executive function in early-treated pku
DESCRIPTION
Executive function in 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. . - PowerPoint PPT PresentationTRANSCRIPT
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Executive function in Executive function in early-treated PKU early-treated PKU
Stephan Huijbregts (Leiden University)For
NSPKU Skipton 2010
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Examples of executive functions
Planning, organization, strategy use, cognitive flexibility, inhibitory control, working memory, monitoring and, if necessary, correcting one’s actions.
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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 Cortex4. Thalamus5. Cerebellum
Example for one of the EFs: working memory
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Assessment of executive functions Different tasks for different ages Paper-and-Pencil tasks Computer tasks Questionnaires (DEX, BRIEF)
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Examples of EF-tasks for young children (< 6 years)
(Inhibitory control)
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Examples of EF-tasks for young children (< 6 years)
(Inhibitory control)
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Examples of EF-tasks for young children (< 6 years)
(Inhibitory control)
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Box 1 Box 2
Examples of EF-tasks for young children (< 6 years)
(Cognitive flexibility)
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Examples of EF-tasks for young children (< 6 years)
(Working Memory) (Planning)
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Examples of EF-tasks for young children (< 6 years)
(Planning)
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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)
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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?
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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 responsesTrial i
Trial i + 1, right
Trial i + 2, left
Task part 3, mixed responsesTrial i
Trial i + 1, left
Trial i + 2, right
Shifting Attentional Set
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0
2
4
6
8
10
12
Fixed Variable
Attentional Set
Erro
r rat
e (N
)
Control
PKUloPKUhi
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
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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
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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
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mouse cursor
start & end positiontrajectory cursor
(not visible)
Tracking (left) and Pursuit (right)
* Trajectory of the asterix (not visible)
In random direction moving asterix
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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
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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
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Dietary interventions: Results
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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
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left-hand responseright-hand response
Central stimulu
s
++
+
1000 ms 200-6000 ms1000 ms 200-6000 ms 1000 ms 200-6000 ms1000 ms 200-6000 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
+
+ +
+
+
+
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+*
*
++
+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
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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
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What about development?
Example: motor function
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What about the developmental trajectory of EF?
Together with the brain, EF continues to develop well into adolescence
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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
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Study into ToM and EF of 229 normally developing children aged 3-6
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Association EF – ToM
r control for age = .45, p < .001, without: .69
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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
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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?)
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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