The broad objective of this research is to study the relationship between particular cognitive events, specifically failure in working memory, attention, and executive function, and particular biological events, specifically amyloid beta (Ab) accumulation, tau deposits, immune reactivity in glial cells, neurogenesis, and cell loss, in an aging nonhuman primate model.
One specific aim i s to develop a set of cognitive tasks that can be used with nonhuman primates to reveal age- dependent losses and to differentiate those from losses emerging from neuropathological conditions. Individuals of a specific species, the cotton top tamarin, are tested in 3 cognitive tasks that have been found to separate unique differences in aging and Alzheimer's disease (AD) in humans. The three tasks developed for primates have been used extensively with humans with high replicability over studies. Differences between elderly human controls and AD patients emerge in tests of immediate forgetting, visuospatial attention, and failures in rule- shifting. The memory task employed in this current project, delayed matching-to-sample, has also been used extensively in comparative cognition with highly consistent results. A visual search task, which has been used both to study humans and other animals, is also employed. A version of the Dimensional Change Card Sort (DCCS) task is created to test flexibility in rule shifting in monkeys. Tamarins are tested daily in short sessions in each task through the end of a natural aging process, and then assessed post mortem by immunohistochemical techniques to estimate the AD markers Ab and hyperphosphorylated tau, glial reactivity, neural death, and neurogenesis. A second specific aim is to determine whether these biological events correlate with age and reveal a particular neural signature that would explain cognitive failures that subjects expressed near the end of life. Disease-modifying treatments for dementia and AD will emerge from understanding how changes in the neural environment induce failures in cognition and attention. Tamarins have demonstrated Ab accumulation in an age-dependent fashion similar to humans, and cognitive, perceptual, and social thinking and cooperative breeding comparable in unique ways to humans. Another goal is to provide biological and cognitive data from a species closely related to the common marmoset, another species in the Callitrichidae primate family which is becoming a prominent model in AD and aging research. The tamarin model is tested as they naturally age, with results from tasks that typically differentiate AD from aging in humans, and correlated with biological events used to diagnose AD in humans.
This research compares cognitive outcomes in aging tamarins in tests of immediate forgetting, visual search, and rule set shifting with biological events measured post mortem which are linked to Alzheimer's disease (AD) and aging in humans. Multiple regression analyses will determine the relationships among these biological events, including Ab and hyperphosphorylated tau, glial reactivity, neural death, level of neurogenesis, measured cognitive outcomes, and aging. Disease-modifying treatments for dementia and AD are more likely to emerge from a deeper understanding of how changes in the neural environment induce failures in cognition and attention.