Clinical severity in Parkinson’s disease is determined by decline in cortical compensation

Abstract

AbstractDopaminergic dysfunction in the basal ganglia, particularly in the post-commissural putamen, is often viewed as the primary pathological mechanism behind motor slowing (i.e., bradykinesia) in Parkinson’s disease. However, striatal dopamine loss fails to account for inter-individual differences in motor phenotype and rate of decline, implying that the expression of motor symptoms depends on additional mechanisms, some of which may be compensatory in nature. Building on observations of increased motor-related activity in the parieto-premotor cortex of Parkinson patients, we tested the hypothesis that inter-individual differences in clinical severity are determined by compensatory cortical mechanisms, and not just by basal ganglia dysfunction.Using functional MRI, we measured variability in motor- and selection-related brain activity during a visuomotor task in 353 patients with Parkinson’s disease (≤5 years disease duration) and 60 healthy controls. In this task, we manipulated action selection demand by varying the number of possible actions that individuals could choose from. Clinical variability was characterized in two ways. First, patients were categorized into three previously validated, discrete clinical subtypes: diffuse-malignant (n=42), intermediate (n=128), or mild motor-predominant (n=150). Second, we used the total bradykinesia score across the entire sample as a continuous measure.Patients showed motor slowing (longer response times) and reduced motor-related activity in the basal ganglia compared to controls. However, basal ganglia activity did not differ between clinical subtypes and was not associated with clinical bradykinesia scores. This indicates a limited role for striatal dysfunction in shaping inter-individual differences in symptom severity. Consistent with our hypothesis, we observed enhanced action selection-related activity in the parieto-premotor cortex of patients with a mild-motor predominant subtype, both compared to patients with a diffuse-malignant subtype and to controls. Furthermore, parieto-premotor activity was inversely related to bradykinesia, which points to a compensatory role.We conclude that parieto-premotor compensation, rather than basal ganglia dysfunction, shapes inter-individual variability in symptom severity in Parkinson’s disease. Future interventions may focus on maintaining and enhancing compensatory cortical mechanisms, rather than only attempting to normalize basal ganglia dysfunction.