OHSU Advanced Imaging...Active Water Molecule Transport in Biological Tissue: Underpinnings of MRI...
Transcript of 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