The research allows us to better understand an elusive symptom of sickle cell – silent stroke

Sickle cell disease is rare but devastating. Due to a genetic mutation affecting hemoglobin, the component of the red blood cell that carries oxygen, a reduced amount of oxygen is supplied to vital tissues and organs. Blood cells also deform into a characteristic crescent shape and lodge in the smallest blood vessels, blocking blood flow and causing excruciating pain. In addition to these symptoms, patients are at high risk of stroke, the leading cause of death in patients with MCS.

Specializing in Unique Challenges Facing Patients With SCD, Physician and Investigator John Wood, MD, Ph.D. of CHLA is studying how blood flow and oxygen delivery are affected by the disease. The compromised hemoglobin characteristic of SCD presents a serious danger to the brain. A few minutes without oxygen can kill the brain cells. "We have learned a lot about how to prevent strokes in large vessels," said Dr. Wood, also a professor of pediatrics at the USC's Keck School of Medicine. It refers to strokes that have immediate and overt effects such as blindness or paralysis. "But patients with MCS still suffer from silent strokes."

Silent strokes can have debilitating effects on executive function, on the brain's ability to perform complex tasks necessary for maintaining a job or succeeding at school. Dr. Wood strives to discover the causes of these silent and devastating strokes. On the surface, the cause of these strokes seems obvious: the blood cells are damaged by the MSC, so the brain receives less oxygen. Less oxygen in the brain leads to strokes. But Dr. Wood discovered that total oxygen in the brain was not actually reduced in patients with MCS. His research shows that the body compensates for the reduced oxygen content of blood by increasing blood flow to the brain. This led him to wonder why these patients continued to suffer from a stroke.

"I started thinking:" maybe there is a distribution problem, "" says Dr. Wood. "The total blood flow is good, but where does he go?" Using an advanced imaging technique called arterial spin labeling to measure blood flow, Dr. Wood's team discovered a disparity between brain areas. While the total oxygen supply to the brain was unchanged, oxygen delivery to the white matter was reduced by more than a third – 35% – in patients with MCS. Crucially, it is in this part of the brain – the white matter – that the majority of silent strokes occur in these patients.

Gray matter is composed of neurons, brain cells that store information. White matter is the network of roads in the brain that neurons use to transmit this information. Dr. Wood's findings demonstrate that the body makes the difference between gray matter and white matter, clearly prioritizing neurons. This makes sense because keeping neurons alive is essential for survival. Strokes in the gray matter are immediately catastrophic, while those in the white matter seem silent as they simply slow down the treatment of the information. Although they do not necessarily cause paralysis or major motor deficits, the effects of strokes to the white matter can significantly hinder important aspects of a patient's daily life.

The idea that blood flow can be adjusted to compensate for problems such as a decrease in oxygen content is part of our design. When our physiological state changes, the body diverts blood to relevant areas. During exercise, for example, the blood flow increases in our muscles to meet the metabolic needs, but decreases in the digestive tract in a less relevant way.

Similarly, under the effect of lack of oxygen in SCD, blood flow is diverted to the neurons of the gray matter to prevent their death. Dr. Wood discovered that the oxygen supply in the white matter was extremely sensitive to hemoglobin – the more severe the anemia, the more the intake of. Oxygen to white matter was low – a powerful correlation that corroborates what he sees at the clinic.

Dr. Wood's study is the first to use arterial spin labeling to quantify oxygen intake separately to the white matter and gray matter of the brain, thereby correcting the severity of anemia of the patient. His research paves the way for a better understanding of stroke in patients with MCS, but they also have wider applications. He says the findings have probably shed light on anemia in general, which is increasingly worrying our aging population. He also hopes that this technique will help the medical community badess the impact of current and future SCD treatments, such as new gene therapy approaches, on the brain. The results of this study were recently published in American Journal of Hematology from lead author Yaqiong Chai, Ph.D. candidate.

Provided by
Los Angeles Children's Hospital