Executive function in Executive function in early-treated PKU early-treated PKU

Stephan Huijbregts (Leiden University)For

NSPKU Skipton 2010

Examples of executive functions

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

For good EF many brain regions must work together

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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

Assessment of executive functions

Different tasks for different ages Paper-and-Pencil tasks Computer tasks Questionnaires (DEX, BRIEF)

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

(Inhibitory control)

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

(Inhibitory control)

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

(Inhibitory control)

Box 1 Box 2

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

(Cognitive flexibility)

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

(Working Memory) (Planning)

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

(Planning)

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)

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?

Shifting Attentional Set: Inhibitory Control and Cognitive Flexibility

Task part 1, compatible responses

Trial i

Trial i + 1, left

Trial i + 2, left

Task part 2, incompatible responses

Trial i

Trial i + 1, right

Trial i + 2, left

Task part 3, mixed responses

Trial i

Trial i + 1, left

Trial i + 2, right

Shifting Attentional Set

0

2

4

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8

10

12

Fixed Variable

Attentional Set

Erro

r rat

e (N

)

Control

PKUlo

PKUhi

0

2

4

6

8

10

12

Fixed Variable

Attentional SetEr

ror r

ate

(N)

Control

PKUlo

PKUhi

Shifting Attentional Set: Results

Age < 11 years

Age 11 years

Sustained Attention + Inhibitory control

N = 200 N = 200

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

Bias

Time on Task

54321

n of

miss

es -

mea

n n

of fa

lse a

larm

s5.0

4.0

3.0

2.0

1.0

0.0

control

PKUphe<=360

PKUphe>360

Sustained Attention + Inhibitory Control

mouse cursor

start & end positiontrajectory cursor

(not visible)

Tracking (left) and Pursuit (right)

* Trajectory of the asterix (not visible)

In random direction moving asterix

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

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

Dietary interventions: Results

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

left-hand response

right-hand response

Central stimulu

s

++

+

1000 ms200-6000 ms

1000 ms200-6000 ms

1000 ms200-6000 ms

1000 ms200-6000 ms

Part 1

Part 2

Compatible: N = 10 Neutral:

N = 10Neutral: N = 10

Compatible: N = 10

Compatible: N = 20 Incompatible:

N = 20 Compatible: N = 20 Incompatible:

N = 20

Flanker Interference: only inhibitory control

+

++

+

+

+

+*

*

++

+h

z g

b

+t

n+

p

r+

j z

m d+

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

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

What about development?

Example: motor function

What about the developmental trajectory of EF?

Together with the brain, EF continues to develop well into adolescence

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

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

Association EF – ToM

r control for age = .45, p < .001, without: .69

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

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?)

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