Hyperpolarized Xenon: Properties and Prospects

1. Hyperpolarized Xenon:Properties and Prospects Bill Hersman Department of Physics, University of New Hampshire http://xenon.unh.edu Hyperpolarized Xenon: Properties and Prospects

2. Overview • Production of hyperpolarized gas • Helium:Xenon differences • Biomedical applications (both gases) • Imaging lung ventilation • Asthma • Lung tissue obliteration • Oxygen uptake (helium only?) • Dissolved-phase applications • Signal strength estimates • Pulse sequence (CSI, ASL) • Xenon imaging of brain, heart, cancer Hyperpolarized Xenon: Properties and Prospects

3. How much polarization is enough? • Boltzmann distribution of spins yields a polarization for protons in water of 5 parts per million in 1.5 T, equilibrating with a time constant of ~3 seconds (T1) • Gas density is 1000 times less than liquid • Imaging with gases requires an increase in polarization by a factor of ~1000 • As a tracer, hyperpolarized gas atoms are <100% so even more polarization is required Hyperpolarized Xenon: Properties and Prospects

4. Rb 3He Spin-exchange collision Rb 3He Gas hyperpolarization • Laser light with circular polarization can deliver angular momentum to atoms if the photons are absorbed • Electrons in alkali metal vapor absorb laser light at 795 nm, acquiring the angular momentum and becoming polarized • Noble gas (3He) atoms collide with these polarized metal atoms, transferring polarization to the noble gas nucleus • Relaxation is suppressed allowing accumulation of polarization Hyperpolarized Xenon: Properties and Prospects

5. Helium:Xenon comparison …also gas diffusion constant Hyperpolarized Xenon: Properties and Prospects

6. Existing technologies • X-ray and CT scans of structure • Lung radio-xenon scintigraphy of ventilation 61 year old male with asbestos lung: a) X-ray b) CT-scan Ventilation images using radioactive xenon scintigraphy Hyperpolarized Xenon: Properties and Prospects

7. Hyperpolarized gas imaging • Applications: Beyond pretty pictures • Spin density distributions measure lung ventilation, sensitive to ventilation defects • Measurements of regional diffusion determine average size of lung structures, tissue damage • Measurements of polarization decay (T1) reveal local alveolar oxygen concentrations. Changes during a single breath indicate oxygen uptake Courtesy University of Virginia Hyperpolarized Xenon: Properties and Prospects

8. Ventilation defects • Obstructions or restrictions of breathing pathways prevent homogeneous ventilation • Image of spin-density can provide early diagnosis Healthy non-smoker Symptom-free smoker B. Eberle, et al, Johannes Gutenberg University, Mainz Hyperpolarized Xenon: Properties and Prospects

9. Spin density scans performed as multiple sequences Normal volunteer shows uniform ventilation Heterogeneous ventilation pattern reveals diseased lungs for patients with severe asthma cystic fibrosis Time-dependent inspiration M. Salerno, et al, Univ. of Virginia Hyperpolarized Xenon: Properties and Prospects

10. Emphysema and diffusion • Emphysema causes degeneration of alveoli • Alveolar compartments restrict diffusion, confining gas atoms near their original location. Dephasing field equals rephasing field. • Randomization of gas positions reduces the quality of the gradient rephasing echo, reducing the signal. J. West, Pulmonary Physiology and Pathophysiology Diffusion distance restricted by tight alveolar boundary Hyperpolarized Xenon: Properties and Prospects

11. Apparent Diffusion Coefficient: comparison a) Healthy lungs show uniform ventilation; consistently low diffusion b) Emphysematous lungs show mottled ventilation; nonuniform, high diffusion University of Virginia group, Salerno, et al. Hyperpolarized Xenon: Properties and Prospects

12. ADC: left lung transplant native transplant Johannes Gutenburg Universitat- Mainz group, Hyperpolarized Xenon: Properties and Prospects

13. Alveolar oxygen concentration and uptake • Paramagnetism of oxygen molecules randomizes the spin directions of the helium nuclei, decreasing the longitudinal polarization lifetime T1 to ~12 sec • Multiple measurements within a single breath-hold can detect changes in T1, identifying oxygen-uptake by the blood Not useful for xenon since blood flow reduces xenon signal by removing xenon Deninger, et al, Johannes Gutenberg Univ., Mainz Hyperpolarized Xenon: Properties and Prospects

14. Dissolved-phase xenon imaging • Xenon is soluble in blood and tissues • Xenon has long T1 (12 s) in oxygenated blood, shorter T1 in deoxygenated blood • Offers a background-free non-recirculating functional imaging contrast agent • Signal strength in blood can be comparable with proton imaging if polarization and quantity are maximized Hyperpolarized Xenon: Properties and Prospects

15. Xenon NMR spectroscopy: chemical shifts NMR spectrum of 129Xe in a rat body at 2 T. A: 209.3 ppm Blood B: 198.4 ppm Tissue C: 191.2 ppm Fat D: 0 ppm Gas M. Rosen (Ph.D. Thesis, U. Michigan) Hyperpolarized Xenon: Properties and Prospects

16. Xenon in cancer Spectra acquired at 11.7 T (500 MHz) Excised rat muscle in saline vs. RIF-1 tumor tissue Peak at 196.5 attributed to saline Peak at 199.2 attributed to tissue Dimitrov, et al. ? Hyperpolarized Xenon: Properties and Prospects

17. Xenon in human brain Spectral lines can provide additional information, but otherwise can be a complication by smearing the image • Kilian, et al acquired 16 x 16 CSI image of human brain using 0.5 liter natural xenon with polarization ~14% • Imaged on a 3.0 T scanner • They report a pronounced line at 197ppm, with additional lines at 185, 193, and 200. Hyperpolarized Xenon: Properties and Prospects

18. Hyperpolarized Xenon: Properties and Prospects

19. Our protocol • Practice with subject to establish metabolic baseline • Fully exhale to residual volume (~ 1 liter), then inhale 1 liter of gas containing 0.7 liter hyperpolarized enriched xenon (and 0.21 liter oxygen). Lungs achieve 35% xenon concentration. • Acquire images during 15 second breath hold. • Exhale and hyperventilate. Repeat only after breathing air one minute or more. • Improvement factor over Kilian: x3-4 (polarization) x3 (enrichment) x2 (quantity) x additional factor if we average over several breaths • FDA conditional approval received last month Hyperpolarized Xenon: Properties and Prospects

20. Xenon alveolar concentration in vivo Assumptions • 65% polarization • 86% enrichment • 70% xenon inhaled • One-liter inhaled gas mixes with one-liter residual volume Polarized proton density in a 1.5 T field is 0.00055 Moles/liter Hyperpolarized Xenon: Properties and Prospects

21. Xenon concentration in blood Signal in tissue (gray matter) is reduced by blood/tissue partition coefficient =0.79 and perfusion rate f=0.85 mL/g/min Polarized proton concentration @1.5 T = 0.00055 M/liter Hyperpolarized Xenon: Properties and Prospects

22. Current status • Lung imaging is funded and work is underway at Brigham and Women’s Hospital (first human image soon?) • Gas polarized at UNH and delivered 70 miles • Portable polarizer under development will enable on-site polarization capability after ~2 years • Diffusion as a function of time D(t) will reveal lung microstructure • Repeated depolarization of dissolved signal will reduce volume polarization by an amount proportional to the surface area for S/V Hyperpolarized Xenon: Properties and Prospects

23. Xenon’s potential • Imaging of arterial blood with little or no background (spin-density) • Imaging of time-dependence to measure permeability or perfusion (vulnerable cap in atherosclerotic plaque?) • Measuring tissue composition by Chemical Shift Imaging (CSI) • Selectively inverting a slice of xenon in an artery and tracking it for several seconds (Arterial Spin Labeling with no magnetization recovery, no background) • Note that cancer produces increased blood-flow and increased arterial blood volume, already observed with proton ASL. Both factors would significantly increase the xenon signal. Hyperpolarized Xenon: Properties and Prospects

24. Goals, plans, prospects • We can propose new research directions for the June 1 submission date. • Topics include: • Dissolved state imaging in general, motivate a dedicated imager at UNH • Cancer imaging • Cardiovascular imaging and angiography • Brain imaging • Our interdisciplinary collaboration enhances quality of proposal, chances of success • Would like to establish hyperpolarized gas imaging on campus at UNH, to maximize the productivity of the UNH researchers and the participation of students (requires an imager installed at UNH) • A hyperpolarized gas imaging center in Southern New Hampshire could be a benefit to the health of the population, local hospitals, and perhaps the State economy Hyperpolarized Xenon: Properties and Prospects