Abnormalities in metabolic network activity precede the onset of motor symptoms in Parkinson's disease

Abstract

Imaging studies show that Parkinson's disease (PD) alters the activity of motor- and cognition-related metabolic brain networks. However, it is not known whether the network changes appear at or before symptom onset. In this study, we examined 15 hemiparkinsonian patients who underwent serial metabolic imaging with [(18)F]-fluorodeoxyglucose (FDG) PET at baseline and again 2.1 +/- 0.6 (mean +/- SD) and 3.9 +/- 0.7 years later. We assessed longitudinal changes in network activity in each cerebral hemisphere, focusing specifically on the "presymptomatic" hemisphere--ipsilateral to the initially involved body side. At the network level, the activity of the PD motor-related pattern (PDRP) increased symmetrically in both hemispheres over time (p < 0.001), with significant bilateral elevations at each of the three time points. Hemispheric expression of the PD cognition-related pattern likewise increased symmetrically (p < 0.001), although significant elevations were not evident on either side until 4 years. At the regional level, putamen metabolism contralateral to the initially affected body side was elevated at all three time points, without longitudinal change. In contrast, in the initially presymptomatic hemisphere, putamen metabolic activity increased steadily over time, reaching abnormal levels only at 4 years. Metabolic activity in the contralateral precuneus fell to subnormal levels by the final time point. These findings suggest that abnormal PDRP activity antecedes the appearance of motor signs by approximately 2 years. The timing and laterality of symptom onset relates to focal asymmetric metabolic changes at the putamenal node of this network.

Figure 1.

Time course of limb UPDRS motor ratings. Off-state UPDRS motor ratings increased over time (p < 0.001) at a similar rate for the initially affected (circles) and presymptomatic (triangles) body sides. The error bars represent one SEM at each time point.

Figure 2.

Time course of hemispheric DAT binding. A, DAT binding values in the caudate were lower (p < 0.01) in the hemisphere (circles) contralateral to the clinically more affected limbs compared to the ipsilateral side (triangles) at baseline and at 2 and 4 years. Over time, caudate binding declined (p < 0.01) at similar rates for the two hemispheres. B, Putamen DAT binding values were lower (p < 0.05) in the contralateral hemisphere (circles) compared to the ipsilateral side (triangles) at each of the three time points. Over time, putamen binding declined at different rates (p < 0.005) for the two hemispheres, with a faster rate on the ipsilateral hemisphere relative to the contralateral side. Binding values in each hemisphere and each region are represented as percentage of the normal mean (100%, broken line) at each time point. Dotted lines represent one SEM above and below the normal mean for each region. *p < 0.05, **p < 0.01, ***p < 0.001, Student's t tests compared to normal controls.

Figure 3.

Time course of hemispheric PD-related network activity. Subject expression of the PD-related motor (A, PDRP) and cognitive (B, PDCP) spatial covariance patterns in the contralateral (circles) and ipsilateral (triangles) hemispheres at baseline and at 2 and 4 years. For both metabolic networks, hemispheric activity was symmetric at each time point. For PDRP, pattern expression in the PD patients was elevated (p < 0.05) in both hemispheres relative to controls at each time point. In contrast, PDCP expression reached abnormally elevated levels (p < 0.01) in both hemispheres only at the third time point. For both sides, the activity of each network increased in parallel over time. Scores for each network were computed for each hemisphere and time point and displayed relative to the mean value (broken line) of 15 age-matched healthy subjects. Dotted lines represent one SEM above and below the normal mean for each pattern. *p < 0.05, **p < 0.01, ***p < 0.001, Student's t tests compared to normal controls.

Figure 4.

Time course of hemispheric differences in regional metabolism. A, B, At baseline, voxelwise searches revealed hemispheric differences in glucose metabolism in the putamen (A, left) and in the anterior cingulate cortex (B, left), with relatively higher metabolism in the contralateral hemisphere compared to the ipsilateral side. Regional metabolism in these regions, however, did not show significant hemispheric differences at 2 and 4 years. In the putamen (A, right), metabolic activity in the contralateral hemisphere (black bars) remained above normal (p < 0.05) at all three time points, while metabolism on the ipsilateral side (white bars) progressively increased, reaching abnormal levels (p < 0.05) only at the third time point. In the cingulate cortex (B, right), contralateral metabolism was elevated at baseline and 2 years (p < 0.05), while ipsilateral metabolism did not differ from normal at all three time points (p > 0.11). C, At 2 years, hemispheric differences in regional metabolism were present in the SMA (left), with relatively higher metabolism in the contralateral hemisphere compared to the ipsilateral side. Hemispheric differences were not significant at baseline and 4 years. Metabolic activity in this region (right) did not differ significantly from normal on either side at any time point (p > 0.16). D, At 4 years, hemispheric differences in metabolism were present in the precuneus (left), with relatively lower metabolic activity in the contralateral hemisphere compared to the ipsilateral side. Hemispheric differences were not significant at baseline and 2 years. In this region, metabolic activity significantly declined in both hemispheres over time (p < 0.05), however, metabolic reductions became abnormal (p < 0.05) only in the contralateral hemisphere at the third time point (right). Relative metabolic increases are displayed in a red–yellow scale and metabolic decreases in a blue–green scale. SPM {t} maps are superimposed on a single-subject MRI brain template and thresholded at t = 2.62, p = 0.01 (peak voxel, uncorrected) within a prespecified hypothesis-testing mask (see Materials and Methods). The hemisphere contralateral to the initially affected body side is displayed on the left. The coordinates refer to the Montreal Neurological Institute standard space. In the bar graphs, the y-axis represents globally adjusted metabolic activity for each region; the normal mean is indicated by the position of the x-axis. The error bars on the right of the x-axis represent one SEM above and below the normal mean for each region. *p < 0.05, **p < 0.01, ***p < 0.001, Student's t tests compared to normal controls.

Figure 5.

Correlations between regional metabolism and other imaging measures. A, At baseline, putamen DAT binding values correlated significantly (p < 0.05) with metabolic activity in this region measured in the contralateral (circles) and ipsilateral (triangles) hemispheres. B, At baseline, PDCP activity across hemispheres correlated significantly (p < 0.05) with regional metabolism in the anterior cingulate cortex.