Modulation of metabolic brain networks aftersubthalamic gene therapy for Parkinson’s diseaseAndrew Feigin*†, Michael G. Kaplitt‡, Chengke Tang*, Tanya Lin*§, Paul Mattis*†, Vijay Dhawan*†, Matthew J. During¶,and David Eidelberg*†储*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 ofNeurological Surgery, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021;§Albert Einstein College of Medicine, 1300Morris Park Avenue, Bronx, NY 10461; and¶Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University,Columbus, OH 43210Edited by Marcus E. Raichle, Washington University School of Medicine, St. Louis, MO, and approved October 18, 2007 (received for review June 26, 2007)Parkinson’s disease (PD) is characterized by elevated expression ofan abnormal metabolic brain network that is reduced by clinicallyeffective treatment. We used fluorodeoxyglucose (FDG) positronemission tomography (PET) to determine the basis for motorimprovement in 12 PD patients receiving unilateral subthalamicnucleus (STN) infusion of an adenoassociated virus vector express-ing glutamic acid decarboxylase (AAV-GAD). After gene therapy,we observed significant reductions in thalamic metabolism on theoperated side as well as concurrent metabolic increases in ipsilat-eral motor and premotor cortical regions. Abnormal elevations inthe activity of metabolic networks associated with motor andcognitive functioning in PD patients were evident at baseline. Theactivity of the motor-related network declined after surgery andpersisted at 1 year. These network changes correlated with im-proved clinical disability ratings. By contrast, the activity of thecognition-related network did not change after gene transfer. Thissuggests that modulation of abnormal network activity underliesthe clinical outcome observed after unilateral STN AAV-GAD genetherapy. Network biomarkers may be used as physiological assaysin early-phase trials of experimental therapies for PD and otherneurodegenerative disease.brain metabolism 兩 positron emission tomographyParkinson’s disease (PD) is characterized by a progressive lossof dopaminergic neurons in the substantia nigra, which leadsto abnormal functioning of interacting inhibitory GABAergicand excitatory glutamatergic pathways in components of neuralnetworks controlling movement (1). The activity of the subtha-lamic nucleus (STN) is increased in PD, largely because ofreduced tone of GABAergic afferent fibers from the externalglobus pallidus (GPe) (2). In turn, the hyperactive glutamatergicefferents drive the internal segment of the globus pallidus (GPi)and the substantia nigra pars reticulata (SNr), resulting in thealterations in thalamic and motor cortical neural activity. Basedon the notion that reducing glutamatergic neurotransmissionmay reverse the motor deficits of PD by normalizing brainactivity within these circuits, we used adenoassociated virus(AAV) to deliver the glutamic acid decarboxylase (GAD) genedirectly into STN (3). Preclinical studies using animal models ofPD suggest that transfer of the GAD gene into the STN can alterits activity while also increasing the evoked release of GABA indownstream targets (3–5). However, these effects cannot bedirectly assessed in human subjects receiving this form of genetherapy for parkinsonism.Metabolic brain imaging with [18F]fluorodeoxyglucose (FDG)and positron emission tomography (PET) can provide a meansof quantifying changes in spatially distributed neural systemsafter antiparkinsonian therapy (6, 7). The motor manifestationsof PD are associated with increased expression of an abnormaldisease-related covariance pattern (PDRP) characterized byincreases in pallidothalamic metabolic activity with relativereductions in premotor and parietal association regions (8, 9).Substantial evidence exists to show that pathological PDRPexpression is reduced by therapeutic lesioning or deep brainstimulation (DBS) of the motor portions of GPi and STN andthat these network changes correlate with clinical outcome aftertreatment (6, 7, 10–12). In contrast to the PDRP, these inter-ventions do not affect the activity of the PD-related cognitivepattern (PDCP), a distinct prefrontal-parietal metabolic net-work associated with memory and executive functioning innondemented PD patients (13, 14). The quantification of treat-ment-mediated changes in the activity of these metabolic net-works may provide an objective means of gauging the effects ofexperimental antiparkinsonian therapy (15).We have recently reported clinical findings from 12 patientswho received unilateral STN AAV-GAD gene therapy foradvanced PD (16). In the current study, we used FDG PET toassess the changes in regional metabolism and network activitythat occurred with treatment. In addition to detecting localizedmetabolic changes in the thalamus and cortical motor regionsipsilateral to gene therapy, we found evidence of significantmodulation of PDRP network activity that correlated with motorbenefit. By contrast, there was no change in PDCP activity afterSTN gene therapy, consistent with the observed preservation ofcognitive functioning in these patients. These data support abiological basis for the observed treatment response in patientsundergoing this antiparkinsonian intervention.ResultsChanges in Regional Glucose Metabolism After Surgery. Regions inwhich glucose metabolism changed significantly after surgeryare presented in Table 1 and Fig. 1. After surgery, metabolicactivity changed in the thalamus and motor cortex of theoperated hemisphere (F2,22⫽ 10.84, P ⬍ 0.001; one-way repeat-ed-measures (RM)ANOVA for each of the two regions). In thethalamus (Fig. 1A Upper), significant metabolic reductions werepresent at 6 months (P ⬍ 0.001) and 12 months (P ⬍ 0.005) aftersurgery (Fig. 1B Upper). This treatment-mediated change wasmost pronounced in the ventroanterior (VA) and ventrolateral(VL) nuclei and in the mediodorsal (MD) nuclei. Additionally,an increase in glucose metabolism after surgery was detected inthe ipsilateral primary motor area extending into the adjacentpremotor cortex (Fig. 1A Lower). In this region, significantAuthor contributions: A.F. and M.G.K. contributed
View Full Document
Unlocking...