Abstract
BackgroundIt is increasingly recognized that non-motor symptoms are a prominent feature of Parkinson's disease and in the case of cognitive deficits can precede onset of the characteristic motor symptoms. Here, we examine in 4 monkeys chronically treated with low doses of the neurotoxin MPTP the early and long-term alterations of rest-activity rhythms in relationship to the appearance of motor and cognitive symptoms.Methodology/Principal FindingsBehavioral activity recordings as well as motor and cognitive assessments were carried out continuously and in parallel before, during and for several months following MPTP-treatment (12–56 weeks). Cognitive abilities were assessed using a task that is dependent on the functional integrity of the fronto-striatal axis. Rest-activity cycles were monitored continuously using infrared movement detectors of locomotor activity. Motor impairment was evaluated using standardized scales for primates. Results show that MPTP treatment led to an immediate alteration (within one week) of rest-activity cycles and cognitive deficits. Parkinsonian motor deficits only became apparent 3 to 5 weeks after initiating chronic MPTP administration. In three of the four animals studied, clinical scores returned to control levels 5–7 weeks following cessation of MPTP treatment. In contrast, both cognitive deficits and chronobiological alterations persisted for many months. Levodopa treatment led to an improvement of cognitive performance but did not affect rest-activity rhythms in the two cases tested.Conclusions/SignificancePresent results show that i) changes in the rest activity cycles constituted early detectable consequences of MPTP treatment and, along with cognitive alterations, characterize the presymptomatic stage; ii) following motor recovery there is a long-term persistence of non-motor symptoms that could reflect differential underlying compensatory mechanisms in these domains; iii) the progressive MPTP-monkey model of presymptomatic ongoing parkinsonism offers possibilities for in-depth studies of early non-motor symptoms including sleep alterations and cognitive deficits.
Highlights
Parkinson’s syndrome (PS) was initially characterized by motor symptoms including rigidity, akinesia and tremor
In one case motor deficits persisted after MPTP treatment cessation and here cognitive and chronobiological deficits could not be dissociated
Despite the different durations of MPTP intoxication required to attain clinical threshold and the different scores attained after MPTP-Off, the three monkeys that spontaneously recovered presented relatively similar temporal dynamics of motor recovery
Summary
Parkinson’s syndrome (PS) was initially characterized by motor symptoms including rigidity, akinesia and tremor. It is increasingly recognized that these motor deficits are accompanied in 88% of PS patients by symptoms affecting cognitive performance, neuropsychiatric states, sleep, autonomic, and sensory domains which are important factors contributing to physical and mental disability [1,2,3,4]. These non-motor symptoms have important consequences contributing to a decline in the quality of life. We examine in 4 monkeys chronically treated with low doses of the neurotoxin MPTP the early and long-term alterations of rest-activity rhythms in relationship to the appearance of motor and cognitive symptoms
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