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

doi:10.1073/pnas.0706006104

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

*Center for Neurosciences, The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, 350 Community Drive, Manhasset, NY 11030;
^†Departments of Neurology and Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016;
^‡Department of Neurological Surgery, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021;
^§Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461; and
^¶Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University, Columbus, OH 43210

Edited by Marcus E. Raichle, Washington University School of Medicine, St. Louis, MO, and approved October 18, 2007 (received for review June 26, 2007)

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.

Footnotes

^‖To whom correspondence should be addressed. E-mail: david1{at}nshs.edu
Author contributions: A.F. and M.G.K. contributed equally to this work; A.F., M.G.K., M.J.D., and D.E. designed research; A.F., M.G.K., P.M., V.D., and D.E. performed research; A.F., M.G.K., C.T., T.L., P.M., and D.E. analyzed data; and A.F., M.G.K., C.T., and D.E. wrote the paper.
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.
This article is a PNAS Direct Submission.