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 Christchristse@missouri.eduhttp://clinicalneurolab.missouri.edu

http://clinicalneurolab.missouri.edu/NPKUA2012.pdf

Thank you!

Questions?Shawn Christchristse@missouri.eduhttp://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