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

Abstract

Dopaminergic dysfunction in the basal ganglia, particularly in the posterior 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 interindividual 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 interindividual 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 that are hypothesized to reflect distinct routes of α-synuclein propagation: diffuse-malignant (n = 42), intermediate (n = 128) or mild motor-predominant (n = 150). Second, we used the scores of bradykinesia severity and cognitive performance across the entire sample as continuous measures. Patients showed motor slowing (longer response times) and reduced motor-related activity in the basal ganglia compared with controls. However, basal ganglia activity did not differ between clinical subtypes and was not associated with clinical scores. This indicates a limited role for striatal dysfunction in shaping interindividual differences in clinical 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 controls. Furthermore, increased parieto-premotor activity was related to lower bradykinesia severity and better cognitive performance, which points to a compensatory role. We conclude that parieto-premotor compensation, rather than basal ganglia dysfunction, shapes interindividual 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.

Keywords: Parkinson’s disease; action selection; compensation; fMRI; interindividual differences.

Figure 1

Action selection task and Parkinson-related deficits. (A) Participants respond to highlighted circles with one out of four response buttons. When multiple circles are highlighted, participants are instructed to select one response button. Action selection demand is parametrically manipulated by varying the number of highlighted circles that are presented. During catch trials, participants are instructed to withhold a response. No feedback was given to indicate the correctness of responses. (B) Parkinson’s disease leads to general deficits in task performance. (C) Parkinson’s disease leads to reduced motor-related activity in a network of core motor regions and reduced selection-related deactivation in the middle temporal gyrus. Box plots show the first and third quartiles (boxes), median (horizontal line), mean (diamond) and 1.5 × interquartile range (whiskers). Brain images show t-values of significant clusters. FWEc = Family-wise error cluster; HC = healthy control; PD = Parkinson’s disease; PD-On = ON-medicated Parkinson’s disease; SE = standard error. *P < 0.05, ***P < 0.001.

Figure 2

Evidence for parieto-premotor compensation. (A) Greater selection-related increase in response times in intermediate compared to mild-motor predominant patients. (B) Reduced motor-related activity in diffuse-malignant compared to mild-motor predominant and intermediate patients. Box plots show the first and third quartiles (boxes), median (horizontal line), mean ( diamond) and 1.5 × interquartile range (whiskers). Brain images show t-values of significant clusters. DM = diffuse-malignant; FWEc = family-wise error cluster; IM = intermediate; L = left; MMP = mild-motor predominant; R = right. ⁺P < 0.09, *P < 0.05, **P < 0.01; ***P < 0.001.

Figure 3

Post hoc comparisons between subtypes and controls. Reduced selection-related activity in diffuse-malignant compared to mild-motor predominant and intermediate patients (MMP > HC, Three > One). In comparison to controls, mild-motor predominant patients show increased selection-related parieto-premotor activity whereas diffuse-malignant patients show the opposite (HC > DM, Three > One). Box plots show the first and third quartiles (boxes), median (horizontal line), mean (diamond) and 1.5 × interquartile range (whiskers). Brain images show t-values of significant clusters. DM = diffuse-malignant; FWEc = family-wise error cluster; HC = healthy control; L = left; MMP = mild-motor predominant; R = right. **P < 0.01, ***P < 0.001.

Figure 4

Associations with specific clinical domains. (A) Task performance predicts bradykinesia severity (left) and cognitive performance (right). (B) Associations with bradykinesia severity. (C) Associations with cognitive performance. Line-plots show linear associations (solid line) and standard errors (outline). Brain images show t-values of significant clusters. Bradykinesia severity was defined as a subscore of the Movement Disorders Society Unified Parkinson Disease Rating Scale part III (MDS-UPDRS part III). Cognitive performance was defined as a composite score of clinical assessments across multiple cognitive domains. FWEc = family-wise error cluster; L = left; PMC = premotor cortex; SE = standard error; SPL = superior parietal lobule; R = right; ± = positive/negative correlation. **P < 0.01, ***P < 0.001.

Figure 5

Model of the relationship between changes in brain activity and motor symptom progression. (A) Parieto-premotor activity is enhanced to compensate for basal ganglia dysfunction during the presymptomatic phase of Parkinson’s disease. Eventually, parieto-premotor compensation begins to decline, leading to the emergence of motor impairments caused by basal ganglia dysfunction. According to this model, decline in motor performance depends on loss of cortical compensation rather than progressive basal ganglia dysfunction. (B) Subtypes may be differentiated by the rate at which cortical compensation declines, the degree to which cortical resources can be recruited for compensatory purposes, or a combination of the two. DM = diffuse-malignant; IM = intermediate; MMP = mild-motor predominant.