april 16, 2004hyperpolarized xenon: properties and prospects1 bill hersman department of physics,...

April 16, 2004April 16, 2004 Hyperpolarized Xenon: Properties and ProspectsHyperpolarized Xenon: Properties and Prospects 11

Hyperpolarized Xenon:Hyperpolarized Xenon:Properties and ProspectsProperties and Prospects

Bill Hersman Bill Hersman Department of Physics, University of New HampshireDepartment of Physics, University of New Hampshire

http://xenon.unh.edu


OverviewOverview

Production of hyperpolarized gasProduction of hyperpolarized gas Helium:Xenon differencesHelium:Xenon differences Biomedical applications (both gases)Biomedical applications (both gases)

Imaging lung ventilation Asthma Lung tissue obliteration Oxygen uptake (helium only?)

Dissolved-phase applications Dissolved-phase applications Signal strength estimates Pulse sequence (CSI, ASL)

Xenon imaging of brain, heart, cancerXenon imaging of brain, heart, cancer


How much polarization is enough?How much polarization is enough?

Boltzmann distribution of spins yields a polarization Boltzmann distribution of spins yields a polarization for protons in water of 5 parts per million in 1.5 T, for protons in water of 5 parts per million in 1.5 T, equilibrating with a time constant of ~3 seconds (Tequilibrating with a time constant of ~3 seconds (T11))

Gas density is 1000 times less than liquidGas density is 1000 times less than liquid

Imaging with gases requires an increase in Imaging with gases requires an increase in polarization by a factor of ~1000polarization by a factor of ~1000

As a tracer, hyperpolarized gas atoms are <100% so As a tracer, hyperpolarized gas atoms are <100% so even more polarization is requiredeven more polarization is required


Gas hyperpolarizationGas hyperpolarization

Laser light with circular polarization Laser light with circular polarization can deliver angular momentum to can deliver angular momentum to atoms if the photons are absorbedatoms if the photons are absorbed

Electrons in alkali metal vapor Electrons in alkali metal vapor absorb laser light at 795 nm, absorb laser light at 795 nm, acquiring the angular momentum acquiring the angular momentum and becoming polarizedand becoming polarized

Noble gas (Noble gas (33He) atoms collide with He) atoms collide with these polarized metal atoms, these polarized metal atoms, transferring polarization to the transferring polarization to the noble gas nucleusnoble gas nucleus

Relaxation is suppressed allowing Relaxation is suppressed allowing accumulation of polarizationaccumulation of polarization

Rb

Rb 3He

3HeSpin-exchange collision


Helium:Xenon comparisonHelium:Xenon comparison

100% Helium-3100% Helium-3 26.4% xenon-12926.4% xenon-129 86% xenon-12986% xenon-129

SupplySupply Artificially produced Artificially produced from decay of tritiumfrom decay of tritium

Naturally occurringNaturally occurring Naturally occurringNaturally occurring

(isotopically enriched)(isotopically enriched)

Present costPresent cost $200/liter$200/liter $4/liter$4/liter $150-$300/liter$150-$300/liter

Gyromagnetic ratioGyromagnetic ratio

(Signal strength)(Signal strength)

0.762 of proton0.762 of proton 0.278 of proton0.278 of proton 0.278 of proton0.278 of proton

Gas fraction in a Gas fraction in a single breathsingle breath

0.790.79

(21% oxygen)(21% oxygen)

0.70.7


0.70.7


Solubility in blood Solubility in blood

in fatin fat

~0~0

~0~0

= 0.17= 0.17

= 1.7= 1.7

= 0.17= 0.17

= 1.7= 1.7

Lifetime TLifetime T1 1 in lungsin lungs

in bloodin blood

TT1 1 ~ 12 sec~ 12 sec

n.a.n.a.

TT1 1 ~ 12 sec~ 12 sec

TT1 1 ~ 12 sec~ 12 sec

TT1 1 ~ 12 sec~ 12 sec

TT1 1 ~ 12 sec~ 12 sec

…also gas diffusion constant


Existing technologiesExisting technologies X-ray and CT scans of structureX-ray and CT scans of structure

Lung radio-xenon scintigraphy of ventilationLung radio-xenon scintigraphy of ventilation

Ventilation images using radioactive xenon scintigraphy

61 year old male with asbestos lung: a) X-ray b) CT-scan


Hyperpolarized gas imagingHyperpolarized gas imaging

Applications: Beyond pretty picturesApplications: Beyond pretty pictures

Spin density distributions measure lung Spin density distributions measure lung ventilation, sensitive to ventilation ventilation, sensitive to ventilation defectsdefects

Measurements of regional diffusion Measurements of regional diffusion determine average size of lung determine average size of lung structures, tissue damagestructures, tissue damage

Measurements of polarization decay (TMeasurements of polarization decay (T11) )

reveal local alveolar oxygen reveal local alveolar oxygen concentrations. Changes during a concentrations. Changes during a single breath indicate oxygen uptakesingle breath indicate oxygen uptake

Courtesy University of Virginia


Ventilation defectsVentilation defects Obstructions or restrictions of breathing pathways Obstructions or restrictions of breathing pathways

prevent homogeneous ventilationprevent homogeneous ventilation

Image of spin-density can provide early diagnosisImage of spin-density can provide early diagnosis

B. Eberle, et al, Johannes Gutenberg University, Mainz

Healthy non-smoker Symptom-free smoker


Time-dependent inspirationTime-dependent inspiration

Spin density scans Spin density scans performed as multiple performed as multiple sequencessequences

Normal volunteer shows Normal volunteer shows uniform ventilationuniform ventilation

Heterogeneous ventilation Heterogeneous ventilation pattern reveals diseased pattern reveals diseased lungs for patients withlungs for patients with

a)a) severe asthmasevere asthma

b)b) cystic fibrosiscystic fibrosis

M. Salerno, et al,Univ. of Virginia


Emphysema and diffusionEmphysema and diffusion Emphysema causes Emphysema causes

degeneration of alveolidegeneration of alveoli

Alveolar compartments Alveolar compartments restrict diffusion, confining restrict diffusion, confining gas atoms near their original gas atoms near their original location. Dephasing field location. Dephasing field equals rephasing field.equals rephasing field.

Randomization of gas Randomization of gas positions reduces the positions reduces the quality of the gradient quality of the gradient rephasing echo, reducing rephasing echo, reducing the signal.the signal.

Diffusion distance restrictedby tight alveolar boundary

J. West, Pulmonary Physiology and Pathophysiology


Apparent Diffusion Coefficient: comparisonApparent Diffusion Coefficient: comparison

a) Healthy lungs show uniform ventilation; consistently low diffusion

b) Emphysematous lungs show mottled ventilation; nonuniform, high diffusionUniversity of Virginia group, Salerno, et al.


ADC: left lung transplantADC: left lung transplant

transplantnative

Johannes Gutenburg Universitat- Mainz group,


Alveolar oxygen concentration and uptakeAlveolar oxygen concentration and uptake Paramagnetism of oxygen molecules randomizes the spin Paramagnetism of oxygen molecules randomizes the spin

directions of the helium nuclei, decreasing the longitudinal directions of the helium nuclei, decreasing the longitudinal polarization lifetime Tpolarization lifetime T11 to ~12 sec to ~12 sec

Multiple measurements within a single breath-hold can detect Multiple measurements within a single breath-hold can detect changes in Tchanges in T11, identifying oxygen-uptake by the blood, identifying oxygen-uptake by the blood

Deninger, et al, Johannes Gutenberg Univ., Mainz

Not useful for xenon since blood flow reduces xenon signal by removing xenon


Dissolved-phase xenon imagingDissolved-phase xenon imaging

Xenon is soluble in blood and Xenon is soluble in blood and tissuestissues

Xenon has long TXenon has long T11 (12 s) in (12 s) in

oxygenated blood, shorter Toxygenated blood, shorter T11 in in

deoxygenated blooddeoxygenated blood

Offers a background-free non-Offers a background-free non-recirculating functional imaging recirculating functional imaging contrast agentcontrast agent

Signal strength in blood can be comparable with proton imaging if polarization and quantity are maximized


Xenon NMR spectroscopy: chemical shiftsXenon NMR spectroscopy: chemical shifts

NMR spectrum of NMR spectrum of 129129Xe in a Xe in a rat body at 2 T.rat body at 2 T.

A:A: 209.3 ppm209.3 ppm BloodBlood

B:B: 198.4 ppm198.4 ppm TissueTissue

C:C: 191.2 ppm191.2 ppm FatFat

D:D: 0 ppm0 ppm GasGas

M. Rosen M. Rosen

(Ph.D. Thesis, U. Michigan)(Ph.D. Thesis, U. Michigan)


Xenon in cancerXenon in cancer

Spectra acquired at 11.7 T (500 MHz)Spectra acquired at 11.7 T (500 MHz)

Excised rat muscle in saline vs. RIF-1 Excised rat muscle in saline vs. RIF-1 tumor tissuetumor tissue

Peak at 196.5 attributed to salinePeak at 196.5 attributed to saline

Peak at 199.2 attributed to tissuePeak at 199.2 attributed to tissue

Dimitrov, et al.Dimitrov, et al. ?


Xenon in human brainXenon in human brain

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.

Spectral lines can provide additional information, but otherwise can be a complication by smearing the image


Our protocolOur 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


Xenon alveolar concentration Xenon alveolar concentration in vivoin 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


Xenon concentration in bloodXenon 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

ff

Gray matterGray matter 0.850.85 0.790.79

White matterWhite matter 0.430.43 1.321.32

MyelinMyelin 0.430.43 17.17.

Adipose FatAdipose Fat 0.040.04 9.89.8

MuscleMuscle 0.060.06 0.580.58

KidneyKidney 4.04.0 0.660.66

LiverLiver 0.2*0.2* 0.720.72

HeartHeart 4.9*4.9* 0.690.69

Polarized proton concentration @1.5 T = 0.00055 M/liter


Current statusCurrent 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


Xenon’s potentialXenon’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.


Goals, plans, prospectsGoals, 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

april 16, 2004hyperpolarized xenon: properties and prospects1 bill hersman department of physics,...

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