A feasibility study for quantitative assessment of cerebrovascular malformations using flutriciclamide ([18F]GE-180) PET/MRI.

Aim: Neuroinflammation plays a key role in both the pathogenesis and the progression of cerebral cavernous malformations (CCM). Flutriciclamide ([18F]GE-180) is a translocator protein (TSPO) targeting positron emission tomography (PET) tracer, developed for imaging neuroinflammation. The objectives of this study were to describe characteristics of flutriciclamide uptake in different brain tissue regions in CCM patients compared to controls, and to evaluate flutriciclamide uptake and iron deposition within CCM lesions. Materials and methods: Five patients with CCM and six controls underwent a 60 or 90 min continuous PET/MRI scan following 315 ± 68.9 MBq flutriciclamide administration. Standardized uptake value (SUV) and standardized uptake value ratio (SUVr) were obtained using the striatum as a pseudo-reference. Quantitative susceptibility maps (QSM) were used to define the location of the vascular malformation and calculate the amount of iron deposition in each lesion. Results: Increased flutriciclamide uptake was observed in all CCM lesions. The temporal pole demonstrated the highest radiotracer uptake; the paracentral lobule, cuneus and hippocampus exhibited moderate uptake; while the striatum had the lowest uptake, with average SUVs of 0.66, 0.55, 0.63, 0.55, and 0.33 for patient with CCM and 0.57, 0.50, 0.48, 0.42, and 0.32 for controls, respectively. Regional SUVr showed similar trends. The average SUV and QSM values in CCM lesions were 0.58 ± 0.23 g/ml and 0.30 ± 0.10 ppm. SUVs and QSM were positively correlated in CCM lesions (r = 0.53, p = 0.03). Conclusion: The distribution of flutriciclamide ([18F]GE-180) in the human brain and CCM lesions demonstrated the potential of this TSPO PET tracer as a marker of neuroinflammation that may be relevant for characterizing CCM disease progression along with QSM.

A nanoparticle probe for the imaging of autophagic flux in live mice via magnetic resonance and near-infrared fluorescence.

Autophagy-the lysosomal degradation of cytoplasmic components via their sequestration into double-membraned autophagosomes-has not been detected non-invasively. Here we show that the flux of autophagosomes can be measured via magnetic resonance imaging or serial near-infrared fluorescence imaging of intravenously injected iron oxide nanoparticles decorated with cathepsin-cleavable arginine-rich peptides functionalized with the near-infrared fluorochrome Cy5.5 (the peptides facilitate the uptake of the nanoparticles by early autophagosomes, and are then cleaved by cathepsins in lysosomes). In the heart tissue of live mice, the nanoparticles enabled quantitative measurements of changes in autophagic flux, upregulated genetically, by ischaemia-reperfusion injury or via starvation, or inhibited via the administration of a chemotherapeutic or the antibiotic bafilomycin. In mice receiving doxorubicin, pre-starvation improved cardiac function and overall survival, suggesting that bursts of increased autophagic flux may have cardioprotective effects during chemotherapy. Autophagy-detecting nanoparticle probes may facilitate the further understanding of the roles of autophagy in disease.

X-ray bi-prism interferometry-A design study of proposed novel hardware.

PURPOSE: Advances in X-ray phase-contrast imaging can obtain excellent soft-tissue contrast of phase-shift, attenuation, and small-angle scatter. Here, we present fringe patterns for different design parameters of X-ray bi-prism interferometry imaging systems. Our aim is to develop bi-prism interferometry imaging systems with excellent polychromatic performance that produce high-contrast fringes with spatially incoherent X-ray illumination. We also introduce a novel X-ray tube design that uses temporal multiplexing to provide simultaneous virtual "electronic phase stepping" that replace "mechanical phase stepping" popular with grating-based interferometry setups. METHODS: In our investigation, we develop expressions for the irradiance distribution pattern of a bi-prism interferometer composed of multiple point sources and multiple bi-prisms. These expressions are used to plot fringe patterns for X-ray design parameters, including size of point source, number of point sources, and point source separation, and bi-prism design parameters including material, angle, number of bi-prisms, period, and bi-prism array to X-ray source and detector distances. RESULTS: Results show that the fringe patterns for a bi-prism interferometry system are not longitudinally periodic as with grating interferometers that produce a Talbot-Lau carpet. It is also shown that at 59 keV X-rays the bi-prism material should be something comparable to nickel to obtain reasonable fringe visibility. CONCLUSION: The irradiance distribution pattern demonstrates that bi-prism interferometry may provide comparable or improved fringe visibility to that of gratings. Special care is given to present our findings within the context of previous advancements. A single-shot image acquisition approach using a temporal multiplexed, high-power X-ray source provides virtual electronic phase stepping without focal spot sweeping. This provides multiple images, each at the same exposure and the same projection view, from different fringe locations that allow one to derive the attenuation, phase, and dark-field images of the sample without mechanical phase stepping of a grating.

Tomography of dark-field scatter including single-exposure Moiré fringe analysis with X-ray biprism interferometry-A simulation study.

PURPOSE: In this work, we present tomographic simulations of a new hardware concept for X-ray phase-contrast interferometry wherein the phase gratings are replaced with an array of Fresnel biprisms, and Moiré fringe analysis is used instead of "phase stepping" popular with grating-based setups. METHODS: Projections of a phantom consisting of four layers of parallel carbon microfibers is simulated using wave optics representation of X-ray electromagnetic waves. Simulated projections of a phantom with preferential scatter perpendicular to the direction of the fibers are performed to analyze the extraction of small-angle scatter from dark-field projections for the following: (1) biprism interferometry using Moiré fringe analysis; (2) grating interferometry using phase stepping with eight grating steps; and (3) grating interferometry using Moiré fringe analysis. Dark-field projections are modeled as projections of voxel intensities represented by a fixed finite vector basis set of scattering directions. An iterative MLEM algorithm is used to reconstruct, from simulated projection data, the coefficients of a fixed set of seven basis vectors at each voxel representing the small-angle scatter distribution. RESULTS: Results of reconstructed vector coefficients are shown comparing the three simulated imaging configurations. The single-exposure Moiré fringe analysis shows not only an increase in noise because of one-eighth the number of projection samples but also is obtained with less dose and faster acquisition times. Furthermore, replacing grating interferometry with biprism interferometry provides better contrast-to-noise. CONCLUSION: The simulations demonstrate the feasibility of the reconstruction of dark-field data acquired with a biprism interferometry system. With the potential of higher fringe visibility, biprism interferometry with Moiré fringe analysis might provide equal or better image quality to that of phase stepping methods with less imaging time and lower dose.

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

PURPOSE: Alteration in mitochondrial membrane potential (ΔΨm) 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 ΔΨm in the myocardium of normal human subjects. METHODS: Thirteen healthy subjects were imaged using [18F]-triphenylphosphonium ([18F]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 (fECS) 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 (ΔΨT), a proxy of ΔΨm, 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 (ΔΨT), representing the sum of cellular membrane potential (ΔΨc) and ΔΨm, 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.

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

BACKGROUND: We recently reported a method using positron emission tomography (PET) and the tracer 18F-labeled tetraphenylphosphonium (18F-TPP+) for mapping the tissue (i.e., cellular plus mitochondrial) membrane potential (ΔΨT) 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 18F-TPP+ and mitochondrial membrane potential (ΔΨm). METHODS: We tested these hypotheses by measuring decreases of 18F-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 18F-TPP+ concentration. More definitive experiments were performed in two additional pigs, in which we administered an intravenous bolus plus infusion of 18F-TPP+ to reach secular equilibrium followed by an intracoronary infusion of BAM15. RESULTS: Intracoronary BAM15 infusion led to a clear decrease in 18F-TPP+ concentration, falling to a lower level, and then recovering. A second BAM15 infusion reduced the 18F-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 18F-TPP+ PET is sensitive to temporal changes in mitochondrial membrane potential.

[18F]-AV-1451 binding profile in chronic traumatic encephalopathy: a postmortem case series.

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 [18F]-AV-1451 on pathologically confirmed CTE postmortem brain tissue samples. METHODS: We performed [18F]-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 [18F]-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.

Multi-atlas cardiac PET segmentation.

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 ([18F]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 r2 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 (r2 = 0.92) with the manual segmentation compared with the single-atlas based (r2 = 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.

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

[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.