executive abilities in individuals with phenylketonuria
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Executive Abilities in Individuals
with PhenylketonuriaDesiree A. White, PhD
Research supported by National Institute of Child Health & Human Development and BioMarin Pharmaceutical. Consultation and speaker fees accepted from BioMarin Pharmaceutical and Merck Serono.
“Numerous advances have been made in our understanding of metabolic disorders over the last century, but optimal outcomes have not been achieved… We stand now on the cusp of a new era of PKU research and treatment. It is time that we thoroughly reevaluate our understanding of PKU so that we may take advantage of current innovations in neuropsychological assessment, scientific technologies, and treatment options that hold promise for improving quality of life for individuals with PKU.” [White Waisbren van Spronsen 2010]
Overview• Brain function• Executive abilities• Recommendation
s• Discussion
• Phenylalanine (Phe) converted to tyrosine (Tyr) by phenylalanine hydroxylase (PAH) in presence of tetrahydrobiopterin (BH4)
• Tyr converted to dopamine (DA), an essential neurotransmitter in function of frontal cortex which subserves executive abilities
BH4Phenylalanine
PAHDopamineTyrosine
(Phe) (Tyr) (DA)
Neuropathology of PKU: Dopamine
[For an overview, de Groot et al 2010]
Myelin increases speed of neural transmission
[For an overview, Anderson Leuzzi 2010]
Neuron
CellBody
Axon
MyelinSheath
Neuropathology of PKU: White Matter
Image from McKinstryWashington University
Mallinckrodt Institute of Radiology
White matterirregularities
Diffusion Tensor Imaging (DTI)
Brain RegionPrefrontal Cortex Centrum Semiovale * Parietal-Occipital Cortex * Optic Radiation Putamen Corpus Callosum * Thalamus Hippocampus
White et al in preparation
* Improvement following treatment with BH4
• Definition: Maintenance & coordination of information processing leading to higher order thought & action
• Executive abilities play critical role in: School performance Social skillEmployment Treatment
• Executive subcomponents:Inhibitory Control Working Memory Monitoring Strategic Processing
Executive Abilities
[For a review, Christ Huijbregts de Sonneville White 2010]
Suppressing information or actions that would otherwise interfere with the
efficient attainment of a goal
Inhibitory Control
Go No-Go05
10152025303540
25
32*
ControlPKU
Num
ber o
f Erro
rs
Go/No-Go Task
[Christ et al 2006]
* Significantly more errors
Inhibitory Control
Detection of errors & adjustments in behavior to facilitate performance
Response Monitoring
Go RT Post-Error RT0
100
200
300
400
500
600
700
800
448
681
449
617*
ControlPKU
RT (m
s)
[Araujo et al 2009]
* Significantly less post-error
slowing
Response Monitoring
Go/No-Go Task
Maintenance & manipulation of information for brief periodsFacilitates a range of abilities
VocabularyReadingMathematicsSpellingComprehensionConversation
Working Memory
Verbal Object Spatial0
1
2
3
4
5
6
5.2
3.9 3.8
4.6*
3.4* 3.3*
ControlPKU
Mem
ory
Span
Recognition Span Task
[White et al 2002]
B N G
*Significantly lower span
Working Memory
5 6 7 8 9 10 11 12 13 14 15 16 17 182
3
4
5
6
7
8ControlPKU
Age (yrs)
Aver
age
Span
[White et al 2002]
Age-Related Difficulty in Working Memory
Flexibly evaluating & altering plans to perform tasks with optimal efficiency
Strategic Processing
Younger (<11 yrs) Older (≥11 yrs)
Trial 1 Trial 5 Trial 1 Trial 5012345678
1.6
2.72.3
7.1
1.62.3 2.2
4.7*
ControlPKU
Clus
ter S
core
List Learning Task
[White et al 2001]
bananasjacket watermelonpeaches strawberriessweater grapesshortsballoonsbeltpuzzleblockscrayonshatmarbles
* Significantly less clustering for older
but not younger PKU
Age-Related Difficulty in Strategy Use
Words Switches Words Switches02468
10121416182022
19.8
10.4 10.3
7.0
16.6*
8.4* 8.0*
5.2*
ControlPKU
Num
ber P
rodu
ced
Verbal Fluency Task
Food/Drink Fluency Letter Fluency
LetterSitSet
ShelfShipSlateSkateState
* Significantly fewer words & switches
Strategic Processing
[Banerjee et al 2011]
Food/DrinkApplePeachMilkSodaBreadSalsaJelly
6 7 8 9 10 11 12 13 14 15 16 17 18 19 2002468
101214161820
ControlPKU
Age (yrs)
Num
ber S
witc
hes
[Banerjee et al 2011]
Age-Related Difficulty in Strategy Use
Verbal Fluency Task: Food/Drink
STATIC WORSENINGIMPROVING
AGE
PERF
ORM
ANCE
Developmental Trajectories
TYPICALDEVELOPMENT
COMPROMISEDDEVELOPMENT
• Maintain Phe control across the lifespan• Discuss and formally screen for
problems in cognitive, psychiatric, & adaptive function in metabolic clinic
• Refer to psychologist, psychiatrist, or neuropsychologist if problems identified
• Coordinate treatment recommendations among all health care professionals
Optimizing Outcomes
Screening for Problems in Clinic
[Waisbren White 2010]
Executive Abilities• BRIEF-P• BRIEF• BRIEF-A
Social-Emotional Function• BASC-II Behavior Assessment System
for Children – II• CBCL Child Behavior Checklist• BAI Beck Anxiety Inventory• BDI-II Beck Depression Inventory – II• BSI Brief Symptom Inventory
Adaptive Function• ABAS Adaptive Behavior Assessment System
Behavior Rating Inventory of Executive Function
Control Hydro-cephalus
PKU0
5
10
15
20
25
5
18
21
% in
Sev
ere
Rang
e
[Anderson et al 2002]
Ratings of Executive BehaviorBehavior Rating Inventory of Executive Function
• Maintain Phe control across the lifespan• Discuss and formally screen for
problems in cognitive, psychiatric, & adaptive function in metabolic clinic
• Refer to psychologist, psychiatrist, or neuropsychologist if problems identified
• Coordinate treatment recommendations among all health care professionals
Recommendations: General (Repeating myself)
Recommendations: Evaluation
• School evaluation for special services for children with learning differences
• Neuropsychological evaluation for assessment of specific areas of cognition
• Psychological evaluation & counseling for social & behavioral difficulties
• Psychiatric evaluation for medication if warranted for ADHD or depression
• Structured school environment • Small class with one-on-one instruction• Arrange environment to enhance
attention• Extra time to complete
tests/assignments• Divide work into small, manageable
units• Written instructions for reference• Time to repeatedly review material• Present material in multiple modalities
Recommendations: School
• Maintain regular routine• Keep calendar of daily activities• Choose specific locations for important
items (calendar, backpack, car keys)• Remind to “stop, look, & think” before
beginning tasks• Alert to key points in conversation &
before transitions between activities
Recommendations: Home
• Instruct through brief statements rather than complicated directives
• Monitor performance as multiple steps of tasks are completed
• Assist in determining the most organized approach before beginning a task
• Suggest cues and meaningful organizers
• Generate checklists for organization • Remind to complete one task before
moving to another
Recommendations: Home
Encourage & provide opportunities for independent completion of tasks
Avoid punitive consequences when tasks are not completed independently
Provide praise & concrete rewards for perseverance & completion of tasks
Use time out & restriction of privileges effectively (choose your battles!)
Recommendations: Home
Thanks!
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