| Autor: |
Corin O, Miller, Liza T, Gantert, Stephen F, Previs, Ying, Chen, Kenneth D, Anderson, Justina M, Thomas, Gerard, Sanacora, Jason M, Uslaner, Douglas L, Rothman, Graeme F, Mason |
| Rok vydání: |
2020 |
| Předmět: |
|
| Zdroj: |
Biol Psychiatry Cogn Neurosci Neuroimaging |
| ISSN: |
2451-9030 |
| Popis: |
BACKGROUND: The development of treatments for cognitive deficits associated with central nervous system disorders is currently a significant medical need. Despite the great need for such therapeutics, a significant challenge in the drug development process is the paucity of robust biomarkers to assess target modulation and guide clinical decisions. We developed a novel, translatable biomarker of neuronal glutamate metabolism, the (13)C-glutamate+glutamine (Glx) H3:H4 labeling ratio, in nonhuman primates using localized (1)H-magnetic resonance spectroscopy combined with (13)C-glucose infusions. METHODS: We began with numerical simulations in an established model of brain glutamate metabolism, showing that the (13)C-Glx H3:H4 ratio should be a sensitive biomarker of neuronal tricarboxylic acid cycle activity, a key measure of overall neuronal metabolism. We showed that this biomarker can be measured reliably using a standard (1)H-magnetic resonance spectroscopy method (point-resolved spectroscopy sequence/echo time = 20 ms), obviating the need for specialized hardware and pulse sequences typically used with (13)C-magnetic resonance spectroscopy, thus improving overall clinical translatability. Finally, we used this biomarker in 8 male rhesus macaques before and after administration of the compound BNC375, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor that enhances glutamate signaling ex vivo and elicits procognitive effects in preclinical species. RESULTS: The (13)C-Glx H3:H4 ratios in the monkeys showed that BNC375 increases neuronal metabolism in nonhuman primates in vivo, detectable on an individual basis. CONCLUSIONS: This study demonstrates that the ratio of (13)C-Glx H3:H4 labeling is a biomarker that may provide an objective readout of compounds affecting glutamatergic neurotransmission and could improve decision making for the development of therapeutic agents. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect