At the National Institutes of Health - National Institute on Aging
From: 2010 NIH / NIA (National Institute of Aging Factbook

Intramural research at the NIH Institute on Aging

Laboratory of Cardiovascular Science
Receptor for advanced glycation end products (RAGE) Unit
Research Overview: Maladaptation of the cardiovascular system to various assaults from the environment during human aging process leads to the development of cardiovascular diseases. Stresses and injuries in the vascular system often lead to persistent inflammation that precedes tissue modeling and pathological changes in the vessel wall, resulting in vascular complications. Our long-term goal is to understand how cell signalingmediated inflammation impacts the development of vascular diseases during aging. Currently we focus on the signaling mechanism of the receptor for advanced glycation end products (RAGE), which has been implicated in atherogenesis and other inflammation-precipitated diseases including diabetes and Alzheimer's disease.

Laboratory of Clinical Investigation
Aging and age-related disorders are often associated with endocrine axes imbalances. These endocrine axes are multi-level entities that require a systems-level mode of investigation. In the face of disease/ pathophysiology, these axes become disrupted and potentially exacerbate the pathology. It is likely that dietary/pharmacological/behavioral readjustment of these disrupted endocrine axes may be the best mechanism to create an effective, long-lasting and least deleterious treatment for age-related disorders such as diabetes, infertility, obesity, metabolic syndrome, and various neurological disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. With endocrine axis re-adjustment, the beneficial effects of the therapeutic intervention may be more stable and greatly amplified by the axis itself, compared to the traditional one-target therapeutic strategies.

Laboratory of Epidemiology, Demography, and Biometry

Tamara B. Harris, M.D., M.S., Senior Investigator
Chief, Geriatric Interdisciplinary Studies Section

The AGES-Reykjavik Study goals include: identification of genetic and other new risk factors for selected diseases and conditions including: atherosclerosis, cognitive impairment, dementia and subtypes (i.e. Alzheimer's disease), stroke, sarcopenia, obesity, osteoporosis, diabetes, and osteoarthritis; characterization of phenotypes for these diseases and conditions to study them in relation to genetic susceptibility, gene function and genetic/environmental contributions to disease; and identification of contributory molecular markers associated with these conditions including markers of cellular maintenance and repair, markers of oxidative stress, and immunologic and endocrine indicators. A genomewide association study has been carried out and is now under analysis.

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Lenore J. Launer, Ph.D., Senior Investigator, Chief, Neuroepidemiology Section The paradigm of Alzheimer's disease (AD) has shifted. Whereas previously co-morbid cardiovascular disease was an exclusion criterion for a diagnosis of AD, many recent epidemiologic studies, including those from the Neuroepidemiology Section show that AD often co-occurs with sub-clinical and clinical cardiovascular disease, and that this comorbidity may contribute to the pathogenesis of the disease or its clinical presentation. Further, neuropathologic data show that there are multiple pathologies in the brains of older persons, all of which may contribute to dementia.

Laboratory of Experimental Gerontology

Sige Zou, Ph.D., Investigator
Chief, Functional Genomics Unit

Recent investigations in the Function Genomics Unit (FGU) demonstrate that cranberry extracts can extend lifespan in D. melanogaster and delay age-related functional decline in rats. We are currently extending this line of investigation to a transgenic mouse model in order to test the potential benefit of cranberry supplementation on brain pathogenesis in the most common age-associated neurodegenerative disorder, Alzheimer's disease (AD). Specifically, these experiments will document the influence of cranberry on cognitive function, amyloid plaque formation, and an extensive panel of inflammatory makers in AD mice. This project is partly funded by the Wisconsin Cranberry Board.

Julie A. Mattison, Ph.D., Staff Scientist/Facility Head
NIA Primate Aging Study

Primate Aging Studies: The NIH Animal Center in Poolesville, Maryland is home to the NIA Primate Aging Studies. Although the primary focus has been a long-term study of calorie restriction, the Laboratory of Experimental Gerontology (LEG) has conducted additional studies of dietary interventions that more specifically affect cardiovascular aging, Parkinson's and Alzheimer's Diseases. Dietary calorie restriction (CR) has been shown to benefit health and longevity in a wide variety of species, although most have maximal lifespans of only a few years. In 1987, the National Institute on Aging Intramural Research Program began the first well controlled long-term study in a species with a considerably longer lifespan and a closer physiology to humans.

Laboratory of Molecular Gerontology

Alzheimer's disease (AD) is the leading cause of dementia in the old. Several lines of evidence indicate that AD may be associated with defects in DNA repair. Recent work from other laboratories suggested that cells from Alzheimer's disease patients are defective in the processing of DNA lesions induced by irradiation with fluorescent light. Specifically, we use mouse models of AD to identify the contribution of DNA repair defects in the progression of the disease. The Baltimore Longitudinal Study of Aging (BLSA) provides a unique collection of biological material to investigate associations of genetic background with age. We are using samples from this cohort to try to identify genetic polymorphisms in DNA repair genes that are associated with shortening/extending life span.

Laboratory of Neurogenetics
Andrew B. Singleton, Ph.D., Senior Investigator
Chief, Molecular Genetics Section

In recent years, an extremely successful approach to understanding disease has arisen from the study of rare familial forms of disorders related to more common "sporadic" disease. This is a research paradigm that was successful in Alzheimer's disease (AD). The identification of the APP, PS-1 and PS-2 mutations as causal of rare forms of early-onset familial AD led to a huge increase in our knowledge of the pathogenic mechanisms underlying the common late-onset form of AD.

Bryan Traynor, M.D., MMSc, MRCPI, Assistant Clinical Investigator
Chief, Neuromuscular Diseases Research Group

Laboratory of Neurosciences (LNS)
Mark P. Mattson, Ph.D., Chief

Laboratory of Personality and Cognition

Phospholipids and their component polyunsaturated fatty acids (PUFAs), including arachidonic acid (AA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3), play critical and dynamic roles in brain development, aging and disease. They influence neurotransmission, synaptic membrane remodeling, gene transcription, cerebral blood flow, and cell membrane structure. Their metabolism is abnormal in a number of human brain diseases, including Alzheimer disease, bipolar disorder and HIV- 1 dementia. These abnormalities may be related to the underlying pathophysiological processes of neuroinflammation and excitotoxicity, and may be influenced by dietary PUFA composition as well as by the liver's ability to synthesize AA and DHA from their respective plant-derived shorter-chain nutritionally-essential precursors, linoleic and α-linolenic acid.

Brain Physiology and Metabolism Section

Francesca Bosetti, Pharm.D., Ph.D., Investigator
Chief, Molecular Neuroscience Unit

Changes in Gene Expression after Lipopolysaccharide-Induced Neuroinflammation: Neuroinflammation is a key component in the progression of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. It remains to be elucidated whether inflammation is either the cause or the effect of the neuropathological changes associated with the diseases. Lipopolysaccharide (LPS) is a component of the bacterial wall of Gram negative bacteria, and is commonly used to induce inflammation in the periphery and in the central nervous system. It stimulates the innate immune system through interactions with CD14 and the tolllike receptor 4 (TLR4), which are expressed by microglia, the primary immunocompetent cells of the brain. Acute administration of LPS directly into the brain leads to neuronal death in the hippocampus. Moreover, behavioral studies have shown that object recognition and spatial memory are both impaired in animals treated with single doses of LPS. In line with these cognitive deficits, long-term potentiation (LTP) is largely blocked following acute LPS injections.

Madhav Thambisetty, M.D., Ph.D., Staff Clinician (Neurology)
Clinical Research Branch, Laboratory of Personality and Cognition, and Brain Physiology and Metabolism Section

In the BPMS, Dr. Thambisetty's research is based on developing novel PET methods for imaging dopaminergic signal transduction in healthy humans as well as neuroinflammation in AD.

Alan B. Zonderman, Ph.D., Senior Investigator
Chief, Cognition Section

His research interests include individual differences in cognition and personality and their relationship with adult morbidity and mortality, predicting the onset of cognitive impairments and Alzheimer's disease, the role of genetics in cognitive declines and personality, and the risks and rates of cognitive change as a function of socioeconomic status and race, particularly the extent to which health disparities moderate these relationships.

Dimitrios Kapogiannis, M.D., Staff Clinician
Translational Research and Medical Services Section

Personality traits have a strong biological basis and are largely heritable. Nevertheless, the neural correlates of these traits are still largely unknown, as well as their potential role as disease modifiers. Dr. Kapogiannis has developed a research program that uses functional and structural neuroimaging to identify the neural correlates of personality traits. Moreover, he will investigate their potential role as disease modifiers in Alzheimer's disease.

Extramural Alzheimer's Disease Research

Terms:

AD - Alzheimer's disease 
DHA - Dietary docosahexanenoic acid - Principal PFUA found in the mammalian brain.
     Supports neurological function, retinal development and overall health.
FTD - Frontotemporal Dementia 
LPS - Lipopolysaccharide - A component of the bacterial walls
      commonly used to induce inflammation in the periphery and in the central nervous system.
LTP - long-term potentiation - A long-lasting enhancement in signal transmission
       between two neurons that results from stimulating them synchronously.
MCI - Mild Cognitive Impairment 
PET - Positron Emission Tomography
PUFAs - PolyUnsaturated Fatty Acids