New Insights into PKU and the Brain
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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.
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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. - PowerPoint PPT Presentation
Transcript of New Insights into PKU and the Brain
New Insights into PKU and the Brain
Shawn Christ, Ph.D.Assoc Director, Brain Imaging
CenterAssoc Professor, Dept of Psych
SciencesUniversity 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.
Thank You!The help & support of individuals and families such as you makes our work possible.
Review of Past Research Cognitive & Behavioral Findings Structural Brain Findings
Our Current Research Functional brain activation &
connectivityConclusions & Future Directions
Talk Overview
http://clinicalneurolab.missouri.edu/NPKUA2012.pdf
Review of Past Research Cognitive & Behavioral Findings Structural Brain Findings
Our Current Research Functional brain activation &
connectivityConclusions & Future Directions
Talk Overview
Results from this work
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)
Neurocognitive Model of PKUReview of Past Research
Cognitive & Behavioral Findings Structural Brain Findings
Our Current Research Functional brain activation &
connectivityConclusions & Future Directions
Talk Overview
Brain Organization 101
Major Tissue Distinction Gray Matter – Brain
areas where ‘data processing’ occurs
White Matter – Insulated ‘wires’ connecting different brain areas with each other.
Brain Organization 101
Major Tissue Distinction Gray Matter – Brain
areas where ‘data processing’ occurs
White Matter – Insulated ‘wires’ connecting different brain areas with each other.
Brain Organization 101
Major Tissue Distinction Gray Matter – Brain
areas where ‘data processing’ occurs
White Matter – Insulated ‘wires’ connecting different brain areas with each other.
Research suggests that >90% of adults with PKU have visible WM abnormality
Increased risk of white matter injury
Anderson & Leuzzi (2010)
30-yr-old with PKU 30-yr-old non-PKU
Research suggests that >90% of adults with PKU have visible WM abnormality
Increased risk of white matter injury
Anderson & Leuzzi (2010)
30-yr-old with PKU 30-yr-old non-PKU
Increased risk of white matter injury
Anderson & Leuzzi (2010)
Increased risk of white matter injury
Anderson & Leuzzi (2010)
Most Recent Research on Microstructure of White Matter
Peng, Peck, White & Christ (in press)
Effect on WM moderated by phe level
Peng, Peck, White & Christ (in press)
White matter matters! 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.
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.
White matter matters!
Review of Past Research Cognitive & Behavioral Findings Structural Brain Findings
Our Current Research Functional brain connectivity
Conclusions & Future Directions
Talk Overview
Structural Integrity
Functional Integrity
vs.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
Functional Magnetic Resonance Imaging (fMRI)
Christ et al. (2010)
Functional Connectivity
Evaluated by looking at the degree of concordance in neural activity among networked brain regions
Christ et al. (2010)
Evaluating Functional Connectivity
z = 53
z = 33
Left SFG
Left IFG
Christ et al. (2010)
Functional Connectivity
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)
Brain Networks
Task “Positive” vs. “Negative” Networks
from Fox et al. (2005)
“Task Positive” Network ConnectivityN-Back Working Memory Task
2-BackK
JX
NG
NP
Christ et al. (2010)
Christ et al. (2010)
The “Task Negative” Brain Network
from Fox et al. (2005)
Function of the DMN
From Buckner & Carroll (2007)
Christ et al. (JIMD, 2012)
Christ et al. (JIMD, 2012)
Review of Past Research Cognitive & Behavioral Findings Structural Brain Findings
Our Current Research Functional brain activation &
connectivityConclusions & Future Directions
Talk Overview
Conclusions
Structural Integrity
Functional Integrity
vs.How well do spatially distinct regions work together to support complex cognitive
functions?
Are the physical connections
(pathways) between regions damaged or otherwise atypical?
YesYes
Conclusions
Structural Integrity
Functional Integrity
vs.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!!!
Future Directions
Why are some individuals more affected than others?
Future Directions
Why are some individuals more affected than others?
Are these problems reversible with treatment?
Thank you!
Questions?Shawn [email protected]://clinicalneurolab.missouri.edu
http://clinicalneurolab.missouri.edu/NPKUA2012.pdf
Thank you!
Questions?Shawn [email protected]://clinicalneurolab.missouri.edu
http://clinicalneurolab.missouri.edu/Vancouver2012.pdf
Additional Slides
What effects does BH4 treatment have on cognition and the brain in individuals with PKU?
Our current research…
Study Protocol & Sample
N M/F
Prior Year Phe LevelsMean Range
Age (yrs)Mean Range
FSIQMean
RangePKU 13 7/6 731 88-1459 22.5 8-33 100 73-115
Non-PKU 13 6/7 22.7 9-33 109 93-120
[RESPONDERS]
[NON-RESPONDERS]PKU
Non-PKU
0 1 2 3 4 5 6MONTH
ASSE
SSM
ENT
ASSE
SSM
ENT
ASSE
SSM
ENT
BH4 Tx
No Meds
Non- Responders(n = 4)
PKU(n = 13)
Responders(n = 7)
4-Week Visit(n = 11)
6-Month Visit(n = 1)
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)
4-Week Visit(n = 12)
Lost to Follow-Up
(n = 1)
6-Month Visit(n = 7)
Lost to Follow-Up
(n = 5)
Behavior Rating Inventory of Executive Function (BRIEF) 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.
BRIEF (cont.)
Clinical Scales
• Inhibit• Shift• Emotional Control• Self-Monitor
• Initiate• Working Memory• Plan/Organize• Task Monitor• Organization of Materials
GlobalExecutiveComposite
MetacognitionIndex
BehavioralRegulation
Index
Results
Baseline 4 Week30
35
40
45
50
55
60
65
CTRL (12) PKU-Resp (7)PKU-NonResp (4)
B.R
.I.E.
F. R
epor
t Mea
sure
Glo
bal E
xecu
tive
Com
posi
te (t
sco
re)
[Low
er =
Bet
ter]
6 Month Follow-Up
Baseline 4 Week 6 Month40
45
50
55
60
65
70
CTRL (9) PKU-Resp (6)T
scor
e(M
ean
= 5
0, S
tD =
10)
Basics of MRI
GM Findings – much less known↓ 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)
Basal Ganglia
Bodner & Christ (in prep)
* *
White Matter Findings
He, Christ et al. (2009). Detecting 3D corpus callosum abnormalities in phenylketonuria. International Journal of Computational Biology and Drug Design, 2, 289-301..
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.
Evidence from Voxel-Based Morphometry
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
Atypical Utilization of FDOPA
(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.
Control PKU
