Glymphatic system dysfunction in pediatric acute lymphoblastic leukemia without clinically diagnosed central nervous system infiltration: a novel DTI-ALPS method

Abstract

Background and objective: Central nervous system (CNS) infiltration commonly occurs in children with acute lymphoblastic leukemia (ALL). Nevertheless, CNS infiltration is rarely detected at the initial diagnosis. The glymphatic system, which regulates cerebrospinal fluid (CSF) and interstitial fluid transport, is considered one of the possible routes of CNS infiltration by leukemia cells. In this study, we used diffusion tensor image analysis along the perivascular space (DTI-ALPS) method to investigate glymphatic system function and obtained CSF volume using synthetic magnetic resonance imaging (SyMRI) in pediatric ALL without clinically diagnosed CNS infiltration.

Materials and methods: Twenty-nine ALL and 29 typically developing (TD) children were prospectively recruited (age 4-16 years) in the present study. Group differences in brain volumetric parameters, brain water diffusivities, and the ALPS index were evaluated after controlling for age, gender, and handedness. Furthermore, significant group-different parameters were correlated with clinical information using partial correlations analysis.

Results: Lower Dxassoc and ALPS index, and increased CSF volume were found in pediatric ALL (all p_{FDR-corrected} < 0.05). Moreover, the ALPS index was negatively associated with the risk classification (r = - 0.59, p_{FDR-corrected} = 0.04) in pediatric ALL.

Conclusions: Dysfunction of the glymphatic system and accumulation of CSF were presented in pediatric ALL without clinically diagnosed CNS infiltration. These novel findings suggested that the glymphatic system might be essential in the early-stage process of ALL CNS infiltration, which provides a new direction for exploring underlying mechanisms and early detection of pediatric ALL CNS infiltration.

Key points: • Lower Dxassoc and ALPS index, and increased CSF volume were found in pediatric ALL (all p_{FDR-corrected} < 0.05). • The ALPS index was negatively associated with the risk classification (r = -0.59, p_{FDR-corrected} = 0.04) in pediatric ALL. • Dysfunction of the glymphatic system and accumulation of CSF were presented in pediatric ALL without clinically diagnosed CNS infiltration, which suggested that the ALPS index and CSF volume might be promising imaging markers for early detection of pediatric ALL CNS infiltration.

Keywords: Central nervous system; Child; Glymphatic system; Magnetic resonance imaging; Precursor cell lymphoblastic leukemia-lymphoma.