Atypical Structural Connectome Organization and Cognitive Impairment in Young Survivors of Acute Lymphoblastic Leukemia - PubMed (original) (raw)

Atypical Structural Connectome Organization and Cognitive Impairment in Young Survivors of Acute Lymphoblastic Leukemia

Shelli R Kesler et al. Brain Connect. 2016 May.

Abstract

Survivors of pediatric acute lymphoblastic leukemia (ALL) are at increased risk for cognitive impairments that disrupt everyday functioning and decrease quality of life. The specific biological mechanisms underlying cognitive impairment following ALL remain largely unclear, but previous studies consistently demonstrate significant white matter pathology. We aimed to extend this literature by examining the organization of the white matter connectome in young patients with a history of ALL treated with chemotherapy only. We applied graph theoretical analysis to diffusion tensor imaging obtained from 31 survivors of ALL age 5-19 years and 39 matched healthy controls. Results indicated significantly lower small-worldness (p = 0.007) and network clustering coefficient (p = 0.019), as well as greater cognitive impairment (p = 0.027) in the ALL group. Regional analysis indicated that clustered connectivity in parietal, frontal, hippocampal, amygdalar, thalamic, and occipital regions was altered in the ALL group. Random forest analysis revealed a model of connectome and demographic variables that could automatically classify survivors of ALL as having cognitive impairment or not (accuracy = 0.89, p < 0.0001). These findings provide further evidence of brain injury in young survivors of ALL, even those without a history of central nervous system (CNS) disease or cranial radiation. Efficiency of local information processing, reorganization of hub connectivity, and cognitive reserve may contribute to cognitive outcome in these children. Certain connectome properties showed U-shaped relationships with cognitive impairment suggesting an optimal range of regional connectivity.

Keywords: cancer; cognition; connectome; diffusion tensor imaging (DTI).

PubMed Disclaimer

Figures

<b>FIG. 1.</b>

**FIG. 1.

Both groups demonstrated expected small-world connectome organization with small-worldness index being greater than 1 across network densities. The ALL group demonstrated significantly lower small-worldness index compared to controls (Con). Error bars show standard deviation. ALL, acute lymphoblastic leukemia.

<b>FIG. 2.</b>

**FIG. 2.

Compared to controls, the ALL group demonstrated significantly altered nodal clustering coefficient in several regions. Warm colors indicate areas of higher clustering, including left cuneus, left middle frontal gyrus, left hippocampus, left insula, left superior occipital gyrus, and right thalamus. Cool colors indicate regions of lower clustering, including left amygdala, right middle frontal orbital gyrus, right lingual gyrus, and bilateral supramarginal gyri.

<b>FIG. 3.</b>

**FIG. 3.

Brain graphs for the control group (top row) and ALL group (bottom row) with edges represented by lines and nodes represented by spheres. Sphere size reflects nodal clustering. Edges are shown with equal weight for illustration purposes. Node color corresponds to module membership. Both groups demonstrated five nearly identical modules, although certain nodes within each module, particularly module 5, showed altered clustering in the ALL group compared to controls.

<b>FIG. 4.</b>

**FIG. 4.

Partial dependence plots from random forest classification for features (predictors) in the final model. These plots illustrate the marginal effect of the feature on the class probability (“impaired”) after partialling out the influence of all other variables in the model. Cognitive impairment in the ALL group was associated with lower right middle orbital frontal clustering coefficient and lower cognitive reserve (maternal education). Nonlinear relationships were noted for left superior occipital clustering coefficient and left cuneus within-module degree _Z_-score, wherein extreme values tended to be associated with greater probability of impairment.

References

    1. Bassett DS, Bullmore E. 2006. Small-world brain networks. Neuroscientist 12:512–523 -PubMed
    1. Bhojwani D, Sabin ND, Pei D, Yang JJ, Khan RB, Panetta JC, Krull KR, Inaba H, Rubnitz JE, Metzger ML, Howard SC, Ribeiro RC, Cheng C, Reddick WE, Jeha S, Sandlund JT, Evans WE, Pui CH, Relling MV. 2014. Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. J Clin Oncol 32:949–959 -PMC -PubMed
    1. Breiman L. 2001. Random forests. Mach Learn 45:5–32
    1. Bruno J, Hosseini SM, Kesler S. 2012. Altered resting state functional brain network topology in chemotherapy-treated breast cancer survivors. Neurobiol Dis 48:329–338 -PMC -PubMed
    1. Calabrese E, Badea A, Cofer G, Qi Y, Johnson GA. 2015. A Diffusion MRI tractography connectome of the mouse brain and comparison with neuronal tracer data. Cereb Cortex 25:4628–4637 -PMC -PubMed

Publication types

MeSH terms

LinkOut - more resources