ohsu advanced imaging...active water molecule transport in biological tissue: underpinnings of mri...

Active Water Molecule Transport in Biological Tissue:Underpinnings of MRI Interpretation

Charles SpringerWilliam Rooney, Xin Li, Wei Huang

OHSUOregon Health & Science University

Advanced ImagingResearch Center

Kahle, Simard, Staley, Nahed, Jones, Sun (2009)

/ edema

0

50

100

350

400

water exchangeincrease

cell size decrease

acute myeloidleukemia cells

yeastcells

murinemyocardiumin vivo/ ex vivo

humanbreast tumor

in vivo

%

kio = 1/τi = C(PW/d)for spherical (cylindrical) cell: C = 6 (4)for d = 20 µm: 1/τi = 2000 PW [τi in s; PW in cm/s]for PW = 5 x 10-­‐4 cm/s: 1/τi = 20 (1/d) [d in µm]

d

H2O H2OPW

τi

Bailey, Giles, Czarnota,

Stanisz (2009)

Zhang, Poirier-­‐Quinot,

Springer, Balschi (2011)

Coelho-­‐Filho, Shah, Mitchell, Neilan,

Moreno, Simonson, Kwong, Rosenzweig,

Das, Jerosch-­‐Herold (2013)

Springer, Li, Tudorica, Oh, Roy, Troxell, Chui, Naik, Holtorf, Afzal, Rooney, Huang (2014)

kio

d

Springer, Li, Tudorica, Oh,Roy, Chui, Naik, Holtorf,

Afzal, Rooney, Huang (2014)

kio CR

Morth, Pedersen, Buch-­‐Pedersen, Andersen, Vilsen, Palmgren, Nissen (2011)

Na+,K+-­‐ATPase [NKA] H+-­‐ATPase [Pma1]

P-­‐type ATPases

τi

ATPi + Hi+ → ADPi + Pi + Ho

+

ATPi + 2Ko+ + 3Nai+ → ADPi + Pi + 2Ki

+ + 3Nao+

Table 1. τi-­‐1 (kio) Reflects Turnover of Driving Membrane P-­‐Type ATPase Ion Pump

P-­‐Type ATPase Ion Pump yeast cardiomyocyte erythrocyte gene dosage ↑↑24

substrate ATPi ↑↑24 ↑↑75 Ko

+ ↑↑26 specific inhibitor

ebselen ↑↓24 ouabain ↑↓26

↑↑ positively related; ↑↓ inversely related 24measured; Zhang, Poirier-­‐Quinot, Springer, Balschi (2011) 26measured; Zhang, Balschi (2013) 75inferred; Kuchel, Benga (2005)

Pma1

NKA

Springer, Li, Tudorica, Oh,Roy, Chui, Naik, Holtorf,

Afzal, Rooney, Huang (2014)

d

H2O

PW

kioCR

H2O

ADPi + PCri ATPi + x H2Oi + 3 Nai+ + 2 Ko+ 2 Ki+ + 3 Nao+ + x H2Oo + ADPi + PiNKA

The Na+,K+-­‐ATPase System

ADPi + PCri ATPi + x H2Oi + 3 Nai+ + 2 Ko+ 2 Ki+ + 3 Nao+ + x H2Oo + ADPi + PiNKACrK

The Na+,K+-­‐ATPase System

ADPi + PCri ATPi + x H2Oi + 3 Nai+ + 2 Ko+ 2 Ki+ + 3 Nao+ + x H2Oo + ADPi + PiNKACrK

II

III

The Na+,K+-­‐ATPase System

ADPi + PCri ATPi + x H2Oi + 3 Nai+ + 2 Ko+ 2 Ki+ + 3 Nao+ + x H2Oo + ADPi + PiNKACrK

II

III

glycolysis

ox-­‐phos.

The Na+,K+-­‐ATPase System

ADPi + PCri ATPi + x H2Oi + 3 Nai+ + 2 Ko+ 2 Ki+ + 3 Nao+ + x H2Oo + ADPi + PiNKACrK

II

III

IV

I

glycolysis

ox-­‐phos.

The Na+,K+-­‐ATPase System

kio (active)

koi (active)

active trans-­‐membrane water cycling

[x = 500 – 1000]

T. Zeuthen (2010)

KCC NKCC1

Wright, Loo, Hirayama (2011)

ATP

ADP

K+

Na+

H2O

H2O

H2O

(+)(-­)

SGLT

NKA

Active Trans-­Plasma Membrane Water Cycling

H2OPW (active)

PW (passive)

K+

Na+

C6H12O6

KcsA

kio [τi-­‐1]

koi

Springer, Li, Tudorica, Oh,Roy, Chui, Naik, Holtorf,

Afzal, Rooney, Huang (2014)

glucose

glucose

glucose

glucose-­‐6-­‐phosphate pyruvate

lactate

HbO2

O2

O2

36 ATP

2 ATP

H+

H+

HCO3-­‐

HK

mitochondrion

MRO2

MRgluc

MRLDH

MRglyc

MRoxphos

MRNKA

MRNKA

kio

kpo

H2OH2O

capillary

Springer

general glucose metabolism

Li, Yu, Moloney, Chen, Huang, Woods, Coakley, Rooney, Garzotto, Springer

3T / malignant prostate no endorectal RF coil

kio [≡ τi-­1](s-­1)

〈kio〉ROI(s-­1) in vivo

adenocarcinoma

Ktrans(min-­1)

66 yo

5 subjects Gleason Score, ex vivo

[Dynamic-­‐Contrast-­‐Enhanced] DCE-­‐MRI

Tudorica, Oh, Chui, Roy, Troxell, Naik, Kemmer, Chen, Holtorf, Afzal, Springer, Li, Huang

3T human breast tumor [No. 13]

(grade 2 IDC; HER2+; BRCA1/BRCA2-­‐; ER+; PR-­‐) paclitaxel/cyclophosphamide + adriamycin

V1–[NACT]-­V2–[NACT]–[NACT]-­V3–[NACT]–[NACT]–[NACT]-­V4-­p

(after 16-­‐18 wks Tx)

29 human primary breast tumors

Accardi (2015)

Zhou, Wong, Cho, van der Hoeven, Liang, Thakur, Luo, Babic, Zinsmaier, Zhu, Hu, Venkatachalam, Hancock (2015)

ADPi + PCri ATPi + x H2Oi + 3 Nai+ + 2 Ko+ 2 Ki+ + 3 Nao+ + x H2Oo + ADPi + PiNKACrK

II

III

IV

I

glycolysis

ox-­‐phos.

The Na+,K+-­‐ATPase System

kio (active)

koi (active)

active trans-­‐membrane water cycling

[x = 500 – 1000]

squamous cell carcinoma of the head and neck

1.5T

Kim, Quon, Loevner, Rosen, Dougherty, Kilger, Glickson, Poptani (2007)

mostly solid

mixed

mostly necrotic/cystic

large ΔKtrans

small ΔKtrans

kio < 7.4 s-­1

kio > 7.4 s-­1

[n = 60;; p > 0.05]

[n = 60;; p = 0.027]

(months)

(months) Poptani

[1/kio]

[1/kio]

[1/kio]

Ktrans (min-­‐1) kio (s-­‐1) vi

pre-­‐

A

R L

PFigure 1.

after 1 session

a b c

d fe

3T human breast tumor [No. 4, pCR]

(grade 2 IDC; HER2+; BRCA1/BRCA2-­‐; ER+; PR+) trastuzumab/paclitaxel

[17 days]

Tudorica, Oh, Chui, Roy, Troxell, Naik, Kemmer, Chen, Holtorf, Afzal, Springer, Li, Huang

V1–[NACT]-­V2–[NACT]–[NACT]-­V3–[NACT]–[NACT]–[NACT]-­V4-­p

29 human primary breast tumors

kio = 5 s-­‐1 (*)ICV = 0.79

kio = 5 s-­‐1 (*)ICV = 0.82

kio = 5 s-­‐1 (*)ICV = 0.84

kio = 5 s-­‐1 (*)ICV = 0.79

kio = 1.7 s-­‐1ICV = 0.56

kio = 4.5 s-­‐1ICV = 0.74

S4

S2

S3

S1

S6

S5

human heart[repaired Tetralogy of Fallot]

1.5T / wash-­‐out shutter-­‐speed method

Rooney, Broberg, Springer (2015)

*set at 〈normal value〉

Myocardial Na+,K+-­‐ATPase Turnovermethod myocardium ECV ICV [= ρ•V] kio (s-­‐1) reference

steady-­‐state shutter-­‐speed

ex vivo rat (perfused/beating) control 5.6

a(no flow) ischemia 3.7

change 36%↓

titration shutter-­‐speed

in vivo / ex vivomouse control [n = 13] 0.25 0.75 5.3

bchronic hypertension [n = 17] 0.42 0.58 2.3

change 23%↓ 57%↓

wash-­‐outshutter-­‐speed

in vivohuman control [n = 12] 0.31 0.69

cchronic hypertension [n = 8] 0.45 0.55

change 20%↓

wash-­‐outshutter-­‐speed

in vivohuman control [n = 6] 0.33 0.67 5.0 d

wash-­‐outshutter-­‐speed

in vivo human control [n = 20] 0.31 0.69 10.0

echronic infarct [n = 20] 0.61 0.39 2.5

change 43%↓ 75%↓

a. Poirer-­Quinot, He, Springer, Balschi (2006). b. Coelho-­Filho, Shah, Mitchell, Neilan, Moreno, Simonson, Kwong, Rosenzweig, Das, Jerosch-­Herold (2013). c. Coelho-­Filho, Mongeon, Mitchell, Moreno, Nadruz, Kwong, Jerosch-­Herold (2013).d. Springer, Broberg, Rooney (2014). e. Goldfarb, Zhao (2014).

GdDTPA2-­

blood

Ktrans

τi

ve

kio

William D. Rooney

Brain Blood Vessel in Cross Section

CR

H2OCR H2O

CRCR

CR

CR

Trans-CapillaryWater Exchange

Modeling

Three variables:

1. 1/T1e

2. Blood volume

3. BloodWater lifetime

Rooney

(pb ~ vb = ρ†•V)

(τb [kpo = τb-1])

pb

[≡ τb-1]

kpo

Rooney, Li, Sammi, Bourdette, Neuwelt, Springer (2015)

22 y femalecontrol

52 y female

late-­‐stage MS

7 Tresting-­‐state

[≡ τb-­‐1]

[≡ τb-­‐1]

Table 2. The Biomarker kpoMeasures Metabolically Activity

SSP DCE-­‐MRI (1H2O) 31PMRSI 23NaMRSI SSP DCE-­‐MRI (1H2O) 31PMRSI-­‐MT

vb kpo [τb-­‐1] (s-­‐1) [ATPt] (mM) [Nat] (mM) kpo•vb (s-­‐1) CMRoxphos (pmol(ATP)/s/µL)

Healthy Controls (n = 6)

NWM 0.014 3.2 2.43 19a 0.045 50

NGM 0.031 2.9 1.62 31a 0.090 160

NGM/NWM 2.0 3.2

Relapsing Remitting MS (n = 6)

NAWM 0.019 2.2 2.11 27a 0.042

NAGM 0.045 2.0 1.29 36a 0.090

lesion 0.012 1.8 35a 0.022

Glioblastoma (n = 5)

NA-­‐frontal WM 0.008 2.6 ↑3%b 0.021

NA-­‐thalamus 0.017 2.9↓12%b

0.049

NA-­‐putamen 0.012 2.5 0.030

tumor 0.046 ≤ 0.18 ↑51%b ≤0.008

References this work 78, 79 19, 80 this work 17

areference (19); brelative to NWM, reference (80).

17. Zhu, Qiao, Du, Xiong, Liu, Zhang, Ugurbil, Chen (2012).19. Inglese, Madelin, Oesingmann, Babb, Wu, Stoekel, Herbert, Johnson (2010)78. Sammi, Berlow, Barbara, Selzer, Grinstead, Kim, Bourdette, Rooney (2012)79. Sammi, Berlow, Selzer, Maloney, Grinstead, Kim, Bourdette, Rooney, submitted80. Ouwerkerk, Bleich, Gillen, Pomper, Bottomley (2003)

Rooney, Li, Sammi, Bourdette, Neuwelt, Springer (2015)

Rinholm, Bergersen (2012)

Figure7. A Neurogliovascular Unit ChainMechanism. Water exchangeprocesses determinemean watermolecule lifetimes in blood (τb, beige), interstitium (τo, aqua), and endothelial (τi', gray), neuroglial(τi, pink), and neuronal (τi’’, blue) cell spaces. The equilibrium paracellular (a), simple diffusion (b),facilitated transcellular (c), and active water cycling (d, stars) pathways are indicated, as are “Magistrettisteps” (e,f,g). Wesuggest thed steps coupleunit metabolic activity toτb.

Rooney, Li, Sammi, Bourdette, Neuwelt, Springer (2015)

kpo

kio

kio

kio

kio

kio

vi

vi

ve

vb

Rooney, Li, Sammi, Bourdette, Neuwelt, Springer (2015)

22 y femalecontrol

52 y female

late-­‐stage MS

7 Tresting-­‐state

[≡ τb-­‐1]

[≡ τb-­‐1]

Metabolic Imaging• mapping metabolic thermodynamics

• metabolite concentrations [e.g., 31PMRSI]

• mapping metabolic kinetics• enzyme fluxes [e.g., 31PMRSI-­MT]

• current modalities [nominal voxel volumes for human study]31PMRSI [(1.3 cm)3 = 2.2 mL];; 1HMRSI [(1 cm)3 = 1 mL];; SPECT [(1 cm)3 = 1 mL];; HP-­13CMRSI [(7 mm)3 = 340 µL];; PET [(5 mm)3 = 125 µL];; 23NaMRSI [(4 mm)3 = 64 µL]

• potential high-­resolution metabolic imaging1H2O MRI [(1 mm)3 = 1 µL]

metaboCEST, metaboCESL• glucoCEST, glucoCESL• creatiCEST

OHSUOregon Health & Science University

Advanced ImagingResearch Center

Rooney, Sammi, Grinstead, Pollaro, Selzer, Li, Springer (2013)

active transmembrane water cycling will alter practice of and/or interpretations of:

• DCE-MRI• cardiological MRI • fMRI• diffusion-weighted MRI• CEST• magnetization transfer• rotating frame relaxation• MR fingerprinting

OHSUOregon Health & Science University

Advanced ImagingResearch Center