Publications by authors named "Sally Ji Who Kim"

5 Publications

  • Page 1 of 1

In vivo quantitative mapping of human mitochondrial cardiac membrane potential: a feasibility study.

Eur J Nucl Med Mol Imaging 2021 02 27;48(2):414-420. Epub 2020 Jul 27.

Department of Radiology, Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, 125 Nashua Street, #6604, Boston, MA, 02114, USA.

Purpose: Alteration in mitochondrial membrane potential (ΔΨ) is an important feature of many pathologic processes, including heart failure, cardiotoxicity, ventricular arrhythmia, and myocardial hypertrophy. We present the first in vivo, non-invasive, assessment of regional ΔΨ in the myocardium of normal human subjects.

Methods: Thirteen healthy subjects were imaged using [F]-triphenylphosphonium ([F]TPP+) on a PET/MR scanner. The imaging protocol consisted of a bolus injection of 300 MBq followed by a 120-min infusion of 0.6 MBq/min. A 60 min, dynamic PET acquisition was started 1 h after bolus injection. The extracellular space fraction (f) was simultaneously measured using MR T1-mapping images acquired at baseline and 15 min after gadolinium injection with correction for the subject's hematocrit level. Serial venous blood samples were obtained to calculate the plasma tracer concentration. The tissue membrane potential (ΔΨ), a proxy of ΔΨ, was calculated from the myocardial tracer concentration at secular equilibrium, blood concentration, and fECS measurements using a model based on the Nernst equation.

Results: In 13 healthy subjects, average tissue membrane potential (ΔΨ), representing the sum of cellular membrane potential (ΔΨ) and ΔΨ, was - 160.7 ± 3.7 mV, in excellent agreement with previous in vitro assessment.

Conclusion: In vivo quantification of the mitochondrial function has the potential to provide new diagnostic and prognostic information for several cardiac diseases as well as allowing therapy monitoring. This feasibility study lays the foundation for further investigations to assess these potential roles. Clinical trial identifier: NCT03265431.
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http://dx.doi.org/10.1007/s00259-020-04878-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839097PMC
February 2021

Imaging of Mitochondrial Depolarization of Myocardium With Positron Emission Tomography and a Proton Gradient Uncoupler.

Front Physiol 2020 15;11:491. Epub 2020 May 15.

Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.

Background: We recently reported a method using positron emission tomography (PET) and the tracer F-labeled tetraphenylphosphonium (F-TPP) for mapping the tissue (i.e., cellular plus mitochondrial) membrane potential (ΔΨ) in the myocardium. The purpose of this work is to provide additional experimental evidence that our methods can be used to observe transient changes in the volume of distribution for F-TPP and mitochondrial membrane potential (ΔΨ).

Methods: We tested these hypotheses by measuring decreases of F-TPP concentration elicited when a proton gradient uncoupler, BAM15, is administered by intracoronary infusion during PET scanning. BAM15 is the first proton gradient uncoupler shown to affect the mitochondrial membrane without affecting the cellular membrane potential. Preliminary dose response experiments were conducted in two pigs to determine the concentration of BAM15 infusate necessary to perturb the F-TPP concentration. More definitive experiments were performed in two additional pigs, in which we administered an intravenous bolus plus infusion of F-TPP to reach secular equilibrium followed by an intracoronary infusion of BAM15.

Results: Intracoronary BAM15 infusion led to a clear decrease in F-TPP concentration, falling to a lower level, and then recovering. A second BAM15 infusion reduced the F-TPP level in a similar fashion. We observed a maximum depolarization of 10 mV as a result of the BAM15 infusion.

Summary: This work provides evidence that the total membrane potential measured with F-TPP PET is sensitive to temporal changes in mitochondrial membrane potential.
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http://dx.doi.org/10.3389/fphys.2020.00491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243673PMC
May 2020

[F]-AV-1451 binding profile in chronic traumatic encephalopathy: a postmortem case series.

Acta Neuropathol Commun 2019 10 28;7(1):164. Epub 2019 Oct 28.

MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA, USA.

Introduction: Chronic traumatic encephalopathy (CTE) is a tauopathy associated to repetitive head trauma. There are no validated in vivo biomarkers of CTE and a definite diagnosis can only be made at autopsy. Recent studies have shown that positron emission tomography (PET) tracer AV-1451 (Flortaucipir) exhibits high binding affinity for paired helical filament (PHF)-tau aggregates in Alzheimer (AD) brains but relatively low affinity for tau lesions in other tauopathies like temporal lobal degeneration (FTLD)-tau, progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). Little is known, however, about the binding profile of this ligand to the tau-containing lesions of CTE.

Objective: To study the binding properties of [F]-AV-1451 on pathologically confirmed CTE postmortem brain tissue samples.

Methods: We performed [F]-AV-1451 phosphor screen and high resolution autoradiography, quantitative tau measurements by immunohistochemistry and Western blot and tau seeding activity assays in brain blocks containing hippocampus, superior temporal cortex, superior frontal cortex, inferior parietal cortex and occipital cortex from 5 cases of CTE, across the stages of disease: stage II-III (n = 1), stage III (n = 3), and stage IV (n = 1). Importantly, low or no concomitant classic AD pathology was present in these brains.

Results: Despite the presence of abundant tau aggregates in multiple regions in all CTE brains, only faint or no [F]-AV-1451 binding signal could be detected by autoradiography. The only exception was the presence of a strong signal confined to the region of the choroid plexus and the meninges in two of the five cases. Tau immunostaining and Thioflavin-S staining ruled out the presence of tau aggregates in those regions. High resolution nuclear emulsion autoradiography revealed the presence of leptomeningeal melanocytes as the histologic source of this off-target binding. Levels of abnormally hyperphosphorylated tau species, as detected by Western Blotting, and tau seeding activity were both found to be lower in extracts from cases CTE when compared to AD.

Conclusion: AV-1451 may have limited utility for in vivo selective and reliable detection of tau aggregates in CTE. The existence of disease-specific tau conformations may likely explain the differential binding affinity of this tracer for tau lesions in different tauopathies.
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http://dx.doi.org/10.1186/s40478-019-0808-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816221PMC
October 2019

Multi-atlas cardiac PET segmentation.

Phys Med 2019 Feb 18;58:32-39. Epub 2019 Jan 18.

Department of Nuclear Medicine, Seoul National University, Seoul, Republic of Korea; Department of Biomedical Sciences, Seoul National University, Seoul, Republic of Korea; Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, Republic of Korea. Electronic address:

Purpose: We propose a multi-atlas based segmentation method for cardiac PET and SPECT images to deal with the high variability of tracer uptake characteristics in myocardium. In addition, we verify its performance by comparing it to the manual segmentation and single-atlas based approach, using dynamic myocardial PET.

Methods: Twelve left coronary artery ligated SD rats underwent ([F]fluoropentyl) triphenylphosphonium salt PET/CT scans. Atlas-based segmentation is based on the spatial normalized template with pre-defined region-of-interest (ROI) for each anatomical or functional structure. To generate multiple left ventricular (LV) atlases, each LV image was segmented manually and divided into angular segments. The segmentation methods performances were compared in regional count information using leave-one-out cross-validation. Additionally, the polar-maps of kinetic parameters were estimated.

Results: In all images, the highest r template yielded the lowest root-mean-square error (RMSE) between the source image and the best-matching templates ranged between 0.91-0.97 and 0.06-0.11, respectively. The single-atlas and multi-atlas based ROIs yielded remarkably different perfusion distributions: only the multi-atlas based segmentation showed equivalent high correlation results (r = 0.92) with the manual segmentation compared with the single-atlas based (r = 0.88). The high perfusion value underestimation was remarkable in single-atlas based segmentation.

Conclusions: The main advantage of the proposed multi-atlas based cardiac segmentation method is that it does not require any prior information on the tracer distribution to be incorporated into the image segmentation algorithms. Therefore, the same procedure suggested here is applicable to any other cardiac PET or SPECT imaging agents without modification.
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http://dx.doi.org/10.1016/j.ejmp.2019.01.003DOI Listing
February 2019

Lessons learned about [F-18]-AV-1451 off-target binding from an autopsy-confirmed Parkinson's case.

Acta Neuropathol Commun 2017 10 19;5(1):75. Epub 2017 Oct 19.

MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA, USA.

[F-18]-AV-1451 is a novel positron emission tomography (PET) tracer with high affinity to neurofibrillary tau pathology in Alzheimer's disease (AD). PET studies have shown increased tracer retention in patients clinically diagnosed with dementia of AD type and mild cognitive impairment in regions that are known to contain tau lesions. In vivo uptake has also consistently been observed in midbrain, basal ganglia and choroid plexus in elderly individuals regardless of their clinical diagnosis, including clinically normal whose brains are not expected to harbor tau pathology in those areas. We and others have shown that [F-18]-AV-1451 exhibits off-target binding to neuromelanin, melanin and blood products on postmortem material; and this is important for the correct interpretation of PET images. In the present study, we further investigated [F-18]-AV-1451 off-target binding in the first autopsy-confirmed Parkinson's disease (PD) subject who underwent antemortem PET imaging. The PET scan showed elevated [F-18]-AV-1451 retention predominantly in inferior temporal cortex, basal ganglia, midbrain and choroid plexus. Neuropathologic examination confirmed the PD diagnosis. Phosphor screen and high resolution autoradiography failed to show detectable [F-18]-AV-1451 binding in multiple brain regions examined with the exception of neuromelanin-containing neurons in the substantia nigra, leptomeningeal melanocytes adjacent to ventricles and midbrain, and microhemorrhages in the occipital cortex (all reflecting off-target binding), in addition to incidental age-related neurofibrillary tangles in the entorhinal cortex. Additional legacy postmortem brain samples containing basal ganglia, choroid plexus, and parenchymal hemorrhages from 20 subjects with various neuropathologic diagnoses were also included in the autoradiography experiments to better understand what [F-18]-AV-1451 in vivo positivity in those regions means. No detectable [F-18]-AV-1451 autoradiographic binding was present in the basal ganglia of the PD case or any of the other subjects. Off-target binding in postmortem choroid plexus samples was only observed in subjects harboring leptomeningeal melanocytes within the choroidal stroma. Off-target binding to parenchymal hemorrhages was noticed in postmortem material from subjects with cerebral amyloid angiopathy. The imaging-postmortem correlation analysis in this PD case reinforces the notion that [F-18]-AV-1451 has strong affinity for neurofibrillary tau pathology but also exhibits off-target binding to neuromelanin, melanin and blood components. The robust off-target in vivo retention in basal ganglia and choroid plexus, in the absence of tau deposits, meningeal melanocytes or any other identifiable binding substrate by autoradiography in the PD case reported here, also suggests that the PET signal in those regions may be influenced, at least in part, by biological or technical factors that occur in vivo and are not captured by autoradiography.
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http://dx.doi.org/10.1186/s40478-017-0482-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648451PMC
October 2017
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