The ability to identify and follow structural brain changes during brain maturation and aging is both fundamental to our understanding of brain function, and crucial in clinical studies. While post-mortem studies of human brain can provide data on local histological changes, they are only cross sectional, brain samples are not optimal, and sample sizes are small. In contrast, non-invasive in vivo imaging can provide powerful longitudinal data for large populations. Moreover, post-processing techniques make it possible to analyze the entire brain, providing anatomically specific data that allows for investigating relationships between imaging and function. Recent developments in diffusion MRI and fiber tractography have revealed correlations between imaging changes and cognitive aging in both monkeys (Makris et al, 2007), and humans (Voineskos et al., 2012). Unfortunately, the biological underpinnings of such imaging changes are largely speculative (Paus 2010) and hence the specificity of imaging measures for histological features is unknown. The lack of such "validation" is largely due to the inability to conduct well-controlled studies of both brain tissu and imaging in humans. In this application we propose a multidisciplinary study using the rhesus monkey model of normal aging. This is enabled by a collaboration of three PIs, with unique and complementary expertise in MRI imaging, morphometry, neuroanatomy and cognitive aging. We have available a cohort of over 50 normal aging rhesus monkeys of both sexes, ranging in age from 5 (young adults) to over 30 (oldest of the old) years of age. Most important is the availability of cognitive and DTI data that can be used for histopathological validation of archived, cryoprotected, unstained tissue from all of these monkeys. The main aims of this proposal are: 1). To establish sensitivity of individual diffusion tensor imaging (DTI) metrics to cognitive maturation and aging, 2). To investigate biological underpinnings of diffusion changes during cognitive maturation and aging, and 3). To develop free imaging tools necessary to accomplish the goals of this proposal. The results of this proposed study will greatly impact our understanding of aging processes and their mechanisms and provide tissue validated understanding of imaging measures that can be applied to studies of normal human aging as well as many other clinical populations including traumatic brain injury, multiple sclerosis, and schizophrenia.

Public Health Relevance

The three PIs and their co-investigators propose a multidisciplinary study of cognitive aging in rhesus monkeys. We plan to combine prior to death acquired cognitive assessments, brain diffusion tensor imaging, and postmortem brain tissue to explore the biological underpinnings and establish the specificity of the imaging biomarkers. The results of this proposed study will greatly impact our understanding of aging processes and their mechanisms and provide tissue validated understanding of imaging measures that can be applied to studies of normal human aging as well as many other clinical populations including traumatic brain injury, multiple sclerosis, and schizophrenia.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AG042512-02
Application #
8731790
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Wagster, Molly V
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
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Preti, Maria Giulia; Makris, Nikos; Papadimitriou, George et al. (2014) A novel approach of groupwise fMRI-guided tractography allowing to characterize the clinical evolution of Alzheimer's disease. PLoS One 9:e92026
Thermenos, H W; Whitfield-Gabrieli, S; Seidman, L J et al. (2013) Altered language network activity in young people at familial high-risk for schizophrenia. Schizophr Res 151:229-37