Modulation of metabolic brain networks after subthalamic gene therapy for Parkinson's disease
Open accessAbstract
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.
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Induction of glutamic acid decarboxylase enzyme as a neuromodulator can evoke synthesis of GABA to perform inhibitory modulation of neuronal activities in the subthalamic nucleus.
“Induction of glutamic acid decarboxylase enzyme as a neuromodulator that can evoke the synthesis of a neurotransmitter Gamma-aminobutyric acid (GABA) to perform inhibitory modulation of neuronal activities in the subthalamic nucleus [162, 163].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [162]
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- Authors
- Feigin, A., Kaplitt, M. G., Tang, C., Lin, T., Mattis, P., Dhawan, V., During, M. J., & Eidelberg, D.
- Affiliations
- Northwell Health (US)
- Cornell University (US)
- Albert Einstein College of Medicine (US)
- The Ohio State University (US)
- Corresponding author
- Eidelberg, David
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-12-04
- Volume
- 104
- Issue
- 49
- Pages
- 19559-19564
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2148328
- OpenAlex
- W2047000182
- Cited by
- 181
- References
- 0
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 5 · 2022: 5 · 2021: 2 · 2020: 5 · 2019: 6 · 2018: 9 · 2017: 10 · 2016: 8 · 2015: 8 · 2014: 9 · 2013: 11 · 2012: 14
- FWCI
- 13.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
- Keywords
- Parkinson's disease, subthalamic nucleus, gene therapy, glutamic acid decarboxylase, adeno-associated virus vectors, brain metabolic network, FDG-PET, motor cortex, premotor cortex, network biomarkers, clinical outcomes, cognitive networks
- MeSH terms
- Dependovirus, Aged, Brain, Female, Glucose, Glutamate Decarboxylase, Humans, Male, Middle Aged, Parkinson Disease, Genetic Therapy, Subthalamic Nucleus, Positron-Emission Tomography, Metabolic Networks and Pathways
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