Mark B. Moss - US grants

Changes in cognitive function, including a decline in various aspects of memory, occur as part of normal aging. However, a far more dramatic memory impairment occurs as a result of certain age-related diseases including Alzheimer's disease (AD) and, in fact, forms its major behavioral symptomatological axis. Neurochemically, the most striking and consistent marker of AD is a widespread depletion of the cholinergic enzymes choline acetyltransferase (CAT) and acetylcholinesterase (AChE) in various cortical and limbic regions. At the same time, neuropathological evidence is accumulating to show that neurons in the nucleus basal of Meynert (NB) and the associated substantia innominata (SI) undergo extensive degeneration in patients with AD. These areas of the basal forebrain contain CAT and AChE positive cells which are known to project to widespread areas of the cerebral cortex and limbic system. The relationship between these neurochemical and neuropathological markers and the steady decline of cognitive function in patients with AD is the principal question addressed in this proposal. Four specific aims of this proposal are 1) to assess the behavioral effects of bilateral lesions of the SI-NB in the rhesus monkey. Four tests of associative and recognition memory which we have found to be sensitive to monkeys with limbic system lesions and to patients with AD will be used. 2) To measure the extent of loss in cholinergic activity in the basal forebrain, cerebral cortex and limbic system in these same monkeys using histochemical, biochemical and immunocytochemical techniques. 3) To correlate the exent of loss in cholinergic activity with the degree of memory impairment and 4) to assess the potential of transplanting cholinergic tissue from the basal forebrain of neonatal monkeys into either the site of lesion and/or into identified areas of cholinergic depletion in the brain of animals with demonstrated memory impairment following SI-NB damage. The efficacy of transplants will be determined by assessing the degree of behavioral recovery on the memory tasks and by measuring the extent of recovery of cholinergic activity in the transplant and target sites. Characterizing the behavioral and neurochemical deficits which may follow SI-NB lesions in monkeys would be a first step in establishing a working animal model of AD.

The overall goal is to identify the neuropathological basis for the memory disorders of Alzheimer's disease (AD) and other age-related dementias. In particular, the role of the cholinergic basal forebrain in relation to other CNS structures implicated in the neuropathology of Alzheimer's disease will be assessed in the rhesus monkey as part of the development of an animal model of AD. The specific aims of the project are: 1) to assess the effects of damage to the entorhinal cortex, amygdala or locous coeruleus (LC), alone or in combination with the basal forebrain on a series of memory and learning tasks sensitive to the memory disorders of AD. This will help determine if the entorhinal area, amygdala and LC act synergistically with the basal forebrain to produce anterograde memory impairments similar to those seen in AD. 2) To assess the effects of entorhinal, amygdals and LC lesions, alone or in combination with lesions of the basal forebrain on the postoperative retention of preoperatively learned tasks. The pattern of retrograde loss will be compared to that found after basal forebrain lesions alone as well as that seen in patients with AD. 3) The progression of cognitive dysfunction, presumably reflecting ongoing neuropathology may be due to the process of anterograde and retrograde transneuronal degeneration. In order to test this hypothesis, the long-term behavioral and anatomical consequences of basal forebrain damage will be assessed. 4) To assess histochemically the extent of cholinergic and/or noradrenergic depletion in selected sites in the limbic system and cerebral cortex following lesions of the basal forebrain and/or locus coeruleus. This would constitute an important step in identifying the role of the basal forebrain and locus coeruleus in the cognitive impairments of AD. 5) To assess the efficacy of neuronal transplantation in restoring normal anatomical and neurochemical relationships and to correlate these results with any improvements in learning or memory function.

An analytical microdensitometer will be acquired to quantitatively measure a variety of reaction products visualized in microscopic sections of biological tissues. The machine is to be applied to a number of projects: 1) Changes in enzyme levels in ovarian cells as a result of exposure to tetrahydrocannabinol: 2) The process of degeneration in pericytes of diabetics; 3) Transmitter related enzymes in the central nervous system of monkeys; 4) The relationship of behavioral change to lesion-induced alterations in transmitter related enzymes in the central nervous system of monkeys; 5) Changes in the superior cervical ganglion as a result of exposure to testosterone or estradiol; and 6) Changes in the motor unit as a result of age or lesion. One of the exciting developments in instrumentation for biological research is the ability to couple microscopes to computers to allow easy quantitative analysis of microscopic images. All projects are critically dependent upon the densitometer as an investigative tool and will exploit the machine's ability to measure product on sections at various wavelengths with a great degree of accuracy and reproducibility. The availability of this instrument will allow several excellent investigators to greatly strengthen their research programs.

This is a multidisciplinary program to assess the separate and combined effects of hypertension and atherogenic diet for periods of 12 to 48 months on the central nervous system of the cynomolgus monkey. This monkey was chosen because hypertension experimentally induced by coarctation of the aorta and determine how these two variables contribute to the development of cerebrovascular disease and the effects of that disease on the brain and behavior. Our overall hypothesis is that hypertension alone, or in combination with a hypercholesterolemic diet, leads to a breakdown of the blood brain barrier with consequent disruption of synaptic function resulting in impaired cognitive function after as little as 12 months of disease. A further hypothesis is that the pathology will progress from scattered microinfarction at 12 months to extensive infarction throughout the brain by 48 months. To test this hypothesis all animals will be behaviorally tested on tasks sensitive to memory impairments in both monkeys and humans. Periodic clinical measures will be taken including physical exams, fundus photography and fluorescein angiography of the retina, clinical blood chemistry as well as MRI and PET scans of the brain. At the end of testing, the effects of disease on the cerebral vasculature, the brain and the eyes will be examined. One project will assess the integrity of the blood brain barrier and determine whether complement proteins are extravasated and whether these might induce cytotoxic damage in the brain. Parallel immunocytochemical studies will localize the presence of such extravasated plasma proteins and reactive astrocytes in the brain. In another project on hemisphere of the brain will be serially sectioned and the distribution of cerebrovascular changes including microinfarction, stroke and white matter changes will be determined. A related study will analyze the temporal lobe limbic system, the areas most likely to account for the early onset of the observed memory deficits. Analyses of the hippocampus, amygdala and entorhinal cortex will include volumetric measures and ligand binding assessment of the major chemical neuroanatomical systems (GABA, glutamateaspartate and acetylcholine). The final study will examine the clinical progression of changes in the eye to determine whether the reflect concomitant changes in the brain. Neuroanatomical studies will examine how specific populations of retinal neurons and glia are affected. Finally an overall statistical analysis of these measures will be performed using structural equation modeling to test the hypothesized relationships among hypertension, atherogenic diet, breakdown of the blood brain barrier and consequent changes in behavior, the brain and the retina.

Hypertension, a common condition among the elderly and even middle aged adults, has long been associated with cognitive dysfunction, particularly in the domain of memory. However, the neurobiological basis for this impairments is not well understood. This project will determine the cognitive effects on monkeys at known risk for cerebrovascular disease from hypertension alone, or in combination with an atherogenic diet. We plan to assess the cognitive function of monkeys using behavioral tasks which were developed for, or adapted from neuropsychological batteries used i the evaluation of geriatric populations and, in particular, patients with cerebrovascular disease. The performance of monkeys will be followed in cohorts at six months intervals for either 12 or 48 months. In this matter, a profile of change in cognitive function, including memory, executive function (cognitive flexibility, attention, visuospatial function and psychometric speed) will be determined. We expect to see measurable cognitive impairment, primarily in memory function, occurring as a consequence of hypertension alone, or in combination with atherogenic diet, but not from atherogenic diet alone. This change should be observable by 12 months following induction of hypertension with or without maintenance on atherogenic diet. We expect the long term consequences (48 months) of hypertension to produce a progressive decline in memory function as well as produce impairments in other cognitive domains including executive system function, visuopatial abilities and attention, producing, in effect, a cerebrovascular dementia. We expect that monkeys with hypertension combined with atherogenic diet will also develop a dementia state, but, owing to possible differences in focal neuropathology, the pattern of deficits may be more variable than that found with hypertension alone. The 48 month behavioral assessment of a subset of monkeys in this project will allow us to determine whether early cognitive changes identified at 12 months will progress toward a "dementia" state, as defined by criteria parallel to those for dementia in humans. Furthermore, the changes in cognition charted in this project will be correlated with anatomical, imaging and neuropathological data collected from the same animals to determine the extent of the relationship between these variables. This approach may also permit the identification of a relevant behavioral or neurobiological marker of cognitive impairment and cerebrovascular dementia. Further, a composite index of cognitive decline will be correlated with an overall index of changes on MRI and PET in the same animals. In this manner, we will be able to determine if metabolic hypofunction identified on PET precedes or occurs concomitantly with cognitive impairment. A composite index of behavioral findings as well as changes in individuals domains will be correlated with the presence of blood brain barrier compromise the and extent and pattern of retinopathy. Finally, the relationship between cognitive decline, systolic blood pressure and serum cholesterol level will be measured.

The Animal Resource Core, together with its main component, the Animal Records Review Committee (ARRC), is that part of the Program Project which is responsible for (1) screening the Yerkes rhesus population in order to select and purchase animals for inclusion in the Program and (2) monitoring those animals throughout the conduct of the project to ensure their continuing suitability. The Core will review the health records of all animals prior to entry into the study to determine if they meet the selection criteria developed jointly by staff members of the NIH and the Program Project. It will also review the health status of all monkeys in the Program on a regular basis to insure that their continued use by the program project is appropriate. The Core will be responsible for the decision to terminate an animal promptly should medical or health conditions warrant. The Animal Core will also have the task of assigning and scheduling animals to behavioral testing, PET and MR imaging and physical exams in an efficient and coordinated manner. The Core will receive and review complete necropsy reports including histopathological assessment of all major organ systems. This is to ensure that no extra neural disease processes that may interact with aging variables being examined in this Program can confound our results. Our neuropathologist will review results of the postmortem autopsies and pathological surveys to determine whether occult problems, the nature of which would warrant exclusion from the data analysis, were present. Finally, the Core will ensure prompt, thorough, and efficient access to all records and to disseminate the decisions of the Core to the remaining scientific personnel of the Program Project. The Core will also collect all data from health records and postmortem examination and will enter them in our unified database for subsequent overall statistical analysis.

We will perform cognitive and functional assessment of the monkeys in this program project. All 57 monkeys will undergo cognitive assessment with a behavioral test battery that includes tasks of recognition memory (delayed nonmatching to sample, delayed recognition span), spatial memory and executive function (delayed response, reversal learning) that have been found to be sensitive to aging in monkeys as well as in humans. Some of the tests have been developed from, or developed for use with, neuropsychologic evaluation of normal aged human subjects and patients with various forms of age-related dementia. A major goal of this project is to classify the extent of cognitive dysfunction for each monkey based on a composite score derived from the behavioral test battery. This score will then be used to classify aged animals as severely cognitively impaired or as only mildly impaired. This classification will serve as a basis for determining the relationship between cognitive function and the morphological, neurohistochemical, biochemical, molecular and imaging measures obtained by the other projects. We will also evaluate retinal function by assessment of contrast sensitivity in a subset of monkeys with peripheral eye examinations to help determine the functional status of the visual pathways. Contrast sensitivity findings can then be compared with the morphological assessment of the visual pathways. A subset of animals will also undergo activation studies on PET using the visual recognition memory task (DNMS) under two different delay conditions. We will identify the locus and degree of metabolic activity that underlies short-term memory function in the aged monkeys function in the aged monkeys with severe cognitive impairment as compared to that in aged monkeys that are only mildly impaired. Finally, we will evaluate the efficiency of conduction in cortical white matter by measuring electrically evoked potentials across the corpus callosum in a subset of monkeys and comparing this across young, cognitively impaired aged and mildly impaired aged monkeys. In line with one aspect of our overall hypothesis that myelin degeneration may play a significant role in age-related cognitive decline, these observations can then be compared with morphological assessments of the splenium. The assessment and classification of cognitive function in the aged monkey will allow us to evaluate the constellation of neurobiological variables that underlie age-related cognitive dysfunction.

Normal human aging is typically characterized by a decline in several domains of cognitive function. However, not all individuals evidence such decline with age. The neurobiological that underlies the differences in the degree of unsuccessful aging remains unclear. Several possibilities have been advanced ranging from widespread cortical loss and the presence and extent of neuritic plaques have now been eliminated as primary factors underlying age-related cognitive decline. Rather, our findings have pointed to white matter degradation, alterations in layer I of the cerebral cortex, and inflammation as possible key factors. Accordingly, in this next stage of our program, we will assess cognition in a group of 96 rhesus monkeys spanning the adult age range, and in particular those of late middle age. We will then relate the behavioral outcome variables from the individual tasks to a set of regional (temporal lobe will then relate to the behavioral outcome variables from the individual tasks to a set of regional (temporal lobe limbic system, area 46 and visual cortex) morphologic, immunocytochemical, physiologic, neuroimaging and biochemical outcome variables measured in the other three projects. One additional variable, based on a composite score derived from the behavioral test battery will be used to assess global cognitive changes with global outcome measures from the other three projects. This latter approach has yielded findings of a significant relationship between cognitive decline and loss of white matter and myelin degeneration in our aged monkeys and points to the possibility that aging in the brain may have widespread and generalized effects. The three specific aims of this project are as follows: Specific Aim 1 is to assess the performance of aged and young adult monkeys on tasks of visual recognition memory, spatial, and memory, spatial memory, and executive system function that are known to be sensitive to aging in both monkey and human populations. Specific Aim 2 is to characterize, for the first time, cognitive function in a group of late middle aged monkeys. Specific Aim 3 (Collaborative with Project 4) is to evaluate visual function by assessment of degraded figures in aged and young adult monkeys.

RE: Lay abstract Proposal IBN-9982889

This is a study to determine if two different regions of the brain, each of which have been separately implicated in memory function, actually work with each other to subserve certain aspects of memory. Work in humans from imaging studies suggest this possibility, but the only way to assess this with any degree of confidence, and to have the ability to understand the nature of the relationship, is to perform an experiment in an animal model. In this case, the rhesus monkey, which has a brain that is structured in a very similar manner to that of humans, is the species of choice. Monkeys will undergo selective damage to these two parts of the brain, one in the temporal lobe, and the other in the frontal lobe. For each structure, the damage will be made on one side of the brain, leaving the other side intact. We will then "disconnect" the two remaining structures to see if this produces a change in how the animals learn and remember. If a significant change occurs, we will have obtained initial evidence in determining that the two different structures participate together in learning and memory function. This study could have important implications in the assessment of memory function in certain disease states and could have eventual bearing on memory rehabilitation efforts.

The central question addressed by this proposal is whether hypertension accelerates the cognitive and neurobiological changes that occur in late middle age. To address this question the separate and combined effects of hypertension and late middle age on cognition and brain integrity in a non-human primate model will be assessed. With the benefit of experience from two well established non-human primate models, one on normal aging and the other on hypertensive cerebrovascular disease, the long-standing clinical issue of the effect of elevated blood pressure and aging on cognition and brain integrity can be pursued. A total of 40 animals will first undergo MR imaging, a battery of behavioral testing, and telemetric blood pressure monitor implants to establish baseline brain white and grey matter volume, cognitive function, and blood pressure, respectively. Upon completion of testing, monkeys will be distributed into four groups in a 2x2 design to assess the separate and combined effects of late middle age and hypertension. Each of the ten late middle aged and ten young adult hypertensive monkeys, together with each of the ten late middle aged and ten young adult normotensive monkeys will be evaluated for a period of 18 months. During this period they will be behaviorally retested at two time intervals and receive a second MRI at the end of the study. Blood pressure will be measured in the awake unrestrained state using telemetric probes. Upon the conclusion of behavioral testing, the brains will be processed for the presence and extent of neuropathological change with emphasis on the pattern and extent of white matter involvement using immunocytochemistry to assess the presence and extent of LN-3 positive microglial cells. The specific aims of this proposal are as follows: 1) to determine the extent to which hypertension exacerbates the effects of late middle age on cognition and brain integrity. 2) To determine if the behavioral and brain degenerative effects of hypertension on aging are additive or act in a synergistic manner and, 3) to assess the individual effects of late middle age and hypertension on cognition and brain integrity.

This training program has been developed to provide predoctoral students and postdoctoral fellows with specific training in the Neurobiology and Neuropsychology of Aging. At the core of this proposal is the merging of the expertise of investigators from two long standing NIA program projects. One is focused on human aging in health and disease (AG-04953) centered at Massachusetts General Hospital (MGH) under the direction of Dr. Marilyn Albert, one of the directors of the proposed training grant, an the other on the neural basis of cognitive decline in a non-human primate model (AG-00001) centered at Boston University School of Medicine (BUSM) of which Dr. Moss, the other director, is Co-PL The training will areas of research that include the neuropsychology and neurobiology of normal aging in humans and animal models, age-related dementia and neurologic disease; neurogenetics and neuroepidemiology; and studies of age-related changes in cellular and synaptic ultrastructure and other related topics. There are six trainers based at Boston University School of Medicine, three based at Harvard Medical School and four based at BUSM affiliated Veterans Administration Hospitals. The program includes in-depth classroom instruction, hands-on laboratory research, interactive web-site, annual field trip and retreat, and experience in one or more of the aireas of the neurobiology and neuropsychology of aging being investigated by the 13 faculty. Additionally,students and fellows will attend a series of seminars on aging at BUSM and at MGH to broaden their knowledge of contemporary aging research. Trainees will also be encouraged to participate in teaching to prepare them for academic faculty positions. Class instruction for all trainees centers around the team taught introductory course in the Neurobiology and Neuropsychology of Aging, a course in Neuroscience, and a summer seminar series on Aging conducted by the Division on Aging at Harvard Medical School. These courses and seminars consist of lectures, discussions, critiques of research paper and laboratory demonstrations.

DESCRIPTION (provided by applicant): This proposal is designed to assess the presence and nature of the relationship between the prefrontal cortex and two medial temporal lobe areas (hippocampal formation and rhinal cortices) in subserving memory and executive function in the primate. In the rhesus monkey, we will use a crossed lesion / split brain technique to isolate and disconnect these two regions of the medial temporal lobe from the prefrontal cortex in order to assess whether there exists a functional interaction between these two brain regions in the performance of memory and executive functions. In order to assess the presence and nature of a functional interaction, it will be necessary to first assess the specific effect of bilateral lesions on each of these three regions. Hence, in the first phase of the study, a cognitive test battery," in which executive function" and "mnemonic" demands within and across tasks will be systematically varied, will be administered to monkeys with bilateral lesions of either the dorsal prefrontal cortex (BFF), the hippocampal formation (BHH), or the rhinal cortices (BRR). In the second phase ("disconnections"), using the same test battery as in the first phase, one experimental group (Group CFHS) will receive a unilateral lesion of the dorsal prefrontal cortex and a contralateral lesion of the hippocampal formation together with a transection of the forebrain commissures. This lesion will disconnect the intact hippocampal formation and prefrontal cortex of the opposite hemispheres. The second experimental group (CFRS) will be prepared with the same unilateral lesion of the dorsal prefrontal cortex but a contralateral lesion of the rhinal cortices with transection of the forebrain commissures. This lesion will disconnect the intact prefrontal cortex from the intact parahippocampal cortices of the opposite hemispheres. In order to assess the effect of these two "disconnections", we will compare their performance to three control groups. The first will be an operated control group (OC) that will also serve as controls for the bilateral lesions in the first phase. The second group (IFHS) will have a unilateral hippocampal formation lesion, an ipsilateral dorsolateral prefrontal lesion, and a transection of the forebrain commissures. This will produce brain damage identical to that in group CFHS, controlling for the total brain damage, but will leave the hippocampal formation and prefrontal cortex on the same side intact and "connected". The third group (IFRS) will have a unilateral lesion of the rhinal cortices along with a unilateral lesion of the dorsolateral prefrontal cortex and transection of the forebrain commissures. This will produce the same degree of brain damage to that in group CFRS, but leave the rhinal and prefrontal cortices on one side intact and "connected".

DESCRIPTION (provided by applicant): Our long-term aim is to rehabilitate neural spatial neglect. Unilateral neglect is a complex neurological disorder induced by unilateral brain damage that is characterized by lack of conscious perception, awareness, attention, and cognition of objects in the space contralateral to the brain damage. In a cat model of spatial neglect, unilateral deactivation of posterior and inferior parietal cortex induces a profound neglect of objects in the contralateral hemifield. Paradoxically, the neglect is reversed by additional deactivation of the homotopic region in the contralateral hemisphere. This model system offers the opportunity to investigate the neural mechanisms which, when damaged, produce neglect, and to develop an effective therapeutic strategy to reverse neglect in humans. The Specific Aims of the proposed work are to test three hypotheses on: 1) the use of repetitive transcranial magnetic stimulation (rTMS) to reverse neglect in a cat model, 2) to learn more about the primary & secondary functional impacts of lesions and stimulations on the attention network, & 3) interactions of lesions & rTMS on distant structures as the impact of the lesion emerges & when it is stable. The knowledge gained will aid the development of therapeutic and interventional strategies for application to human patients suffering from neglect. Animal studies provide the best possibility of studying the neglect syndrome, and its paradoxical reversal, in a highly systematic way and with considerable anatomical rigor. Our model of spatial neglect will allow systematic identification and dissection of pathways affected by the lesion, provide insights into the brain mechanisms underlying the reversal of neglect, lead to the development of therapeutic strategies to rehabilitate and ultimately reverse neurological neglect in human patients. Our over riding goal is to minimize rTMS parameters yet provide maximum therapeutic duration. It is a realistic goal that can be achieved with the proposed whole-animal behavioral assays and supplemented by the brain-wide network analyses on the functional impacts and interactions of parietal lesions and applied TMS on neurons. The data are of obvious translational importance for neurorehabilitation of neglect and may have wider-ranging impact on other neurologic and psychiatric diseases.

The Animal Resource and Clinical Core, together with its main component, the Animal Records Review Committee (ARRC), is that part of the Program Project which is responsible for (1) screening the Yerkes rhesus population in order to select and purchase animals for inclusion in the Program;(2) monitoring those animals throughout the conduct of the project to ensure their continuing suitability. The Core will review the health records of all animals prior to entry into the both the cross-sectional and longitudinal study to determine if they meet the selection criteria developed jointly by staff members of the NIA and the Program Project. It will also review the health status of all monkeys in the Program on a regular basis to insure that their continued use by the Program Project is appropriate. The Core will be responsible for the decision to terminate an animal promptly should medical or health conditions warrant;(3) To review results of the postmortem autopsies and pathological surveys to determine whether occult problems, whose nature would warrant exclusion from the data analysis, were present;(4) To ensure prompt, thorough, and efficient access to all records required in the work of the Core, and to disseminate the decisions of the Core to the remaining scientific personnel of the Program Project;(5) To assign animals to behavioral testing, and to coordinate scheduling of MRI scans and physical examinations in a timely manner.

DESCRIPTION (provided by applicant): Predoctoral and postdoctoral students will receive comprehensive training in the Neurobiology and Neuropsychology of Aging through the combined efforts of a total of 17 mentors that include neurobiologists, neuropsychologists and neuroimagers at Boston University School of Medicine (N=12) and Massachusetts General Hospital, Harvard Medical School (N=5). Training will include research and didactics in (1) animal models of normal aging and age-related disease, (2) neuropsychology of aging and age-related neurologic disease, and (3) state-of-the art techniques in neuroimaging. Resources are founded on extensive research activity and grant support of the trainers that include several NIA funded program projects, two Alzheimer Disease Centers, and over 20 individual grants. With experience gained through active participation as one of the selected partners in the Carnegie Initiative for the Doctorate, a Roadmap grant to create one of the first Interdisciplinary Courses in Aging (Introduction to Interdisciplinary Systems Science: Dynamic Modeling), specific courses in the Foundations of Neuroimaging, and the Vesalius Program in Teaching in the Biomedical Sciences, this program provides a unique and progressive training in the neurobiology of aging. The areas of research represented among the training cadre include the neuropsychology and neurobiology (including neurogenetics) of Alzheimer's disease and Parkinson's disease, normal aging and cerebrovascular disease in non-human primate models, and studies of age-related changes at the cellular, synaptic ultrastructure and neuroimaging levels. All students will have a training experience with animal models (non-human primates and rodent) and humans encompassing (1) neuropsychological (2) structural and (3) imaging studies. The program includes, among other features, in-depth classroom instruction, methods in neuroscience with an emphasis on aging, hands-on laboratory research, the Vesalius course in biomedical teaching, and a course in interdisciplinary systems science and dynamic modeling.

DESCRIPTION (provided by applicant): Epidemiologic studies support the finding that cognitive decline is evidenced as early as the fifth decade of life and further, that the estimated prevalence of more marked decline (MCI) for people over 65 years of age is between 10% and 20%. Several lines of evidence point to alterations in white matter as the neural basis of cognitive decline that, in turn, may be the consequence of oxidative stress and inflammation. As a result, by virtue of their anti-inflammatory and antioxidant effects, dietary polyphenols are gaining serious attention as potential candidates to slow, arrest, or perhaps even reverse, age-related cognitive decline. Toward this evolving hypothesis, Curcumin, a natural phenol and member of the ginger family, has been shown to evidence such positive effects and provide a strong rationale to pursue the hypothesis that Curcumin could be an effective therapeutic intervention in age-related cognitive decline. Accordingly, in this project, we will test, for the irst time in a non-human primate model, the hypothesis that the compound, Curcumin (Curcuma longa) will alter the course of age-related cognitive decline using behavioral tasks adapted directly from, or applied to, humans. In addition, we will use established and innovative MRI scanning protocols to assess changes in brain integrity and immunohistochemistry assays to quantify the histopathological markers of damaged myelin. Outcome measures will be assessed against changes in cognitive performance during and at the end of a three-year period. It is hypothesized that monkeys receiving Curcumin will evidence less severe myelin pathology and degeneration, and hence, less age-related cognitive impairment than age-matched controls.