Executive system dysfunction occurs as early as middle-age in the rhesus monkey

Abstract

As our understanding of age-related cognitive decline advances, studies are now focusing on identification of those areas of cognitive function that undergo the first changes with age. In the present study, in order to determine whether executive function is sensitive to the aging process, we assessed the performance of 16 monkeys of middle-age (12–19 years of age) on the conceptual set-shifting task, an analogue of the Wisconsin Card Sorting Test (WCST). We compared their performance to that of seven young adult (5–9 years of age) and 18 aged monkeys (20–30). The findings showed that middle-aged monkeys, like those of advanced age, were significantly impaired on the conceptual set-shifting task (CSST). These findings parallel those of recent studies in humans demonstrating an increase in perseverative errors on the WCST by middle-aged as well as aged individuals and, in turn, support the notion that disruption of executive function is one of the earliest changes in cognition to occur in normal aging.

Introduction

It is well established that normal aging is characterized by a decline in multiple domains of cognitive function including short-term memory, psychomotoric speed, naming, and executive function [1], [2], [4], [37], [54]. Of these, executive function (EF) is one of earliest cognitive domains to evidence change in humans [3], [25] and non-human primates alike [8], [9], [41], [60], [61], [76]. Although views on the exact components of EF vary, it is generally agreed that it includes the abilities of set-shifting, planning, working memory, and response suppression (Trans-NIH Executive Function Workshop, January 2003). Among the many tasks that have been developed to assess EF in humans, perhaps the most commonly employed is the Wisconsin Card Sorting Test (WCST [10], [31]). This task, which heavily emphasizes set-shifting and response suppression, has been used in studies of normal aging [26], the effects of focal cortical lesions [46], [47], head injury [42], attention deficit disorder [40], depression [12], and a host of other neurologic and psychiatric disorders [38]. The popularity of the WCST for use in clinical studies and neuropsychological assessment is due in large measure to its simplicity of design, use of common stimulus classes, amenability to error analyses, and minimum dependence on language. Toward the goal of bringing behavioral studies in humans and animals into parallel, the WCST has been successfully adapted in nearly identical form [49], [51], [52], or in forms that are analogous to it [24] for use in non-human primates.

With regard to normal aging, the WCST was first used 15 years ago to show that subjects in their 70s and 80s were impaired in executive function [34]. Together with findings from more recent studies [11], [32], [36], [64], [65] it is clear that even in earlier stages of aging, there is a diminution in the ability to shift and maintain set, as well as an increased tendency to respond to previously correct stimuli (i.e., perseverative errors). We have developed the conceptual set-shifting task (CSST), a direct adaptation of the WCST, as a tool for the study of EF in a rhesus monkey model of normal cognitive aging. In studies using the CSST in aged monkeys, we demonstrated deficits in abstraction, set-shifting and set maintenance in aged rhesus monkeys that parallel those seen in the human studies [49], [51]. Specifically, monkeys of advanced age (20–30 years of age, roughly equivalent to humans ages of 60–90 years) were impaired in abstraction and set-shifting on the CSST relative to young adults (5–9 years of age, equivalent to human ages of 15–27 years). Moreover, as found in aged humans, aged monkeys made significantly more perseverative errors during each shift in stimulus set of the CSST [51].

Although these data clearly demonstrate an age-related deficit in executive function, they do not pinpoint the age at which cognitive decline begins. In the present study, we have addressed this important question by using the CSST to determine whether deficits in EF are already evident in monkeys 12–19 years, a range spanning early to late middle-age.