White matter volume changes in adult beta‐thalassemia: Negligible and unrelated to anemia and cognitive performances
Authors: Renzo Manara, Antonietta Canna, Martina Caiazza, Sara Ponticorvo, Andrea G. Russo, Rosanna Di Concilio, Angela Ciancio, Elisa De Michele, Pasquale Alessandro Carafa, Federica Ammendola, Domenico Roberti, Maddalena Casale, Andrea Elefante, Mario Cirillo, Francesco Di Salle, Fabrizio Esposito, Silverio Perrotta, Immacolata Tartaglione
Journal: American Journal of Hematology (2020)

We read with great interest the study by Choi on brain involvement in anemic patients, showing white matter volume reduction according to anemia and cognitive impairment severity.1 The findings that they reported with a quantitative analysis and showing the interplay among anemia, white matter volume changes and cognition, were both fascinating and reasonable. However, the miscellaneous recruitment of anemic patients did not help understand whether the phenomenon of white matter volume decrease was effectively a biomarker of any type of anemia. Indeed, white matter involvement has been widely shown in sickle cell disease,2 while brain involvement is still uncertain or not fully studied in other forms of anemia. For example, recent studies with control groups have failed to detect significantly increased vascular-like white matter changes in beta-thalassemia patients.3, 4 Even very sensitive advanced MRI analyses (ie, magnetization transfer and diffusion tensor based techniques) failed to reveal structural white matter changes in beta thalassemia patients.5 On these premises, the finding of a significant supratentorial white matter volume decrease in anemic patients in the paper by Choi appears rather in conflict with the increasing evidence of no white matter involvement in beta-thalassemia (both at conventional and advanced MR imaging investigations), at least among patients treated according to current treatment guidelines. Even though beta-thalassemia patients were only a subgroup with a limited sample size in the paper by Choi, they still represented the majority of non-sickle anemia patients (ie, 14/26 patients). For these reasons, white matter structural and volumetric changes were investigated in our large samples of adult beta-thalassemia patients (48 transfusion dependent patients, age = 38 ± 10 years, and 23 non transfusion dependent patients, age = 30 ± 11.5 years) and controls (56 healthy subjects, age = 34 ± 11 years) using a high-resolution 3DT1 MPRAGE sequence that was part of our MRI study protocol for all study participants (the same 3 T scanner and the same sequence was used, see Russo et al5 for reference). Notably, most patients and controls had undergone a comprehensive cognitive test battery (WAIS-IV), and data on hemoglobin levels in beta-thalassemia patients were available thus allowing for a full comparison among cognitive, laboratory and white matter volume findings. First of all, using the most validated analysis of white matter volume quantification (voxel based morphometry, VBM, see Supplementary material) we detected only a small cluster close to the ventricular wall in the left temporal lobe (coordinate: x = −30 y = −27 z = −8) of significant volume increase in TDT patients vs healthy controls (P < .05 cluster level corrected, cluster size = 277 voxels; Figure 1). No other subgroup comparison showed significant differences (whole group of patients vs controls, NTDT vs TDT, NTDT vs controls). In addition, no correlations were found in the patients' group between the mean white matter volumes (extracted from the above mentioned cluster), and both the hemoglobin values and the full scale Intelligence Quotient scores, that were significantly worse in beta thalassemia patients (see Tartaglione et al.6). Considering the striking contrast between the present study and the study by Choi, we also applied to our sample a tensor-based morphometry analysis (TBM; see Supplementary material), i.e. the less common white matter analysis performed by Choi. By means of TBM, we failed to find any significant difference by comparing either patients subgroups or healthy controls and beta-thalassemia patients (as a whole group or according to disease severity). Our analysis, performed on a large sample of beta-thalassemia patients with two different methods to study the morphometry of the white matter, revealed no structural changes comparing patients (whole group) and healthy controls or comparing beta-thalassemia patients subgroups. More precisely, just the VBM analysis revealed a small alteration in the white matter volume in the TDT subgroup (compared to controls) but, even in this small cluster, we were not able to detect any correlation between the white matter changes and anemia severity or cognitive performances. Whether discrepancies between the present study and the study by Choi were due to differences in sample size, recruitment criteria, treatments or environmental/genetic factors remains unknown. In any case, our experience on a large sample of patients does not confirm the relationship among anemia, cognition and white matter changes at least among beta-thalassemia patients, thus challenging the statement by Choi and colleagues at the hemoglobin levels maintained in our patients (93.7 ± 9.7 g/L). In addition, adding this piece of evidence, our findings further strengthen the suspicion of a limited value of MRI brain monitoring in neurologically asymptomatic beta thalassemia patients, at least when the current treatments guidelines are observed. Appendix S1: Supplementary material. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.