Attention and executive function deficits in chronic low‐dose MPTP‐treated non‐human primates

Abstract

Parkinson's disease (PD) is a complex disorder consisting of motor deficits coupled with dysfunction in cognitive domains that are dependent upon the integrity of the frontal lobes and/or the fronto-striatal axis. Although it is increasingly acknowledged that PD patients have attentional and executive function deficits, it has been difficult to model these in nonhuman primates because of the nature of the cognitive tasks that have been used previously. The present studies were conducted to further define the nature of the cognitive impairment in a nonhuman primate model of early parkinsonism consequent to chronic low dose MPTP exposure and to further validate this model in monkeys trained to perform a battery of attentional and executive function tasks. Following chronic low dose MPTP exposure, monkeys developed deficits in maintenance of a response set as well problems in shifting attentional sets, suggesting decreased mental flexibility. On other tasks inattentiveness, an impaired ability to sustain spatial attention or to focus attention, a deficit in motor readiness and planning, and impaired time estimation were also observed. These results provide direct evidence of attention and executive function deficits in a nonhuman primate model of early parkinsonism. Based on these findings, we suggest that in addition to being useful for studying the cognitive deficits related to early PD and for developing new therapeutics for these problems, this model and these testing procedures may also provide a useful large animal model for studying attention deficit disorder and for developing new therapeutics for that condition as well.

Toxin-induced models of Parkinson’s disease

“…Impaired ability to sustain spatial attention or to focus attention, deficit in motor readiness and planning, and impaired time estimation were observed in these animals. 70 Collectively, these cognitive alterations are consistent with attention and executive functional deficits following MPTP intoxication, which is very similar to some of the cognitive alterations seen in PD patients. As emphasized by Stern,68 it is also remarkable to note that none of the symptomatic individuals who were intoxicated with MPTP showed neurological signs others than those expected for PD; a similar statement may be true for MPTP-injected monkeys.…”

“…Cognitive impairments evidenced by poor performances on constructive, verbal fluency and executive function tests were demonstrated in MPTP patients. 68,69 Apparently, not in humans 68,69 but in monkeys intoxicated with MPTP, 70 deficits in maintenance of a response set and difficulties in shifting attentional sets were also found. Impaired ability to sustain spatial attention or to focus attention, deficit in motor readiness and planning, and impaired time estimation were observed in these animals.…”

Understanding cognitive deficits in Parkinson’s disease: lessons from preclinical animal models

“…In this case, before the screen is lowered the examiner alerts the animal to the baiting of the well to ensure that the monkey pays attention to the wells. Interestingly, this protocol did not change control animals' score, but significantly improved the performance of MPTPtreated monkeys (Decamp et al 2004a). An additional variant of VDR is the modified delayed response (MDR) task, in which the attentional demands of the task are manipulated to allow good performance in trials with low attentional load and impaired performance in trials with higher attentional load by increasing the length of time of cue presentation.…”

Initial clinical manifestations of Parkinson's disease: features and pathophysiological mechanisms

“…However, a recent ¹¹C-raclopride study of spatial working memory concluded that executive dysfunction in patients with early PD is associated with impaired nigrostriatal function and that mesocortical dopaminergic function is well preserved in early PD. 22 Similarly, data from several studies in monkeys with minimum motor defi cits after low and slow MPTP exposure have shown defi cits in executive function and attention, 101 which were best explained by a nigrostriatal lesion. 102 These fi ndings suggest that dysfunction of cortico-basal ganglia associative areas secondary to dopamine depletion might have an important role in early executive problems in patients with PD.…”