Cortical morphological alterations and structural covariant network topology changes in children with acute lymphoblastic leukemia

Abstract

Background: The mechanisms underlying chemotherapy-induced cognitive impairment (CICI) and structural brain changes in children with acute lymphoblastic leukemia (ALL) remain unclear. This study investigated early chemotherapy-induced alterations in cortical morphology and structural covariance network (SCN) reorganization in children with ALL.

Methods: In total, 26 children (7.07±3.09 years old) with ALL were included in the study. A surface-based morphometry (SBM) analysis was carried out to estimate changes in cortex morphology in the children with ALL. A statistical analysis of cortical morphological changes using the paired t-test (P<0.05) with family-wise error (FWE) correction was conducted. The global and local SCN parameters of the brain covariance network were calculated. A statistical analysis was performed using the 1,000-permutation test (P<0.05) with a false discovery rate to correct the attributes of the local network.

Results: On days 46-52 of chemotherapy, the cortical thickness of multiple brain regions in children with ALL became extensively thinner (cluster size ≥50, P<0.05, FWE corrected). The gyrification index was reduced in the bilateral frontal lobe and right insula. A fractal dimension reduction was observed in the left inferior medial frontal gyrus. The degree (Deg) in the left supplementary motor area (LSMA; P=0.029) increased, and the betweenness (Bet) in the left precuneus (LPCUN) decreased (P=0.034). However, no statistically significant differences were found between the other parameters, including the clustering coefficient (Cp; P=0.159), local efficiency (Eloc; P=0.325), characteristic path length (P=0.522), global efficiency (Eg; P=0.702), assortativity (P=0.956), transitivity (P=0.753), and modularity (P=0.628). The absence of contemporaneous neurocognitive assessments precluded the exploration of relationships between cortical morphological alterations/SCN changes and neurocognition.

Conclusions: On days 46-52 of chemotherapy, changes in the morphology of the cerebral cortex, and changes in the Deg, Bet, and hub values in the SCN were already present in children with ALL. The bilateral frontal lobe may be the most susceptible brain region for CICI among children with ALL. These results appear to suggest that the topological properties in the brains of these children were reorganized as a compensatory mechanism after chemotherapy.

Keywords: Acute lymphoblastic leukemia (ALL); chemotherapy-induced cognitive impairment (CICI); magnetic resonance imaging (MRI); structural covariance network (SCN); surface-based morphometry (SBM).

Figure 1

Flowchart of patient inclusion in the study. 3D-MPRAGE, three-dimensional magnetization-prepared rapid acquisition gradient echo sequences; ALL, acute lymphoblastic leukemia; MR, magnetic resonance; MRI, magnetic resonance imaging.

Figure 2

The brain regions with statistically significant differences in the cortical morphology between children with acute lymphoblastic leukemia before chemotherapy and on days 46–52 of chemotherapy are shown in color (A-D). Cluster size ≥50, P<0.05 (family-wise error corrected). The brain segmentation method used the AAL90 template. The standard brain template was developed by Professor Yong He’s team at Beijing Normal University (https://www.nitrc.org/projects/chn-pd); subjects with segmentation quality ≤ grade C were excluded from the study. AAL90, Automated Anatomical Labeling 90.

Figure 3

The distribution and intergroup differences of the small world parameters and global network parameters in children with acute lymphoblastic leukemia before and after chemotherapy (A-T). Cluster size ≥50, P<0.05, family-wise error corrected. Brain tissue segmentation was performed according to the Automated Anatomical Labeling 90 template. The standard brain template was drawn by Professor Yong He’s team at the Laboratory of Cognitive Neuroscience and Learning of Beijing Normal University (https://www.nitrc.org/projects/chn-pd); subjects with segmentation quality ≤ grade C were excluded from the study. After chemo, after chemotherapy; Before chemo, before chemotherapy; CI, confidence interval.

Figure 4

The difference maps of local network properties (including Deg and Bet) before and after chemotherapy in children with ALL. The arrow in (A) shows an increased Deg in the LSMA in children with ALL after chemotherapy (P=0.029). The arrow in (B) shows that Bet in the LPCUN decreased in children with ALL after chemotherapy (P=0.034). After chemo, after chemotherapy; ALL, acute lymphoblastic leukemia; Before chemo, before chemotherapy; Bet, betweenness; CI, confidence interval; Deg, degree; LPCUN, left precuneus; LSMA, left supplementary motor area; ROI, region of interest.

Figure 5

Brain graphs based on degree and betweenness in children with acute lymphoblastic leukemia before and after chemotherapy (A-D). ACC, anterior cingulate & paracingulate gyri; IFGoperc, inferior frontal gyrus-opercular part; INS, insula; IOG, inferior occipital gyrus; ITG, Inferior temporal gyrus; L, left; MCC, middle cingulate & paracingulate gyri; MFG, middle frontal gyrus; MTG, middle temporal gyrus; OLF, olfactory cortex; PAL, lenticular nucleus-pallidum; PCC, posterior cingulate gyrus; PCUN, precuneus; PreCG, precentral gyrus; PUT, lenticular nucleus-putamen; R, right; REC, gyrus rectus; ROL, Rolandic operculum; SFGmedial, superior frontal gyrus-medial; SMG, supra marginal gyrus; STG, superior temporal gyrus.