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Field dependence study of in vivo brain (31) P MRS up to 16.4 T.

ABSTRACT: In vivo (31) P MRS provides a unique tool for studying bioenergetics of living organs. Although its utility has been limited by the relatively low (31) P NMR sensitivity, increasing magnetic field strength (B0 ) could significantly improve the quality and reliability of the (31) P MR spectra for biomedical research. To quantitatively understand the field dependence of in vivo (31) P MRS for brain applications, (31) P NMR sensitivity of phosphocreatine (PCr) in rat brains was measured and compared at 9.4 T and 16.4 T. Additionally, the linewidths and T1 relaxation times of PCr and adenosine triphosphate (ATP) resonances obtained from human and animal brains over a wide B0 range from 4 T, 7 T, and 9.4 T to 16.4 T were examined and their field dependences were quantified. The results indicate an approximate 1.74-fold (31) P signal-to-noise ratio (SNR) gain for PCr at 16.4 T compared with 9.4 T. An approximate power 1.4 dependence of (31) P SNR on B0 was concluded. Substantial improvements in spectral resolution and significantly shortened T1 values of brain PCr and ATP were observed at high/ultrahigh fields, contributing to an additional sensitivity gain and spectral improvement. In summary, the overall findings from this study suggest that in vivo (31) P MRS should greatly benefit from high/ultrahigh fields for noninvasive assessment of altered bioenergetics and metabolic processes associated with brain function and neurological diseases.

SUBMITTER: Lu M

PROVIDER: S-EPMC4180101 | biostudies-other | 2014 Sep

REPOSITORIES: biostudies-other

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Project description:The topoisomerase I inhibitor, irinotecan, and its active metabolite SN-38 have been shown to induce G(2) /M cell cycle arrest without significant cell death in human colon carcinoma cells (HCT-116). Subsequent treatment of these G(2) /M-arrested cells with the cyclin-dependent kinase inhibitor, flavopiridol, induced these cells to undergo apoptosis. The goal of this study was to develop a noninvasive metabolic biomarker for early tumor response and target inhibition of irinotecan followed by flavopiridol treatment in a longitudinal study. A total of eleven mice bearing HCT-116 xenografts were separated into two cohorts where one cohort was administered saline and the other treated with a sequential course of irinotecan followed by flavopiridol. Each mouse xenograft was longitudinally monitored with proton ((1) H)-decoupled phosphorus ((31) P) magnetic resonance spectroscopy (MRS) before and after treatment. A statistically significant decrease in phosphocholine (p?=?0.0004) and inorganic phosphate (p?=?0.0103) levels were observed in HCT-116 xenografts following treatment, which were evidenced within twenty-four hours of treatment completion. Also, a significant growth delay was found in treated xenografts. To discern the underlying mechanism for the treatment response of the xenografts, in vitro HCT-116 cell cultures were investigated with enzymatic assays, cell cycle analysis, and apoptotic assays. Flavopiridol had a direct effect on choline kinase as measured by a 67% reduction in the phosphorylation of choline to phosphocholine. Cells treated with SN-38 alone underwent 83?±?5% G(2) /M cell cycle arrest compared to untreated cells. In cells, flavopiridol alone induced 5?±?1% apoptosis while the sequential treatment (SN-38 then flavopiridol) resulted in 39?±?10% apoptosis. In vivo (1) H-decoupled (31) P MRS indirectly measures choline kinase activity. The decrease in phosphocholine may be a potential indicator of early tumor response to the sequential treatment of irinotecan followed by flavopiridol in noninvasive and/or longitudinal studies.

Project description:BackgroundThe human brain has high energy requirements that continuously support healthy neuronal activity and cognition. A disruption in brain energy metabolism (BEM) may contribute to early neuropathological changes such as accumulation of β-amyloid and tau in vulnerable populations. One such population is amnestic mild cognitive impairment (aMCI) where some individuals are at risk for developing dementia, i.e. Alzheimer's disease (AD). Recent advances in imaging technology are providing new avenues to measure BEM accurately using 31phosphorus magnetic resonance spectroscopy (31P MRS) at ultra-high-field (UHF) magnetic strength 7-Tesla. This study investigates whether a methodology using partial volume-coil 31P MRS at 7T over parieto-occipital lobes can accurately quantify high-energy phosphate and membrane phospholipid metabolites in aMCI. A secondary objective was to explore BEM and membrane phospholipid indices' correspondence with cognitive performance in domains of executive function (EF), memory, attention, and visuospatial skills in aMCI, a heterogeneous population.Methods19 aMCI participants enrolled in the study completed cognitive assessment and 31P MRS scan. BEM indices were measured using three energy indicators: energy reserve (PCr/t-ATP), energy consumption (intracellular_Pi/t-ATP), and metabolic state (PCr/intracellular_Pi) along with regulatory co-factors of BEM-intracellular Mg2 + and pH; whereas the ratio of phosphomonoesters (PMEs) to phosphodiesters (PDEs) - membrane phospholipid indicator.Results31P MRS scan showed thirteen well-resolved peaks with precise quantification of the phosphorus metabolites at UHF. The higher BEM indices were associated with lower cognitive performance of memory [(energy reserve indicator: CVLT p = 0.004), (metabolic state indicator: CVLT p = 0.007)], executive function [(metabolic state indicator: TOSL (p = 0.044)], and attention [(pH: selective auditory task, p = 0.044)]. The finding of an inverse relationship observed in the parieto-occipital lobes suggests an association between neuronal energy markers with cognition in aMCI.ConclusionThe significant contribution of this preliminary research was to establish the feasibility of utilizing a methodology at UHF to accurately measure high-energy phosphate and membrane phospholipid metabolites in a population with heterogeneous outcomes. This work offers a novel approach for future work to further elucidate early dementia biomarkers or precursors to the downstream accumulation of amyloid and tau using the combination of MRS-PET imaging modalities in AD.

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Field dependence study of in vivo brain (31) P MRS up to 16.4 T.

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