Evaluation of fluorine-19 magnetic resonance imaging of the lungs using octafluorocyclobutane in a rat model.

PURPOSE: To test octafluorocyclobutane (OFCB) as an inhalation contrast agent for fluorine-19 MRI of the lung, and to compare the image quality of OFCB scans with perfluoropropane (PFP) scans THEORY AND METHODS: After normalizing for the number of signal averages, a theoretical comparison between the OFCB signal-to-noise ratio (SNR) and PFP SNR predicted the average SNR advantage of 90% using OFCB during gradient echo imaging. The OFCB relaxometry was conducted using single-voxel spectroscopy and spin-echo imaging. A comparison of OFCB and PFP SNRs was performed in vitro and in vivo. Five healthy Sprague-Dawley rats were imaged during single breath-hold and continuous breathing using a Philips Achieva 3.0T MRI scanner (Philips, Andover, MA). The scan time was constant for both gases. Statistical comparison between PFP and OFCB scans was conducted using a paired t test and by calculating the Bayes factor. RESULTS: Spin-lattice (T1 ) and effective spin-spin ( T2∗ ) relaxation time constants of the pure OFCB gas were determined as 28.5 ± 1.2 ms and 10.5 ± 1.8 ms, respectively. Mixing with 21% of oxygen decreased T1 by 30% and T2∗ by 20%. The OFCB in vivo images showed 73% higher normalized SNR on average compared with images acquired using PFP. The statistical significance was shown by both paired t test and calculated Bayes factors. The experimental results agree with theoretical calculations within the error of the relaxation parameter measurements. CONCLUSION: The quality of the lung images acquired using OFCB was significantly better compared with PFP scans. The OFCB images had higher a SNR and were artifact-free.

Cyclodextrin-Based Contrast Agents for Medical Imaging.

Cyclodextrins (CDs) are naturally occurring cyclic oligosaccharides consisting of multiple glucose subunits. CDs are widely used in host-guest chemistry and biochemistry due to their structural advantages, biocompatibility, and ability to form inclusion complexes. Recently, CDs have become of high interest in the field of medical imaging as a potential scaffold for the development of a large variety of the contrast agents suitable for magnetic resonance imaging, ultrasound imaging, photoacoustic imaging, positron emission tomography, single photon emission computed tomography, and computed tomography. The aim of this review is to summarize and highlight the achievements in the field of cyclodextrin-based contrast agents for medical imaging.

Hyperpolarized 129Xe Time-of-Flight MR Imaging of Perfusion and Brain Function.

Perfusion measurements can provide vital information about the homeostasis of an organ and can therefore be used as biomarkers to diagnose a variety of cardiovascular, renal, and neurological diseases. Currently, the most common techniques to measure perfusion are 15O positron emission tomography (PET), xenon-enhanced computed tomography (CT), single photon emission computed tomography (SPECT), dynamic contrast enhanced (DCE) MRI, and arterial spin labeling (ASL) MRI. Here, we show how regional perfusion can be quantitively measured with magnetic resonance imaging (MRI) using time-resolved depolarization of hyperpolarized (HP) xenon-129 (129Xe), and the application of this approach to detect changes in cerebral blood flow (CBF) due to a hemodynamic response in response to brain stimuli. The investigated HP 129Xe Time-of-Flight (TOF) technique produced perfusion images with an average signal-to-noise ratio (SNR) of 10.35. Furthermore, to our knowledge, the first hemodynamic response (HDR) map was acquired in healthy volunteers using the HP 129Xe TOF imaging. Responses to visual and motor stimuli were observed. The acquired HP TOF HDR maps correlated well with traditional proton blood oxygenation level-dependent functional MRI. Overall, this study expands the field of HP MRI with a novel dynamic imaging technique suitable for rapid and quantitative perfusion imaging.

Decacationic Pillar[5]arene: A New Scaffold for the Development of 129Xe MRI Imaging Agents.

A decacationic water-soluble pillar[5]arene possessing a nonsolvated hydrophobic core has been designed and synthesized. This supramolecular host is capable of binding xenon, as evidenced by hyperCEST depletion experiments. Fluorescence-based studies also demonstrate that xenon binds into the cavity of the pillararene with an association constant of 4.6 × 103 M-1. These data indicate that the water-soluble pillararene is a potential scaffold for building contrast agents that can be detected by xenon-129 magnetic resonance imaging.

Brain Imaging Using Hyperpolarized 129Xe Magnetic Resonance Imaging.

Hyperpolarized (HP) 129Xe magnetic resonance imaging (MRI) is a novel iteration of traditional MRI that relies on detecting the spins of 1H. Since 129Xe is a gaseous signal source, it can be used for lung imaging. Additionally, 129Xe dissolves in the blood stream and can therefore be detectable in the brain parenchyma and vasculature. In this work, we provide detailed information on the protocols that we have developed to image 129Xe within the brains of both rodents and human subjects.

Inhaled Xenon Washout as a Biomarker of Alzheimer's Disease.

Biomarkers have the potential to aid in the study of Alzheimer’s disease (AD); unfortunately, AD biomarker values often have a high degree of overlap between healthy and AD individuals. This study investigates the potential utility of a series of novel AD biomarkers, the sixty second 129Xe retention time, and the xenon washout parameter, based on the washout of hyperpolarized 129Xe from the brain of AD participants following inhalation. The xenon washout parameter is influenced by cerebral perfusion, T1 relaxation of xenon, and the xenon partition coefficient, all factors influenced by AD. Participants with AD (n = 4) and healthy volunteers (n = 4) were imaged using hyperpolarized 129Xe magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to determine the amount of retained xenon in the brain. At 60 s after the breath hold, AD patients retained significantly higher amounts of 129Xe compared to healthy controls. Data was fit to a pharmacokinetic model and the xenon washout parameter was extracted. Xenon washout in white and grey matter occurs at a slower rate in Alzheimer’s participants (129Xe half-life time of 42 s and 43 s, respectively) relative to controls (20 s and 16 s, respectively). Following larger scale clinical trials for validation, the xenon washout parameter has the potential to become a useful biomarker for the support of AD diagnosis.

Cyclodextrin-Based Pseudorotaxanes: Easily Conjugatable Scaffolds for Synthesizing Hyperpolarized Xenon-129 Magnetic Resonance Imaging Agents.

Hyperpolarized (HP) xenon-129 (Xe) magnetic resonance (MR) imaging has the potential to detect biological analytes with high sensitivity and high resolution when coupled with xenon-encapsulating molecular probes. Despite the development of numerous HP Xe probes, one of the challenges that has hampered the translation of these agents from in vitro demonstration to in vivo testing is the difficulty in synthesizing the Xe-encapsulating cage molecule. In this study, we demonstrate that a pseudorotaxane, based on a γ-cyclodextrin macrocycle, is easily synthesized in one step and is detectable using HyperCEST-enhanced 129Xe MR spectroscopy.

Recent Progress in Alzheimer's Disease Research, Part 2: Genetics and Epidemiology.

This is the second part of a three-part review series reviewing the most important advances in Alzheimer's disease (AD) research since 2010. This review covers the latest research on genetics and epidemiology. Epidemiological and genetic studies are revealing important insights into the etiology of, and factors that contribute to AD, as well as areas of priority for research into mechanisms and interventions. The widespread adoption of genome wide association studies has provided compelling evidence of the genetic complexity of AD with genes associated with such diverse physiological function as immunity and lipid metabolism being implicated in AD pathogenesis.

Recent Progress in Alzheimer's Disease Research, Part 1: Pathology.

The field of Alzheimer's disease (AD) research has grown exponentially over the past few decades, especially since the isolation and identification of amyloid-ß from postmortem examination of the brains of AD patients. Recently, the Journal of Alzheimer's Disease (JAD) put forth approximately 300 research reports which were deemed to be the most influential research reports in the field of AD since 2010. JAD readers were asked to vote on these most influential reports. In this 3-part review, we review the results of the 300 most influential AD research reports to provide JAD readers with a readily accessible, yet comprehensive review of the state of contemporary research. Notably, this multi-part review identifies the "hottest" fields of AD research providing guidance for both senior investigators as well as investigators new to the field on what is the most pressing fields within AD research. Part 1 of this review covers pathogenesis, both on a molecular and macro scale. Part 2 review genetics and epidemiology, and part 3 covers diagnosis and treatment. This part of the review, pathology, reviews amyloid-ß, tau, prions, brain structure, and functional changes with AD and the neuroimmune response of AD.

In vivo detection of cucurbit[6]uril, a hyperpolarized xenon contrast agent for a xenon magnetic resonance imaging biosensor.

The Hyperpolarized gas Chemical Exchange Saturation Transfer (HyperCEST) Magnetic Resonance (MR) technique has the potential to increase the sensitivity of a hyperpolarized xenon-129 MRI contrast agent. Signal enhancement is accomplished by selectively depolarizing the xenon within a cage molecule which, upon exchange, reduces the signal in the dissolved phase pool. Herein we demonstrate the in vivo detection of the cucurbit[6]uril (CB6) contrast agent within the vasculature of a living rat. Our work may be used as a stepping stone towards using the HyperCEST technique as a molecular imaging modality.

Recent Progress in Alzheimer's Disease Research, Part 3: Diagnosis and Treatment.

The field of Alzheimer's disease (AD) research has grown exponentially over the past few decades, especially since the isolation and identification of amyloid-ß from postmortem examination of the brains of AD patients. Recently, the Journal of Alzheimer's Disease (JAD) put forth approximately 300 research reports which were deemed to be the most influential research reports in the field of AD since 2010. JAD readers were asked to vote on these most influential reports. In this 3-part review, we review the results of the 300 most influential AD research reports to provide JAD readers with a readily accessible, yet comprehensive review of the state of contemporary research. Notably, this multi-part review identifies the "hottest" fields of AD research providing guidance for both senior investigators as well as investigators new to the field on what is the most pressing fields within AD research. Part 1 of this review covers pathogenesis, both on a molecular and macro scale. Part 2 review genetics and epidemiology, and part 3 covers diagnosis and treatment. This part of the review, diagnosis and treatment, reviews the latest diagnostic criteria, biomarkers, imaging, and treatments in AD.

Effect of Copper and Zinc on the Single Molecule Self-Affinity of Alzheimer's Amyloid-ß Peptides.

The presence of trace concentrations of metallic ions, such as copper and zinc, has previously been shown to drastically increase the aggregation rate and neurotoxicity of amyloid-ß (Aß), the peptide implicated in Alzheimer's disease (AD). The mechanism of why copper and zinc accelerate Aß aggregation is poorly understood. In this work, we use single molecule force spectroscopy (SMFS) to probe the kinetic and thermodynamic parameters (dissociation constant, Kd, kinetic dissociation rate, koff, and free energy, ΔG) of the dissociation of an Aß dimer, the amyloid species which initiates the amyloid cascade. Our results show that nanomolar concentrations of copper do not change the single molecule affinity of Aß to another Aß peptide in a statistically significant way, while nanomolar concentrations of zinc decrease the affinity of Aß-Aß by an order of magnitude. This suggests that the binding of zinc ion to Aß may interfere with the binding of Aß-Aß, leading to a lower self-affinity.

HyperCEST detection of cucurbit[6]uril in whole blood using an ultrashort saturation Pre-pulse train.

Xenon based biosensors have the potential to detect and localize biomarkers associated with a wide variety of diseases. The development and nuclear magnetic resonance (NMR) characterization of cage molecules which encapsulate hyperpolarized xenon is imperative for the development of these xenon biosensors. We acquired (129) Xe NMR spectra, and magnetic resonance images and a HyperCEST saturation map of cucurbit[6]uril (CB6) in whole bovine blood. We observed a mean HyperCEST depletion of 84% (n = 5) at a concentration of 5 mM and 74% at 2.5 mM. Additionally, we collected these data using a pulsed HyperCEST saturation pre-pulse train with a SAR of 0.025 W/kg which will minimize any potential RF heating in animal or human tissue. Copyright © 2016 John Wiley & Sons, Ltd.

Testing synthetic amyloid-ß aggregation inhibitor using single molecule atomic force spectroscopy.

Alzheimer's disease is a neurodegenerative disease with no known cure and few effective treatment options. The principal neurotoxic agent is an oligomeric form of the amyloid-ß peptide and one of the treatment options currently being studied is the inhibition of amyloid aggregation. In this work, we test a novel pseudopeptidic aggregation inhibitor designated as SG1. SG1 has been designed to bind at the amyloid-ß self-recognition site and prevent amyloid-ß from misfolding into ß sheet. We used atomic force spectroscopy, a nanoscale measurement technique, to quantify the binding forces between two single amyloid peptide molecules. For the first time, we demonstrate that single molecule atomic force spectroscopy can be used to assess the effectiveness of amyloid aggregation inhibitors by measuring the experimental yield of binding and can potentially be used as a screening technique for quick testing of efficacy of inhibitor drugs for amyloid aggregation.