Mark Bitsch Vestergaard1, Hashmat Ghanizada2, Ulrich Lindberg1, Nanna Arngrim2, Olaf Paulson3, Messoud Ashina2, and Henrik Bo Wiberg Larsson1
1Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital Rigshospitalet, Glostrup, Denmark, 2Danish Headache Center, Department of Neurology., Copenhagen University Hospital Rigshospitalet, Glostrup, Denmark, 3Neurobiology Research Unit, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
Synopsis
In present study we demonstrate that in healthy
humans the cerebral lactate concentration increases during inhalation of
hypoxic air but not after exposure to carbon monoxide. This suggests a
regulatory mechanism of cerebral glycolytic activity possibly mediated by
sensing of arterial oxygen pressure and that the lactate production is not solely
a result of hindered oxidative metabolism, at least during non-threatening
hypoxic exposure. Phase-contrast mapping and susceptibility-based oximetry were
used to acquire global cerebral blood flow and oxygen consumption and MR-spectroscopy
was used to measure the lactate concentration in the occipital lope in a total
of 51 healthy humans.
Introduction
Brain physiology and metabolism is tightly regulated to ensure
normal neuronal function. Hypoxic exposure causes increased cerebral perfusion
to maintain adequate oxygen delivery to the brain. However, inhalation of
hypoxic air also increases the cerebral lactate production even though the
brain oxygen consumption is unaffected, suggesting a metabolic adaption1,2.
In
present study we investigate the mechanism of this lactate production from
hypoxic exposure and explore for possible correlation with brain perfusion,
oxygen availability and oxygen consumption. This was done by examining a group
of healthy humans inhaling hypoxic air while lying in the MRI-scanner and a
group that immediately before scanning was exposed to air with carbon monoxide
(CO).
Inhalation
of hypoxic air causes desaturation of arterial oxyhemoglobin (SaO2)
and decreases the arterial oxygen partial pressure (PaO2),
whereas inhalation of CO only decreases SaO2, by
CO-molecules binding to the hemoglobin, but PaO2 is
maintained at normal pressure3,4. This enables us to
distinguish between the effects from general lowered oxygen concentration in
the arterial blood from that of arterial oxygen partial pressure.
Global
mean cerebral blood flow (gCBF) and global mean cerebral metabolic rate of
oxygen (gCMRO2) were acquired noninvasively using phase-contrast MRI
technique and lactate concentration were acquired using MR spectroscopy. Methods
51
subjects participated in the study. 30 subjects inhaled hypoxic air, and 21
were exposed to air with CO. All MRI
scans were performed on a Philips 3T Achieva dSTREAM MRI scanner
(Philips Medical Systems, Best, The Netherlands) using a 32-channel phase array
head coil. The acquisition of parameters was covered in one MRI session.
Lactate concentration, gCBF and gCMRO2 were acquired at resting
baseline and measurements were repeated during inhalation of hypoxic air or
after CO exposure. The approximate timing of the acquisition of the parameters is
demonstrated in figure 1.
Phase-contrast
mapping (PCM) were used to acquire the blood flow in the feeding cerebral
arteries by acquiring blood velocity maps using a turbo field echo sequence (1 slice, voxel size=0.75×0.75×8 mm3; velocity encoding=100
cm/s, without cardiac gating).
Susceptibility-based
oximetry (SBO) was used to measure the venous oxygen saturation in the blood
leaving the brain in the sagittal sinus5. SBO utilizes that the different
magnetic susceptibility between deoxyhemoglobin and oxyhemoglobin can be
related to oxygen saturation. Susceptibility-weighted images were obtained by a dual-echo gradient-echo sequence and
subtracting the phase-images from each echo (voxel size=0.7×0.7×8 mm3; TE1=10.89 ms; TE2=24.16 ms; velocity
encoding=100 cm/s). The sequence was
interleaved with a velocity-encoding scheme to also acquire the blood flow in
the sagittal sinus. By using the Fick’s principle gCMRO2 could then
be calculated.
Cerebral lactate concentration was measured
in the occipital lobe by MR-spectroscopy using a water-suppressed
point-resolved spectroscopy (PRESS) pulse sequence (TE=36 ms; voxel size=30×35×30 mm3).
Anatomical images were obtained by a 3D
T1-weighted turbo field echo sequence (voxel size=1.1×1.1×1.1 mm3;
TE=2.78 ms; TR=6.9 ms; flip angle=9°).
The effects
from exposure to hypoxic air or CO on gCBF, gCMRO2 and lactate
concentration were assessed by a linear mixed model.Results
The arterial
oxyhemoglobin saturation was on average 75.5±8.0%
during inhalation of hypoxic air and 79.2±1.9% after
carbon monoxide exposure at the time of acquisition of the MRI parameters.
Cerebral
lactate concentration, gCBF
and gCMRO2 at baseline and during exposure to hypoxic air or
after exposure to CO are shown in figure 2.
Inhalation
of hypoxic air caused an increase in gCBF of 20% from 50.7±5.5
ml/100g/min to 60.5±9.5 ml/100g/min (p<10-6).
The gCMRO2 was unaffected from 136.3±25.49 mmol/100g/min at baseline to 147.8±38.2 mmol1gmin (p=0.13) during inhalation of hypoxic air.
Lactate concentration increased with 71% from 0.54±0.24
mmol/l to 0.81±0.30 mmol/l (p<10-6).
Exposure
to CO increased CBF with 33.0% from 57.3±7.9 ml/100g/min to 75.9±9.7 ml/100g/min
(p<10-6). The increase was significantly higher than that from inhalation
of hypoxic air (p=0.0024). The gCMRO2 was unaffected from CO
exposure (p=0.071), and with no difference compared to inhalation of hypoxic
air (p=0.30). Exposure to CO did not increase lactate concentration from 0.56±0.19 mmol/l at baseline to 0.61±0.22 mmol/l
after exposure to CO (p=0.26). The lactate increase from the hypoxic challenge was
significantly different than from CO exposure (p<10-3). Discussion and conclusion
In present
study we found that CO exposure does
not affect the cerebral lactate concentration, whereas
inhalation of hypoxic air robustly increases the lactate concentration. The
higher lactate production occurs even though the cerebral oxygen consumption
was unaffected. This suggests that glycolytic
activity and lactate production in the human brain is dynamically regulated,
possible by a direct sensing mechanism of arterial oxygen partial pressure, and
hypoxia-stimulated cerebral lactate production is not solely a result of
inadequate oxygen availability and hindered oxygen metabolism. It remains to be
established whether CO2 alteration is involved in the lactate change
and future studies should address the influence of CO2 on the
lactate flux.Acknowledgements
No acknowledgement found.References
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