Brain Aging and Cognitive Function Agerelated Neuropathology

Among other age-related changes in neural anatomy and function, rhesus monkeys also develop pathological characteristics of Alzheimer's disease (AD), specifically regional deposition of amyloid-^ (A^) plaques similar to aged humans (Gearing et al., 1996). These A^ plaques are associated with angiopathy. Although A^ accumulates in rhesus brains, neurofibrillary tangles, another hallmark AD pathology, are not formed (Nelson et al., 1996). Paralleling success in mice, current interest is emerging for producing transgenic monkeys in which AD can be accurately modeled.

Studies have also examined age-related changes in rhesus brain. While brain mass does not decline with age (Herndon et al., 1998), reductions have been observed in specific regional volumes, for example, the basal ganglia (Matochik et al., 2000). The age-related decline in fine motor behavior has been associated with diminished nigrostriatal system function and was not improved in aging female monkeys given ethinyl estradiol treatment (Lacreuse and Herndon, 2003). Interestingly, males showed greater slowing of fine motor function; both males and females had age-related decreases in normalized caudate and putamen volumes (Lacreuse et al., 2005). Furthermore, the age-related decrease in delay-match-to-sample and nonmatch-to-sample cognitive performance was linked to prefrontal cortex activity on fMRI (Lamar et al., 2005).

Also similar to humans, no significant age-related loss of hippocampal or neocortical neurons is observed in rhesus monkeys (Duan et al., 2003; Keuker et al., 2003). Rather, behavioral deficits associated with hippocampal dysfunction appear to result from neurophysiological deficits in interneuronal signaling rather than cell death

(Small et al., 2004). Cerebral blood volume decreases with age in hippocampal dentate gyrus (Small et al., 2004). Cerebral cortex loses dendrites and arbors with advancing age (Duan et al., 2003). Neurotransmitter receptor and transporter binding in specific regions, including post-synaptic dopamine receptors and presynaptic vesicular acetylcholine transporters (Voytko, 2000, 2002; Tinkler and Voytko, 2005), show age-related loss in basal ganglia. Hippocampal cholinergic fibers are also lost with age (Calhoun et al., 2004) as well as changes in the integrity of white matter (Peters et al., 1996).

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