1. ¹Wisconsin National Primate Research Center, University of Wisconsin, Madison, Wisconsin, USA
2. ²Department of Anatomy, University of Wisconsin, Madison, Wisconsin, USA
3. ³Center for Neurosciences, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, USA
4. ⁴Department of Medical Physics, University of Wisconsin, Madison, Wisconsin, USA
5. ⁵Department of Radiology, University of Wisconsin, Madison, Wisconsin, USA
6. ⁶Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
7. ⁷Department of Neurosurgery, University of Illinois, Chicago, Illinois, USA
8. ⁸Department of Neurosurgery, Weill Medical College of Cornell University, New York, New York, USA

Correspondence: Dr D Eidelberg, Center for Neurosciences, Institute for Medical Research, North Shore-LIJ Health System, 350 Community Drive, Manhasset, NY 11030, USA. E-mail: david1@nshs.edu

^†These authors contributed equally to this work.

Received 14 March 2006; Revised 12 May 2006; Accepted 28 May 2006; Published online 12 July 2006.

Abstract

Parkinson's disease (PD) is associated with increased excitatory activity within the subthalamic nucleus (STN). We sought to inhibit STN output in hemiparkinsonian macaques by transfection with adeno-associated virus (AAV) containing the gene for glutamic acid decarboxylase (GAD). In total, 13 macaques were rendered hemiparkinsonian by right intracarotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injection. Seven animals were injected with AAV-GAD into the right STN, and six received an AAV gene for green fluorescent protein (GFP). Videotaped motor ratings were performed in a masked fashion on a weekly basis over a 55-week period. At 56 weeks, the animals were scanned with ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Histological examination was performed at the end of the study. No adverse events were observed after STN gene therapy. We found that the clinical rating scores for the two treatment groups had different patterns of change over time (group time interaction, P<0.001). On FDG PET, the GAD animals exhibited an increase in glucose utilization in the right motor cortex relative to GFP controls (P<0.001). Metabolism in this region correlated with clinical ratings at end point (P<0.01). Histology confirmed GAD expression in treated animals. These findings suggest that STN AAV-GAD is well tolerated and potentially effective in a primate model of PD. The changes in motor cortical glucose utilization observed after gene therapy are consistent with the modulation of metabolic brain networks associated with this disorder.