Biology subjects

Grist, J. T.

Publications and source records attributed to Grist, J. T..

4 recordsLinked to original sources

bioRxiv2026

Feasibility of multimodal metabolic analysis for detecting early changes in acute neuroinflammation

Given the prevalence of metabolic perturbations in a variety of neurological and neurodegenerative diseases, understanding and monitoring brain metabolism is a key step in our advancement of therapies. The details of the citric acid cycle were established at the beginning of the last century but only recently have its metabolic intermediates been observed in vivo in the brain. In this study, we employed orthogonal analyses to investigate metabolic alterations in response to acute neuroinflammation in vivo, demonstrating a multi-technique approach that could be used for future studies. Hyperpolarized 13C-pyruvate spectroscopy revealed an early decline in pyruvate metabolism via pyruvate dehydrogenase (PDH), leading to reduced 13C-bicarbonate formation. This metabolic disruption occurred despite the absence of structural or perfusion changes on conventional MRI. Further analysis of polar metabolites in the ipsilateral hemisphere confirmed ongoing inflammatory processes. These findings highlight the potential of this dual technique approach to inform upon metabolic changes due to neuroinflammation. Combining methods to probe metabolism in invasive (metabolomics) and non-invasive (hyperpolarized MRI) manners, this represents a promising translational approach for real-time metabolic assessments in an area of the body, the brain, where studying processes such as metabolism has traditionally been challenging. This study has demonstrated the approach to monitor changes in metabolism in response to inflammation in the brain.

neuroscience↗

bioRxiv2025

The effects of elevated serum lactate on measures of apparent cerebral metabolism and perfusion in the anesthetised rodent brain.

Cerebral metabolism is coupled to perfusion and can be probed using a combination of hyperpolarized carbon-13 MRI and perfusion weighted imaging. It is unknown how alterations in serum lactate affect apparent lactate exchange and pyruvate dehydrogenase flux using hyperpolarized 13C MRI, and so this pre-clinical study was designed to assess the sensitivity of MRI to detect changes in perfusion and apparent metabolism in the anesthetized rodent brain due to sodium lactate administration. Results demonstrated significant differences in cerebral blood flow between the saline and sodium L-lactate administered at 0.5 g/kg (112 {+/-} 5 vs 127 {+/-} 2 mL/100g/min), saline and sodium L-lactate administered at 1 g/kg (112 {+/-} 5 vs 90 {+/-} 5 mL/100g/min), and between sodium L-lactate at 0.5 g/kg and sodium L-lactate at 1 g/kg (127 {+/-} 2 vs 90 {+/-} 5 mL/100g/min). There was excellent reproducibility of cerebral perfusion measurements (ICC > 0.95) between observers, indicating high reliability in these results. There were significant differences in [1-13C] lactate:[1-13C] pyruvate between saline vs 0.5 g/kg (0.22 {+/-} 0.05 vs 0.59 {+/-} 0.15) and saline vs 1 g/kg (0.22 {+/-} 0.05 vs 0.62 {+/-} 0.04), but no significant differences in 13C bicarbonate:[1-13C] pyruvate (p = 0.1). In conclusion, perfusion and [1-13C] lactate:[1-13C] pyruvate are sensitive to changes in serum lactate, but 13C bicarbonate:[1-13C] pyruvate were not. This has implications for brain studies using [1-13C] pyruvate, and understanding the impact of serum lactate on clinical hyperpolarised imaging is needed.

neuroscience↗

bioRxiv2024

Modulating Cardiac Energetics in Cardio-Metabolic Syndromes: A mechanistic, hyperpolarized MR Trial of Ninerafaxstat Treatment

BackgroundType 2 diabetes (T2D) and obesity are key contributors for heart failure (HF)- development, especially for HF with a preserved ejection fraction (HFpEF). On a molecular basis, excessive use of fatty acids (FA) induces lipotoxicity which in turn promotes inflammation, reduces mitochondrial pyruvate dehydrogenase (PDH) activity and impairs myocardial energetics and -function. Harnessing in-vivo, real time measurement of cellular metabolism via hyperpolarized pyruvate MR, we aimed to assess the effects of ninerafaxstat, a selective FA oxidation inhibitor, on cardiac energetics, metabolism & diastolic function in patients with cardio-metabolic syndromes. MethodsIMPROVE-DiCE was an open-label, mechanistic phase 2a trial. 21 participants received 200mg ninerafaxstat twice daily for four (n=5) or eight weeks (n=16). Myocardial energetics (phosphocreatine to adenosine triphosphate ratio, PCr/ATP), metabolism and function were assessed pre-& post-treatment using magnetic resonance imaging (MRI), 31P- and 1H-MR spectroscopy (MRS). We utilised hyperpolarized [1-13C]pyruvate MRS to assess in-vivo PDH-flux (n=9) and plasma metabolomics and proteomics to assess whole body metabolism. ResultsPatients presented with impaired PCr/ATP, (median 1.6 [IQR 1.4, 2.1]), myocardial steatosis (2.2 % [IQR 1.5, 3.2]) and LV diastolic dysfunction (peak circumferential diastolic strain rate 0.86/s [IQR 0.82, 1.06]) at baseline. Ninerafaxstat treatment improved myocardial energetics by 32% (p<0.01), reduced myocardial triglyceride content by 34% (p=0.03) and showed a trend towards improved PDH-flux (mean 45% increase, p=0.08). Diastolic function was significantly improved post-treatment (peak diastolic strain rate by 10%, peak LV filling rate by 11%, both p<0.05). ConclusionsMetabolic modulation with ninerafaxstat significantly improved myocardial energetics, reduced myocardial steatosis and improved LV diastolic filling. Combining hyperpolarized MRS and metabolomics, is a powerful approach to examine the mechanism of action of novel metabolic modulators. REGISTRATIONURL: https://clinicaltrials.gov; Unique identifier: NCT04826159 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/591019v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@86fae1org.highwire.dtl.DTLVardef@1c1037eorg.highwire.dtl.DTLVardef@cc5ca9org.highwire.dtl.DTLVardef@d789d1_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2022

Metabolic clearance rate modeling: A translational approach to quantifying cerebral metabolism using hyperpolarized pyruvate.

Hyperpolarized carbon-13 MRI is a promising technique for in vivo metabolic interrogation of alterations between health and disease. This study introduces a model-free formalism for quantifying the metabolic information in hyperpolarized imaging. This study investigated a novel model-free perfusion and metabolic clearance rate (MCR) model in pre-clinical stroke and in the healthy human brain. Simulations showed that the proposed model was robust to perturbations in T1, transmit B1, and kPL. A significant difference in ipsilateral vs contralateral pyruvate derived cerebral blood flow (CBF) was detected in rats (140 {+/-} 2 vs 89 {+/-} 6 mL/100g/min, p < 0.01, respectively) and pigs (139 {+/-} 12 vs 95 {+/-} 5 mL/100g/min, p = 0.04, respectively), along with an increase in fractional metabolism (26 {+/-} 5 vs 4 {+/-} 2 %, p < 0.01, respectively) in the rodent brain. In addition, a significant increase in ipsilateral vs contralateral MCR (0.034 {+/-} 0.007 vs 0.017 {+/-} 0.02 s-1, p = 0.03, respectively) and a decrease in mean transit time (MTT) (31 {+/-} 8 vs 60 {+/-} 2, p = 0.04, respectively) was observed in the porcine brain. In conclusion, MCR mapping is a simple and robust approach to the post-processing of hyperpolarized magnetic resonance imaging.

physiology↗