2. CNS-Directed Therapy for Childhood Leukemia Neurodevelopmental Consequences of Neurologic Injury

3. BRAIN Initiative 1.The Brain in Action a.dynamic picture of the functioning brain b.molecular genetics 2.Advancing Human Neuroscience a.maximize collection of human samples for research on mechanisms of human brain disorders 3. Human Neural Technology a.technology to restore lost function

4. Acute Lymphoblastic Leukemia 1.One in 330 children is diagnosed with cancer by age 20 2.One in 530 young adults 20 to 39 years of age is a childhood cancer survivor 3.Most prevalent cancer among children & adolescents is ALL a. once fatal b. 5 year survival approaches 90%

5. Improved Survival from ALL 1. Use of multi-agent therapy 2. Know risk factors for recurrence a.minimal residual disease b.treatment intensity matched to recurrence risk 3.Aggressive CNS-directed treatment for subclinical disease in the brain a.primary site of initial disease relapse

6. What are the Consequences of CNS- Directed Therapy? 1.Neurodevelopmental and academic problems 2. Experienced by up to 60% of ALL survivors a.Memory b.Visual spatial abilities c.fine motor speed d.attention e.processing speed f.academic achievement 3. Associated with secondary effects on a.psychological well being (anxiety, depression) b.social & adaptive skills c.vocational success

7. Cognitive Measure Post-Induction Mean SD Continuation Mean SD End of Therapy Mean SD Visual Spatial Skills 97.07 13.95 97.07 13.95 94.14 16.83 94.14 16.83 89.6 8.10 89.6 8.10 Fine Motor Speed* -1.19 1.28 -1.19 1.28 -0.42 1.02 -0.42 1.02 -0.39 1.23 -0.39 1.23 Visual Working Memory * -0.17 1.39 -0.17 1.39 -0.08 0.99 -0.08 0.99 -0.34 0.95 -0.34 0.95 Verbal Working Memory* -0.35 0.96 -0.35 0.96 -0.25 0.83 -0.25 0.83 -0.39 0.75 -0.39 0.75 Processing Speed* -0.80 1.68 -0.80 1.68 -0.68 1.27 -0.68 1.27 -0.67 0.98 -0.67 0.98 Cognitive Abilities Over Time * reported as Z scores with mean of 0 and SD of 1 * reported as Z scores with mean of 0 and SD of 1

8. Cognitive Abilities can Impact Academic Outcomes Visual Motor Integration Visual Memory Verbal Memory Fine Motor Abilities Letter/Word Identification r = 0.748 p < 0.001 r = 0.624 p < 0.001 r = 0.534 p < 0.001 r = 0.465 p < 0.001 Calculation r = 0.536 p < 0.001 r = 0.340 p = 0.015 r = 0.321 p = 0.020 r = 0.290 p = 0.040

9. Why do children with ALL have long-term neurodevelopmental & academic problems?

10. CNS Directed Chemotherapy Model of Neurologic Injury : Oxidative Stress & Apoptosis

11. Oxidative Stress & Apoptosis Biomarkers 1.Oxidized phospholipids by HPLC with diode array detection a. 206 detects unoxidized phospholipids b. 234 detects oxidized phospholipids 2.Caspase enyzme activity by Promega Glo™ assays a. capase 8 & 9 initiate apoptosis b. caspase 3/7 execute apoptosis

12. CSF Phospholipid Composition in Children

13. Unoxidized Phospholipids 206nm PI PC Oxidized Phospholipids 234nm

14. Oxidized PC by Treatment Phase F = 22.135; df = 4; p < 0.001

15. Oxidized PI by Treatment Phase F = 16.747; df = 4; p < 0.001

17. Oxidative Stress Biomarkers of Neurologic Injury Oxidized PI Visual Spatial/Fine Motor Abilities Inductionr = - 0.24; p < 0.05 Post Inductionr = - 0.29; p < 0.05 Continuationr = - 0.32; p < 0.05 Oxidized PC Treatment-related Symptoms Post-Inductionr = 0.33; p < 0.05 Continuationr = 0.52; p < 0.01

18. Human Neural Technology Development Can we restore cognitive and academic abilities cognitive and academic abilities in children with ALL?

19. Improving Academic Outcomes: Math Intervention Determine if Math Intervention prevents declines in academic math scores in children with ALL

20. Nonverbal Working Memory: Changes over Time by Group F [2, 29] = 5.53, p < =.009

21. Math Skills in Intervention Group: Changes Over Time F [2, 29] = 12.47, p <0.001