Broadband excitation and detection of cross-relaxation NMR spectra

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29632/1/0000721.pd

Transient decay of longitudinal magnetization in heterogeneous spin systems under selective saturation

The transient behavior of the longitudinal magnetization of the mobile protons in aqueous heterogeneous materials is investigated both theoretically and experimentally when selective saturation is applied by off resonance, RF irradiation to the homogeneously broadened, immobile protons which are coupled to the mobile protons through cross relaxation. Analytical solution of this problem is obtained by a generalization of H. C. Torrey's solution to the Bloch equations. Progressive (but indirect) saturation of the magnetization of the mobile protons under this RF irradiation is dynamically monitored using very-small-tip-angle sampling pulses. The apparent relaxation rate of heat-denatured egg albumin was measured as a function of frequency offset of the saturating RF with different amplitudes using a new dispersion method modified from a broadband technique recently invented for the rapid acquisition of a cross-relaxation z spectrum.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30350/1/0000752.pd

Magnetic field perturbation of neural recording and stimulating microelectrodes

To improve the overall temporal and spatial resolution of brain mapping techniques, in animal models, some attempts have been reported to join electrophysiological methods with functional magnetic resonance imaging (fMRI). However, little attention has been paid to the image artefacts produced by the microelectrodes that compromise the anatomical or functional information of those studies. This work presents a group of simulations and MR images that show the limitations of wire microelectrodes and the potential advantages of silicon technology, in terms of image quality, in MRI environments. Magnetic field perturbations are calculated using a Fourier-based method for platinum (Pt) and tungsten (W) microwires as well as two different silicon technologies. We conclude that image artefacts produced by microelectrodes are highly dependent not only on the magnetic susceptibility of the materials used but also on the size, shape and orientation of the electrodes with respect to the main magnetic field. In addition silicon microelectrodes present better MRI characteristics than metallic microelectrodes. However, metallization layers added to silicon materials can adversely affect the quality of MR images. Therefore only those silicon microelectrodes that minimize the amount of metallic material can be considered MR-compatible and therefore suitable for possible simultaneous fMRI and electrophysiological studies. High resolution gradient echo images acquired at 2 T (TR/TE = 100/15 ms, voxel size = 100 × 100 × 100 µm3) of platinum–iridium (Pt–Ir, 90%–10%) and tungsten microwires show a complete signal loss that covers a volume significantly larger than the actual volume occupied by the microelectrodes: roughly 400 times larger for Pt–Ir and 180 for W, at the tip of the microelectrodes. Similar MR images of a single-shank silicon microelectrode only produce a partial volume effect on the voxels occupied by the probe with less than 50% of signal loss.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58101/2/pmb7_8_003.pd

A unique anisotropic R2 of collagen degeneration (ARCADE) mapping as an efficient alternative to composite relaxation metric (R2â R1Ï ) in human knee cartilage study

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148373/1/mrm27621.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148373/2/mrm27621_am.pd

Polarized 129Xe129Xe optical pumping/spin exchange and delivery system for magnetic resonance spectroscopy and imaging studies

We describe the design and construction of a laser-polarized 129Xe129Xe production and delivery system that is used in our in vitro and in vivo magnetic resonance imaging (MRI) experiments. The entire apparatus including lasers and optics, rapidly actuated valves, heating and cooling, and transport tubing lies in the high magnetic field environment of a 2 T MRI magnet. With approximately 7.5% 129Xe129Xe polarization, 157 cc atm of xenon gas is produced and stored as xenon ice every 5 min. Large quantities of polarized 129Xe129Xe can be obtained by cycling this process. The xenon is subsequently delivered in a controlled fashion to a sample or subject. With this device we have established the feasibility of using laser-polarized 129Xe129Xe as a magnetic tracer in MRI. This reliable, effective, and relatively simple production method for large volumes of 129Xe129Xe can be applied to other areas of research involving the use of laser-polarized noble gases. © 1999 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/69879/2/RSINAK-70-2-1546-1.pd

Magnetic Resonance Imaging with laser polarized 129Xe129Xe

Magnetic Resonance Imaging with laser-polarized 129Xe129Xe can be utilized to trace blood flow and perfusion in tissue for a variety of biomedical applications. Polarized xenon gas introduced in to the lungs dissolves in the blood and is transported to organs such as the brain where it accumulates in the tissue. Spectroscopic studies combined with imaging have been used to produce brain images of 129Xe129Xe in the rat head. This work establishes that nuclear polarization produced in the gas phases survives transport to the brain where it may be imaged. Increases in polarization and delivered volume of 129Xe129Xe will allow clinical measurements of regional blood flow. © 1998 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87439/2/200_1.pd

Consistency of Efficacy Results Across Various Clinical Measures and Statistical Methods in the Lecanemab Phase 2 Trial of Early Alzheimer’s Disease

BACKGROUND: Lecanemab (BAN2401) is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (protofibrils) with activity at insoluble fibrils and slowed clinical decline in an 18-month phase 2 proof-of-concept study (Study 201; ClinicalTrials.gov NCT01767311) in 856 subjects with early Alzheimer\u27s disease (AD). In this trial, subjects were randomized to five lecanemab dose regimens or placebo. The primary efficacy endpoint was change from baseline in the Alzheimer\u27s Disease Composite Score (ADCOMS) at 12 months with Bayesian analyses. The key secondary endpoints were ADCOMS at 18 months and Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) and Alzheimer\u27s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) at 18 months. The results have been published previously. Herein, we describe the results of sensitivity analyses evaluating the consistency of the lecanemab efficacy results in Study 201 at the identified dose, the ED90, across multiple statistical methods and multiple endpoints over the duration of the study. METHODS: The protocol-specified analysis model was a mixed model for repeated measures (MMRM). Sensitivity analyses address the consistency of the conclusions using multiple statistical methods. These include a disease progression model (DPM), a natural cubic spline (NCS) model, a quadratic mixed model (QMM), and 2 MMRMs with additional covariates. RESULTS: The sensitivity analyses showed positive lecanemab treatment effects for all endpoints and all statistical models considered. The protocol-specified ADCOMS analysis showed a 29.7% slower decline than placebo for ADCOMS at 18 months. The various other analyses of 3 key endpoints showed declines ranging from 26.5 to 55.9%. The results at 12 months are also consistent with those at 18 months. CONCLUSIONS: The conclusion of the primary analysis of the lecanemab Study 201 is strengthened by the consistently positive conclusions across multiple statistical models, across efficacy endpoints, and over time, despite missing data. The 18-month data from this trial was utilized in the design of the confirmatory phase 3 trial (Clarity AD) and allowed for proper powering for multiple, robust outcomes

Comparison of noncontrast MRI magnetization transfer and T2‐Weighted signal intensity ratios for detection of bowel wall fibrosis in a Crohn's disease animal model

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/113105/1/jmri24815.pd

Lecanemab for Patients With Early Alzheimer Disease: Bayesian Analysis of a Phase 2b Dose-Finding Randomized Clinical Trial

IMPORTANCE: Bayesian clinical trial designs are increasingly common; given their promotion by the US Food and Drug Administration, the future use of the bayesian approach will only continue to increase. Innovations possible when using the bayesian approach improve the efficiency of drug development and the accuracy of clinical trials, especially in the context of substantial data missingness. OBJECTIVE: To explain the foundations, interpretations, and scientific justification of the bayesian approach in the setting of lecanemab trial 201, a bayesian-designed phase 2 dose-finding trial; to demonstrate the efficiency of using a bayesian design; and to show how it accommodates innovations in the prospective design and also treatment-dependent types of missing data. DESIGN, SETTING, AND PARTICIPANTS: This study was a bayesian analysis of a clinical trial comparing the efficacy of 5 lecanemab 201 dosages for treatment of early Alzheimer disease. The goal of the lecanemab 201 trial was to identify the effective dose 90 (ED90), the dose achieving at least 90% of the maximum effectiveness of doses considered in the trial. This study assessed the bayesian adaptive randomization used, in which patients were preferentially assigned to doses that would give more information about the ED90 and its efficacy. INTERVENTIONS: Patients in the lecanemab 201 trial were adaptively randomized to 1 of 5 dose regimens or placebo. MAIN OUTCOMES AND MEASURES: The primary end point of lecanemab 201 was the Alzheimer Disease Composite Clinical Score (ADCOMS) at 12 months with continued treatment and follow-up out to 18 months. RESULTS: A total 854 patients were included in trial treatment: 238 were in the placebo group (median age, 72 years [range, 50-89 years]; 137 female [58%]) and 587 were assigned to a lecanemab 201 treatment group (median age, 72 years [range, 50-90 years]; 272 female [46%]). The bayesian approach improved the efficiency of a clinical trial by prospectively adapting to the trial\u27s interim results. By the trial\u27s end more patients had been assigned to the better-performing doses: 253 (30%) and 161 (19%) patients to 10 mg/kg monthly and 10 mg/kg biweekly vs 51 (6%), 52 (6%), and 92 (11%) patients to 5 mg/kg monthly, 2.5 mg/kg biweekly, and 5 mg/kg biweekly, respectively. The trial identified 10 mg/kg biweekly as the ED90. The change in ADCOMS of the ED90 vs placebo was -0.037 at 12 months and -0.047 at 18 months. The bayesian posterior probability that the ED90 was superior to placebo was 97.5% at 12 months and 97.7% at 18 months. The respective probabilities of super-superiority were 63.8% and 76.0%. The primary analysis of the randomized bayesian lecanemab 201 trial found in the context of missing data that the most effective dose of lecanemab nearly doubles its estimated efficacy at 18 months of follow-up in comparison with restricting analysis to patients who completed the full 18 months of the trial. CONCLUSIONS AND RELEVANCE: Innovations associated with the bayesian approach can improve the efficiency of drug development and the accuracy of clinical trials, even in the context of substantial data missingness. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01767311