Soyoung Choi1,2, Chau Vu3, Richard M Leahy4, and John Wood5
1Neuroscience Graduate Program, University of Southern California, LOS ANGELES, CA, United States, 2Children's Hospital Los Angeles, LOS ANGELES, CA, United States, 3Biomedical Engineering, University of Southern California, LOS ANGELES, CA, United States, 4Signal and Image Processing Institute, University of Southern California, Los Angeles, CA, United States, 5Division of Hematology, Children's Hospital Los Angeles, Los Angeles, CA, United States
Synopsis
Patients with chronic anemia has been shown to be susceptible
to structural, functional and cognitive impairments. This study explores
differences in white matter microstructure (measured by ADC) and
cerebrovascular perfusion patterns (measured by MTT) and their relationship to
hemoglobin in patients with sickle cell anemia, non-sickle anemia and controls.
Larger ADC values
and faster MTT is found along the anterior circulation of the brain in
sickle-cell anemic patients. Relationships were found between hemoglobin, ADC
and MTT in controls that were not observed in sickle-cell patients possibly
indicating microvascular dysregulation. Our observations
indicate possible microvascular dysregulation in sickle cell anemic patients.
Introduction
Patients with chronic anemia has been reported to show
structural, functional and cognitive impairments in the brain. The brain is
autoregulated to respond to low hemoglobin and oxygen through compensatory
cerebral vasodilation. Although a global rise in cerebral blood flow has been
shown in anemic patients,[1]
it has been proposed that microvascular dysregulation may still be adversely
affecting these patients.[2]
Our laboratory previously characterized lower white matter brain volume in
sickle and non-sickle anemic patients associated with low cognitive scores.[3], [4]
and found that oxygen delivery in white matter was 35% lower in anemic patients
in comparison to controls.[5]
Based on these observations, we hypothesize that loss of integrity in white
matter tissue could be related to disrupted hyperemic response.
Here we investigate whether differences in white matter
tissue microstructure can be detected in our anemic patients. Diffusion weighted
imaging allows us to infer information about microstructure as we can measure
the restricted diffusion of water in white matter tissue. We used apparent
diffusion coefficient (ADC) to measure white matter integrity as increased
values of ADC has been associated with compromised brain tissue.
We then explore how tissue microstructure relates to the
brain’s perfusion patterns using deoxygenation-based DSC. Red blood cells deliver oxygen to tissue along
capillaries. Mean transit time (MTT) measures the amount of time that blood
dwells at the capillaries, allowing sufficient oxygen exchange with the
surrounding tissue. We hypothesize that insufficient mean transit time would
explain local disruptions to tissue microstructure. We tested our hypothesis in
sickle cell anemic (SCA) patients, non-sickle anemic (NSA) patients and
controls (CTL).Methods
MRI data and complete blood panels were obtained from SCA
(age=20.7±8.1, F=17, M=17, HgB = 9.8±1.8), NSA (age=25.3±9.5, F=8, M=4, HgB=10.7±2.0)
and CTL subjects (age=26.4±10.8, F=27,M=7, HgB=13.3±1.2). (Recruited with
informed consent or assent; IRB: CHLA CCI#11-00083; 3T Philips Achieva
v.3.2.1., 8-channel head coil).
3D T1-weighted images (TE =3.8ms TR =8.3ms; resolution =
1mm3) were pre-processed using BrainSuite (brainsuite.org, v18a) and labeled
using the USCLobes atlas. DWI (TE = 2.5ms; TR = 4.8ms; resolution=2.5mm3)
included 30 diffusion-encoding directions at b-value=1000m/s2 and a
reverse-gradient b=0. Fieldmaps were estimated using FSL’s topup module.
BrainSuite Diffusion Pipeline (BDP18a) performed distortion correction,
co-registration to T1-weighted images and calculated ADC maps. Only ADC values
in white matter tissue were retained.
BOLD images (TE/TR=50ms/2000ms; flip angle=90°; resolution=2.3x2.3x5mm)
were acquired while subjects were fitted with a rebreathing apparatus where 5
inhalations of 100% nitrogen gas administered then replaced by room air gas
mixture. FSL was used for motion correction, registration to MNI template
(labelled by USCLobes atlas) and smoothing (8mm3 gaussian kernel). Arterial
input function was extracted from the middle cerebral artery. Regional cerebral
blood volume and blood flow was computed from adapted DSC equations [6].
Mean transit time was calculated as the ratio between blood volume and blood
flow based on central volume theorem.[7]
Mean ADC and MTT were computed in each ROI of the USCLobes
atlas then controlled for age and sex. SCA, NSA and CTL subjects were compared
using student’s t-tests. Pearson’s correlations were run between ADC and MTT in
each ROI by group.Results
Sickle cell anemic patients had larger ADC values bilaterally
in the frontal and temporal lobes, right parietal lobe, brainstem and corpus
callosum in comparison to controls. MTT was lower in SCA patient compared to
controls in the bilateral frontal and parietal lobes and the left temporal
lobe. (Table 1)
Hemoglobin was negatively correlated to ADC in the brainstem
and cerebellum of NSA subjects but positively correlated in the brainstem of
control subjects. Lower hemoglobin levels were associated with faster MTT
bilaterally in the parietal and occipital lobes in controls only. SCA patients
only showed a positive correlation between hemoglobin and MTT in deep white matter.
(Table 2)
ADC and MTT were positively correlated throughout the brain
in control subjects while no correlations were observed in anemic patients.
(Table 2)Discussion
Evidence of compromised white matter microstructure and
short perfusion time was found in SCA along anterior cerebral circulation
territories. Lower red blood cell dwelling time in capillaries may explain lower
oxygen delivery in white matter tissue observed previously.[5]
While hemoglobin alone could not predict ADC values, longer MTT was associated with higher hemoglobin and larger ADC in control subjects. This may be indicative of the intricacies of the
autoregulatory system in response to both oxygen supply and demand. Short MTT in
response to low hemoglobin may indicate increased cerebral blood flow to maintain normal oxygen delivery to the brain while long MTT in response to high ADC
may indicate cerebral vasodilation in response to higher demand of oxygen in
compromised tissue. Regardless of hemoglobin level or ADC, we did not observe
significant difference in MTT, possibly indicating microvascular dysregulation.
Significant differences in ADC and MTT were not observed in NSA
subjects possibly due to low sample size. The deoxygenation-based DSC used in
this report was utilized to mirror dynamic susceptibility contrast (DSC)
imaging that requires the use of a contrast agent. While we assume that brief
duration of desaturation does not cause significant change in global flow, we recognize
that acute hypoxia may have confounded our MTT measures.Acknowledgements
This
work was supported by National Heart, Lung, and Blood Institute
(1U01-HL-117718-01, 1RO1HL136484-A1 and a Minority Supplement to 1U01-HL-117718-01),
the National Center for Research (5UL1TR000130-05) through the Clinical
Translational Science Institute at Children’s Hospital Los Angeles, the
National Institute of Neurological Disorders and Stroke (grant 5R01NS074980-07,
1F31NS106828-01A1, R01NS074980) and the National Institutes of Health
Predoctoral Training in Interdisciplinary Neurosciences (1T32MH111360-1A1). Philips
Healthcare provided support for protocol development and applications
engineering on a support-in-kind basis.References
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