Abstract
Parkinson's disease (PD) evolves over an extended and variable period in humans; years prior to the onset of classical motor symptoms, sleep and biological rhythm disorders develop, significantly impacting the quality‐of‐life of patients. Circadian‐rhythm disorders are accompanied by mild cognitive deficits that progressively worsen with disease progression and can constitute a severe burden for patients at later stages. The gold‐standard 6‐methyl‐1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridin (MPTP) macaque model of PD recapitulates the progression of motor and nonmotor symptoms over contracted periods of time. Here, this multidisciplinary/multiparametric study follows, in five animals, the steady progression of motor and nonmotor symptoms and describes their reversal following grafts of neural precursors in diverse functional domains of the basal ganglia. Results show unprecedented recovery from cognitive symptoms in addition to a strong clinical motor recuperation. Both motor and cognitive recovery and partial circadian rhythm recovery correlate with the degree of graft integration, and in a subset of animals, with in vivo levels of striatal dopaminergic innervation and function. The present study provides empirical evidence that integration of neural precursors following transplantation efficiently restores function at multiple levels in parkinsonian nonhuman primates and, given interindividuality of disease progression and recovery, underlines the importance of longitudinal multidisciplinary assessments in view of clinical translation.
Highlights
INTRODUCTIONParkinson’s disease (PD) is a neurodegenerative condition affecting up to 10M of the worldwide population with incidences increasing with age, making PD the fastest growing neurological disorder in a globally aging population [1]
Non-motor symptoms have a significant impact on quality of life; the cognitive abilities of the vast majority of PD patients deteriorate leading to psychiatric disturbances [6]
Clinical scores and behavioral measures were divided into quantiles (Q1-5, as described in [25], see Materials and Methods) in order to compare cases on the basis of the presumed DA-lesion rather than on the time spent in the premotor (MPTP), motor and post-graft periods
Summary
INTRODUCTIONParkinson’s disease (PD) is a neurodegenerative condition affecting up to 10M of the worldwide population with incidences increasing with age, making PD the fastest growing neurological disorder in a globally aging population [1]. 60-80% of DA cells are lost prior to the onset of clinically diagnosed motor symptoms [3] During this so-called premotor period preceding the clinical threshold, the DA-lesion is progressive and accompanied by the manifestation and further deterioration of non-motor symptoms including cognitive disorders as well as perturbation of circadian rhythm and sleep disorders [4, 5]. Cell replacement therapy for PD has been recently re-evaluated as a potential cure for PD [11], leading to recent trials [12] aimed at improved grafting procedures, and to pave the way for stem-cell based transplantation in humans In this respect there is a recognized need for more detailed perspectives from pre-clinical investigations in animal models [13]
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