Modulation of metabolic brain networks after subthalamic gene therapy for Parkinson s disease Andrew Feigin Michael G Kaplitt Chengke Tang Tanya Lin Paul Mattis Vijay Dhawan Matthew J During and David Eidelberg 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 brain metabolism positron emission tomography P arkinson s disease PD is characterized by a progressive loss of dopaminergic neurons in the substantia nigra which leads to abnormal functioning of interacting inhibitory GABAergic and excitatory glutamatergic pathways in components of neural networks controlling movement 1 The activity of the subthalamic nucleus STN is increased in PD largely because of reduced tone of GABAergic afferent fibers from the external globus pallidus GPe 2 In turn the hyperactive glutamatergic efferents drive the internal segment of the globus pallidus GPi and the substantia nigra pars reticulata SNr resulting in the alterations in thalamic and motor cortical neural activity Based on the notion that reducing glutamatergic neurotransmission may reverse the motor deficits of PD by normalizing brain activity within these circuits we used adenoassociated virus AAV to deliver the glutamic acid decarboxylase GAD gene directly into STN 3 Preclinical studies using animal models of PD suggest that transfer of the GAD gene into the STN can alter its activity while also increasing the evoked release of GABA in downstream targets 3 5 However these effects cannot be directly assessed in human subjects receiving this form of gene therapy for parkinsonism Metabolic brain imaging with 18F fluorodeoxyglucose FDG and positron emission tomography PET can provide a means of quantifying changes in spatially distributed neural systems after antiparkinsonian therapy 6 7 The motor manifestations of PD are associated with increased expression of an abnormal disease related covariance pattern PDRP characterized by increases in pallidothalamic metabolic activity with relative reductions in premotor and parietal association regions 8 9 www pnas org cgi doi 10 1073 pnas 0706006104 Substantial evidence exists to show that pathological PDRP expression is reduced by therapeutic lesioning or deep brain stimulation DBS of the motor portions of GPi and STN and that these network changes correlate with clinical outcome after treatment 6 7 10 12 In contrast to the PDRP these interventions do not affect the activity of the PD related cognitive pattern PDCP a distinct prefrontal parietal metabolic network associated with memory and executive functioning in nondemented PD patients 13 14 The quantification of treatment mediated changes in the activity of these metabolic networks may provide an objective means of gauging the effects of experimental antiparkinsonian therapy 15 We have recently reported clinical findings from 12 patients who received unilateral STN AAV GAD gene therapy for advanced PD 16 In the current study we used FDG PET to assess the changes in regional metabolism and network activity that occurred with treatment In addition to detecting localized metabolic changes in the thalamus and cortical motor regions ipsilateral to gene therapy we found evidence of significant modulation of PDRP network activity that correlated with motor benefit By contrast there was no change in PDCP activity after STN gene therapy consistent with the observed preservation of cognitive functioning in these patients These data support a biological basis for the observed treatment response in patients undergoing this antiparkinsonian intervention Results Changes in Regional Glucose Metabolism After Surgery Regions in which glucose metabolism changed significantly after surgery are presented in Table 1 and Fig 1 After surgery metabolic activity changed in the thalamus and motor cortex of the operated hemisphere F2 22 10 84 P 0 001 one way repeated measures RM ANOVA for each of the two regions In the thalamus Fig 1 A Upper significant metabolic reductions were present at 6 months P 0 001 and 12 months P 0 005 after surgery Fig 1B Upper This treatment mediated change was most 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 in the ipsilateral primary motor area extending into the adjacent premotor cortex Fig 1 A Lower In this region significant 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 To whom correspondence should be addressed E mail david1 nshs edu 2007 by The National Academy of Sciences of the USA PNAS December 4 2007 vol 104 no 49 19559 19564 NEUROSCIENCE 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
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