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Neurocognitive, Behavioral, and Social Outcomes With PKU: Raising the Bar

Neurocognitive, Behavioral, and Social Outcomes With PKU: Raising the Bar. Neurocognitive, Behavioral, and Social Outcomes With PKU: Raising the Bar. Current status Physiological hypotheses Dopamine and prefrontal cortex function White matter and speed of processing Executive function

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Neurocognitive, Behavioral, and Social Outcomes With PKU: Raising the Bar

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  1. Neurocognitive, Behavioral, and Social Outcomes With PKU: Raising the Bar

  2. Neurocognitive, Behavioral, and Social Outcomes With PKU: Raising the Bar • Current status • Physiological hypotheses • Dopamine and prefrontal cortex function • White matter and speed of processing • Executive function • Behavior and psychosocial functioning • Speed of processing • Raising the bar

  3. Children With PKU on Diet Are at Risk for Significantly Lower IQ than Unaffected Peers and Sibling Controls n = 21 n = 26 n = 55 n = 55 † *Controls were age- and sex-matched. †PKU patients (ages 7–19 years old) managed early and continuously with Phe-restricted diet. Gassio R, et al. Pediatr Neurol. 2005;33:267-271. Koch R, et al. J Inherit Metab Dis. 1984;7:86-90.

  4. Blood Phe and IQ Are SignificantlyCorrelated in Patients With PKU* *This data is based on a meta-analysis of 40 studies and 3,361 patients with PKU. Waisbren SE, et al. Mol Genet Metab. 2007;92:63-70.

  5. Outcomes for Adults With PKU Were Worse for Those Who Discontinued Diet *Two highest socioeconomic classes in the Hollingshed classification system. Koch R, et al. J Inherit Metab. 2002;25:333-346.

  6. (n = 178) (n = 77) (n = 137) (n = 98) 15–19 0–4 5–9 10–14 Dietary Compliance in PKU Is a Serious Issue • Nearly one in three PKU children under the age of 10 have blood Phe above recommended target range • Noncompliance increases as patients enter adolescence (n = 77) (n = 137) (n = 98) Adapted from Table 2 of Walter JH, et al. Lancet. 2002;360:55-57.

  7. Example Low Variability IQ = 116 Example High Variability IQ = 92 2000 2000 Mean* (389 μmol/L) ±SD† (325 μmol/L) Mean* (412 μmol/L) ±SD† (166 μmol/L) 1600 1600 1200 1200 Blood Phe Level (umol/L) Blood Phe Level (umol/L) 800 800 400 400 0 0 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70 Consecutive Phe Measurements in 6yo male Consecutive Phe Measurements in 7yo female Stability of Blood Phe Appears to Be Important to Cognitive Function in Early and Continuously Treated PKU • Correlation of lifetime blood Phe with FSIQ was -0.17 (P = 0.038) • Correlation of SD of blood Phe with FSIQ was -0.36 (P = 0.058) • FSIQ decreased 4.3 points with 1 point increase in SD of blood Phe *Lifetime blood Phe levels. †Mean standard deviations for lifetime blood Phe levels. Anastasoaie V, et al. Mol Genet Metab. 2008;95:17-20.

  8. Neurocognitive, Behavioral, and Social Outcomes With PKU: Raising the Bar • Current status • Physiological hypotheses • Dopamine and prefrontal cortex function • White matter and speed of processing • Executive function • Behavior and psychosocial functioning • Speed of processing • Raising the bar

  9. basal ganglia frontal lobe prefrontal cortex dopamine pathways Dopamine Is Critically Involved in Executive Function, Emotion, and Social Behavior • Neurotransmitter related to attention, mood, and movement • Precursor to norepinephrine and epinephrine Image from http://nobelprize.org/nobel_prizes/medicine/laureates/2000/press.html

  10. BH4 Is Critical in the Synthesis of Dopamine Blood Brain Barrier Periphery (mostly liver) Brain TH = tyrosine hydroxylase BH4 = endogenous tetrahydrobiopterin PAH = phenylalanine hydroxylase AADC = aromatic amino acid decarboxylase Adapted from Youdim MBH, et al. Nature Rev Neurosci. 2006;7:295-309.

  11. Rate of FDOPA utilization is reduced in striatum of PKU patients s k3 FDOPA = 6-[18F]-L-dopamine k3 = rate of FDOPA utilization s Dopamine Activity Is Reduced in Adults With PKU 100 90 80 70 60 50 40 30 20 10 0 FDOPA uptake in first 6 minutes after injection is reduced in PKU % Control* PKU* 0.01 0.009 0.008 0.007 0.006 0.005 0.004 0.003 0.002 0.001 0 *Images are summed, stereotactically normalized composites for 7 control and 7 PKU subjects. Landvogt C, et al. J Cereb Blood Flow Metab. 2008;28(4):824-831.

  12. Prefrontal Cortex Is Critical to Mental Function • Executive function • Cognitive abilities that control and regulate other abilities and behaviors • Includes • Planning • Attention • Working memory • Problem solving • Impulse control • Social behavior • Emotional control

  13. Neurocognitive, Behavioral, and Social Outcomes With PKU: Raising the Bar • Current status • Physiological hypotheses • Dopamine and prefrontal cortex function • White matter and speed of processing • Executive function • Behavior and psychosocial functioning • Speed of processing • Raising the bar

  14. Myelin Insulates Axons Which Increases the Speed of Processing of Nerve Signals White matter contains nerve fibers surrounded by myelin Image from: http://kvhs.nbed.nb.ca/gallant/biology/schwann_myelin.html.

  15. White Matter Abnormalities Associated With PKU Leuzzi V, et al. J Inherit Metab Dis. 2007

  16. White Matter Hypothesis of PKU and Neurocognitive Deficits • Individuals with PKU have abnormal white matter • Abnormalities may be due to • Increased myelin turnover • Elevated water content • Disturbed myelin synthesis • White matter abnormalities may reduce speed of processing leading to neurocognitive deficits observed with PKU Anderson P, et al. Devel Neuropsychol. 2007;32:645-668.

  17. Neurocognitive, Behavioral and Social Outcomes With PKU: Raising the Bar • Current status • Physiological hypotheses • Dopamine and prefrontal cortex function • White matter and speed of processing • Executive function • Behavior and psychosocial functioning • Speed of processing • Raising the bar

  18. Why Is Executive Function Important to Individuals With PKU? • Planning diet • Remembering Phe intake for records • Remembering to take formula • Helps with inhibiting responses, resisting foods not allowed on diet • Maintaining medical formula and food supplies • Monitoring blood Phe and making appropriate adjustments in intake

  19. (n = 80) (n = 45) (n = 44) Frequency of Impairment of Executive Function Is High for Children With Early-treated PKU *P < 0.001 compared to control. **Based on Behavior Rating Inventory of Executive Function (BRIEF) global executive composite score. Severe range is > 1 SD above the mean. Anderson VA, et al. Child Neuropsychol. 2002;8:231-240.

  20. Executive Function Deficits Occur in Early and Continuously Treated PKU Across All Age Groups • Infants1 • Working memory • Behavioral inhibition • Children (7–14)2 • Impulse control • Attentional flexibility • Adults3 • Attention • Working memory • Verbal Fluency 1. Diamond A, et al. Monogr Soc Res Child Dev. 1997;62:1-208. 2. Huijbregts SC, et al. NeuroSci Biobehav Rev. 2002;26:697-712. 3. Channon S, et al. Neuropsychology. 2004;18:613-620.

  21. Subcomponents of Executive Function • Working memory • Strategic planning • Impulse control

  22. Working Memory Is Impaired in Children and Teens With PKU on Diet n = 20 n = 20 * * * ± *P < 0.05 compared with control. White DA, et al. J Int Neuropsychol Soc. 2002;8:1-11.

  23. 8 Control (n = 20)** 7 slope = 0.29† PKU (n = 20)* 6 5 Summary Memory Score 4 slope = 0.08† 3 2 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Age (years) Many Children With PKU Develop Deficits in Working Memory Despite the Benefits of Diet *Subjects in the PKU group (ages 6–17) were on a diet control program to limit Phe intake. **Control subjects matched for age, sex, and years of education. †Test for separate slopes: t(15) = -3.05, P < 0.005. White DA, et al. J Int Neuropsychol Soc. 2002;8:1-11.

  24. Working Memory Is Impaired in Adults With PKU Continuously on Diet * * * *(Mean + SD).P < 0.01 for effect of group (control or PKU) across all three set sizes in ANOVA. Channon S, et al. Neuropsychology. 2004;18:613-620.

  25. Subcomponents of Executive Function • Working memory • Strategic planning • Impulse control

  26. PKU Normative Data Strategic Planning Is Impaired in Children and Adolescents With PKU * * † N = 15 (11 on dietary treatment). *P < 0.05 compared to normative data. †Normative sample scores for all subtests set to 10 ± 3 (mean ± SD). Van Zutphen KH, et al. Clin Genet. 2007;72:13-18.

  27. * Children With PKU on Diet Exhibit Deficits in Organizational Strategies for Learning and Memory n = 23 n = 23 Younger < 11 yo Older ≥ 11 yo California Verbal Learning Test *P< 0.05 compared with control. White DA, et al. Neuropsychol. 2001;15(2):221-229.

  28. Subcomponents of Executive Function • Working memory • Strategic planning • Impulse control

  29. Complex Impulse Control Is Impaired in Children With PKU on Diet * (n = 23) (n = 26) Go/no-go Test *P < 0.05 compared with control. Christ SE, et al. Dev Neuropsychol. 2006;30:845-864.

  30. Neurocognitive, Behavioral, and Social Outcomes With PKU: Raising the Bar • Current status • Physiological hypotheses • Dopamine and prefrontal cortex function • White matter and speed of processing • Executive function • Behavior and psychosocial functioning • Speed of processing • Raising the bar

  31. Children With PKU on Diet Present More School Problems Than Unaffected Peers *P = 0.028 vs controls. Gassio R, et al. Pediatr Neurol. 2005;33:267–271.

  32. (n = 38) (n = 76) Significant Increase in Medication for Attentional Dysfunction Was Observed in Children With PKU *P < 0.006 as compared with children with diabetes mellitus. Arnold GL, et al. J Inherit Metab Dis. 2004;27:137-143.

  33. Adults With PKU Demonstratean Increase in Psychiatric Symptoms *P < 0.05 as compared to 18-year-old controls. Adapted from Table 3 of Pietz J, et al. Pediatrics. 1997;99:345-350.

  34. rs = 0.43 Young Adults With PKU Are More Susceptible to Agoraphobia Blood Phe level and score on AAL Scale† are significantly correlated Score on AAL Scale† Blood Phenylalanine Level (μmol/L) †From the Mobility Inventory, measuring avoidance behavior when alone (AAL). Waisbren SE and Levy HL. J Inherit Metab Dis. 1991;14:755-764.

  35. Multiple Psychiatric Symptoms Are Associated With PKU INCREASED DECREASED • Phobia [Waisbren et al., 1991] • Depressed mood [Weglage et al., 2000] • Isolation/withdrawal [Smith et al., 1998][Weglage et al., 2000] • Anxiety [Smith et al., 1998] [Weglage et al., 2000] • Positive emotions [Landolt et al., 2002] • Autonomy [Stemerdink et al., 2000][Weglage et al., 1992] • Social competence [Kazak et al., 1988][Lundstedt et al., 2001] [Matthews et al., 1986] [Weglage et al., 1996]

  36. Neurocognitive, Behavioral, and Social Outcomes With PKU: Raising the Bar • Current status • Physiological hypotheses • Dopamine and prefrontal cortex function • White matter and speed of processing • Executive function • Behavior and psychosocial functioning • Speed of processing • Raising the bar

  37. Large Medium Small Significant Cognitive Deficits Are Observed in Patients With PKU Meta-analysis of 11 studies demonstrates deficits in multiple cognitive domains Range: Control 91–221; PKU 100–218. *Hedge’s g effect size with 95% confidence intervals. Adapted from Figure 1 of Moyle JJ, et al. Neuropsychol Rev. 2007;17:91-101.

  38. Speed of Processing Is Reduced in Children With PKU* † † † Processing Speed Test *Dietary restrictions varied from strict (20) to moderate (11) to none (3). †P < 0.01 for control group compared to PKU group. Anderson PJ, et al. Dev Neuropsychol. 2007;32:645-668.

  39. Neurocognitive, Behavioral, and Social Outcomes With PKU: Raising the Bar • Current status • Physiological hypotheses • Dopamine and prefrontal cortex function • White matter and speed of processing • Executive function • Behavior and psychosocial functioning • Speed of processing • Raising the bar

  40. It Is Time to Raise the Bar!

  41. Protect the Brain With Awareness, Assessment, Aggressive Treatment, and Action for Patients With PKU Awareness of neurocognitive, behavior and psychosocial functioning Assessment of neurocognitive, behavior and psychosocial functioning Aggressive treatment for tighter Phe control Act with additional tools

  42. Back-up Slides

  43. (n = 14) (n = 14) (n = 14) (n = 14) Children With PKU on Diet Have Reduced Executive Function Compared With Unaffected Peers Mean age in years was 10.9 for control (range 8–13) and 10.8 for PKU (range 8–13). Phe measured on day of testing and calculated from age 0 to 4 years using medical records. Adapted from Table 1 of Leuzzi V, et al. J Inherit Metab Dis. 2004;27:115–125.

  44. The Success of the Phe-Restricted Diet: The US Collaborative Study (1967–1999) • Milestones for PKU treatment • Result is a philosophy of “Treatment for Life” at most clinics in the United States3 1. Dobson JC, et al. Pediatrics. 1977;60:822-827. 2. Koch R, et al. J Inherit Metab Dis. 1984;7:86-90. 3. Koch R, et al. Consensus Development Conference on Phenylketonuria (PKU): Screening and Management. October 16–18, 2000;59-65.

  45. Many Adult Patients Who Claim to Be on Diet Are Not Achieving Blood Phe Targets 59% of adult PKU patients on diet had blood Phe above recommended target range* *Recommended target range for this study was < 726 µmol/L. Modan-Moses D, et al. J Inherit Metab Dis. 2007;300:202-208.Modan-Moses D. E-mail communication. September 18, 2007.

  46. PKU Patients on Early and Late Dietary Management Show Decreased Brain Volume **P = 0.009. †P = 0.001. Perez-Duenas B, et al. Neurology. 2006;66:1074-1076.

  47. White Matter Abnormalities Associated With PKU Leuzzi V, et al. J Inherit Metab Dis. 2007

  48. Working Memory I’m going to read you a list of words. Just listen. Then see how many you can remember and write them down, in any order

  49. Apple Leg Hockey Hot Dog Chicken Raisins Knee Tennis Elbow Spinach Carrots Frisbee Swimming Eggs Eyebrow

  50. Letters B N G Objects Locations Working Memory: Recognition Span White et al., 2002

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