Nutrients that Affect Early Brain Development

1. Nutrients that Affect Early Brain Development Michael K. Georgieff, M.D. Professor of Pediatrics and Child Psychology Division of Neonatology Institute of Child Development Director, Center for Neurobehavioral Development University of Minnesota

2. Objectives • Recognize the major nutrients that are most needed by the developing brain • Identify the perinatal brain processes that are at risk in nutrient deficient infants • Recognize the association between those brain regions and behaviors dependent on those regions • Recognize the different roles for nutrients and growth factors in determining brain growth rates

3. I have nothing to disclose

4. Overview of Talk Basic Principles of Nutrient/Brain Interactions Timing, Dose and Duration Ascribing Behavioral Effects to Nutrients Nutrients of Particular Importance to Early Brain Development Protein, fats, iron, zinc, iodine, choline Are Nutrients Sufficient? The Role of Growth Factors Integration through neuronal mTOR signaling

5. Basic Principles of Nutrient/Brain Interactions

6. Early Nutrition and Brain Development:General Principles Positive or negative nutrient effects on brain development Based on… Timing, Dose and Duration of Exposure Kretchmer, Beard, Carlson (1996)

7. Nutrient-Brain-Behavior Relationships • Brain regions/processes have different developmental trajectories • The vulnerability of a brain region to a nutrient deficit is based on • When nutrient deficit is likely to occur in a lifetime • Brain’s requirement for that nutrient at that time • Behavioral changes must map onto those brain structures altered by the nutrient deficit

8. Nutrients and Brain Development: Processes Affected • NEUROANATOMY • Neurons • Division (numbers of neurons) • Growth (size of neurons) • Development (complexity of neurons, synaptogenesis, dendritic arborization) • Supporting cells • Oligodendrocytes=> myelination • Astrocytes=>nutrient delivery • Microglia=>trafficking Nutrient examples include protein, energy, iron, zinc, &LC-PUFAs (“fish oils”)

9. Nutrients and Brain Development: Processes Affected • NEUROCHEMISTRY • Neurotransmitter concentration • Receptor numbers • Neurotransmitter uptake transporter numbers Nutrient examples include protein, iron, zinc, choline • NEUROPHYSIOLOGY • Neuronal metabolism • Efficiency of electrical activity of brain Nutrient examples include glucose, protein, iron, zinc, choline

10. What is happening in the brain during fetal and early postnatal life?

11. Fetus Late Infancy/Toddler Pubertal Thompson & Nelson, 2001

12. Nutrients with Particularly Large Effects on Early Brain Development and Behavior • Macronutrients • Protein • Specific fats (e.g. LC-PUFAs) • Glucose • Micronutrients • Zinc • Copper • Iodine (Thyroid) • Iron • Vitamins/Cofactors • B vitamins (B6, B12) • Vitamin A • Vitamin K • Folate • Choline (example of potential enhancement)

13. Protein-Energy Malnutrition Why does the brain need protein and energy? Effects of early protein-energy malnutrition

14. What the Brain Does with Protein • DNA, RNA synthesis and maintenance • Neurotransmitter production (synaptic efficacy) • Growth factor synthesis • Structural proteins • Neurite extension (axons, dendrites) • Synapse formation (connectivity)

15. Evidence From Animal Models • Deleterious effect of early life PEM on brain development • Reduced cell number • Reduced cell protein synthesis • Reduced brain size • Ultrastructural changes in synapses • Reduced neurotransmitter production • Altered myelination • Reduced growth factor concentrations

16. Protein-Energy Malnutrition • Clinical conditions early in life • Intrauterine growth restriction (IUGR) • Likely occurred in significant number of orphaned children (untreated maternal diseases) • Postnatal Growth Failure • Starvation/poor food access during childhood • Chronic illness • prematurity/neonatal illness • chronic renal, hepatic, cardiac, pulmonary, infectious diseases (CHF, cystic fibrosis, HIV)

17. Protein-Energy Malnutrition • None of the clinical conditions are pure PEM • Unethical to randomize to malnutrition or not • PEM in a population is associated with • Multiple other nutrient deficiencies (e.g. protein is major zinc source) • Environmental stressors that affect behavioral outcomes

18. IUGR: Evidence from Clinical Studies • IUGR=>Poor developmental outcome • Verbal outcome • Visual recognition memory • 6.8 point IQ deficit at 7 years (Strauss & Dietz, 1998) • Dose responsive based on degree of IUGR • 15% with mild neurodevelopmental abnormalities • Compounded by postnatal growth failure (prenatal + postnatal malnutrition) (Casey et al, 2006; Pylipow et al., 2009)

20. Previous Research: Growth Failure in International Adoptees z score

21. Eastern Europe • Children adopted from Eastern Europe • N=57 • Age range: 9-46 months (M=19, SD=9) • Baseline & six month follow-up • Macronutrient & iron status Fuglestad et al., J Pediatrics, 2009

22. Macronutrient StatusConfirmed Previous Data zscores *** *** *** ***

23. Fats

24. Why the brain needs fats • Cell membranes • Synapse formation • Myelin

25. Long Chain Polyunsaturated Fatty Acids Aka “Fish oils” Docosohexaenoic Acid (DHA)

27. Neurobiological Effects of LC-PUFAs • Essentiality of LC-PUFAs derived from studies of severe essential fatty acid deficiency • Hypomyelination • Altered fatty acid profile • Abnormal behavior including visual speed of processing • Findings in mice, rats, non-human primates • Proposed effects on • Myelin • Neuronal membranes • Synaptogenesis • Cell Signaling • Unknown: how much deficiency gives behavioral effects

28. LC-PUFAs and Mental Development • More consistent effect seen newborns (premies > terms) • Outcome measurements are short-term and generally gross (MDI) and not generally predictive of later function • Long term studies unavailable- early acceleration may result in • No long term advantage (most likely) • Permanent advantage (not shown) • Studies are underpowered to draw conclusions about long-term efficacy

29. Micronutrients Iron Zinc Iodine

30. World-wide Impact of Micronutrient Deficiencies • Iron • 2 billion people (1/3 of world’s population) are iron deficient • Also causes low thyroid hormone state • Zinc • 1.8 billion people are zinc deficient • Usually co-morbid with protein deficiency • Iodine • 600 million people world-wide are deficient • I Deficiency =>thyroid hormone deficiency =>cretinism (global delays) ELIMINATION OF THESE MICRONUTRIENT DEFICIENCIES WOULD INCREASE THE WORLD’S IQ BY 10 POINTS!

31. Nutritional Status in Internationally Adopted Children • Macronutrient status • Anthropometry • Serum proteins [albumin, Retinol Binding Protein (RBP)] • Micronutrients • Iron • Zinc • Vitamin D • Vitamin A • Folic acid • Vitamin B12 • Iodine & Selenium (TSH)

32. Population

33. Baseline Micronutrient/Vitamin Status: 58% with at Least 1 Abnormality

34. Baseline Nutritional Deficiencies by Region

35. Follow-up Nutritional Status: Better Zn, No Change in Iron, Worse Vit D

36. Iron Deficiency Why does the developing brain need iron? Effects of early ID

37. Iron: A Critical Nutrient for the Developing Brain • Delta 9-desaturase, glial cytochromes control oligodendrocyte production of myelin • Iron Deficiency=> Hypomyelination • Cytochromes mediate oxidative phosphorylation and determine neuronal and glial energy status • Iron Deficiency=> Impaired neuronal growth, differentiation, electrophysiology • Tyrosine Hydroxylase involved in monamine neurotransmitter and receptor synthesis (dopamine, serotonin, norepi) • Iron Deficiency=> Altered neurotransmitter regulation

38. Typical Time Periods of Iron Deficiency Fetus Late Infancy/Toddler Pubertal

39. ID in Infancy: Who is at risk? Most postnatal ID is due to inadequate dietary intake ± low stores at birth ± blood loss • Low stores at birth • Maternal anemia, hypertension, smoking, diabetes mellitus • Inadequate dietary intake • Low iron formula • Early change to cow milk • Blood loss • Hemorrhage at birth (anemia) • Parasitic infection, food intolerance (GI loss)

40. Catch-up Growth & ID at 6 Months Fuglestad et al., 2009 * * * Change in z scores

41. Neurobehavioral Sequelae of Early Iron Deficiency in Humans Over 40 studies demonstrate dietary ID between 6 and 24 months leads to: • Behavioral abnormalities(Lozoff et al, 2000) • Motor and cognitive delays while iron deficient • Profound affective symptoms • Cognitive delays 19-23 years after iron repletion • Arithmetic, writing, school progress, anxiety/depression, social problems and inattention (Lozoff et al, 2000) • Electrophysiologic abnormalities (delayed EP latencies) • At 6 months while iron deficient (Roncagliolo et al, 1998) • At 2-4 years after iron repletion (Algarin et al, 2003) • Characteristic of impaired myelination

42. Effect of Iron Deficiency in Infancy on Affect and Engagement Courtesy of B. Lozoff

43. Effect of Iron Deficiency in Infancy on Affect and Engagement Courtesy of B. Lozoff

44. Iron Status: Cognitive & Motor Outcomes Cognitive Motor *** *** * BSID III Standardized Score

45. Iron Status: Speed of Neural Processing (VEP) p < 0.10 Milliseconds

46. Iron Status: Socio-emotional & Exploratory Behavior Behavior Rating

47. Zinc Deficiency Why does the brain need zinc? Effects of early zinc deficiency

48. Zinc: What is the Biology? • Cellular/Molecular • Important role in enzymes mediating protein and nucleic acid biochemistry • Decreased embryonic/fetal brain DNA, RNA and protein content • Decreased brain IGF-I and GH receptor gene expression • Biochemistry/Neurochemistry • Zn deficiency inhibits GABA stimulated Cl influx into hippocampal neurons • Zn deficiency inhibits opioid receptor function in cerebral cortex • Zn released from presynaptic boutons

49. Zinc Deficiency: Human Evidence for Neurobehavioral Effects on Brain • Fetuses of zinc deficient mothers demonstrate: • Decreased movement • Decreased heart rate variability • Altered ANS stability • Postnatally, zinc deficiency causes • Decreased preferential looking behavior behavior (more random looks and equal looking times) • No difference in Bayley Scales of Infant Development Suggests fetal ANS, cerebellar and hippocampal effects

50. Zinc Status: Cognitive & Motor Outcomes Cognitive Motor *** *** BSID III Standardized Score