Author
G. Frederick Wooten
Other affiliations: Washington University in St. Louis, University of Virginia Health System
Bio: G. Frederick Wooten is an academic researcher from University of Virginia. The author has contributed to research in topics: Striatum & Substantia nigra. The author has an hindex of 28, co-authored 56 publications receiving 3559 citations. Previous affiliations of G. Frederick Wooten include Washington University in St. Louis & University of Virginia Health System.
Topics: Striatum, Substantia nigra, Dopamine, Dopamine receptor, Dopaminergic
Papers published on a yearly basis
Papers
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TL;DR: An in vivo method for use with positron emission tomography (PET) that results in a quantitative characterization of neuroleptic binding sites using radiolabeled spiperone, the first direct evidence that PET can be used to characterize quantitatively, locally and in vivo, drug binding sites in brain.
Abstract: We propose an in vivo method for use with positron emission tomography (PET) that results in a quantitative characterization of neuroleptic binding sites using radiolabeled spiperone. The data are analyzed using a mathematical model that describes transport, nonspecific binding, and specific binding in the brain. The model demonstrates that the receptor quantities Bmax (i.e., the number of binding sites) and KD-1 (i.e., the binding affinity) are not separably ascertainable with tracer methodology in human subjects. We have, therefore, introduced a new term, the binding potential, equivalent to the product BmaxKD-1, which reflects the capacity of a given tissue, or region of a tissue, for ligand-binding site interaction. The procedure for obtaining these measurements is illustrated with data from sequential PET scans of baboons after intravenous injection of carrier-added (18F)spiperone. From these data we estimate the brain tissue nonspecific binding of spiperone to be in the range of 94.2 to 95.3%, and the regional brain spiperone permeability (measured as the permeability-surface area product) to be in the range of 0.025 to 0.036 cm3/(s X ml). The binding potential of the striatum ranged from 17.4 to 21.6; these in vivo estimates compare favorably to in vitro values in the literature. To ourmore » knowledge this represents the first direct evidence that PET can be used to characterize quantitatively, locally and in vivo, drug binding sites in brain. The ability to make such measurements with PET should permit the detailed investigation of diseases thought to result from disorders of receptor function.« less
951 citations
TL;DR: Physical examination shows a minimal rest tremor in the left hand that disappears with use of the limb, mild rigidity at the left wrist and elbow, slowness of finger tapping with theleft hand, and decreased arm swing on the left while walking.
Abstract: A 62-year-old man presents with an intermittent tremor in his left hand and some vague discomfort in the left arm. Physical examination shows a minimal rest tremor in the left hand that disappears with use of the limb, mild rigidity at the left wrist and elbow, slowness of finger tapping with the left hand, and decreased arm swing on the left while walking. How should he be evaluated and treated?
296 citations
University of Rochester1, National Institutes of Health2, Medical University of South Carolina3, Rush University Medical Center4, University of Virginia5, University of Vermont6, Rutgers University7, University of Alabama8, University of Southern California9, Dartmouth College10, Oregon Health & Science University11, University of Pennsylvania12, University of Maryland, Baltimore13, University of South Florida14, University of Calgary15, Louisiana State University16, University of California, San Francisco17, University of Colorado Denver18, University of Miami19, Washington University in St. Louis20, Southern Illinois University Carbondale21, Georgia Regents University22, Veterans Health Administration23, University of Texas Southwestern Medical Center24, Baylor College of Medicine25, University of Alberta26, Indiana University – Purdue University Indianapolis27, University of Michigan28, Johns Hopkins University29, University of Kansas30, Vanderbilt University31, North Shore-LIJ Health System32, Mayo Clinic33, Duke University34, St. Joseph's Hospital and Medical Center35, SUNY Downstate Medical Center36, Thomas Jefferson University37, Beaumont Hospital38, Harvard University39, Henry Ford Health System40, Emory University41, University of Florida42, Toronto Western Hospital43, University of Georgia44
TL;DR: Coenzyme Q10 and GPI-1485 may warrant further study in Parkinson disease, although the data are inconsistent, and additional factors should be considered in the selection of agents for Phase III studies.
Abstract: Objective: To determine if future studies of coenzyme Q10 and GPI-1485 in Parkinson disease (PD) may be warranted. Methods: We conducted a randomized, double-blind, calibrated futility clinical trial of coenzyme Q10 and GPI-1485 in early untreated PD using placebo data from the DATATOP study to establish the futility threshold. Results: The primary outcome measure (change in total Unified Parkinson's Disease Rating Scale scores over 1 year) did not meet the prespecified criteria for futility for either agent. Secondary analyses using calibration controls and other more recent placebo data question the appropriateness of the predetermined definition of futility, and suggest that a more restrictive threshold may be needed. Conclusions: Coenzyme Q10 and GPI-1485 may warrant further study in Parkinson disease, although the data are inconsistent. Additional factors (cost, availability of other agents, more recent data on placebo outcomes, other ongoing trials) should also be considered in the selection of agents for Phase III studies. NEUROLOGY 2007;68:20-28
209 citations
TL;DR: A precedent for inherited mtDNA mutation in some persons with PD is supported, present in cybrid lines containing mtDNA from maternal descendants with PD as well as in currently asymptomatic young maternal descendants.
Abstract: Recent data suggesting complex I dysfunction in Parkinson's disease (PD) arises from mitochondrial DNA (mtDNA) mutation does not conclusively answer whether the responsible genetic lesion is inherited (primary) or somatic (secondary). To address this question, we identified a family in which multiple members over three generations are affected with PD through exclusively maternal lines. Cytoplasmic hybrids (cybrids) were created for 15 family members over two generations by transferring each individual's mtDNA to mtDNA-depleted human neuroblastoma cells. Eight of the 15 cybrid lines contained mtDNA obtained from maternally descended family members and seven contained mtDNA from paternally descended family members. After 6 weeks of culture, cybrid cell lines were assayed for complex I activity and oxidative stress, and mitochondrial morphology was analyzed by electron microscopy. Compared with the cybrid lines containing mtDNA from paternal descendants, cybrid lines containing mtDNA from maternal descendants had lower complex I activity, increased reactive oxygen species production, increased radical scavenging enzyme activities, and more abnormal mitochondrial morphologic features. These findings were present in cybrid lines containing mtDNA from maternal descendants with PD as well as in currently asymptomatic young maternal descendants, and support a precedent for inherited mtDNA mutation in some persons with PD.
149 citations
TL;DR: Comparison of D1 and D2 binding following a unilateral volkensin injection into the substantia nigra has demonstrated that striatal D1 binding sites are selectively localized to striatonigral projection neurons.
149 citations
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TL;DR: It is reported that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity.
Abstract: The cause of Parkinson's disease (PD) is unknown, but epidemiological studies suggest an association with pesticides and other environmental toxins, and biochemical studies implicate a systemic defect in mitochondrial complex I. We report that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity. Nigral neurons in rotenone-treated rats accumulate fibrillar cytoplasmic inclusions that contain ubiquitin and alpha-synuclein. These results indicate that chronic exposure to a common pesticide can reproduce the anatomical, neurochemical, behavioral and neuropathological features of PD.
3,472 citations
1,914 citations
National Institutes of Health1, Imperial College London2, Aarhus University3, University of Oxford4, University of Wisconsin-Madison5, University of Toronto6, University of California, Los Angeles7, Columbia University8, National Institute of Radiological Sciences9, University of Michigan10, University of Copenhagen11, University of Turku12, VU University Amsterdam13, Brookhaven National Laboratory14, Pfizer15, Washington University in St. Louis16, Indiana University – Purdue University Indianapolis17, University of Pittsburgh18, University of British Columbia19, Emory University20, Johns Hopkins University21, Yale University22
TL;DR: An international group of experts in pharmacokinetic modeling recommends a consensus nomenclature to describe in vivo molecular imaging of reversibly binding radioligands.
Abstract: An international group of experts in pharmacokinetic modeling recommends a consensus nomenclature to describe in vivo molecular imaging of reversibly binding radioligands.
1,858 citations
TL;DR: General equations are derived that can be used to analyze tissue uptake data when the blood–plasma concentration of the test substance cannot be easily measured and for situations when trapping of theTest substance is incomplete and for a combination of these two conditions.
Abstract: The method of graphical analysis for the evaluation of sequential data (e.g., tissue and blood concentrations over time) in which the test substance is irreversibly trapped in the system has been expanded. A simpler derivation of the original analysis is presented. General equations are derived that can be used to analyze tissue uptake data when the blood–plasma concentration of the test substance cannot be easily measured. In addition, general equations are derived for situations when trapping of the test substance is incomplete and for a combination of these two conditions. These derivations are independent of the actual configuration of the compartmental system being analyzed and show what information can be obtained for the period when the reversible compartments are in effective steady state with the blood. This approach is also shown to result in equations with at least one less nonlinear term than those derived from direct compartmental analysis. Specific applications of these equations are illustr...
1,623 citations
TL;DR: Strategies aimed at restoring complex I activity, reducing oxidative stress and α-synuclein aggregation, and enhancing protein degradation may hold particular promise as powerful neuroprotective agents in the treatment of PD.
Abstract: Parkinson's disease (PD) is a complex disorder with many different causes, yet they may intersect in common pathways, raising the possibility that neuroprotective agents may have broad applicability in the treatment of PD. Current evidence suggests that mitochondrial complex I inhibition may be the central cause of sporadic PD and that derangements in complex I cause α-synuclein aggregation, which contributes to the demise of dopamine neurons. Accumulation and aggregation of α-synuclein may further contribute to the death of dopamine neurons through impairments in protein handling and detoxification. Dysfunction of parkin (a ubiquitin E3 ligase) and DJ-1 could contribute to these deficits. Strategies aimed at restoring complex I activity, reducing oxidative stress and α-synuclein aggregation, and enhancing protein degradation may hold particular promise as powerful neuroprotective agents in the treatment of PD.
1,606 citations