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: On occasion, 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. The help & support of individuals and families such as you makes our work possible.

3.  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.  Review of Past Research  Cognitive & Behavioral Findings  Structural Brain Findings  Our Current Research  Functional brain activation & connectivity  Conclusions & Future Directions

5.  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.  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.  Major Tissue Distinction  Gray Matter – Brain areas where ‘data processing’ occurs  White Matter – Insulated ‘wires’ connecting different brain areas with each other.

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

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

10. Research suggests that >90% of adults with PKU have visible WM abnormality Anderson & Leuzzi (2010) 30-yr-old with PKU30-yr-old non-PKU

11. Research suggests that >90% of adults with PKU have visible WM abnormality Anderson & Leuzzi (2010) 30-yr-old with PKU30-yr-old non-PKU

12. Anderson & Leuzzi (2010)

14. Peng, Peck, White & Christ (in press)

16.  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.  Review of Past Research  Cognitive & Behavioral Findings  Structural Brain Findings  Our Current Research  Functional brain connectivity  Conclusions & Future Directions

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

20. Christ et al. (2010)

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

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

23.  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.  Task “Positive” vs. “Negative” Networks from Fox et al. (2005)

25. N-Back Working Memory Task 2-Back K J X N G N P Christ et al. (2010)

27. from Fox et al. (2005)

28. From Buckner & Carroll (2007)

29. Christ et al. (JIMD, 2012)

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

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

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

34.  Why are some individuals more affected than others?

35.  Are these problems reversible with treatment?

36. Shawn Christ christse@missouri.edu http://clinicalneurolab.missouri.edu http://clinicalneurolab.missouri.edu/NPKUA2012.pdf

37. Shawn Christ christse@missouri.edu http://clinicalneurolab.missouri.edu http://clinicalneurolab.missouri.edu/Vancouver2012.pdf

40. NM/F Prior Year Phe Levels Mean Range Age (yrs) Mean Range FSIQ Mean Range PKU 137/673188-145922.58-3310073-115 Non-PKU 136/722.79-3310993-120 [RESPONDERS] [NON-RESPONDERS] PKU Non-PKU 0123456 MONTH ASSESSMENT BH4 Tx No Meds

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

42.  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. Clinical Scales Inhibit Shift Emotional Control Self-Monitor Initiate Working Memory Plan/Organize Task Monitor Organization of Materials Global Executive Composite Global Executive Composite Metacognition Index Metacognition Index Behavioral Regulation Index Behavioral Regulation Index

47.  ↓ 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. Bodner & Christ (in prep) * *

49. 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.

51. Perez-Duenas et al. (2006). Global and regional volume changes in the brains of patients with phenylketonuria. Neurology, 66, 1074-78. Statistical parametric t map showing relative decreases of gray matter volume in patients with PKU

52. (Upper row) Early summed emission images (1–6 mins after injection, relative uptake: standardized uptake value and stereotactical normalized) (Lower row) k3S images (stereotactical normalized, scale showing k3S values). Landvogt et al. (2008). Reduced cerebral fluoro-L-dopamine uptake in adult patients suffering from phenylketonuria. Journal of Cerebral Blood Flow & Metabolism, 28, 824-831. ControlPKU