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Beta-thalassemia, a congenital anemia secondary to defective production in the 尾-globin chain of hemoglobin, has 2 forms: transfusion-dependent and non鈥搕ransfusion-dependent. One of the difficulties in managing 尾-thalassemia is balancing the benefits of raising the hemoglobin (to 鈮� 9.5 g/dL) with the consequences of iron overload from hypertransfusion.¹

There are several body systems that can be affected by 尾-thalassemia鈥攈eart, liver, endocrine, and brain. The effects on the brain are lower white matter volume and a decrease in the microstructural integrity in the watershed areas. These changes have the potential to lead to cognitive dysfunction.¹

An evaluation of brain perfusion

To look at this topic further, a team of researchers from Italy and the University of Minnesota investigated brain perfusion in patients with 尾-thalassemia, using magnetic resonance imaging (MRI).¹ The goals of their study were to characterize the changes in perfusion and their association with phenotype, demographics, laboratory findings (hemoglobin, ferritin, and liver iron concentration), parenchymal abnormalities, and impairment in cognitive function (using the Wechsler Adult Intelligence Scale鈥擣ourth Edition and the Full-Scale Intelligence Quotient [FSIQ]). They compared 54 transfusion-dependent and 23 non鈥搕ransfusion-dependent patients with 尾-thalassemia to 56 healthy controls.

The investigators found that the patients with 尾-thalassemia (in both the transfusion-dependent and non鈥搕ransfusion-dependent cohorts) had higher brain perfusion versus the healthy controls.¹ After adjusting for age and sex, and scaled for global cerebral blood flow, the patients with 尾-thalassemia had relative hyperperfusion in the white matter of the centrum semiovale and both cerebral and the cerebellar watershed areas compared to healthy controls.

There was a significant correlation between the hemoglobin levels and the hyperperfusion areas (P = .013). When patients had a lower hemoglobin (< 9.5 g/dL), there were persistent clusters of hyperperfusion versus when patients鈥� hemoglobin was 鈮� 9.5 g/dL, which defined those who did not have the hyperperfusion clusters. Of particular interest was the lack of correlation between the perfusion values and ferritin, liver iron concentration, or chelation treatment, suggesting that iron excess was not a factor in the pathogenesis of the observed white matter changes. This may indicate that the severity of the anemia directly affects the level of brain hyperperfusion leading to these changes. However, another recent study of cognitive impairment in thalassemia did demonstrate that not only severity of anemia but also increased ferritin levels and lack of iron chelation therapy were independent factors associated with these changes in the brain. Thus, further study is needed to define the role of iron overload in the cognitive impairment of patients with beta-thalassemia major.²

White matter changes are observed

Compared to healthy controls, the white matter density was significantly decreased in the hyperperfused areas (P = .0003) in both cohorts (P = .00047 and P = .0049, respectively). Additionally, in the non鈥搕ransfusion-dependent patients, the decrease in white matter density was inversely correlated with FSIQ (P = .007). However, no correlation was found in the patients who were transfusion-dependent (P =.96). This may indicate that there are other factors that may be impacting cognitive function in patients with more disease severity, such as transfusion-related complications and higher rates of hospitalization.

Traditionally, white matter brain injury is thought to be secondary to hypoperfusion, but this study shows the opposite鈥攖hat relative hyperperfusion in the watershed areas contributes to this injury in 尾-thalassemia, possibly by the breakdown of the blood-brain barrier, abnormal cerebrovascular reserve, and increase in the velocity of blood flow. The authors mention that, based on these findings and the Thalassemia International Federation鈥檚 recommendations, pretransfusion hemoglobin levels should be kept > 9.5 g/dL, in order to prevent brain injury while avoiding the risk of iron overload at higher levels.

Limitations and conclusions

Despite some interesting findings, this study had several possible limitations. For one, noninvasive MRIs were used for the evaluations; however, there are other modalities, such as contrast-enhanced perfusion MRI and positron emission tomography, that should be used to validate the findings. Additionally, the authors didn鈥檛 have access to the hemoglobin levels of the healthy controls at the time of the MRI. Lastly, this study was done only at Italian centers, making it difficult to generalize the findings to other populations.

This research offers new possibilities for the pathogenesis of brain injury in patients with 尾-thalassemia and other hereditary anemias, particularly related to the relative hyperperfusion of the watershed territories. It also points out how important it is to carefully manage the anemia in order to prevent structural brain changes and consequent long-term cognitive impairment. To further investigate this, the authors recommend that studies should be done with other advanced imaging techniques (in addition to MRI) and on other populations outside of Italy.

鈥淎 multicenter study including other European and extra-European centers is required to validate our data in a multiracial and multi-environment setting,鈥� the authors concluded.¹

Published: June 28, 2024