Motor sequence analysis as a sensitive biomarker of dopaminergic degeneration in a non-human primate model of parkinsonism

Abstract

Parkinsons disease is characterized by progressive dopaminergic degeneration, yet motor symptoms emerge only after substantial neuronal loss - a dissociation that challenges the sensitivity of conventional behavioral endpoints in preclinical models. Here, we present a proof-of-principle study establishing a graded hemiparkinsonism model in adult male capuchin monkeys (Sapajus apella) through unilateral, MRI-guided stereotaxic injection of 6-hydroxydopamine into the substantia nigra pars compacta. Three toxin concentrations (4, 10, and 40 mg/mL; n = 3) were tested alongside a vehicle-injected sham control (n = 1). Motor function was assessed longitudinally before and after surgery using a three-task battery comprising the Staircase test, Tube test, and Brinkman board, capturing complementary dimensions of motor functions, including gross lateralization, forelimb use asymmetry, and fine digit coordination. Critically, we introduce a novel sequence-deviation metric applied to Brinkman board performance data to quantify disruption in the spatial organization of pellet retrieval independently of task success. Post-surgical tyrosine hydroxylase immunohistochemistry combined with optical fractionator stereology revealed ipsilateral dopaminergic cell losses of 47%, 59%, and 44% relative to the contralateral hemisphere across the three treated animals, with the sham showing no meaningful hemispheric difference. Behavioral impairments were heterogeneous and strategy-dependent: task completion rates were largely preserved, whereas fine motor strategy analysis revealed post-lesion increases in retrieval sequence disorganization in two of three animals. Exploratory regression analyses suggested that strategy-level metrics were more sensitive to nigrostriatal degeneration than global performance measures. These findings demonstrate that capuchin monkeys subjected to unilateral 6-hydroxydopamine lesions reproduce clinically relevant features of hemiparkinsonism and that motor sequence analysis constitutes a sensitive readout of subclinical dopaminergic dysfunction, and can outperform conventional performance-based metrics detecting early motor alterations, therefore a potential biomarker of subclinical dopaminergic dysfunction, with implications for early detection paradigms in Parkinsons disease research.