Structural brain alteration in survivors of acute lymphoblastic leukemia with chemotherapy treatment: A voxel-based morphometry and diffusion tensor imaging study

doi:10.1016/j.brainres.2017.01.017

Brain Research

Volume 1658, 1 March 2017, Pages 68-72

https://doi.org/10.1016/j.brainres.2017.01.017 Get rights and content

Highlights

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ALL chemotherapy survivors exhibited GM alterations.
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WM integrity changes through lower FA and AD value, higher MD and RD values in ALL patients.
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VBM and DTI can reveal GM and WM alteration in ALL patients.

Abstract

Objective

To assess structural brain changes in survivors of acute lymphoblastic leukemia (ALL) with chemotherapy treatment by combining voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS).

Methods

28 ALL patients (mean age: 40.71 ± 8.58 years, years since diagnosis: 7–38) and 20 age-matched control subjects (mean age: 42.95 ± 6.39 years) selected in this study with 3D T1 and diffusion tensor imaging acquired on a 3.0T Siemens MRI scanner. The ALL group had a history of chemotherapy treatment and off-therapy at least for 3 years was enrolled. VBM and TBSS analysis were performed to detect regional grey matter (GM) volume changes and white matter (WM) alternation measured by fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD).

Results

VBM revealed decreased GM volume in ALL patients in lingual gyrus, left occipital middle gyrus, left temporal middle gyrus, left postcentral gyrus, left parietal inferior gyrus, left precentral gyrus, left frontal superior gyrus and increased GM volume in right caudate and frontal lobe. WM integrity changes measured by TBSS which showed decreased FA and AD in several WM regions, and increased MD and RD in ALL patients with chemotherapy treatment.

Conclusion

Our results indicate that ALL patients had smaller GM volume and WM integrity changes in several regions. The current study may shed further light on the potential brain effects of chemotherapy treatment in ALL patients.

Introduction

Acute lymphoblastic leukemia (ALL) is the most prevalent cancer in children, accounting for 74% of all leukemia and 18% of all cancers (Kanellopoulos et al., 2016). The historical treatment of cranial radiation therapy (CRT) has result in a 5 year event-free survival rate of approximately 80% in standard risk ALL after intensive chemotherapy treatment of the central nervous system (Cheung and Krull, 2015, Gaynon et al., 2010). However, it is also reported that ALL survivors suffer from long-term neurocognitive impairment, and it has a negative impact on their health related quality of life (QoL) (Huang et al., 2013). Possible mechanisms for cognitive impairment include direct neurotoxic effects causing atrophy of grey matter (GM) and/or demyelination of the white matter (WM), secondary immunologic responses leading to inflammatory reactions and microvascular damage (Saykin et al., 2003, Seigers and Fardell, 2011).

Neuroimaging may provide insights to anatomic substrates of potential toxic treatment effects. Previous studies using conventional magnetic resonance imaging (MRI) (Ashford et al., 2010, Krappmann et al., 2007, Reddick et al., 2014), functional MRI (Kesler et al., 2014, Luxton et al., 2014, Robinson et al., 2010), and diffusion tensor imaging (Edelmann et al., 2013, Schuitema et al., 2013) has enhanced our understanding of possible underlying pathophysiologic mechanisms.

Voxel-based morphometry (VBM) is an automated technique for evaluating brain structures, which requires no a priori regional assumptions. Compared to VBM, DTI provides information on the WM integrity by measuring the motion of water molecules (Tu et al., 2016). Tract-based spatial statistics (TBSS) analysis has been used for assessing WM integrity by fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) (Smith et al., 2006). Generally, decreased FA means demyelination, axonal loss and inflammation. AD refers to identify axonal damage or degeneration, whereas RD shows myelin injury selectively (Assaf and Pasternak, 2008).

In the present study, we sought to characterize possible brain changes in ALL patients with chemotherapy treatment by combining VBM and TBSS methods. In this approach, we wanted to assess whether GM and WM alterations in ALL patients.

Section snippets

Participants

Between June 2015 and June 2016, 32 ALL patients who had completed all anti-cancer treatment with chemotherapy treatment in Second hospital of Anhui Medical University were recruited. Four of the 32 survivors withdrew during data collection, leaving 28 participants (mean age: 40.71 ± 8.58 years, years since diagnosis: 7–38) were included. Systemic chemotherapy included prednisolone, vincristine, cyclophosphamide, daunorubicin, doxorubicin, asparaginase, teniposide, cytarabine, 6-mercaptopurine,

Results

There was no significant difference for age and gender between the ALL patients and healthy controls (p > 0.05, Table 1).

Discussion

In the present study, we found a alteration in GM volume and a widespread changes in WM microstructural (decreased FA and AD, increase in MD and RD) in ALL patients when compared to healthy controls.

For GM changes in ALL patients, our study demonstrated that decreased GM volumes occurred in several brain areas of ALL patients with chemotherapy treatment, which indicated that cortical atrophy occurs in ALL patients with chemotherapy treatment. Compared to healthy controls, the ALL groups have

Acknowledgements

This work was supported by Anhui Provincial Public Linkage Projects (1604f0804025), Anhui Provincial General Medicine Clinical Scientific Projects (2016QK089) and Anhui Provincial Quality Projects (2014jxtd119).

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Research reportStructural brain alteration in survivors of acute lymphoblastic leukemia with chemotherapy treatment: A voxel-based morphometry and diffusion tensor imaging study

Highlights

Abstract

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Participants

Results

Discussion

Acknowledgements

Neuroimage

Int. J. Radiat. Oncol. Biol. Phys.

Neurosci. Biobehav. Rev.

Neuroimage

Neurosci. Biobehav. Rev.

Neuroimage

Brain Lang.

Clin. Neurophysiol.

Attention and working memory abilities in children treated for acute lymphoblastic leukemia

Cancer

Diffusion tensor imaging (DTI)-based white matter mapping in brain research: a review

J. Mol. Neurosci.

Radiation induced CNS toxicity–molecular and cellular mechanisms

Br. J. Cancer

Relationship of iron to oligodendrocytes and myelination

Glia

Late structural alterations of cerebral white matter in long-term survivors of childhood leukemia

J. Magn. Reson. Imaging

Dexamethasone exposure and memory function in adult survivors of childhood acute lymphoblastic leukemia: a report from the SJLIFE cohort

Pediatr. Blood Cancer

Diffusion tensor imaging and neurocognition in survivors of childhood acute lymphoblastic leukaemia

Brain

Long-term results of the children’s cancer group studies for childhood acute lymphoblastic leukemia 1983–2002: a Children’s Oncology Group Report

Leukemia

Research report
Structural brain alteration in survivors of acute lymphoblastic leukemia with chemotherapy treatment: A voxel-based morphometry and diffusion tensor imaging study