New Insights into PKU and the Brain

1. New Insights into PKU and the Brain Shawn Christ, Ph.D. Assoc Director, Brain Imaging Center Assoc Professor, Dept of Psych Sciences University of Missouri • Disclosure: Onoccasion, I also serve as an outside consultant for BioMarin Pharmaceutical Inc., and they are funding some of our current research on PKU and BH4.

2. Thank You! The help & support of individuals and families such as you makes our work possible.

3. Talk Overview • Review of Past Research • Cognitive & Behavioral Findings • Structural Brain Findings • Our Current Research • Functional brain activation & connectivity • Conclusions & Future Directions http://clinicalneurolab.missouri.edu/NPKUA2012.pdf

4. Talk Overview • Review of Past Research • Cognitive & Behavioral Findings • Structural Brain Findings • Our Current Research • Functional brain activation & connectivity • Conclusions & Future Directions

5. Results from this work • ETPKU associated with increased risk of: • Slight decrease in overall intellectual ability • Executive control problems • Slowed processing speed • Difficulties with anxiety & depression • Impact may be moderated by: • Timing of treatment (earlier = better) • Adherence to diet (stricter = better) • Consistency of treatment (stable = better)

6. Talk Overview • Neurocognitive Model of PKU • Review of Past Research • Cognitive & Behavioral Findings • Structural Brain Findings • Our Current Research • Functional brain activation & connectivity • Conclusions & Future Directions

7. Brain Organization 101 • Major Tissue Distinction • Gray Matter – Brain areas where ‘data processing’ occurs • White Matter – Insulated ‘wires’ connecting different brain areas with each other.

8. Brain Organization 101 • Major Tissue Distinction • Gray Matter – Brain areas where ‘data processing’ occurs • White Matter – Insulated ‘wires’ connecting different brain areas with each other.

9. Brain Organization 101 • Major Tissue Distinction • Gray Matter – Brain areas where ‘data processing’ occurs • White Matter – Insulated ‘wires’ connecting different brain areas with each other.

10. Increased risk of white matter injury Research suggests that >90% of adults with PKU have visible WM abnormality 30-yr-old with PKU 30-yr-old non-PKU Anderson & Leuzzi (2010)

11. Increased risk of white matter injury Research suggests that >90% of adults with PKU have visible WM abnormality 30-yr-old with PKU 30-yr-old non-PKU Anderson & Leuzzi (2010)

12. Increased risk of white matter injury Anderson & Leuzzi (2010)

13. Increased risk of white matter injury Anderson & Leuzzi (2010)

14. Most Recent Research on Microstructure of White Matter Peng, Peck, White & Christ (in press)

15. Effect on WM moderated by phe level Peng, Peck, White & Christ (in press)

16. White matter matters! • Complex behavior relies on a host of underlying processes that are each carried out in a single region of brain. In other words, complex behavior relies on a network of brain regions.

17. White matter matters! • Complex behavior relies on a host of underlying processes that are each carried out in a single region of brain. In other words, complex behavior relies on a network of brain regions.

18. Talk Overview • Review of Past Research • Cognitive & Behavioral Findings • Structural Brain Findings • Our Current Research • Functional brain connectivity • Conclusions & Future Directions

19. vs. Functional Integrity Structural Integrity Are the physical brain regions and their connections damaged or otherwise atypical? How well do spatially distinct regions work together to support complex cognitive functions? Yes ???

20. Functional Magnetic Resonance Imaging (fMRI) Christ et al. (2010)

21. Functional Connectivity • Evaluated by looking at the degree of concordance in neural activity among networked brain regions Christ et al. (2010)

22. Left SFG z = 53 Left IFG z = 33 Evaluating Functional Connectivity Christ et al. (2010)

23. Functional Connectivity • Evaluated by looking at the degree of concordance in neural activity among networked brain regions • Strength of functional connectivity positively correlated with cognitive performance (Hampson et al, 2006) Christ et al. (2010)

24. Brain Networks • Task “Positive” vs. “Negative” Networks from Fox et al. (2005)

25. 2-Back “Task Positive” Network Connectivity N-Back Working Memory Task K J X N G N Time P Christ et al. (2010)

26. Christ et al. (2010)

27. The “Task Negative” Brain Network from Fox et al. (2005)

28. Function of the DMN From Buckner & Carroll (2007)

29. Christ et al. (JIMD, 2012)

30. Christ et al. (JIMD, 2012)

31. Talk Overview • Review of Past Research • Cognitive & Behavioral Findings • Structural Brain Findings • Our Current Research • Functional brain activation & connectivity • Conclusions & Future Directions

32. vs. Functional Integrity Conclusions Structural Integrity Are the physical connections (pathways) between regions damaged or otherwise atypical? How well do spatially distinct regions work together to support complex cognitive functions? Yes Yes

33. vs. Functional Integrity Conclusions Structural Integrity ***IMPORTANT*** Evidence that these effects are moderated by phe levels!!! Are the physical connections (pathways) between regions damaged or otherwise atypical? How well do spatially distinct regions work together to support complex cognitive functions?

34. Future Directions • Why are some individuals more affected than others?

35. Future Directions • Why are some individuals more affected than others? • Are these problems reversible with treatment?

36. Thank you!Questions? Shawn Christ christse@missouri.edu http://clinicalneurolab.missouri.edu http://clinicalneurolab.missouri.edu/NPKUA2012.pdf

37. Thank you!Questions? Shawn Christ christse@missouri.edu http://clinicalneurolab.missouri.edu http://clinicalneurolab.missouri.edu/Vancouver2012.pdf

38. Additional Slides

39. Our current research… What effects does BH4 treatment have on cognition and the brain in individuals with PKU?

40. Study Protocol & Sample [NON-RESPONDERS] PKU [RESPONDERS] BH4 Tx No Meds ASSESSMENT ASSESSMENT ASSESSMENT Non-PKU 0 1 2 3 4 5 6 MONTH

41. PKU (n = 13) Non-PKU (n = 13) Lost to Follow-Up (n = 2) Lost to Follow-Up (n = 1) 4-Week Visit (n = 11) 4-Week Visit (n = 12) Non- Responders (n = 4) Responders (n = 7) Lost to Follow-Up (n = 5) Lost to Follow-Up (n = 3) Lost to Follow-Up (n = 1) 6-Month Visit (n = 1) 6-Month Visit (n = 6) 6-Month Visit (n = 7)

42. Behavior Rating Inventory of Executive Function (BRIEF) • The BRIEF is a standardized questionnaire designed to assess executive function within the context of a child’s day-to-day environment. • Items comprise 9 non-overlapping clinical scales reflecting different aspects of executive function including inhibitory control, self-monitoring ability, planning and organizational skill, emotional control, and working memory.

43. BRIEF (cont.) • Clinical Scales • Inhibit • Shift • Emotional Control • Self-Monitor • Initiate • Working Memory • Plan/Organize • Task Monitor • Organization of Materials Behavioral Regulation Index Global Executive Composite Metacognition Index

44. Results

45. 6 Month Follow-Up

46. Basics of MRI

47. GM Findings – much less known • ↓ Decreased Whole Brain Volume • ↓ Decreased Volume in Motor, Premotor Cortex, Thalamus, Hippocampus, & Pons • Our Current Work on Basal Ganglia… (Perez-Duenas et al., 2006; Pfaender et al, 2006)

48. Basal Ganglia * * Bodner & Christ (in prep)

49. White Matter Findings He, Christ et al. (2009). Detecting 3D corpus callosum abnormalities in phenylketonuria. International Journal of Computational Biology and Drug Design, 2, 289-301..

50. White et al. (2010). Age-related decline in the microstructural integrity of white matter in children with early- and continuously-treated PKU: A DTI study of the corpus callosum. Molecular Genetics & Metabolism, 99, S41-46.