Elens Iris, Deprez Sabine, Billiet Thibo, Sleurs Charlotte, Labarque Veerle, Uyttebroeck Anne, Van Gool Stefaan, Lemiere Jurgen, D'Hooge Rudi
Laboratory of Biological Psychology, KU Leuven, Leuven, Belgium.
Department of Child and Adolescent Psychiatry, KU Leuven, University Psychiatric Centre Leuven, Leuven, Belgium.
PLoS One. 2021 Apr 30;16(4):e0250228. doi: 10.1371/journal.pone.0250228. eCollection 2021.
This retrospective correlation study investigated the putative link between methylene tetrahydrofolate reductase (MTHFR) A1298C mutations and chemotherapy-related brain function changes in adult childhood-leukemia survivors. To this end, we determined the relationship between the particular MTHFR1298 genotype (AA, AC or CC) of 31 adult childhood-leukemia survivors, and (1) their CSF Tau and phosphorylated Tau (pTau) levels at the time of treatment, (2) their adult performance intelligence quotient (PIQ), and (3) their regional brain connectivity using diffusion magnetic resonance imaging (dMRI) and resting-state functional MRI (rsfMRI). We confirmed that neuropathology markers Tau and pTau significantly increased in CSF of children after intrathecal methotrexate administration. Highest concentrations of these toxicity markers were found during the induction phase of the therapy. Moreover, CSF concentrations of Tau and pTau during treatment were influenced by the children's particular MTHFR1298 genotype. CSF Tau (but not pTau) levels significantly dropped after folinic acid supplementation. At adult age (on average 13.1 years since the end of their treatment), their particular MTHFR1298 genotype (AA, AC or CC) influenced the changes in PIQ and cortical connectivity that we found to be related to their childhood exposure to chemotherapeutics. In summary, we suggest that homozygous MTHFR1298CC individuals are more vulnerable to the adult sequelae of antifolate chemotherapy.
这项回顾性相关性研究调查了成年期儿童白血病幸存者中亚甲基四氢叶酸还原酶（MTHFR）A1298C突变与化疗相关脑功能变化之间的假定联系。为此，我们确定了31名成年期儿童白血病幸存者的特定MTHFR1298基因型（AA、AC或CC）与以下因素之间的关系：（1）治疗时他们脑脊液中的Tau蛋白和磷酸化Tau蛋白（pTau）水平；（2）他们的成人表现智商（PIQ）；（3）使用扩散磁共振成像（dMRI）和静息态功能磁共振成像（rsfMRI）测量的脑区连接性。我们证实，鞘内注射甲氨蝶呤后，儿童脑脊液中的神经病理学标志物Tau和pTau显著增加。在治疗的诱导期发现这些毒性标志物的浓度最高。此外，治疗期间脑脊液中Tau和pTau的浓度受儿童特定的MTHFR1298基因型影响。补充亚叶酸后，脑脊液中Tau蛋白（而非pTau）水平显著下降。在成年期（平均自治疗结束后13.1年），他们特定的MTHFR1298基因型（AA、AC或CC）影响了PIQ和皮质连接性的变化，我们发现这些变化与他们儿童期接触化疗药物有关。总之，我们认为纯合子MTHFR1298CC个体更容易受到抗叶酸化疗成年后遗症的影响。
