Publications by authors named "Edward P Hackett"

7 Publications

  • Page 1 of 1

Probing Cerebral Metabolism with Hyperpolarized C Imaging after Opening the Blood-Brain Barrier with Focused Ultrasound.

ACS Chem Neurosci 2021 08 22;12(15):2820-2828. Epub 2021 Jul 22.

Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.

Transient disruption of the blood-brain barrier (BBB) with focused ultrasound (FUS) is an emerging clinical method to facilitate targeted drug delivery to the brain. The focal noninvasive disruption of the BBB can be applied to promote the local delivery of hyperpolarized substrates. In this study, we investigated the effects of FUS on imaging brain metabolism using two hyperpolarized C-labeled substrates in rodents: [1-C]pyruvate and [1-C]glycerate. The BBB is a rate-limiting factor for pyruvate delivery to the brain, and glycerate minimally passes through the BBB. First, cerebral imaging with hyperpolarized [1-C]pyruvate resulted in an increase in total C signals ( = 0.05) after disrupting the BBB with FUS. Significantly higher levels of both [1-C]lactate (lactate/total C signals, = 0.01) and [C]bicarbonate ( = 0.008) were detected in the FUS-applied brain region as compared to the contralateral FUS-unaffected normal-appearing brain region. The application of FUS without opening the BBB in a separate group of rodents resulted in comparable lactate and bicarbonate productions between the FUS-applied and the contralateral brain regions. Second, C imaging with hyperpolarized [1-C]glycerate after opening the BBB showed increased [1-C]glycerate delivery to the FUS-applied region ( = 0.04) relative to the contralateral side, and [1-C]lactate production was consistently detected from the FUS-applied region. Our findings suggest that FUS accelerates the delivery of hyperpolarized molecules across the BBB and provides enhanced sensitivity to detect metabolic products in the brain; therefore, hyperpolarized C imaging with FUS may provide new opportunities to study cerebral metabolic pathways as well as various neurological pathologies.
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http://dx.doi.org/10.1021/acschemneuro.1c00197DOI Listing
August 2021

Cardiac measurement of hyperpolarized C metabolites using metabolite-selective multi-echo spiral imaging.

Magn Reson Med 2021 09 6;86(3):1494-1504. Epub 2021 Apr 6.

Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Purpose: Noninvasive imaging with hyperpolarized (HP) pyruvate can capture in vivo cardiac metabolism. For proper quantification of the metabolites and optimization of imaging parameters, understanding MR characteristics such as s of the HP signals is critical. This study is to measure in vivo cardiac s of HP [1- C]pyruvate and the products in rodents and humans.

Methods: A dynamic C multi-echo spiral imaging sequence that acquires [ C]bicarbonate, [1- C]lactate, and [1- C]pyruvate images in an interleaved manner was implemented for a clinical 3 Tesla system. of each metabolite was calculated from the multi-echo images by fitting the signal decay of each region of interest mono-exponentially. The performance of measuring using the sequence was first validated using a C phantom and then with rodents following a bolus injection of HP [1- C]pyruvate. In humans, of each metabolite was calculated for left ventricle, right ventricle, and myocardium.

Results: Cardiac s of HP [1- C]pyruvate, [1- C]lactate, and [ C]bicarbonate in rodents were measured as 24.9 ± 5.0, 16.4 ± 4.7, and 16.9 ± 3.4 ms, respectively. In humans, of [1- C]pyruvate was 108.7 ± 22.6 ms in left ventricle and 129.4 ± 8.9 ms in right ventricle. of [1- C]lactate was 40.9 ± 8.3, 44.2 ± 5.5, and 43.7 ± 9.0 ms in left ventricle, right ventricle, and myocardium, respectively. of [ C]bicarbonate in myocardium was 64.4 ± 2.5 ms. The measurements were reproducible and consistent over time after the pyruvate injection.

Conclusion: The proposed metabolite-selective multi-echo spiral imaging sequence reliably measures in vivo cardiac s of HP [1- C]pyruvate and products.
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http://dx.doi.org/10.1002/mrm.28796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212421PMC
September 2021

Imaging Acute Metabolic Changes in Patients with Mild Traumatic Brain Injury Using Hyperpolarized [1-C]Pyruvate.

iScience 2020 Dec 30;23(12):101885. Epub 2020 Nov 30.

Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Traumatic brain injury (TBI) involves complex secondary injury processes following the primary injury. The secondary injury is often associated with rapid metabolic shifts and impaired brain function immediately after the initial tissue damage. Magnetic resonance spectroscopic imaging (MRSI) coupled with hyperpolarization of C-labeled substrates provides a unique opportunity to map the metabolic changes in the brain after traumatic injury in real-time without invasive procedures. In this report, we investigated two patients with acute mild TBI (Glasgow coma scale 15) but no anatomical brain injury or hemorrhage. Patients were imaged with hyperpolarized [1-C]pyruvate MRSI 1 or 6 days after head trauma. Both patients showed significantly reduced bicarbonate (HCO ) production, and one showed hyperintense lactate production at the injured sites. This study reports the feasibility of imaging altered metabolism using hyperpolarized pyruvate in patients with TBI, demonstrating the translatability and sensitivity of the technology to cerebral metabolic changes after mild TBI.
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http://dx.doi.org/10.1016/j.isci.2020.101885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736977PMC
December 2020

Assessment of hepatic pyruvate carboxylase activity using hyperpolarized [1- C]-l-lactate.

Magn Reson Med 2021 03 16;85(3):1175-1182. Epub 2020 Sep 16.

Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Purpose: To evaluate the utility of hyperpolarized [1- C]-l-lactate to detect hepatic pyruvate carboxylase activity in vivo under fed and fasted conditions.

Methods: [1- C]-labeled sodium L-lactate was polarized using a dynamic nuclear polarizer. Polarization level and the T were measured in vitro in a 3 Telsa MR scanner. Two groups of healthy rats (fasted vs. fed) were prepared for in vivo studies. Each rat was anesthetized and intravenously injected with 60-mM hyperpolarized [1- C]-l-lactate, immediately followed by dynamic acquisition of C (carbon-13) MR spectra from the liver at 3 Tesla. The dosage-dependence of the C-products was also investigated by performing another injection of an equal volume of 30-mM hyperpolarized [1- C]-l-lactate.

Results: T and liquid polarization level of [1- C]-l-lactate were estimated as 67.8 s and 40.0%, respectively. [1- C]pyruvate and [1- C]alanine, [ C]bicarbonate ( ) and [1- C]aspartate were produced from hyperpolarized [1- C]-l-lactate in rat liver. Smaller and larger aspartate were measured in the fed group compared to the fasted group. Pyruvate and alanine production were increased in proportion to the lactate concentration, whereas the amount of and aspartate production was consistent between 30-mM and 60-mM lactate injections.

Conclusion: This study demonstrates that a unique biomarker of pyruvate carboxylase flux, the appearance of [1- C]aspartate from [1- C]-l-lactate, is sensitive to nutritional state and may be monitored in vivo at 3 Tesla. Because [ C] is largely produced by pyruvate dehydrogenase flux, these results suggest that the ratio of [1- C]aspartate and [ C] (aspartate/ ) reflects the saturable pyruvate carboxylase/pyruvate dehydrogenase enzyme activities.
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http://dx.doi.org/10.1002/mrm.28489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718288PMC
March 2021

Simultaneous Assessment of Intracellular and Extracellular pH Using Hyperpolarized [1-C]Alanine Ethyl Ester.

Anal Chem 2020 09 14;92(17):11681-11686. Epub 2020 Aug 14.

Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8568, United States.

Tissue pH is tightly regulated in vivo, being a sensitive physiological biomarker. Advent of dissolution dynamic nuclear polarization (DNP) and its translation to humans stimulated development of pH-sensitive agents. However, requirements of DNP probes such as biocompatibility, signal sensitivity, and spin-lattice relaxation time (T) complicate in vivo translation of the agents. Here, we developed a C-labeled alanine derivative, [1-C]-l-alanine ethyl ester, as a viable DNP probe whose chemical shift is sensitive to the physiological pH range, and demonstrated the feasibility in phantoms and rat livers in vivo. Alanine ethyl ester readily crosses cell membrane while simultaneously assessing extracellular and intracellular pH in vivo. Following cell transport, [1-C]-l-alanine ethyl ester is instantaneously hydrolyzed to [1-C]-l-alanine, and subsequently metabolized to [1-C]lactate and [C]bicarbonate. The pH-insensitive alanine resonance was used as a reference.
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http://dx.doi.org/10.1021/acs.analchem.0c01568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522639PMC
September 2020

In vivo assessment of increased oxidation of branched-chain amino acids in glioblastoma.

Sci Rep 2019 01 23;9(1):340. Epub 2019 Jan 23.

Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, USA.

Altered branched-chain amino acids (BCAAs) metabolism is a distinctive feature of various cancers and plays an important role in sustaining tumor proliferation and aggressiveness. Despite the therapeutic and diagnostic potentials, the role of BCAA metabolism in cancer and the activities of associated enzymes remain unclear. Due to its pivotal role in BCAA metabolism and rapid cellular transport, hyperpolarized C-labeled α-ketoisocaproate (KIC), the α-keto acid corresponding to leucine, can assess both BCAA aminotransferase (BCAT) and branched-chain α-keto acid dehydrogenase complex (BCKDC) activities via production of [1-C]leucine or CO (and thus HCO), respectively. Here, we investigated BCAA metabolism of F98 rat glioma model in vivo using hyperpolarized C-KIC. In tumor regions, we observed a decrease in C-leucine production from injected hyperpolarized C-KIC via BCAT compared to the contralateral normal-appearing brain, and an increase in HCO, a catabolic product of KIC through the mitochondrial BCKDC. A parallel ex vivo C NMR isotopomer analysis following steady-state infusion of [U-C]leucine to glioma-bearing rats verified the increased oxidation of leucine in glioma tissue. Both the in vivo hyperpolarized KIC imaging and the leucine infusion study indicate that KIC catabolism is upregulated through BCAT/BCKDC and further oxidized via the citric acid cycle in F98 glioma.
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http://dx.doi.org/10.1038/s41598-018-37390-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344513PMC
January 2019

Cognitive performance of juvenile monkeys after chronic fluoxetine treatment.

Dev Cogn Neurosci 2017 08 1;26:52-61. Epub 2017 May 1.

Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.

Potential long term effects on brain development are a concern when drugs are used to treat depression and anxiety in childhood. In this study, male juvenile rhesus monkeys (three-four years of age) were dosed with fluoxetine or vehicle (N=16/group) for two years. Histomorphometric examination of cortical dendritic spines conducted after euthanasia at one year postdosing (N=8/group) suggested a trend toward greater dendritic spine synapse density in prefrontal cortex of the fluoxetine-treated monkeys. During dosing, subjects were trained for automated cognitive testing, and evaluated with a test of sustained attention. After dosing was discontinued, sustained attention, recognition memory and cognitive flexibility were evaluated. Sustained attention was affected by fluoxetine, both during and after dosing, as indexed by omission errors. Response accuracy was not affected by fluoxetine in post-dosing recognition memory and cognitive flexibility tests, but formerly fluoxetine-treated monkeys compared to vehicle controls had more missed trial initiations and choices during testing. Drug treatment also interacted with genetic and environmental variables: MAOA genotype (high- and low transcription rate polymorphisms) and testing location (upper or lower tier of cages). Altered development of top-down cortical regulation of effortful attention may be relevant to this pattern of cognitive test performance after juvenile fluoxetine treatment.
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http://dx.doi.org/10.1016/j.dcn.2017.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557667PMC
August 2017
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