Changes in network activity with the progression of Parkinson's disease

Abstract

Parkinson's disease (PD) is associated with abnormal activity in spatially distributed neural systems mediating the motor and cognitive manifestations of this disorder. Metabolic PET studies have demonstrated that this illness is characterized by a set of reproducible functional brain networks that correlate with these clinical features. The time at which these abnormalities appear is unknown, as is their relationship to concurrent clinical and dopaminergic indices of disease progression. In this longitudinal study, 15 early stage PD patients (age 58.0 +/- 10.2 years; Hoehn and Yahr Stage 1.2 +/- 0.3) were enrolled within 2 years of diagnosis. The subjects underwent multitracer PET imaging at baseline, 24 and 48 months. At each timepoint they were scanned with [18F]-fluorodeoxyglucose (FDG) to assess longitudinal changes in regional glucose utilization and in the expression of the PD-related motor (PDRP) and cognitive metabolic covariance patterns (PDCP). At each timepoint the subjects also underwent PET imaging with [18F]-fluoropropyl betaCIT (FP-CIT) to quantify longitudinal changes in caudate and putamen dopamine transporter (DAT) binding. Regional metabolic changes across the three timepoints were localized using statistical parametric mapping (SPM). Longitudinal changes in regional metabolism and network activity, caudate/putamen DAT binding, and Unified Parkinson's Disease Rating Scale (UPDRS) motor ratings were assessed using repeated measures analysis of variance (RMANOVA). Relationships between these measures of disease progression were assessed by computing within-subject correlation coefficients. We found that disease progression was associated with increasing metabolism in the subthalamic nucleus (STN) and internal globus pallidus (GPi) (P < 0.001), as well as in the dorsal pons and primary motor cortex (P < 0.0001). Advancing disease was also associated with declining metabolism in the prefrontal and inferior parietal regions (P < 0.001). PDRP expression was elevated at baseline relative to healthy control subjects (P < 0.04), and increased progressively over time (P < 0.0001). PDCP activity also increased with time (P < 0.0001). However, these changes in network activity were slower than for the PDRP (P < 0.04), reaching abnormal levels only at the final timepoint. Changes in PDRP activity, but not PDCP activity, correlated with concurrent declines in striatal DAT binding (P < 0.01) and increases in motor ratings (P < 0.005). Significant within-subject correlations (P < 0.01) were also evident between the latter two progression indices. The early stages of PD are associated with progressive increases and decreases in regional metabolism at key nodes of the motor and cognitive networks that characterize the illness. Potential disease-modifying therapies may alter the time course of one or both of these abnormal networks.

Fig. 1

Parkinson’s Disease-Related Spatial Covariance Patterns. (A) Parkinson’s Disease-Related Pattern (PDRP). This motor-related metabolic pattern was identified by network analysis of [¹⁸F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans from 33 PD patients and 33 age-matched healthy volunteers (Ma et al., 2007). This pattern was characterized by relative increases in pallidothalamic, pontocerebellar and motor cortical/supplementary motor area (SMA) metabolic activity (top), associated with reductions in the lateral premotor and posterior parietal areas (bottom). PDRP expression was significantly increased in the PD cohort (P<0.001) compared to controls. (B) Parkinson’s Disease-Related Cognitive Pattern (PDCP). This cognition-related metabolic pattern was identified in the network analysis of FDG PET scans from 15 non-demented PD patients with mild-moderate motor symptoms (Huang et al., 2007). This pattern was characterized by relative hypometabolism of dorsolateral prefrontal cortex, rostral supplementary motor area (preSMA) and superior parietal regions, associated with relative cerebellar/dentate nucleus metabolic increases. PDCP expression correlated significantly (P<0.01) with psychometric indices of memory and executive functioning. [The displays represent voxels that contribute significantly (P<0.001) to each of the two networks. Voxels with positive region weights (metabolic increases) are colour-coded from red to yellow; those with negative region weights (metabolic decreases) are colour-coded from blue to purple.]

Fig. 2

Mean off-state Unified Parkinson’s Disease Rating Scale (UPDRS) motor ratings at baseline, 24 and 48 months. These scores increased linearly over time (P<0.0001; RMANOVA), at a rate of 2.1 units per year (see text). [Bars represent the standard error at each timepoint.]

Fig. 3

Mean striatal DAT binding at baseline, 24 and 48 months. Values for the caudate (squares) and putamen (triangles) are represented as percent of the normal mean value for each region (see text). In both regions, DAT binding declined linearly over time (P<0.003; RMANOVA). [Bars represent the standard error at each timepoint.]

Fig. 4

(A) Voxel-based analysis of longitudinal changes in regional metabolic activity. Metabolic increases with disease progression (top) are displayed using a red–yellow scale. Progressive metabolic declines (bottom) are displayed using a blue–purple scale. Both displays were superimposed on a single-subject MRI brain template and thresholded at t = 3.48, P = 0.001 (peak voxel, uncorrected). (B) Displays of the metabolic data for these individual regions at each timepoint (Table 2). The significance level (P-value) of the repeated measures analysis of variance (RMANOVA) is presented for each region (see text). [The coordinates refer to the Montreal Neurological Institute (MNI) standard space. GPi: internal globus pallidus, STN: subthalamic nucleus, BA: Brodmann area.]

Fig. 5

Mean network activity at baseline, 24 and 48 months. Values for the PD-related motor and cognitive spatial covariance patterns (PDRP and PDCP; see Fig. 1) were computed at each timepoint and displayed relative to the mean for 15 age-matched healthy subjects (see text). Network activity increased significantly over time for both patterns (P<0.0001; RMANOVA), with the PDRP progressing faster than the PDCP (P<0.04). Relative to controls, PDRP activity in the patient group was elevated at all three timepoints, while PDCP activity reached abnormal levels only at the final timepoint. [Bars represent the standard error at each timepoint.]