation. Detecting synaptic dysfunction with anatomical precision has emerged as an important goal, both to improve our diagnostic abilities and for the purposes of drug development. Synaptic dysfunction typically affects basal brain metabolism. Among the hemodynamic correlates of brain metabolism that can be assessed with magnetic resonance imaging (MRI), cerebral blood volume (CBV) is the one that can most readily visualize individual hippocampal subregions. The first goal of this proposal is to determine whether high-resolution measures of CBV do in fact reflect underlying physiology and metabolism, and whether it can detect AD-related and age-related neuronal dysfunction. The second goal is to confirm that AD-related and age-related hippocampal dysfunction target separate hippocampal subregions. The third goal is to demonstrate that CBV measures can reliably detect the effect of a pharmacological intervention, thereby testing whether this approach can be used for drug development. Independent validation of neuronal dysfunction requires invasive techniques--such as ex vivo slice electrophysiology and in vitro histochemistry-- and therefore these goals can only be achieved in experimental animals. Here we focus on mice because they are the only species that provide both a model of AD and a model of normal aging. Furthermore, because of their relatively short life span, we can follow mice longitudinally, thereby mapping the temporal as well as spatial pattern of dysfunction. With these advantages in mind, we have constructed an MRI laboratory tailored exclusively to mouse MRI, and have optimized CBV approaches for subregional analysis of the hippocampus.

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.

DESCRIPTION (provided by applicant): In the US, increased length of life and reduced morbidity and mortality have resulted in a growing number of older adults, the demographic time bomb often referred to in discussions of public policy. According to the Census Bureau, the population aged 65 and over will double in size within the next 25 years. Moreover, these older adults will live healthier lives than their predecessors. While this increased length of a healthy life is an undeniable societal benefit, it brings with it a major societal problem: an epidemic of aging-related cognitive decline. The need to develop interventions to address this growing problem is urgent. Aging-related cognitive dysfunction is not diffuse; rather it targets selected brain areas, in particular the frontal lobes and the hippocampal formation. The separate but interconnected subregions of the hippocampus are differentially vulnerable to pathogenic mechanisms, including the normal aging process. A range of in vivo and post-mortem studies have converged on the dentate gyrus (DG) as the hippocampal subregion differentially targeted by the aging process. As with pathogenic processes, any intervention that improves brain function does so with regional selectivity. One such intervention is physical exercise, which has been shown to improve both frontal lobe and hippocampal function. Using a high-resolution variant of functional magnetic resonance imaging (fMRI), we have demonstrated that aerobic training selectively benefitted DG function both humans and mice. In addition, improvement in DG function was associated with improved performance on a word list learning task but not in tasks conventionally thought to be frontal lobe dependent. The human part of the study had significant shortcomings, however: it was small (N = 11), lacked a control group, enrolled only young subjects (age 20-45 years), and employed only a limited neuropsychological testing battery. The overall goal of this proposal is to use the high-resolution variant of fMRI to test the hypothesis that aerobic training will induce improvements in DG function in a sample of younger (age 20-35) and older (50-65) adults, assigned randomly to an active training condition or wait list control group. We will use more comprehensive neuropsychological testing to examine the relationship between changes in DG function and selected cognitive capacities. Taken together with the observation that normal aging differentially targets the DG, this research program will establish that physical exercise is an effective approach for ameliorating the insidious cognitive slide that occurs in all of us as we age. Thus, the potential significance of this application is substantial. PUBLIC HEALTH RELEVANCE: According to the US Census Bureau, the United States population aged 65 and over is expected to double in size within the next 25 years, and this demographic time bomb will bring with it an epidemic of aging-related cognitive decline, imposing burdens on individuals and their families and on the healthcare system and society as a whole. The need to understand the pathophysiology of cognitive decline and then develop interventions to address this growing problem is urgent and in this application, we propose to test the impact of aerobic exercise training on cognitive function in a sample of young and older adults. In addition, because recent evidence suggests that 1) the dentate gyrus (DG) of the hippocampal formation is differentially targeted by cognitive aging and 2) that exercise improves DG function, we also use fMRI to test whether exercise-induced improvement in cognitive function is mediated by increased cerebral blood volume to the DG.

DESCRIPTION (provided by applicant): During the previous funding cycle we have: A) Optimized and validated a high-resolution variant of mouse fMRI that can be used longitudinally and in translational human-rodent imaging studies. B) Applied the fMRI variant to investigate a mouse model of Alzheimer's disease (AD) to suggest that the within the hippocampal formation the entorhinal cortex (EC) is the hippocampal subregion differentially vulnerable to AD and A-related toxicity. C) Showied that genetically-modified mice with retromer-deficiency develop hippocampal dysfunction and A accumulation, which together with other studies suggests that retromer-deficiency isolated in the EC of patients is relevant to disease pathogenesis. As a natural extension of the anatomical and molecular findings made during the first cycle of research, two interrelated questions have emerged about the EC in the pathophysiology of AD: A) What are the intracellular mechanisms that account for the vulnerability of the EC, and do they provide insight into general mechanisms of disease? B) Because AD pathology 'spreads' over time, might dysfunction in the EC be linked to dysfunction in other brain regions? As developed in the current proposal, we have relied on a convergence of empirical evidence to generate a 'intracellular hypothesis' that informs the first question, and a 'inter-regional hypothesis' that informs the second. Briefly, the intracellular hypothesis is based on studies showing that, beyond its established role in A production, the retromer also plays a key role in wnt signaling, and that the EC differentially expresses molecules related to the retromer and wnt pathways. Together, we hypothesize a feedback system whereby retromer, A, and wnt are in dynamic equilibrium, which when disrupted can account for key features of the disease. The inter-regional hypothesis is based on lesion studies in non-human primates and on synaptic properties of A that suggest that EC dysfunction can drive dysfunction in other brain regions. The overall goal of this current proposal is to combine mouse fMRI with cellular and molecular techniques to confirm, refine, or refute these testable hypotheses. Although the proposed experiments are hypothesis-driven, in the proposal we also include exploratory studies that can be considered hypothesis- generating, in the case that the hypotheses are completely refuted. Confirming or refining these hypotheses will significantly expand our mechanistic understanding of AD and might suggest novel avenues for therapeutic intervention. We will achieve these goals by completing the following specific aims:

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.

DESCRIPTION (provided by applicant): It is important to evaluate schizophrenia in its early stages in order to identify brain sites that are affected, such that causes of illness may be better understood and appropriate preventive interventions developed. A major research goal has been to use magnetic resonance imaging (MRI) to identify areas of brain abnormality which would inform our knowledge as to the mechanisms underlying the early evolution and emergence of schizophrenia. Our group identified a promising imaging biomarker using a high-resolution variant of functional MRI using gadolinium contrast- increased basal function in hippocampal subregions, which was associated with schizophrenia itself, related to the severity of positive psychotic symptoms across illness stages such as delusions, and predicted progression to psychosis from a prodromal or clinical high-risk state in a small cohort (Schobel, Lewandowski et al. 2009) Importantly, these findings to date are based upon a relatively small cohort of subjects, 27 patients with schizophrenia, 27 patients who are at high clinical risk for psychosis, and 24 comparison subjects. We aim to build upon our previous published study by expanding the cohort of schizophrenia and patients at clinical risk for psychosis to test the predictive value of the putative marker, and include longitudinal assessment of brain function and structure. The significance of this proposal is to definitively test the utility of using a high-resolution fMRI variant to detect the earliest stages of schizophrenia, to test the utility of using a lower-resolution non- invasive fMRI variant to detect the earliest stages of schizophrenia, and to clarify the relationship between abnormal brain function and structure in its onset. If the proposed aims are achieved, our diagnostic capabilities in prodromal stages of disease will be enhanced as well as our understanding of the pathophysiology of emergent psychotic illness, both of which are key to developing preventative interventions in an effort to reduce the significant morbidity of schizophrenia and related psychotic disorders. PUBLIC HEALTH RELEVANCE: Schizophrenia, like all diseases of the brain, targets specific brain regions more than others. Pinpointing these targeted regions with brain imaging is challenging but important, for diagnostic purposes and for understanding mechanisms of disease. In this application we will use two variants of functional brain imaging that can detect disease-associated dysfunction in small regions of the brain and apply this to patients at clinical risk for psychosis who are followed prospectively for clinical and brain imaging outcomes. The main project goal is to definitively test the hypothesis of hippocampal hyperfunction as a pathogenic driver in schizophrenia and related disorders.

DESCRIPTION (provided by applicant): The ADRC at Columbia seeks to advance and disseminate knowledge of the causes, prevention and treatment of Alzheimer's Disease and other age-related dementing disorders. To do this, we maintain and follow a multi-ethnic and multi-racial patient population of normal elderly and the elderly with cognitive disorders to establish the natural history of the disease as a function of age and of genetic makeup. In this application we propose to use a variety of neuropsychological, neurological and imaging tools to examine the earliest stages of AD and to follow these subjects throughout their lives and to compare them to other dementing diseases. A comprehensive neuropathologic examination will be performed on the deceased participants correlated with the clinical, radiological and genetic data. Tissues and DNA obtained from these subjects will be available for research on the biology and genetics of the disease. Individual research projects within the ADRC will examine various aspects of the cellular and molecular biology of AD with emphasis on lipids, on retromer function and on the relationship of GBA mutations to dementia. Patients enrolled in the ADRC will have the opportunity to participate in trials of new drugs and treatments for dementing diseases as they become available. The well-documented cognitive status of these patients makes them highly suitable for inclusion in clinical trials. The Education and Information Core of the Columbia ADRC endeavors to educate both lay and medical communities about AD, about the latest advances in research and about the care of the AD patient. The ADRC serves as a resource for scientists with Columbia as well as outside of it, encouraging new research avenues by the award of pilot grants, by providing tissues and other biological samples, by providing access to a carefully documented patient population and by numerous seminars and Clinical Pathological Correlation Conferences. The Genetics Core serves as the major organizer of family recruitment and identification across the ADRCs and ADCs as well as resources for genotyping and gene expression studies. HIPAA compliant data organization and statistical consulting services are provided under the ADRC to the research community at Columbia and external to it.

ADMINISTRATIVE CORE PROJECT SUMMARY/ABSTRACT The general goals of this application for a new P30 ADRC at Columbia University include creating an infrastructure for research on AD and related disorders, fostering interdisciplinary collaborations across many departments, providing a rich training environment, and supporting outreach and patient recruitment. More globally, the goals of our Center will extend to include participation in national coordinating efforts, working with the national network of AD centers, and working with the National Institute on Aging and other organizations in their advocacy efforts. Embedded within the general goals, the Center?s thematic goal will be on better understanding the three biological pathways now considered to act as pathogenic drivers in AD: An ?immune response? pathway, a ?cholesterol metabolism? pathway, and an ?endosomal trafficking? pathway. Both the general and thematic goals were conceived with NAPA?s ambitious milestones in mind-- to prevent or treat AD and related disorders, to optimize patient care, to extend patient support, and to enhance public awareness. The Administrative Core will act as the executive governing body of the Center that, with the guidance of its various committees, will provide the vision and leadership necessary to achieve the Center?s general and thematic goals. The Core will implement this vision by exercising managerial oversight over all aspects of the Center, which includes assuring the highest standards of scientific and bioethical conduct, and a judicious use of resources and funds. More specifically, the Core will achieve its goals by: Directing regular meeting with the Center?s Core leaders and administrators; working with an external and internal advisory committee; assuring delivery of data and biospecimens to investigators and to national consortia; and assuring and enhancing the Center?s community outreach and research education mission.

DESCRIPTION (provided by applicant): The general objective of this proposed renewal for an ADRC at Columbia University is to foster innovative research on AD and related disorders, both locally in our extensive campus and more globally with other institutions and organizations. Informed by the funding opportunity announcement and influenced by recent advancements, a general theme of this renewal is better defining normal aging and the transition from normal aging to the earliest stages of AD. Since its inception 24 years ago, the ADRC at Columbia has established an elaborate infrastructure for research, fostered interdisciplinary collaborations, established a rich training environment, and promoted outreach and patient recruitment. At the same time the ADRC has become an active participant in a more global network comprised of other institutions, national consortia, and community organizations. During its latest cycle, the ADRC has attained most of its goals and its success is evidenced, for example, by the breadth of its scientific achievements and by its #1 ranking in the number of enrolled and active patients. In this proposed renewal, our ADRC will build off of these prior accomplishments moving forward, and will be motivated by two general goals. The first broad goal is to continue, as in previous cycles, to foster innovative research on AD and related disorders, while the second more specific goal is to support the theme of this cycle. These goals will be accomplished via a number of specific aims, which include: 1) Supporting and integrating the cores and other resources to facilitate research on AD and related disorders. 2) Fostering and expanding our multidisciplinary and multi-department local network at Columbia University with a focus on better understanding the relationship between aging and AD. 3) Fostering and expanding our participation in a global network outside of Columbia University, by playing active roles in national efforts and consortia that collect clinical, genetic, and neuroimaging data, as well as biospecimens. 4) Supporting the development of new techniques and methodologies, particularly in delineating the transition from aging to AD, and supporting the translation of thes findings into better diagnostic, prevention and treatment strategies. 5) Fostering and expanding education and outreach to patients, particularly individuals in the earliest stages of disease, and in the training of young and new investigators. The cores provide the structural backbone of our ADRC. As evidenced by the success of the cores during the previous cycle the same cores and their leaders will be part of this renewal, thereby assuring smooth continuity and the promise of future success. Besides the Administrative Core, these cores include: A Clinical Core led by Dr. Larry Honig; a Data Management and Statistical Core led by Dr. Howard Andrews; a Neuropathology Core led by Dr. Jean-Paul Vonsattel; a Human Genetics Core led by Dr. Richard Mayeux; and, an Outreach, Retention, and Education Core led by Dr. Karen Bell. The specific projects allow the ADRC to mobilize towards its scientific goals, and towards its expansionist goals of fostering new science, investigators, and careers. In this proposed renewal the ADRC will support three new projects, all led by new investigators. Dr. Adam Brickman will lead Project 1 entitled, Hippocampal circuitry and white matter abnormalities in aging and AD. Drs. Sandra Barral and Christiane Reitz will co-lead Project 2 entitled, Genetic variations linked to the aging hippocampus. Dr. John Crary will lead Project 3 entitled, Post- transcriptional regulation of tau in aging and AD.

DESCRIPTION (provided by applicant): The general objective of this proposed renewal for an ADRC at Columbia University is to foster innovative research on AD and related disorders, both locally in our extensive campus and more globally with other institutions and organizations. Informed by the funding opportunity announcement and influenced by recent advancements, a general theme of this renewal is better defining normal aging and the transition from normal aging to the earliest stages of AD. Since its inception 24 years ago, the ADRC at Columbia has established an elaborate infrastructure for research, fostered interdisciplinary collaborations, established a rich training environment, and promoted outreach and patient recruitment. At the same time the ADRC has become an active participant in a more global network comprised of other institutions, national consortia, and community organizations. During its latest cycle, the ADRC has attained most of its goals and its success is evidenced, for example, by the breadth of its scientific achievements and by its #1 ranking in the number of enrolled and active patients. In this proposed renewal, our ADRC will build off of these prior accomplishments moving forward, and will be motivated by two general goals. The first broad goal is to continue, as in previous cycles, to foster innovative research on AD and related disorders, while the second more specific goal is to support the theme of this cycle. These goals will be accomplished via a number of specific aims, which include: 1) Supporting and integrating the cores and other resources to facilitate research on AD and related disorders. 2) Fostering and expanding our multidisciplinary and multi-department local network at Columbia University with a focus on better understanding the relationship between aging and AD. 3) Fostering and expanding our participation in a global network outside of Columbia University, by playing active roles in national efforts and consortia that collect clinical, genetic, and neuroimaging data, as well as biospecimens. 4) Supporting the development of new techniques and methodologies, particularly in delineating the transition from aging to AD, and supporting the translation of thes findings into better diagnostic, prevention and treatment strategies. 5) Fostering and expanding education and outreach to patients, particularly individuals in the earliest stages of disease, and in the training of young and new investigators. The cores provide the structural backbone of our ADRC. As evidenced by the success of the cores during the previous cycle the same cores and their leaders will be part of this renewal, thereby assuring smooth continuity and the promise of future success. Besides the Administrative Core, these cores include: A Clinical Core led by Dr. Larry Honig; a Data Management and Statistical Core led by Dr. Howard Andrews; a Neuropathology Core led by Dr. Jean-Paul Vonsattel; a Human Genetics Core led by Dr. Richard Mayeux; and, an Outreach, Retention, and Education Core led by Dr. Karen Bell. The specific projects allow the ADRC to mobilize towards its scientific goals, and towards its expansionist goals of fostering new science, investigators, and careers. In this proposed renewal the ADRC will support three new projects, all led by new investigators. Dr. Adam Brickman will lead Project 1 entitled, Hippocampal circuitry and white matter abnormalities in aging and AD. Drs. Sandra Barral and Christiane Reitz will co-lead Project 2 entitled, Genetic variations linked to the aging hippocampus. Dr. John Crary will lead Project 3 entitled, Post- transcriptional regulation of tau in aging and AD.

PROJECT SUMMARY Studies suggest that abnormal elevations in extracellular glutamate can act as a pathogenic driver of schizophrenia, including in the hippocampus a brain region that neuroimaging studies suggest might be affected first and foremost. If this formulation is correct, then high glutamate should be considered a molecular target for drug discovery and agents that reduce extracellular glutamate should be an effective intervention. Pomaglumetad methionil (which we will call ?POMA?) is one such agent, because as an agonist of presynaptic metabotropic glutamate 2/3 receptors this class of drug has been found to reduce glutamate release. Nevertheless, trials that have used POMA have to date shown little efficacy in patients with schizophrenia. Despite these failures, we believe that, based on the accumulative evidence, high glutamate is indeed a valid target and that two reasons might account for these initial failures. First, as these trials did not use a reliable brain biomarker of glutamate elevations there was no readout of ?target engagement?, and thus it remains possible that these trials were false negatives. Second, and more importantly, schizophrenia is now thought to start in a prodromal phase before the onset of psychosis, and there is evidence to suggest that the prodromal stage might represent a unique time-window for therapeutic interventions, and so it possible that the drug was given at the wrong stage of the disease. Pathophysiological support for these conclusions comes from our studies (Schobel et al, Neuron, 2013) in which we applied fMRI indicators of metabolism and volumetric MRI to patients in prodromal stages of the disease who then progressed to the psychotic stage, and to a mouse model of the disease. Collectively, these studies suggested that glutamate is a driver of hippocampal dysfunction, that fMRI measures are sensitive to glutamate elevations, and that glutamate-reducing drugs can ameliorate hippocampal dysfunction. We also have completed preliminary studies using magnetic resonance spectroscopy, in which we show that hippocampal glutamate is elevated in prodromal stages of the disease. Based on the results of these and other studies, we have recently proposed a mechanistic model of disease progression (Small, Neuron, 2014), which predicts that because of its distinct pathophysiological features the prodromal stage of disease is a unique time-window that is most amenable to glutamate-reducing interventions. This mechanistic model motivates this proposal in which we hypothesize that: 1) MRI based measures of hippocampal metabolism and glutamate can be used as in vivo biomarkers of target engagement when using a glutamate-reducing intervention. 2) Glutamate-reducing interventions will be most effective when administered to prodromal patients, and only when they are shown to engage their target. The R61 phase of this proposal is designed to test the first hypothesis, and the R33 phase is designed to the second.

Within 25 years, the US population aged 65 and over will double in size to 80 million bringing, with it an epidemic of aging-related cognitive decline, from normal cognitive aging to neurodegenerative disorders including Alzheimer?s Disease (AD). These conditions impair quality of life and functional status, impose an enormous burden on individuals, their families, the healthcare system, and require elucidation of mechanisms and development of new treatments to prevent or at least slow their progression. The use of plant-based food and drink for health purposes has a long and well-documented history. Cocoa beans contain the flavanol epicatechin, an anti-oxidant with beneficial effects on blood pressure, endothelium- dependent vasomotor function, platelet reactivity, insulin sensitivity, vascular inflammation, and circulating progenitor cells. Importantly, flavanols have neuroprotective effects, suppressing oxidative stress and inflammation and promoting neurogenesis, neuronal survival and synaptic plasticity, all of which are relevant to the pathophysiology of neurodegenerative disorders like AD, amyotrophic lateral sclerosis (ALS), and Parkinson?s Disease (PD). Evidence from humans, non-human primates, and rodents points to a role for the hippocampus and its subregions in aging-related neurodegenerative disorders including AD. We recently reported that dietary intake of cocoa flavanols increased hippocampal function, measured as fMRI cerebral blood volume (CBV) and a pilot mediation analysis showed that cocoa flavanols led to a decrease in the sentinel pro-inflammatory mediator HMGB1, an activator of the innate immune system. In turn, this decrease in HMGB1 was linked to improved hippocampal function. Recent evidence implicates HMGB1 in cognitive decline and impairment. HMGB1 binds to Toll-like receptor 4 (TLR4), triggering the production of pro-inflammatory cytokines including TNFa via NFkB-dependent pathways. In rodent models of endotoxemia and surgical trauma, HMGB1 mediated hippocampal-dependent memory impairment similar to that seen in septic patients, an effect eliminated by neutralizing HMGB1. These data mechanistically link HMGB1 to neurodegenerative impairment, suggesting its potential as a therapeutic target, consistent with evidence that amplified systemic inflammation is associated with a variety of age-related pathologies including Alzheimer?s Disease. They strongly support our major hypothesis that cocoa flavanols improve hippocampal function by their effects on neuroinflammation, specifically HMGB1, via a TLR4-NFkB-TNFa signaling pathway. We propose to test this model in a randomized controlled trial of 146 participants, age 50-69, receiving high or low daily cocoa flavanol for 12 weeks. Such a trial has potential for significant clinical impact.

OVERALL PROJECT SUMMARY (Abbreviated from the original application) The general objective of this proposed renewal for the Columbia University A D R C is to foster innovative research on AD and related disorders (ADRD). Informed by the funding opportunity announcement and influenced by recent advancements, a general theme of this renewal is ?better defining normal aging and the transition from normal aging to the earliest stages of AD?. Since its inception 24 years ago, our ADRC has established an infrastructure for research, fostered interdisciplinary collaborations, established a rich training environment, and promoted outreach and patient recruitment. T he ADRC has a l s o become an active participant in a more global network comprising other institutions, consortia, and community organizations. During its latest cycle, the ADRC has attained most of its goals and its success is evidenced, for example, by the breadth of its scientific achievements and by its #1 ranking in the number of enrolled and active patients. In this proposed renewal, our ADRC will build off of these prior accomplishments and will be motivated by two general goals. The first broad goal is to continue to foster innovative research on ADRD; the second more specific goal is to support the theme of this cycle. These goals will be accomplished with the following specific aims: 1) Supporting and integrating the cores and other resources to facilitate research on ADRD. 2) Fostering our multidisciplinary and multi-department ?local network? at Columbia University with a focus on better understanding the relationship between aging and AD. 3) Fostering our participation in a ?global network? outside of C olumbia University, by playing active roles in national efforts and consortia. 4) Supporting the development of new methodologies, particularly in delineating the transition from aging to AD, and supporting the translation of these findings into better diagnostic, prevention and treatments. 5) Fostering education to patients and in the training of young and new investigators. The cores provide the structural backbone of our ADRC. As evidenced by the success during the previous cycle the same cores and their leaders will be part of this renewal, thereby assuring smooth continuity and the promise of future success. Besides the Administrative Core, these cores include: A Clinical Core led by Dr. Larry Honig; a ?Data Management and Statistical? Core led by Dr. Howard Andrews; a Neuropathology Core led by Dr. Jean-Paul Vonsattel; a Human Genetics Core led by Dr. Christiane Reitz; and, an ?Outreach, Retention, and Education? Core led by Dr. Karen Bell. The specific projects allow the ADRC to mobilize towards its scientific goals, and towards its expansionist goals of fostering new science, investigators, and careers. The ADRC will support three new projects, all led by new investigators. Dr. Adam Brickman will lead Project 1 titled, ?Hippocampal circuitry and white matter abnormalities in aging and AD?. Dr. Sandra Barral will co-lead Project 2 titled, ?Genetic variations linked to the aging hippocampus?. Dr. Ismael Santa-Maria will lead Project 3 titled, ?Post-transcriptional regulation of tau in aging and AD?.

Project Abstract Perceptual decision making relies on cognitive processes such as acquiring and integrating sensory information, holding information in working memory, incorporating biases, setting a speed-accuracy regime, and planning a motor response. Many of these processes are affected (compared to age-matched controls) in patients with early Alzheimer's disease (AD). The neural correlates of these cognitive processes have been identified in persistently active neurons in frontal and parietal association cortex. We will test the hypothesis that disruption of persistent activity underlies some of the deficits seen in decision making in AD. Our first aim is to characterize the ability of patients with AD to incorporate evidence, environmental biases, and time pressure into their decisions. We will leverage the insights into the neural and computational basis of these abilities obtained from a well-studied perceptual decision making task. By comparing the performance of patients in this task against age matched controls, we will gain insights into the nature of the neural computations that are disrupted in early AD. The experiments also have the potential to uncover new behavioral markers for early AD. Our second aim is to mimic the deficits seen in AD in the macaque monkey by manipulating persistent activity in parietal association cortex while they perform the same perceptual decision task. We will bilaterally express inhibitory chemogenetic DREADD receptors (Designed Receptors Exclusively Activated by Designer Drugs) in a subregion of parietal cortex with neurons that show persistent activity in this decision making task. Preliminary data shows that we can successfully change decision making behavior with this approach. We will build upon these results by investigating how integrating evidence, incorporating biases, and deciding under time pressure is affected by this manipulation in the same task as used with AD patients. Together, our results will provide insights into the computations that underlie decision making, their neural implementation in the primate brain, and how failure to sustain persistent activity in association cortex can lead to deficits in decision making in AD. Our long-term goal is to develop behavioral assays for early diagnosis and to gain insight into fundamental mechanisms that will ultimately lead to new therapeutic targets in AD.