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 we propose to assess the separate and combined effects of hypertension and late middle age on cognition and brain integrity in a non-human primate model. With the benefit of experience from two well established non-humanprimate models, one on normal aging and the other on hypertensive cerebrovascular disease, we believe we are now ready to pursue the long-standing clinical issue of the effect of elevated blood pressure and aging on cognition and brain integrity. A total of 40 rhesus monkeys, 20 of late middle age, and 20 young adults, will be used in this study. All 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 2 x 2 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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG017609-09
Application #
7414734
Study Section
Special Emphasis Panel (NSS)
Program Officer
Wagster, Molly V
Project Start
2000-03-01
Project End
2010-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
9
Fiscal Year
2008
Total Cost
$413,611
Indirect Cost
Name
Boston University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Roberts, D E; Killiany, R J; Rosene, D L (2012) Neuron numbers in the hypothalamus of the normal aging rhesus monkey: stability across the adult lifespan and between the sexes. J Comp Neurol 520:1181-97
Peters, Alan; Sethares, Claire; Moss, Mark B (2010) How the primate fornix is affected by age. J Comp Neurol 518:3962-80
Moore, Tara L; Schettler, Stephen P; Killiany, Ronald J et al. (2009) Effects on executive function following damage to the prefrontal cortex in the rhesus monkey (Macaca mulatta). Behav Neurosci 123:231-41
Killiany, Ronald J (2009) Isn't amyloid more than just a marker for Alzheimer disease? Neurology 73:1174-5
Wisco, Jonathan J; Killiany, Ronald J; Guttmann, Charles R G et al. (2008) An MRI study of age-related white and gray matter volume changes in the rhesus monkey. Neurobiol Aging 29:1563-75
Moore, Tara L; Killiany, Ronald J; Herndon, James G et al. (2006) Executive system dysfunction occurs as early as middle-age in the rhesus monkey. Neurobiol Aging 27:1484-93
Moore, Tara L; Killiany, Ronald J; Herndon, James G et al. (2005) A non-human primate test of abstraction and set shifting: an automated adaptation of the Wisconsin Card Sorting Test. J Neurosci Methods 146:165-73
Moore, Tara L; Schettler, Stephen P; Killiany, Ronald J et al. (2005) Cognitive impairment in aged rhesus monkeys associated with monoamine receptors in the prefrontal cortex. Behav Brain Res 160:208-21
Moore, Tara L; Killiany, Ronald J; Herndon, James G et al. (2003) Impairment in abstraction and set shifting in aged rhesus monkeys. Neurobiol Aging 24:125-34
McDannold, Nathan; Moss, Mark; Killiany, Ron et al. (2003) MRI-guided focused ultrasound surgery in the brain: tests in a primate model. Magn Reson Med 49:1188-91

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