Metabolic brain networks associated with cognitive function in Parkinson's disease

Abstract

The motor manifestations of Parkinson's disease (PD) have been linked to an abnormal spatial covariance pattern involving basal ganglia thalamocortical pathways. By contrast, little is known about the functional networks that underlie cognitive dysfunction in this disorder. To identify such patterns, we studied 15 non-demented PD patients using FDG PET and a voxel-based network modeling approach. We detected a significant covariance pattern that correlated (p<0.01) with performance on tests of memory and executive functioning. This PD-related cognitive pattern (PDCP) was characterized by metabolic reductions in frontal and parietal association areas and relative increases in the cerebellar vermis and dentate nuclei. To validate this pattern, we analyzed data from 32 subsequent PD patients of similar age, disease duration and severity. Prospective measurements of PDCP activity predicted memory performance (p<0.005), visuospatial function (p<0.01), and perceptual motor speed (p<0.005) in this validation sample. PDCP scores additionally exhibited an excellent degree of test-retest reliability (intraclass correlation coefficient, ICC=0.89) in patients undergoing repeat FDG PET at an 8-week interval. Unlike the PD-related motor pattern, PDCP expression was not significantly altered by antiparkinsonian treatment with either intravenous levodopa or deep brain stimulation (DBS). These findings substantiate the PDCP as a reproducible imaging marker of cognitive function in PD. Because PDCP expression is not altered by routine antiparkinsonian treatment, this measure of network activity may prove useful in clinical trials targeting the progression of non-motor manifestations of this disorder.

Fig. 1

Parkinson’s disease-related cognitive pattern (PDCP) identified by spatial covariance analysis of FDG PET scans from 15 PD patients (see text). This pattern was characterized by covarying metabolic reductions in the rostral supplementary motor area (pre-SMA) and precuneus (left), as well as in the dorsal premotor (PMC) and posterior parietal regions (middle), and in the left prefrontal cortex (right). Relative metabolic increases in the cerebellar vermis and dentate nuclei (DN) were also identified as part of this cognition-related topography. [The display represents regions that contributed significantly to the network at Z>2.44 (p≤0.01) and were demonstrated to be reliable (p<0.05) by bootstrap resampling (Efron and Tibshirani, 1994). Voxels with positive region weights (metabolic increases) are color-coded red, those with negative region weights (metabolic decreases) are color-coded blue].

Fig. 2

(A) Plots of mean (±SE) and individual values for PDCP expression in the original identification group (PD1, n=15; filled squares) and in the subsequent validation group (PD2, n=32; filled triangles). For reference, network scores were also computed on an individual case basis in an age-matched group of healthy control subjects (CN, n=15; open circles). PDCP activity was elevated in both patient groups (PD1: p <0.005; PD2: p<0.0001, Student’s t test) relative to control values. There was no difference in PDCP expression between the two patient cohorts (p=0.76). (B) Correlation between measures of PDCP expression obtained in 20 PD patients scanned at baseline (test) and 8 weeks later (retest) (R²=0.82, p<0.0001). The fitted regression line had a slope of 1.09 (95% confidence interval (CI) 0.84 to 1.34), indicating no difference from the diagonal reference line (dots). These data are consistent with high within-subject reproducibility (see text).

Fig. 3

Correlations between PDCP expression and neuropsychological test performance in the original identification group (PD1, n=15; filled squares) and in the prospective validation group (PD2, n=32; filled triangles). Significant linear relationships between network activity and performance (p<0.01) on the following tests are displayed for the whole sample (fitted regression lines and 95% confidence intervals): (A) Trails Making Test B (Trails B), (B) California Verbal Learning Test: Sum 1 to 5 (CVLT Sum), (C) Symbol Digit Modality Test (SDMT), and (D) the Hooper Visual Organization Test (Hooper VOT).

Fig. 4

Bar graph illustrating mean (±SE) treatment-mediated changes in the expression of the PDCP (left) and PDRP (right) disease-related spatial covariance patterns (see text). ON–OFF differences in network activity with levodopa infusion (LD; black) and subthalamic nucleus deep brain stimulation (DBS; gray) compared with changes in network activity without intervention (CN; white). Significant treatment-mediated changes were observed only for the motor-related PDRP network (*p<0.05, **p<0.01).