MK could reflect the microstructure complexity of tissues; on the other hand, MK and RK could detect the integrity of myelin. Our study found that the patients had significantly lower MK and RK in the corpus callosum after CR, indicating that short-term chemotherapy could cause demyelinating changes in the corpus callosum. However, there were no significant changes in DKI parameters in bilateral frontal lobe WM indicating that chemotherapeutics had varying effects on different brain regions.
Our patients were mainly given intravenous VCR and DNR, Pred, L-Asp, supplemented by intrathecal injection of MTX during the induction therapy. It is common knowledge that VCR can cause peripheral neuropathy [2], but it can also lead to generalized brain volume reduction, especially in terms of WM volume. The acute toxic reaction affects the organization of normal growth processes causing brain volume loss. DNR can also cause brain volume loss; however, DNR mainly affects GM volume[16]. Neither Pred nor L-Asp cause extensive injuries to WM[17, 18].
The volume of myelin in the corpus callosum increases sharply in early childhood, reaching 86% of the final volume at the age of 5[14, 19]. We observed that the patients ≤ 5 years old had significantly lower MK and RK after induction, while the patients ༞5 years old had not undergone similarly significant change DKI parameters, in the genu and splenium of CC. It is speculated that the WM damage was caused by VCR, which mainly affects the normal growth of tissues. However, whether this change could persist upon later treatment remains to be further studied. However, according to existing studies, younger patients with ALL treated with chemotherapy may experience more severe brain damage[20].
Previous studies have shown that the volume of the corpus callosum and bilateral frontal WM in patients who have completed chemotherapy were significantly lower in patients with ALL [8, 21]. As the brain finally matures, the frontal lobe WM is the most vulnerable to damage[22]. Our research found that bilateral frontal WM volume change was not obvious. Our findings suggested that the frontal WM could not be easily affected by VCR. Alternatively, there may be a threshold effect, where the damage to the frontal lobe caused by the current chemotherapy regimen was not sufficiently detectable by DKI.
AK increases reflect axonal injury. One of the main functions of the myelin sheath is to protect axons from injury. Once demyelination occurs and repair mechanisms are exhausted, axonal degeneration occurs in a predictable manner[23]. Therefore, axons remain intact in the early stage of demyelination, and the results of this study support the idea. Consequently, if demyelination can be detected quickly, it will help prevent axonal damage when remyelination is promoted. There is increasing evidence that inflammation is necessary for myelin repair; recent studies have found that celecoxib has anti-demyelinating effects and promotes myelin regeneration by improving the immune and inflammatory microenvironment[24].
ALL patients undergoing chemotherapy have long-term cognitive dysfunction such as diminishing executive power, working memory, processing speed and attention, and they are related to changes in brain microstructure in different regions[1, 5, 25]. However, different intervention measures can increase the volume of white matter used to complete different task areas; on the contrary, reduced external stimulation will lead to myelin sheath decline and impaired cognitive function[14]. Therefore, timely implementation of interventions, such as skill learning and memory exercises, is very important for patients with ALL undergoing chemotherapy.
The corpus callosum is the largest WM junction in the human brain, serving as a connection between the left and right cerebral hemispheres. It is important for motor and sensory integration, attention, memory, and general cognitive functions[26]. It is necessary to further evaluate whether early WM damage in patients will cause related cognitive dysfunction, to detect potential problems early and provide timely intervention. However, this study did not perform a cognitive function test.
Current results suggest that WM damage can occur early in chemotherapy. There are several limitations in this study that could be addressed in future research. First, the study focused on brain structural changes after CR; the study cannot determine whether DKI changes were temporary. Second, this study did not have a neurocognitive function test component, so it could not assess the relationship between brain structural changes and cognitive function. Lastly, patients with immunosuppression and incomplete remission following induced remission were also excluded, so the number of patients in our study was relatively small.