Background: Most childhood cancer survivors will develop ionizing radiation treatment-related health conditions that, in many instances, resemble age-associated pathologies. Treatment-induced premature senescence could be an underlying mechanism. Findings: Here we wanted to know whether the expression of p16^INK4a, a senescence/aging biomarker, is increased in skin biopsies of acute lymphoblastic leukemia survivors (ALL), previously exposed to chemotherapy and radiation therapy. Several years post-treatments, we found p16^INK4a mRNA levels are 5.8 times higher in scalp skin biopsies (targeted by cranial irradiation therapy) compared to buttocks skin biopsies (n = 10, p = 0.01). Conclusions: These results demonstrate for the first time that premature senescence is induced in pediatric cancer survivors and that p16^INK4a expression could be used as a potential biomarker in this population.

Objective: Neuropsychological problems occurrence varies among childhood cancer survivors, and associated risk factors have not been fully deciphered. We wanted to study the role of genetic variants in behavioral problems in this population. Study Design: Behavioral problems in pediatric acute lymphoblastic leukemia patients (n=138) were investigated longitudinally, using the Child Behavior Checklist questionnaire and multilevel statistical modeling. Thirty-four candidate polymorphisms, related to anticancer drug effects, were investigated. Results: NOS3 gene functional polymorphisms showed significant association: patients homozygous for the minor allele at investigated loci showed decreased externalizing behavioral problems scores over time (t tests: T-786C n=69, P=0.003; G894T n=71, P=0.065). The effect was even more pronounced for individuals that are homozygous for the −786C844T haplotype (t test, n=69, P<0.001) and results were supported by multilevel modeling analyses (P<0.001). No such association was observed for internalizing behavioral problems. Conclusion: NOS3 variants modulate externalizing problems individual trajectories, likely in relationship with glucocorticoid exposure.

Reinforcement learning, crucial for behavior in dynamic environments, is driven by rewards and punishments, modulated by dopamine (DA) changes. This study explores the dopaminergic system's influence on learning, particularly in Parkinson's disease (PD), where medication leads to impaired adaptability. Highlighting the role of tonic DA in signaling the valence of actions, this research investigates how DA affects response vigor and decision-making in PD. DA not only influences reward and punishment learning but also indicates the cognitive effort level and risk propensity in actions, which are essential for understanding and managing PD symptoms. In this work, we adapt our existing neurocomputational model of basal ganglia (BG) to simulate two reversal learning tasks proposed by Cools et al. We first optimized a Hebb rule for both probabilistic and deterministic reversal learning, conducted a sensitivity analysis (SA) on parameters related to DA effect, and compared performances between three groups: PD-ON, PD-OFF, and control subjects. In our deterministic task simulation, we explored switch error rates after unexpected task switches and found a U-shaped relationship between tonic DA levels and switch error frequency. Through SA, we classify these three groups. Then, assuming that the valence of the stimulus affects the tonic levels of DA, we were able to reproduce the results by Cools et al. As for the probabilistic task simulation, our results are in line with clinical data, showing similar trends with PD-ON, characterized by higher tonic DA levels that are correlated with increased difficulty in both acquisition and reversal tasks. Our study proposes a new hypothesis: valence, signaled by tonic DA levels, influences learning in PD, confirming the uncorrelation between phasic and tonic DA changes. This hypothesis challenges existing paradigms and opens new avenues for understanding cognitive processes in PD, particularly in reversal learning tasks.

Acute lymphoblastic leukemia (ALL) stands as the most prevalent form of pediatric cancer in North America, with a current five-year survival rate of 85%. While more children achieved ALL remission and transition into adulthood, the prevalence of long-term treatment-related effects, especially neurocognitive sequelae, remains significant. This study pursues two objectives. Firstly, it investigates if Magnetization Transfer Ratio (MTR), a method assessing myelin integrity, is sensitive to white matter (WM) microstructural changes in long-term ALL survivors and whether these relate to cognitive impairments. Secondly, it examines the dose-related effects of chemotherapy agents on the MTR and its relationship to other risk factors such as female sex, early age diagnosis, and cranial radiotherapy. Magnetization transfer imaging was utilized to assess WM integrity in 35 survivors at a mean of 18.9 years after the onset of ALL (range since diagnosis: 6.9–26.8). Additionally, 21 controls matched for age, sex, and education level, with no history of cancer, were included. MTR was extracted from both the entire brain’s WM and the corpus callosum through semi-automated procedures. The results indicated lower MTR means in survivors, which is linked to cognitive function. Negative associations between MTR means and intrathecal agents’ (MTX, cytarabine, and hydrocortisone) cumulative doses received were highlighted. This study offers valuable insights into the connections between myelin deterioration, cognitive impairment, and the implications of IT chemotherapy, enhancing our understanding of ALL survivorship dynamics. It underscores MTR’s relevance in monitoring neurotoxicity during oncological drug follow-up examinations.