Modulation of metabolic brain networks after subthalamic gene therapy for Parkinson's disease

Abstract

Parkinson's disease (PD) is characterized by elevated expression of an abnormal metabolic brain network that is reduced by clinically effective treatment. We used fluorodeoxyglucose (FDG) positron emission tomography (PET) to determine the basis for motor improvement in 12 PD patients receiving unilateral subthalamic nucleus (STN) infusion of an adenoassociated virus vector expressing glutamic acid decarboxylase (AAV-GAD). After gene therapy, we observed significant reductions in thalamic metabolism on the operated side as well as concurrent metabolic increases in ipsilateral motor and premotor cortical regions. Abnormal elevations in the activity of metabolic networks associated with motor and cognitive functioning in PD patients were evident at baseline. The activity of the motor-related network declined after surgery and persisted at 1 year. These network changes correlated with improved clinical disability ratings. By contrast, the activity of the cognition-related network did not change after gene transfer. This suggests that modulation of abnormal network activity underlies the clinical outcome observed after unilateral STN AAV-GAD gene therapy. Network biomarkers may be used as physiological assays in early-phase trials of experimental therapies for PD and other neurodegenerative disease.

Conflict of interest statement

Conflict of interest statement: M.G.K. and M.J.D. are founders of and consultants to Neurologix, Inc., which funded the current study. Either they or their families have significant ownership interest in the company. None of the remaining authors has involvement in Neurologix, and there are no other conflicts of interest.

Figures

Fig. 1.

Changes in regional metabolism after gene therapy. (A) Voxel-based analysis of changes in regional metabolic activity after unilateral STN AAV-GAD gene therapy for advanced PD. After unilateral gene therapy, a significant reduction in metabolism (Upper) was found in the operated thalamus, involving the ventrolateral and mediodorsal nuclei. The analysis also revealed a significant metabolic increase (Lower) after surgery in the ipsilateral primary motor region (BA 4), which extended into the adjacent lateral premotor cortex (PMC; BA 6). Representative axial T1-weighted MRI with merged FDG PET slices; the operated (OP) side is signified on the left. Metabolic increases after surgery are displayed by using a red–yellow scale. Metabolic declines are displayed by using a blue–purple scale. The displays were thresholded at P < 0.05, corrected for multiple comparisons. (B) Displays of the metabolic data for these regions at each time point. [In both regions, metabolic values (Table 1) exhibited significant changes over time. (Upper) Decreases for the thalamus. (Lower) Increases for the motor/PMC areas; P < 0.001; RMANOVA).] These regional changes were present on the operated side (filled circles) but not in homologous regions of the unoperated side (open circles). *, P < 0.05; **, P < 0.005; ***, P < 0.001; Bonferroni tests relative to baseline values.

Fig. 2.

Unilateral gene therapy: hemispheric changes in motor-related metabolic network activity. (A) PD-related metabolic pattern (PDRP). This motor-related spatial covariance pattern (9, 21) is characterized by relative pallidothalamic hypermetabolism (left) associated with relative metabolic reductions in the lateral premotor and posterior parietal areas (right). Put/GP, putamen/globus pallidus; PMC, premotor cortex. (B) Changes in mean PDRP network activity over time for the operated (filled circles) and the unoperated (open circles) hemispheres. After gene therapy, there was a significant difference (P < 0.002) in the time course of PDRP activity across the two hemispheres. In the unoperated hemisphere, network activity increased continuously over the 12 months after surgery. By contrast, in the operated hemisphere, a decline in network activity was evident during the first 6 months. Over the subsequent 6 months, network activity on this side increased in parallel with analogous values on the unoperated side. The dashed line represents one standard error above the normal mean value of zero. (C) Postoperative changes in PDRP activity controlling for the effect of disease progression. These progression-corrected values (PDRPc scores) reflect the net effect of STN AAV-GAD on network expression for each subject and time point (see Materials and Methods). Relative to baseline, PDRPc scores declined after gene therapy (P < 0.001, RMANOVA), with significant reductions relative to baseline at both 6 (gray bar) and 12 (black bar) months. These changes correlated (P < 0.03) with clinical outcome over the course of the study. **, P < 0.005; Bonferroni tests; bars represent standard error. (D) The time course of PDRPc scores according to viral vector dose. A continuous decline in network values was observed in patients receiving high-dose therapy (1 × 1012 viral genomes (vg) per milliliter (circles) but not in those receiving low (1 × 1011 vg per milliliter) (squares) or medium (3 × 1011 vg per milliliter) (triangles) doses. Four patients were treated per dose group (15). For all subjects PDRPc scores at each time point were adjusted by subtracting baseline values.

Fig. 3.

Unilateral gene therapy: hemispheric changes in cognition-related metabolic network activity. (A) PD-related cognitive pattern (PDCP). This spatial covariance pattern (13) is characterized by relative hypometabolism in the dorsal prefrontal, premotor, and posterior parietal regions (right), associated with relative metabolic increases in the cerebellar vermis and dentate nuclei (left). pre-SMA, presupplementary motor area; PMC, premotor cortex; DN, dentate nuclei. (B) Changes in mean PDCP network activity over time for the operated (filled circles) and the unoperated (open circles) hemispheres. After gene therapy, there was no change in PDCP activity over time in either of the two hemispheres (P = 0.72). The dashed line represents one standard error above the normal mean value of zero.

Fig. 4.

Comparison of subthalamic gene therapy and lesioning. Bar graph illustrating changes in regional glucose metabolism in the thalamus (Left) and the globus pallidus (GP) (Right) after the unilateral subthalamotomy (black bar) or gene therapy (gray and white bars) for the high and low clinical response subgroups, respectively; see Discussion). In operated hemispheres, the declines in thalamic metabolism were not different across the three treatment groups. By contrast, reduced GP metabolism was observed only after STN lesioning but not after gene therapy. *, P < 0.05; **, P < 0.005; Bonferroni tests relative to the lesioning group; bars represent standard error.

Fig. 5.

Disease progression in the unoperated hemisphere. The time course of PDRP expression on the unoperated hemisphere of the AAV-GAD-treated subjects (open circles) was compared with that measured in 15 early-stage PD patients (open triangles) who underwent longitudinal FDG PET imaging over a 4-year period (13). The network values were plotted against the duration of disease at each time point. There was no difference (P = 0.60; Student t test) in the rate of change in network activity over time between the two groups. PDRP expression in the AAV-GAD group was observed to be in continuity with the natural history data, suggesting that the changes observed in the unoperated hemisphere were a reflection of disease progression (see Materials and Methods).