Description (from grant):

Anemia leaves patients vulnerable to white matter damage due to inadequate cerebrovascular reserve (CVR), causing increased Cerebral Blood Flow (CBF), reduced Oxygen extraction Fraction (OEF), and ultimately local CVR problems and vascular events, including ischemia with risk of infarction. We will validate CVR measured by MRI as a biomarker for clinical trials of silent stroke prophylaxis.

There are approximately 100,000 patients with sickle cell disease (SCD) in the United States. Despite regular transcranial Doppler screening, 38% have silent white matter strokes detectable by MRI before their 14th birthday, leading to significant cognitive dysfunction. Similar brain lesions are seen in patients with thalassemia intermedia, obstructive sleep apnea, severe acute anemia, and the elderly, suggesting a general, non-sickle-related, mechanism. We postulate that anemia itself, by diminishing CVR, predisposes the brain to injury in key vulnerable areas. Our arguments are based on our following preliminary data: 1) Anemic patients increase their resting CBF such that oxygen delivery is normal, independent of the anemia mechanism. 2) CVR declines inversely with resting CBF, approaching 0% in some SCD patients. 3) we observe white matter loss and abnormal diffusivity in both SCD patients and non-sickle-cell anemia patients. 4) The pattern of volume loss and abnormal diffusivity predicts regions of low CVR from a completely different patient cohort.

We propose to study the relationship between CVR, anemia, and white matter loss in chronic anemia patients at particularly high risk for silent stroke (sickle cell anemia, thalassemia, and other rare anemias). Specifically, we will determine if focal areas of decreased CVR occur in the same distribution as silent strokes and preclinical white matter injury, and whether transfusion improves CVR these vulnerable regions. Increase in regional CBF measured by ASL MRI in response to acetazolamide is a measure of CVR. Thus the goal of this project is validate CVR as a biomarker for white matter vulnerability that can be used as a means of discovery for future clinical trials of silent stroke prophylaxis. To accomplish this, we will first identify its relationship with hemoglobin level and known vascular biomarkers to identify potentially modifiable risk factors. We will determine whether low CVR predicts decreased white matter volume, loss of axonal integrity, silent stroke, and impaired neurocognitive function in chronically anemic subjects as compared to controls. Lastly, we will test whether raising hemoglobin (simple transfusion), lowering hemoglobin S (isocrit exchange transfusion) or hydroxyurea improve CVR in the regions at risk for stroke. Although targeted toward high-risk groups (hemoglobinopathies), this research has profound implications regarding white matter disease found in the general population, including the elderly, patients with sleep apnea, diabetes, and hypertension.


Bush AM, Coates TD, Wood JC. Diminished cerebral oxygen extraction and metabolic rate in sickle cell disease using T2 relaxation under spin tagging MRI. Magn Reson Med. 2018 Jul;80(1):294-303.

Bush A, Borzage M, Detterich J, Kato RM, Meiselman HJ, Coates T, Wood JC. Empirical model of human blood transverse relaxation at 3 T improves MRI T2 oximetry. Magn Reson Med. 2017 Jun;77(6):2364-2371.