Exploring human brain oxidative metabolism and
neurotransmitter cycling at 7T
Sergey Cheshkov, Ph.D.
Advanced Imaging Research Center (AIRC)
UT Southwestern Medical Center
Bench Meets Bedside
September 28, 2015
Outline
•  Neural activity, metabolism, brain glucose
consumption
•  Measuring metabolism
•  High-field Multinuclear MRS –
•  Recent results at UTSW 7T
•
13C
•
31P
•  Conclusion
13C
and 31P
Neural Activity and glucose consumption
CMRglucose
CBF
Neural
Activity
Metabolic-Vascular
coupling
CMRO2
Glucose
pyruvate
lactate
90%
TCA
cycle
ETC
ATP
Measuring neural metabolism
•  PET (18FDG, 15O)
•  SPECT
•  Oxygenation-dependent MRI (BOLD, TRUST, …)
•
Tracer 13C MRS
31P
MRS
31P
MRS
Informational Content
13C
MRS
>>> PET
SPECT
1H
MRI
Jalloh et al.,2015
Sensitivity
13C
>>> •
PET
SPECT
1H
MRI
How to increase the sensitivity of 13C MRS ?
Ø
Hyperpolarization
Ø
Biopsies
Maher et al., NMR Biomed 2012;25
Ø
High Field
•
•
13C
MRS often requires 1H decoupling (100ms @ 20µT)
13C-infusion
protocols are quite long 90-120 min
Proton MRS at 7 Tesla
Tkac et al., Magn. Res Med. 2009
Investigate Neural Metabolism with 13C MRS
Ø  Capitalize on the advantages of high field without SAR limitations
Ø  Develop a 13C-tracer infusion protocol that is humanly tolerable
Ø  Investigate biomarkers for CMRglucose and neurotransmitter cycling
UTSW 7T Philips Scanner
Only 7T in the Southwest!
Methods
•
•
7T scanner; 5 normal volunteers
•
Infusion is outside the magnet
•
Quadrature 1H/13C transmit/receive partial volume coil
•
•
Non-localized 13C spectra, TR = 5 s, 5 min/dyn
[U-13C]glucose: bolus (8 g) + 90-120 min infusion (8g/hour)
No Decoupling: C1, C5
glutamate
Steady state information (1/4)
Infusion performed outside the magnet
•
glutamine C5 and
aspartate C4
glutamine C1
glutamine C1
aspartate C1
Metabolic substrate selection
glutamate C5
Infusion summed.esp
Glu C5
J45 = 52 Hz
Glu C5
Gln C5 Asp C4
bicarbonate
Glu C1
Gln C1 Asp C1
triglycerides
lactate C1
(GLU C5)
D45/S à C5 enrichment 21%
185
180
175
170
Chemical Shift (ppm)
165
160
Steady state information (2/4)
•
•
Metabolic substrate selection
Bicarbonate
Glu C1
Gln C1 Asp C1
Glu C5
Gln C5 Asp C4
CO2
CO2
Bicarbonate
Infusion performed outside the magnet
Steady state information (3/4)
Infusion performed outside the magnet
•
•
•
Metabolic substrate selection
Bicarbonate
Anaplerosis (neurotransmitter cycling)
GLU1/GLU5 = GLN1/GLN5
ASP1 = ASP4
GLU/ GLN = 10/3
GLU1/GLU5 = 0.74
20% anaplerosis
21%
Steady state information (4/4)
Infusion performed outside the magnet
•
•
•
•
Metabolic substrate selection
Bicarbonate – TCA cycle marker
CMRglucose
Glucose
Anaplerosis (neurotransmitter cycling)
No Lactate
pyruvate
TCA
cycle
lactate
Stable time course allows out-of-magnet infusions
Ø  Goal: Develop a 13C-tracer infusion protocol that is humanly tolerable
Normalized Signal Intensity 4 -­‐20 bicarb 3 glu C5 gln C5 / asp C4 glx C1 2 1 0 -­‐10 0 -­‐1 10 20 30 40 50 60 Time aFer infusion, min discontinued
70 Apply in mild TBI?
•
•
•
Glucose metabolism depressed?
Bicarbonate – TCA cycle marker
Anaplerosis – increased in TBI; leaky
neurotransmitter cycling
•
Lactate – a binary marker?
•
Cost considerations (per subject):
•
•
•
7T scan time, at $750hr. 1-2hrs
13C
Tracer, $2400
Supplies; nurse support; subject payments
CMRglucose
Glucose
pyruvate
TCA
cycle
lactate
bi-product or
fuel?
Carpenter et al.,
Eur J Pharm Sci, 2014
Summary of 13C MRS
Ø  Capitalize on the advantages of high field without SAR limitations √
Ø
Develop a 13C-tracer infusion protocol that is clinically applicable √
Ø
Investigate biomarkers for CMRglc and neurotransmitter cycling ?
What 31P MRS Can Offer for Brain Studies?
PCr in Pi
Piex PC PE GPE GP
C γ-­‐ ATP α-­‐ β-­‐ ppm Ren et al NMR Biomed 2015 Non-invasive Measurement of ATP Synthesis
EBIT Ren et al Mag Reson Med 2015 Rate of ATP synthesis Pi → γ-­‐ATP 9.9 ± 2.1 mmol/min/kg (n = 12) Advanced Imaging Research Center (AIRC):
Ivan Dimitrov, Ph.D.
Craig Malloy, M.D.
Dean Sherry, Ph.D.
Jimin Ren, Ph.D.
Neurology and Neurotherapeutics:
Vikram Jakkamsetti, Ph.D.
Levi Good, Ph.D.
Dorothy Kelly, M.A.
Karthik Rajasekaran, Ph.D.
Juan Pascual, M.D., Ph.D.
Thank you!
Results: Is the infusion protocol effective?
0.6 0.5 0.4 0.3 0.2 0.1 6E-­‐16 -­‐0.1 0 30 60 90 120 150 160 140 120 100 80 60 40 20 0 0 Time aFer start of infusion, min Blood fractional 13C enrichment:
~ 50%
30 60 90 120 10 9 8 7 6 5 4 3 2 1 0 150 Total blood lactate, mM FracLonal Enrichment Glucose m+6 Total blood glucose, mg/dL [by blood draws and glucometer / lactate meter]
[by blood draws and mass spec]
Time aFer start of infusion, min Normal physiological loading