The rhesus monkey is a model of normal human aging that enables cognitive testing to be followed by optimal preservation of brain tissue for multidisciplinary studies. The proposed studies will test the hypothesis that age-related cognitive decline results from a cascade of mild degenerative changes beginning in early middle age with inflammation and damage in white matter that leads to functional changes in axons and progresses to functional and structural changes in neurons. We will study three cohorts of monkeys to test various aspects of this hypothesis. The first cohort of 36 monkeys will be used in a cross-sectional study and consist of subjects covering the adult life span from 5 to 30 years old. After behavioral testing, MRI scans will be followed by in vivo neurophysiology and a new two stage perfusion fixation to provide fresh and fixed tissue to identify brain changes underlying cognitive decline. A second cohort of 6 middle aged monkeys will be treated like cohort 1 except they will be perfusion fixed with mixed aldehydes for electron microscopy to supplement existing samples and allow identification of the ultrastructural changes that are the first changes to appear in middle age in association with cognitive decline. A third cohort of 12 early middle aged monkeys (ages 13-15) will be followed longitudinally for 4+ years with repeated behavioral testing, MRI scans of the brain, and samples of blood and CSF. As the prevalence of cognitive impairment is low at 13-15 but high by 20, behavioral data will identify the cognitive profile and rate of decline of individual monkeys. Longitudinal MRIs will reveal concurrent changes in the in vivo brain structure, and CSF and blood samples will allow biomarkers to be followed. For cohorts 1 and 3, perfusion fixation will be preceded by in vivo neurophysiological assessment of compound action potentials. Then the two stage perfusion will follow to allow immediate collection of unfixed samples from one hemisphere before the remainder of the brain is fixed. Fresh tissue will be used for in vitro neurophysiology of synaptic currents and action potentials, for single cell PCR, and for biochemical and molecular studies of underlying mechanisms. Fixed tissue will be used for anatomical studies, including stereological studies of neuron numbers and immunocytochemical studies of inflammation and other degenerative processes.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
3P01AG000001-34S1
Application #
8700824
Study Section
Special Emphasis Panel (ZAG1-ZIJ-7 (O1))
Program Officer
Wagster, Molly V
Project Start
1998-02-01
Project End
2014-03-31
Budget Start
2013-08-15
Budget End
2014-03-31
Support Year
34
Fiscal Year
2013
Total Cost
$156,830
Indirect Cost
$61,027
Name
Boston University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Faburay, Bonto; Wilson, William C; Gaudreault, Natasha N et al. (2016) A Recombinant Rift Valley Fever Virus Glycoprotein Subunit Vaccine Confers Full Protection against Rift Valley Fever Challenge in Sheep. Sci Rep 6:27719
Shivanna, Vinay; McDowell, Chester; Wilson, William C et al. (2016) Complete Genome Sequence of Two Rift Valley Fever Virus Strains Isolated from Outbreaks in Saudi Arabia (2000) and Kenya (2006 to 2007). Genome Announc 4:
Wilson, William C; Davis, A Sally; Gaudreault, Natasha N et al. (2016) Experimental Infection of Calves by Two Genetically-Distinct Strains of Rift Valley Fever Virus. Viruses 8:
Liu, Qinfang; Mena, Ignacio; Ma, Jingjiao et al. (2015) Newcastle Disease Virus-Vectored H7 and H5 Live Vaccines Protect Chickens from Challenge with H7N9 or H5N1 Avian Influenza Viruses. J Virol 89:7401-8
Medalla, Maria; Luebke, Jennifer I (2015) Diversity of glutamatergic synaptic strength in lateral prefrontal versus primary visual cortices in the rhesus monkey. J Neurosci 35:112-27
Coskren, Patrick J; Luebke, Jennifer I; Kabaso, Doron et al. (2015) Functional consequences of age-related morphologic changes to pyramidal neurons of the rhesus monkey prefrontal cortex. J Comput Neurosci 38:263-83
Luebke, Jennifer I; Medalla, Maria; Amatrudo, Joseph M et al. (2015) Age-related changes to layer 3 pyramidal cells in the rhesus monkey visual cortex. Cereb Cortex 25:1454-68
Clement, Travis; Kutish, Gerald F; Nezworski, Jill et al. (2015) Complete Genome Sequence of a Highly Pathogenic Avian Influenza Virus (H5N2) Associated with an Outbreak in Commercial Chickens, Iowa, USA, 2015. Genome Announc 3:
Chen, Ci-Di; Li, Hu; Liang, Jennifer et al. (2015) The anti-aging and tumor suppressor protein Klotho enhances differentiation of a human oligodendrocytic hybrid cell line. J Mol Neurosci 55:76-90
Kistler, Whitney M; Stallknecht, David E; DeLiberto, Thomas J et al. (2015) Subtype-specific influenza A virus antibodies in Canada geese (Branta canadensis). Vet Microbiol 177:296-301

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