1. Executive function in early- treated PKU Stephan Huijbregts (Leiden University) For NSPKU Skipton 2010

2. Examples of executive functions Planning, organization, strategy use, cognitive flexibility, inhibitory control, working memory, monitoring and, if necessary, correcting one’s actions.

3. For good EF many brain regions must work together 3 5 2 1 4 1.Dorsolateral Prefrontal Cortex 2.Ventrolateral Prefrontal Cortex 3.Parietal Association Cortex 4.Thalamus 5.Cerebellum Example for one of the EFs: working memory

4. Assessment of executive functions Different tasks for different ages Paper-and-Pencil tasks Computer tasks Questionnaires (DEX, BRIEF)

5. Examples of EF-tasks for young children (< 6 years) (Inhibitory control)

6. Examples of EF-tasks for young children (< 6 years) (Inhibitory control)

7. Examples of EF-tasks for young children (< 6 years) (Inhibitory control)

8. Box 1 Box 2 Examples of EF-tasks for young children (< 6 years) (Cognitive flexibility)

9. Examples of EF-tasks for young children (< 6 years) (Working Memory)(Planning)

10. Examples of EF-tasks for young children (< 6 years) (Planning)

11. Dutch study: EF (and other cognitive abilities) in ETPKU 67 PKU patients and 73 controls aged 7 to 14 years performed 9 tasks of the Amsterdam Neuropsychological Test (ANT) battery (De Sonneville, 1999). A blood sample was taken before neuropsychological assessment to determine concurrent Phe and Tyr levels. PKU-patients were allocated to a high Phe group when they had concurrent Phe levels > 360 µmol/L and to a low Phe group when they had concurrent Phe levels  360 µmol/L. Subjects were allocated to the younger group when they were younger than 11 years and to an older group when age was  11 years. Historical phe-levels (TNO-Leiden) Dietary interventions (University Medical Center Groningen)

12. Main Research Questions Which cognitive functions are impaired in early- and continuously treated PKU patients and which are not? Is neuropsychological task performance associated with concurrent and historical Phe levels? Is performance level related to age/does the level of impairment decrease with age? Do short-term dietary interventions affect cognition in ETPKU?

13. Shifting Attentional Set: Inhibitory Control and Cognitive Flexibility

14. Shifting Attentional Set: Results Age < 11 years Age  11 years

15. Sustained Attention + Inhibitory control N = 200 Variables of interest: Bias: Error rate 4-dot presentations (misses) - mean error rate 3- and 5-dot presentations (false alarms) Tempo (MSTAcc) Fluctuation of Tempo (SDMST) Time on Task

16. Sustained Attention + Inhibitory Control

17. mouse cursor start & end position trajectory cursor (not visible) Tracking (left) and Pursuit (right) * Trajectory of the asterix (not visible) In random direction moving asterix

18. Historical phe levels For the children with PKU, the mean phe level throughout life (from the time they were born) had the strongest relation with how well they did on executive function-tasks. This relation was stronger than the relation with phe on the day of testing. This may mean that it is more important to take good care with food and food supplements from birth onwards in a consistent way than to be very strict every day

19. Patients with Phe-levels > 360  mol/L at the first assessment maintained a stricter diet for two weeks Patients with Phe-levels  360  mol/L at the first assessment went on a more relaxed diet for one week Patients were allocated to a Phe Down group when they had lower Phe levels at the second assessment and to a Phe Up group when they had higher Phe levels at the second assessment Controls also underwent a second neuropsychological assessment to control for a learning effect Dietary Intervention

20. Dietary interventions: Results

21. Summary of results 1)There are EF-difficulties, even in treated PKU 2)Treatment does help: with lower phe levels there are fewer EF- problems 3)The younger the patients the more important the treatment, because they have most problems with EF if their phe levels are high 4)But it also looks like it is important to continue the diet + treatment after childhood because some EFs take longer to develop

22. left-hand response right-hand response Central stimulus + + + 1000 ms 200-6000 ms 1000 ms 200-6000 ms 1000 ms 200-6000 ms 1000 ms 200-6000 ms Part 1 Part 2 Compatible: N = 10 Neutral: N = 10 Compatible: N = 10 Compatible: N = 20 Incompatible: N = 20 Compatible: N = 20 Incompatible: N = 20 Flanker Interference: only inhibitory control + + + + + +

23. + * * + + + h zg b + t n + p r + jz md + Target: ‘j’,’n’ or ‘s’ No target: N = 20 Target on irrelevant diagonal: N = 20 Target on relevant diagonal: N = 40 Focused Attention: mainly inhibitory control

24. Summary of results 1)There are EF-difficulties, even in treated PKU 2)Treatment does help: with lower phe levels there are fewer EF- problems 3)The younger the patients the more important the treatment, because they have most problems with EF if their phe levels are high 4)But it also looks like it is important to continue the diet + treatment after childhood because some EFs take longer to develop

25. What about development? Example: motor function

26. What about the developmental trajectory of EF? Together with the brain, EF continues to develop well into adolescence

27. How does EF relate to daily lives of PKU-patients? The impact of EF-deficits on social information processing (e.g. emotion recognition, theory of mind, i.e. how well do you understand other people’s intentions, knowledge, desires, and emotions?) and social functioning should be examined

28. Study into ToM and EF of 229 normally developing children aged 3-6

29. Association EF – ToM r control for age =.45, p <.001, without:.69

30. BH4-replacement (e.g. Kuvan)? BH4: natural substance in body BH4 helps enzyme PAH, which breaks down Phe into Tyr Not enough Tyr reaches brain, possibly resulting in shortages in other chemical messengers such as dopamine and serotonine Dopamine and serotonine are important for EF and for social-cognitive functioning Lowering Phe could also prevent or perhaps even reverse myelin damage In addition to testing of for example Kuvan’s effectiveness in lowering Phe, it should be examined whether it improves EF

31. Challenges/new EF-research in PKU Perform Long-term follow-up studies Fluctuations in Phe v mean or concurrent Phe Study effects of EF-deficits on social information processing and social functioning Find out the best possible way to improve EF in PKU (training, diet, medication?)

32. And we thank you for listening Thanks to the participants and their families Thanks to Francjan van Spronsen, Leo de Sonneville, Shawn Christ, Desiree White, Paul Verkerk, Greet van Rijn, Joe Sergeant, and Adele Diamond