Glutamate-Related Biomarkers in Drug Development for Disorders of the Nervous System Workshop Summary (2011) / Chapter Skim
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3 Glutamate Biomarkers
3 Glutamate Biomarkers
Pages 11-26
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From page 11... ...
The first, by Jeffrey Conn, professor of pharmacology at Vanderbilt University, divided glutamate biomarkers into three general types: (1) biomarkers of structural engagement with a molecular target; (2)
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PET displacement studies of potential biomarkers binding with endogenous ligands, however, do not specify the functional aspects of the probe's interaction with the target. For that purpose, PET can be combined with other imaging techniques, electrophysiology, or another biomarker.
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Conn indicated that biomarkers of functional engagement have the strong advantage of providing insight into whether or not a compound may demonstrate or predict efficacy. Functional biomarkers are the most common type of glutamate biomarker currently being studied.
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Several speakers described electrophysiological biomarkers of glutamate dysfunction that rely on specific types of auditory or visual ERPs. ERP biomarkers have been studied in relation to cognitive impairment and negative symptoms in schizophrenia.
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. Gregory Light, associate professor at the University of California–San Diego, explained that changes in MMN and P3a are linked to a broad array of other features of schizophrenia, including decrements in higher order cognitive processes, measures of drug efficacy, and patients' daily functioning, among other measures of global assessment.
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16 P3a 5.0 2.5 µV 0.0 RON -2.5 MMN -5.0 135 ms - 210 ms 240ms - 315ms 350ms - 475ms -100 0.0 100 200 300 400 500 -4.50 µV 4.50 µV -4.50 µV 4.50 µV -1.00 µV 1.00 µV FIGURE 3-2 Automatic sensory information processing abnormalities across illness course of schizophrenia. Figure 3 Broadside SOURCE: Jahshan et al., in press.
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The magnocellular pathway transmits visual information of low resolution from the retina through the thalamus to the visual cortex, as opposed to high-resolution information transmitted by the parvocellular pathway. As measured by psychophysical tests, the deficits include dot-motion trajectory discrimination, grating velocity discrimination, and contrast sen
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. Although only tested in normal animals, not humans, the NMDA antagonist ketamine impairs discrimination of horizontal and vertical lines formed by spatial proximity of dots (Kurylo and Gazes, 2008)
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receptor potentiators of synaptic plasticity and an NMDA antagonist both displayed rapid antidepressant effects in clinical trials (Brennan et al., 2010; Sanacora et al., 2008; Zarate et al., 2006, 2010)
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In summary, these newly combined electrophysiological measures may serve as a biomarker to predict drug efficacy. Animal Models The basis of many electrophysiological findings, which have been developed in humans, may be correlated with positive outcomes in disease treatment, but they may not be fully understood.
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. While AX-CPT may be sensitive to other neurotransmitter antagonists, such as muscarinic receptor antagonists, the ketamine challenge finding suggests that NMDA receptors are dysfunctional in schizophrenia.
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Knowledge gained through these methods can streamline biomarker development and drug development, said most workshop presenters. Many presenters described a variety of imaging techniques used in the pursuit of glutamate biomarkers.
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. It can assess in vivo function of brain chemistry by exploiting the fact that hydrogen atoms in distinct chemical environments, depending on the molecules in which they are bonded, possess distinct resonant properties.
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Today, however, PET has dramatically improved, as has the introduction of more PET ligands and new techniques to reconstruct PET images for better spatial resolution. The foremost barrier holding back PET applications for glutamate neurotransmission is the scarcity of PET radioligands that expressly bind to particular molecules at the glutamate synapse.
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. SPECT and PET are similar techniques except that SPECT directly emits gamma radiation, whereas PET emits two gamma photons in opposite directions.
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