DETECTION OF HYPOXIA IN SICKLE CELL ANEMIA BY SUSCEPTIBILITY EFFECTS IN MRI

  • Schilsky, Michael (PI)
  • Nagel, Ronald (PI)
  • Santoro, Nanette F. (PI)
  • Fabry, Mary (PI)
  • Wozniak, Robert (PI)
  • Rieder, Jessica (PI)
  • Kennan, Richard (PI)
  • Pan, Jullie (PI)
  • Nagel, Ronald (PI)
  • Santoro, Nanette F. (PI)
  • Hetherington, Hoby (PI)
  • Klein, Robert (PI)
  • Bookchin, Robert (PI)
  • Howard, Andrea (PI)
  • Rieder, Jessica (PI)
  • Somlo, Stefan (PI)
  • Roy-Chowdhury, Jayanta (PI)
  • Wadler, Scott (PI)
  • Rubenstein, Arye (PI)
  • Purpura, Dominick (PI)
  • Spiegel, Allen (PI)
  • Wylie-Rosett, Judith (PI)
  • Noyer, Charles (PI)
  • Kaufman, Howard L. (PI)
  • Weber, Thomas (PI)
  • Roy-Chowdhury, Namita (PI)
  • Diamond, Betty (PI)
  • Segal-Isaacson, C.J. (PI)
  • Engel, Samuel (PI)
  • Alderman, Michael (PI)
  • Wylie-Rosett, Judith (PI)
  • Weber, Thomas (PI)
  • Bigal, Marcelo (PI)
  • Pollard, Jeffrey W. (PI)
  • Kaskel, Frederick (PI)
  • Segal-Isaacson, C.J. (PI)
  • Dimartino-Nardi, Joan (PI)
  • Ilowite, Norman (PI)
  • Eugene, Fine (PI)
  • Mossavar-Rahmani, Yasmin (PI)
  • Khan, Unab (PI)
  • Rivas, Yolanda (PI)
  • Morrow, Bernice E. (PI)
  • Roy-Chowdhury, Namita (PI)
  • Barzilai, Nir (PI)
  • Shamoon, Harry (PI)
  • Crystal, Howard (PI)
  • Weiss, Louis M. (PI)
  • Diamond, Betty (PI)
  • Bloom, Barry (PI)
  • Rossetti, Luciano (PI)
  • Frishman, William (PI)
  • Somlo, Stefan (PI)
  • Schilsky, Michael (PI)
  • Roy-Chowdhury, Jayanta (PI)
  • Weiss, Louis M. (PI)
  • Santoro, Nanette F. (PI)
  • Kaufman, Howard L. (PI)
  • Segal-Isaacson, C.J. (PI)
  • Santoro, Nanette F. (PI)
  • Pollard, Jeffrey W. (PI)
  • Segal-Isaacson, C.J. (PI)
  • Morrow, Bernice E. (PI)
  • Engel, Samuel (PI)
  • Pan, Jullie (PI)
  • Klein, Robert (PI)
  • Alderman, Michael (PI)
  • Nagel, Ronald (PI)
  • Santoro, Nanette F. (PI)
  • Hetherington, Hoby (PI)
  • Segal-Isaacson, C.J. (PI)

Project: Research project

Project Details

Description

The pathology of sickle cell disease results from vasoocclusion caused by
blockage of the microcirculation by non-deformable red cells filled with
polymers of deoxy-hemoglobin S. The disease is characterized by chronic
vasocclusive injury to several organs and acute events that include painful
crises (which largely involves marrow infarct), acute chest syndrome, acute
splenic sequestration, acute sickle liver, cerebral infarcts, renal papillary
necrosis, femoral and humeral head necrosis, acute retinal vasoocclusion, and
other manifestations. Finding objective criteria to evaluate risk factors and
treatment protocols for sickle cell disease is a long-standing goal. To date,
MRI of painful crisis has yielded results which are intriguing but difficult to
evaluate. Detection of hypoxia may yield a useable marker. These experiments
were designed to detect regions of hypoxia which may occur under ambient
conditions in patients with sickle cell disease. The image intensity in T2 and
T2* weighted images is influenced by the presence of deoxygenated hemoglobin
because deoxygenated hemoglobin has a different magnetic susceptibility than
oxygenated hemoglobin or tissue. The difference in magnetic susceptibility
between the red cells and plasma and between the intra- and extravascular
spaces results in more rapid loss of water proton transverse magnetization and
ultimately results in reduced image intensity in spin-echo or gradient echo
pulse sequences. The change in oxygen saturation in sickle cell patients in
brain and bone marrow was investigated while the patient was breathing room air
or high oxygen through a face mask and comparing the signal intensity changes
in T2 or T2*-weighted images. These results were contrasted to results for
normal human controls. A goal of these studies is to separate acute, ongoing
events from the results of previous episodes of ischemia and fibrosis or
expansion of hematopoietic tissue. Using magnetic resonance imaging (MRI)
which is blood oxygenation level dependent (BOLD), we found that transgenic
mice with human `- and S-globin have higher levels of deoxyHb in brain, liver,
and kidney (areas with pathology) than control mice. We used this technique to
examine the level of deoxyHb in the brain and bone marrow of sickle cell
patients. In the brain, nine SCD patients and seven normal individuals were
scanned while they were breathing first room air and then 100% O2 through a
face mask. All SCD patients showed significant global increases in signal
intensity caused by O2 inhalation (+5.7%). In contrast, all normal controls
showed small or negligible positive change in intensity (+0.57%), which was in
agreement with what found in normal subjects reported previously. The
intensity change averaged over the brain area scanned for each patient and
normal control in response to O2 was measured. While the mean standard
deviation of the intensity change obtained on normal subjects is small, there
is a large degree of variation in the magnitude among patients. With the only
one patient who has had a previously known stroke, the z statistic maps
obtained using the pixelwise intensity difference indicates prominently
elevated positive z score around the areas of infarct identified in anatomical
images. The highlighted region of greater response to O2 also extends beyond
the infarcted area medial-posteriolly. O2 saturation recorded with a pulse
oximeter throughout the experiments indicated that all sickle cell patients
have had resting O2 saturation of less than 94%. We were able to verify in all
cases that the O2 saturation increased to 97% or more when the patient was
breathing 100% O2 through a face mask. Without any abnormality found in T1
weighted anatomical images, the detected brain signal changes related to
inspired oxygen concentration showed significantly higher values than those of
normal volunteers. In this study of sickle cell patients and control subjects,
we have demonstrated that brain signal changes designed to detect
deoxyhemoglobin using MRI can be used to separate patients with SCD and healthy
individuals. Furthermore, the experiment showed correlation of the intensity
changes in and highlighted the area of infarct in a patient with a history of
stroke. Very different patterns emerged in the patients and controls. This
technique shows promise for the detection of deoxyhemoglobin in SCA and may
help to identify infarcted areas in patients at an early phase. Further
studies are needed in order to determine the potential usefulness of this
method in evaluating sickle cell patients for the risk of stroke, along with
the technical improvements on imaging signal stability over the long period of
time required for the studies. we found a mean global change in signal
intensity with an increase of 3.7% in SS patients in contrast to a 0.98%
increase in normal controls. Signal increases in SS patients were localized to
the gray matter and were of a different extent and magnitude for each patient.
A high percent deoxyHb under ambient conditions may not imply that the brain is
hypoxic because SS RBCs have low oxygen affinity.
In bone marrow, we examined sixteen patients both with and without pain femur
and hips. Patients with present or past history of hip pain or in steady state
were first imaged breathing room air through a face mask. O2 saturation (sat)
was monitored by pulse oximetry. O2 then was delivered for two five minute
periods and new images were collected and compared, begining at 2 cm above the
femoral head and covered a total span of 24 cm in 24 axial slices. Twenty
imaging sessions were conducted on 16 SS patients; 8 males and 8 females.
Seven sets of images could not be interpreted due to excessive motion. Initial
O2 sats were 93% q 3%; final O2 sats were 98-99%. Positive signal, that is
presence of deoxyHb under room air conditions, required more than 5 minutes to
develop after onset of O2 delivery. DeoxyHb was found predominantly in bone
marrow (BM), but was also detected in muscle in patients suffering pain. Nine
patients had deoxyHb in BM or muscle, but 4 of these patients had no pain at
the time of the examination. Strong positive deoxyHb signal in the femoral
heads was found both in patients without cMRI findings of AVN and those with
cMRI findings of AVN. Four SS patients without MRI findings of AVN and no pain
had no deoxyHb in BM or other tissues. In summary, deoxyHb is detectable in
femoral heads during hip pain episodes and occasionally during steady state in
patients with a past history of hip pain. Localized areas of deoxyHb are found
in some but not all SS patients. In addition, we find that hip pain can be
associated with deoxyHb in BM and contiguous muscle mass. We conclude that
BOLD-MRI detects areas with high levels of deoxyHb, which can be either
ischemic or presumably pre-ischemic. Unlike conventional MRI, it reflects only
present pathology. BOLD-MRI is minimally invasive and highly sensitive to
areas with deoxyHb, but cannot inform on vascular areas that are not perfused.
BOLD-MRI will be useful in further understanding the pathophysiology of VOEs
and the evaluation of treatment protocols.
StatusFinished
Effective start/end date10/1/9811/30/99

Funding

  • National Center for Research Resources
  • National Center for Research Resources
  • National Center for Research Resources
  • National Center for Research Resources

ASJC

  • Clinical Neurology
  • Endocrine and Autonomic Systems
  • Genetics(clinical)
  • Physiology (medical)
  • Medical Laboratory Technology
  • Pharmacology (medical)
  • Genetics
  • Endocrinology
  • Molecular Medicine
  • Molecular Biology
  • Hematology
  • Biochemistry
  • History and Philosophy of Science
  • Internal Medicine
  • Clinical Biochemistry
  • Endocrinology, Diabetes and Metabolism
  • Immunology

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