To each, his/her own

See the article by Bledsoe et al. in this issue, pp. 1310–1318.

In the largest and best-balanced study yet to be published, Bledsoe et al report in this issue¹ that cognitive recovery after treatment for pediatric brain tumors is greater in female compared with male survivors. This report is important news! Measurable cognitive and performance deficits may be present in at least one domain in all survivors of pediatric brain tumors, and disabling deficits are commonplace.² As the number of survivors continues to increase, prevention and remediation of cognitive and performance deficits have emerged as among the greatest challenges and missions in pediatric neuro-oncology, and an area in which advancement holds an opportunity for tremendous impact on survivorship.

The reasons for these cognitive and performance deficits are manifold and complex. Large cross-sectional studies have identified a number of relevant risk factors, including tumor location, brain irradiation, age less than 6 years at the time of diagnosis and treatment, and hydrocephalus.³ As valuable as these data are, they represent a relatively static and narrow view of cognition that has yet to fully incorporate (i) the impact that factors such as genetics, environment, and their cascading interactions have on the developmental dynamics of brain structure and function, and (ii) the mechanisms by which all of these elements culminate in an individual’s cognition and performance. Without a more realistic and comprehensive model for how brain tumors and their treatment impact cognitive development, it will not be possible to effectively modify treatment regimens to reduce risk or to rationally design interventions to optimize cognitive and functional outcomes.

Cognitive development is dynamic and plastic, to a point. In general, human brain development undergoes a characteristic sequence of stages where brain systems are optimally sensitive to experience-expectant and experience-dependent stimuli. For example, the infant brain is ideally suited to language exposure—absence of exposure during a critical period for language acquisition often results in language impairment (eg, experience expectant). However, the infant brain is capable of learning any human language to which it is exposed (eg, experience dependent). Optimal cognitive development requires appropriate exposures, such as to language, as well as absence of adverse exposures, such as to hypoxia/ischemia, toxins, or malnutrition. Early exposures or injuries to the developing brain can be particularly devastating, especially if they interfere with the processing of experience-expectant development. There are ample clinical observations after diverse brain injuries to indicate that mechanisms for repair of cognitive injury exist but that in many cases, they are not adequate for full recovery.

We have known about the influence of age on vulnerability to injury and potential for recovery for some time. This knowledge has guided the design of treatment regimens to avoid unrecoverable injury that occurs after whole brain irradiation in children less than 3 years old. Thus, it follows that at less than 3 years, there must be a developmental stage at which the brain cannot tolerate or accommodate radiation injury, necessarily resulting in an abnormal developmental trajectory. If vulnerabilities to injury and potential for recovery are related to developmental stage, then risk is not a simple function of chronological age. Thus, relevant to this study, sexual maturation rating may be a more appropriate means to assess risk specific to developmental stage.

The sex-related differences in cognitive development are also reflected in differential vulnerabilities to intellectual and developmental disabilities. For example, autism spectrum disorder, Tourette syndrome, and attention deficit hyperactivity disorder all have a male to female ratio of roughly 4:1. Intellectual disability per se has a male predominance of 1.5:1. This consistent observation has been termed the “female protective effect,” supported by evidence for a higher required mutational burden for females compared with males to manifest symptoms of neurodevelopmental disability⁴. It is intriguing to consider whether the relative resilience for females in Bledsoe et al could also be related to a comparable female protective effect. Thus, we should consider whether placing pediatric brain tumor–related injury into the broader context of intellectual and developmental disabilities would be beneficial when implementing approaches to mitigate risk and promote recovery of cognitive deficits.

The admonition that children less than 3 years old should not get whole brain irradiation, while true, is insufficient. Instead, we should develop treatments that are informed by insights from an increasingly deeper understanding of brain and cognitive development. We should leverage information related to sex and development from multiple sources, such as connectomics and other imaging-based approaches, to apply developmental stage–specific measures of relevant neuro-biology, such as the extent of myelination, functional connectivity, brain region volumes, and brain lipid and glucose metabolism. Such an integrative, multivariate approach is more likely to identify patients with different levels of risk than age alone.⁵ Characterizing relative risk and resilience could guide risk-adapted treatments with the potential to develop more individualized treatment strategies that increase cures, decrease toxicity, and improve cognitive outcomes. In this context, it will also be important to make careful assessments of the impact that targeted therapeutics that modulate key developmental epigenetic and intracellular signaling pathways have on cognition during and after treatment.

Finally, our experience is that clinical and laboratory investigators frequently make the mistake of shying away from the complexity of including rigorous evaluations of sex effects. Rigorously addressing sex as a biological variable may be more complicated, but it is the reality and is mandated by the National Institutes of Health. There are few domains in constitutively sexually dimorphic species like humans that are not affected by the biology of sexual differentiation. The process begins at conception for all sexually dimorphic species and includes genetic and epigenetic mechanisms that impact on growth, metabolism, and immunity, among other cellular and systemic processes.⁶ This area is ripe for important discovery and essential, if truly personalized approaches to cure and reduced toxicity are to be realized. As scientists, we should capitalize on sex effects to help us understand the mechanisms of brain maturation and cognitive development, injury, and recovery. As clinicians, we should embrace this direction as following through on our commitment to provide the best possible care to each and every one of our patients.

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