Monitoring cerebrospinal fluid biomarkers, imaging of brain injuries may identify abnormal neurodevelopment

According to a study recently published online March 29 in the Journal of the American Medical Association, monitoring cerebrospinal fluid (CSF) biomarkers and imaging for genetic mediators of brain injuries in children may help identify those at risk of abnormal brain development in the long-term.   

Researchers led by Kevin Krull, MS, PhD, from the department of epidemiology and cancer control at St. Jude Children's Research Hospital in Memphis, Tenn. sought to find whether cerebrospinal fluid biomarkers of brain injury are associated with neurotoxic effects in children who receive chemotherapy for acute lymphoblastic leukemia. 

"Our results suggest that CSF biomarkers of central nervous system injury have clinically relevant associations with treatment characteristics and long-term outcomes; monitoring levels of t-tau within CSF may estimate the risk of leukoencephalopathy and abnormal neurodevelopment," according to the researchers. "Coupled with knowledge of genetic mediators of central nervous system injury, the present results may advance the development of personalized medicine whereby treatments for and prevention of late effects are tailored to characteristics of individuals."  

A total 235 child patients (51.1 percent boys, mean age of 7 years) with acute lymphoblastic leukemia who had received chemotherapy treatment were recruited from St. Jude's and provided CSF samples after diagnosis and throughout treatment. The patients were treated from June 1, 2000, through October 31, 2010. Five years after diagnosis, 198 patients met eligibility requirements for long-term follow-up examinations and 138 participated, which was completed on October 21, 2014. 

"We identified biomarkers related to myelin integrity, neuronal injury, astrogliosis and neuroinflammation a priori and examined concentration of these biomarkers at diagnosis and during therapy," according to the researchers regarding follow-up examinations. "Associations were examined with acute leukoencephalopathy, long-term neurocognitive and neuroimaging outcomes and polymorphisms in enzymes related to chemotherapy, oxidative stress and central nervous system susceptibility." 

Methotrexate exposure positively correlated with markers of neuronal damage. Markers of demyelination and axonal damage were associated with as much as a 70 percent higher risk of developing leukoencephalopathy during therapy, worse long-term frontal lobe white matter integrity and poorer neurocognitive function. Also, carriers of the Val allele in the COMT gene demonstrated greater biomarker level elevations after methotrexate exposure than did carriers of the Met allele. 

"Glial injury may be present at diagnosis of acute lymphoblastic leukemia; neuronal injury was associated with intrathecal chemotherapy," the researchers wrote. "The CSF biomarkers may be useful in identifying individuals at risk for worse neurologic outcomes, particularly those with genetic susceptibility to poor brain function."