Our initial idea was to produce cognitive deficits in monkeys pretrained to perform a variety of cognitive tasks by administering the dopaminergic neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in doses too low to induce gross parkinsonian motor deficits. Since the clinical literature indicated that cognitive deficits are present at the earliest stages of PD, our goal was try to model this early stage of PD in nonhuman primates. Over several years we developed and refined the chronic-low-dose MPTP administration protocol to produce cognitive deficits in monkeys with minimal or no motor impairments. With continued MPTP exposure, animals develop parkinsonian motor deficits superimposed on earlier appearing cognitive deficits.
In the chronic-low-dose MPTP model of "early" parkinsonism, animals develop cognitive deficits analogous to those described in early PD patients [25-28], including deficits in attention, attention set shifting, cognitive flexibility, planning, and problem solving, but not in working or reference memory per se. Although it has been suggested that there may be a visuospatial working-memory deficit in early medicated PD patients , it is possible that this deficit may not be a working-memory deficit per se but may reflect an impairment in attentional processes involved in visuospatial working-memory tasks . This latter interpretation would be consistent with our data from MPTP-treated monkeys.
Continued administration of low doses of MPTP after cognitive deficits have appeared can result in the development of parkinsonian motor symptoms . Patients with more advanced PD exhibit a broad range of cognitive impairments that include attentional and other "frontal-related" deficits but also impaired performance on at least some memory tasks . Monkeys with moderate parkinsonism continue to have frontal-related cognitive deficits  that interestingly do not respond to the same pharmacotherapies that improve attentional and executive functioning in "early" parkinsonian monkeys, suggesting that pharmacological strategies to improve cognition in PD may need to change as symptoms evolve and as the disease progresses.
ATTENTIONAL AND EXECUTIVE FUNCTION DEFICITS CHARACTERIZE "EARLY" PARKINSONIAN MPTP-TREATED MONKEYS
In the first studies of chronic-low-dose MPTP-treated monkeys, deficits were observed in performance of spatial delayed response (both with fixed and variable delays), delayed alternation, delayed matching-to-sample, visual discrimination reversal, and object retrieval tasks [26, 27]. Deficits in variable delayed-response performance have proven to be particularly interesting and have led to further insights into the nature of the cognitive deficits in these animals. In the variable delayed-response task, the monkeys perform a spatial delayed-response task with different delay lengths randomly distributed over the trials that make up a daily test session. These delay conditions yield approximately chance performance at the longest delay, and normal monkeys perform this task with a delay-dependent increase in errors that reflects the limits of their short-term spatial memory. This task appears to place little load on executive processes, since there is no specific requirement for manipulation or reorganization of the information in working memory.
Chronic-low-dose MPTP-treated monkeys are significantly impaired on performance of this task, with deficits in performing short- and medium-duration delay trials, suggesting an attentional deficit . Because of the nature of the variable delayed-response task, it is difficult to unequivocally separate attention from memory components of task performance. Thus, an additional study was conducted to try to assess more directly the degree to which deficiencies in variable delayed-response task performance could be attributed to attentional or working-memory disturbances. To do this, we used a modified variable delayed-response task with attentional cueing .
On the standard variable delayed-response task, an opaque screen is lifted, and cue presentation (baiting of one of two food wells) occurs over a fixed 2-sec interval. The opaque screen is then lowered for an intratrial delay, and the food wells are covered with two identical sliding plates. The screen is then raised, and the animal is presented with the two wells and is allowed to respond (i.e., uncover one of the two wells and retrieve the reward).
The protocol for the variable delayed-response task with attentional cueing was identical to the variable delayed-response procedures described above, except that the examiner alerted the animal to the baiting of the well to ensure that the monkey was attending to the cue presentation before the opaque screen was lowered. Cue presentation still occurred over a standard 2-sec interval. Test sessions with atten-tional cueing were given to each animal once per week between standard variable delayed-response (VDR) testing sessions. Attentional cueing significantly improved overall task performance in comparison with standard VDR performance in chronic-low-dose MPTP-treated monkeys, and restored a normal pattern of responding. In particular, performance at short- to medium-duration delays was significantly improved by attentional cueing, while cueing had no significant effect on performance of long-duration delay trials (Figure 9.1). Thus, directing the animal's attention to the target presentation significantly improved performance on a spatial working-memory task. Interestingly, attentional cueing, as described above, had no effect on performance of short-, medium-, or long-delay trials in intact animals. It appears then that the main contributor to impaired variable delayed-response performance of chronic-low-dose MPTP-treated monkeys is an attentional deficit that disrupts the encoding of behaviorally relevant information to be kept in short-term memory.
Other studies have shown additional attentional and executive functioning deficits in motor-asymptomatic chronic-low-dose MPTP-treated monkeys . Animals were trained to perform the following attentional and executive function tasks that had low memory demands.
Attention set-shifting ability: This test of cognitive flexibility and set-shifting ability is based on the principle of the Wisconsin Card Sorting Test (WCST), which is known to be impaired in patients with frontal lobe dysfunction and in PD patients, and was modeled after the intradimensional/extradi-mensional set-shift task from the Cambridge Neuropsychological Test Automated Battery . In this task, monkeys were required to shift attention from one perceptual dimension of a complex stimulus to another, e.g., from line to shape. The task consisted of five subtests: simple visual discrimination, simple visual discrimination reversal, compound visual discrimination, and intra/extradimensional shifts (IDS/EDS).
10 20 Delay (sec)
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