Brain Volume May Serve as Biomarker of Brain Injury in Patients With Sickle Cell Disease

Anemia and reduced arterial oxygen content (CaO2) are linked with reductions in gray matter volume (GMV) and white matter volume (WMV) in patients with sickle cell disease (SCD), a recent study found.

Elevated cerebral blood flow (CBF) and infarct burden were also linked with reduced volume in subcortical structures among patients, according to the results, published in Frontiers in Neurology.

Taken together, the data highlight that silent cerebral infarcts represent just a portion of brain injury that occurs in patients with SCD, and brain volume can serve as another potential biomarker of brain injury in those with the disease, researchers wrote.

It is established that SCD increases the risk of cerebral infarct, however its reported effects on brain volume have varied, while more detailed information encompassing larger cohorts “could motivate the use of longitudinal brain volume assessment in SCD as an automated marker of disease stability or future progression,” authors explained.

Silent cerebral infarcts are also increasingly present with age in patients with SCD. Among children, the infarcts are linked with risk of overt stroke and academic deficits. Because of these risks, “2020 American Society of Hematology guidelines recommend MRI of the brain to screen for [silent cerebral infarcts] at least once in childhood and adulthood,” researchers wrote.

To evaluate whether children and young adults with SCD have reduced GMV and WMV compared with healthy controls, participants underwent 3 T brain MRI. All evaluations were carried out at a single institution, and any patients undergoing regular blood transfusions were excluded from the study.

A total of 49 healthy controls and 88 patients with SCD without overt stroke were included in the study. All participants were between the ages 7 and 32. Silent cerebral infarcts were present in 31 (35%) of patients with SCD.

Analyses revealed:

• Reduced hemoglobin was associated with reductions in both GMV (P =  .032) and WMV (P =  .005)
• Reduced CaO2 was also associated with reductions in GMV (P = . 035) and WMV (P =  .006)
• Elevated gray matter CBF was associated with reduced WMV (P =  .018)
• Infarct burden was associated with reductions in WMV 30-fold greater than the infarct volume itself (P =  .005)
• Increased GM CBF correlated with volumetric reductions of the insula and left and right caudate nuclei (P =  .017; .017; .036; respectively)
• Infarct burden was associated with reduced left and right nucleus accumbens, right thalamus, and anterior corpus callosum volumes (P = .002; .002; .009; .002; respectively)

The measured brain volume deficits were subtle, researchers found. “The small magnitude of the volume difference hints at the complexity of volumetric brain analysis of individuals with SCD and may explain the variable findings in prior studies of volumetric deficits related to SCD,” they said.

Authors also noted the WMV losses observed are too large to be explained by loss of tissue volume at the site of infarction alone, suggesting global white matter injury cannot be easily visualized with typical clinical imaging methods and could co-occur with silent infarction.

Findings might not be representative of deficits in patients with overt stroke and those receiving aggressive therapies. The study’s cross-sectional design marks a limitation, as researchers were unable to easily detect subtle effects or the ordering of associations.

“The findings presented in this work suggest that common physiological consequences of SCD (reduced hemoglobin, reduced CaO2, increased GM CBF, increased risk of silent infarction) and SCD itself result in both diffuse and focal brain tissue volume deficits,” researchers concluded.

“Still, these deficits are subtle, and so brain volume measurements at a single timepoint should be treated cautiously.”

Reference

Jones RS, Donahue MJ, Davis LT, et al Silent infarction in sickle cell disease is associated with brain volume loss in excess of infarct volume. Front Neurol. Published online March 31, 2023. doi:10.3389/fneur.2023.1112865