Nutrition and the Brain: Nutrient Priorities and Measurement

1. Nutrition and the Brain: Nutrient Priorities and Measurement Michael K. Georgieff, M.D. Professor of Pediatrics and Child Development Director, Center for Neurobehavioral Development Head, Section of Neonatology University of Minnesota

2. Objectives • Identify nutrients in the neonatal period that are particularly important for brain development • Understand which brain regions and processes are particularly vulnerable to fetal/neonatal malnutrition • Understand the array of clinical tests that assess global and specific brain functions in the neonate and young child For recent reviews of all topics in this talk see: • Georgieff MK. Nutrition and the Developing Brain: Nutrient Priorities and Management. Am J Clin Nutr, 85:614S-620S, 2007 • Fugelstad A, Rao R, Georgieff MK. The Role of Nutrition in Cognitive Development. In Handbook in Developmental Cognitive Neuroscience. (2nd Edition) Cambridge, MA: MIT Press, 2008; pp.623-641.

3. I have nothing to disclose and no conflicts of interest

4. Overview • Nutrient-Brain Interactions • Specific Nutrients (Protein, fats, Fe, Zn) • Requirements • Studies • Assessment of Nutrient Status • Brain • Total Body • Assessment of the Premature Brain • Available tools • Fit to Nutrients

5. Early Nutrition and Brain Development:General Principles • Nutrients and Growth Factors regulate brain development during prenatal and postnatal life • Rapidly growing brain • more vulnerable to damage • more amenable to repair following nutritional perturbations “Vulnerability outweighs Plasticity” (NIH, in 1994 RFA)

6. Early Nutrition and Brain Development:General Principles • Nutrient deficiencies may cause negative effects or no effects (head sparing) • Nutrient overabundance/supplementation may produce positive, negative or no effects What happens is based on… Timing, Dose and Duration Kretchmer, Beard, Carlson (AJCN, 1996)

7. Nutrients with Particularly Large Effects on Early Brain Development • Macronutrients • Protein-Energy • Specific fats (e.g. LC-PUFAs) • Micronutrients • Iron • Zinc • Copper • Selenium, Iodine (Thyroid) • Vitamins/Cofactors • B vitamins (B6, B12) • Vitamin A • Vitamin K • Folate • Choline

8. Fundamental Questions • If a nutrient affects the brain, does it affect behavior? • How close is the linkage? • For each nutrient? • For each time period of development? • Is the effect • Transient (only during deficiency)=> acute dysfunction • Long-term (beyond time of deficiency)=>altered developmental trajectory

9. What is happening in the brain during this time period?

11. Fetus Late Infancy/Toddler Pubertal

12. Protein

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

14. IUGR Outcomes: Human Studies(Reviewed in Fuglestad et al, 2008; Handbook of Developmental Cognitive Neuroscience; MIT Press) • IUGR=>Poor developmental outcome • verbal outcome • visual recognition memory • 6.8 point IQ deficit at 7 years (Strauss & Dietz, 1998) • dose response 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)

15. Protein Status: Assessment in the Neonate • Brain Protein • OFC (sensitive to severe malnutrition) • MRI volumetrics (gray matter) • Total Body Protein Long-term • Length; Linear Growth Trajectory • Lean Body Mass (MAMC; DEXA; Air Plethysmography) • Serum Albumin; Serum Creatinine Short-term • Serum BUN • Rapid Turnover Serum Proteins (Prealbumin) • Amino Acid Profile (“aminogram”)

16. Neuroimaging: Volumetrics Cerebral Cortex (Protein) Cerebral White Matter (Fat; Iron) Caudate Putamen Subcortical Nuclei Thalamus Psychiatry Iowa Neuroimaging Consortium Courtesy of P. Nopoulos

17. Fats

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

19. Long Chain Polyunsaturated Fatty Acids

20. Neurobiological Effects of LC-PUFAs • LC-PUFA deficiency • Altered fatty acid profile • Abnormal behavior including visual speed of processing • Suspected effects on fetal and neonatal brain • Myelin production • Neuronal membrane fatty acid composition • Synaptogenesis • Additional effects may include cell signaling • Unknown: how much deficiency gives behavioral effects

21. LC-PUFAs and Mental Development • Effect size: preterms > terms • Outcome studies are short term • Generally gross (MDI) and not generally predictive of later function • Long term studies underway; early acceleration may result in • No long term advantage (most likely) • Permanent advantage • Conclusion- Studies are underpowered re: long-term efficacy

22. Fat Status: Assessment • Brain Fat (experimental) • MRI Volumetrics (white matter) • Magnetic Resonance Spectroscopy • Red Cell Membrane Fatty Acid Content • Best way to assess LC-PUFA status ( S Innis, Pediatric Research, 1995) • Body Fat Long-term • Weight Gain; Body proportionality (W/L) • Skinfold thickness; Arm Fat Area • DEXA; Air Plethysmography Short-term • Serum Triglyceride

23. Iron

24. Why does the Brain Need Iron? • Energy • Iron found in cytochromes that make ATP • Brain energy (ATP) utilization high in fetus and neonate • Neurotransmitters • Iron needed to make dopamine, serotonin, norepinephrine • Myelin • Iron containing enzymes to make fatty acids in myelin

25. Iron: What Can Negatively Affect Neonatal Brain Iron Status? • Maternal Anemia • Fetus with very iron deficient mother (Hgb<8.5) • Common (>30%) in developing countries (WHO report) • Intrauterine Growth Restriction • Usually due to maternal hypertension (Georgieff et al, 1995) • Diabetes Mellitus in Pregnancy • Pre-existing or Gestational (Georgieff et al, 1990) • Maternal Smoking in Pregnancy • Prematurity • [Reduced iron accretion + phlebotomy ]- [transfusion + intake]

26. Perinatal Iron Deficiency: Human Outcomes • Behavioral abnormalities • Poorer recognition memory in newborns (Siddappa et al, 2004) • Poorer school age neurodevelopment(Tamura et al, J. Pediatr; 2002) • Impaired working memory at 3.5 years after iron repletion (Riggins et al, Dev Neuropsych, 2009) • Abnormal neurologic reflexes in premies at 36 week PCA(Armady-Sivan, et al, J Perinatol, 2004).

27. Mom: “Hi Baby” Stranger: “Hi Baby”

28. Event Related Potentials (ERPs) in Newborns Iron Sufficient Iron Deficient Siddappa et al., 2004, Pediatr. Res.

29. Assessment of Iron Status(For review, see JL Beard et al, Lab Med, 38:103-108, 2007) • Brain Iron • No direct measures • Newborn Serum Ferritin < 35 mcg/L = brain iron deficiency • Body Iron • Hemoglobin, MCV • Zn or free erythrocyte protoporphyrin • Serum transferrin receptor • Serum ferritin (measures iron stores) Anemia is a LATE sign of ID. Brain is already affected!

30. Why the Brain Needs Zinc • Interacts with DNA (zinc finger proteins) • Needed for growth factor (IGF-1 and GH) synthesis • Important for neurotransmitter release • Autonomic nervous system development • Development of hippocampus (learning and memory)

31. Zinc Deficiency: Who is at Risk? • Offspring of Zn deficient mothers • Protein malnourished infants • Infants on prolonged TPN with inadequate Zn intake • Short bowel/ malabsorption conditions

32. Zinc Deficiency: Human Studies • Fetuses of zinc deficient mothers demonstrate: • Decreased fetal movement • Decreased heart rate variability • Altered autonomic nervous system stability • Postnatally: • Poorer memory • Decreased preferential looking behavior behavior • But, no difference on Bayley Mental Developmental Index

33. Assessment of Zinc Status • Brain Zinc- • No direct assessment • Body Status • Tricky! Since red cells contain Zn, serum may not reveal total body stores • Most practical approach is serum zinc level (<70 mcg/dL) • Most accurate approach is serum or RBC metallothionein concentrations

34. Can we see nutrient effects on the brain? Sensitivity- yes Specificity- not really!

35. Nutrients and Perinatal Brain Circuitry

36. Circuit Specific Assessment of Nutrient Effects on the Premature Brain

37. Limitations to Neurologic Assessment & Developmental Prediction in the Premature • Limited cortical expression => poor direct prediction of later functioning • Ongoing illness confound => “not at their best” • Later plasticity/catch-up => “it is not as bad as it might seem”

38. Pre D/C Assessment at 36 weeks PCA: What is in the Repertoire? • Head Circumference (OFC) • Neurologic Exam • Electrophysiology (EEG) • EEG maturity • HR, BP response to stressor-ANS stability • ABR/ERG latency- speed of processing (Birch et al, 1992) • ERP (functional EEG)- recognition memory (deRegnier et al, 2000) • Neuroimaging • Cranial Ultrasound • Structural MRI + Regional Volumetrics (Peterson et al, 2001) • Diffusion Tensor Imaging to assess myelinated tracts (Huppi et al, 2005)

39. Assessments and At Risk NutrientsWhat can you diagnose with what you can measure?

40. Assessments and At Risk NutrientsWhat can you diagnose with what you can measure?

41. Functional Assessments in Year 1: Beyond the Bayley • The 12 month Bayley is a general assessment with poor predictive capacity for year 7 IQ • Easily performed; widely available; used in nutritional trials (e.g. LC-PUFA) • Specific, significant neuromorbidities can be embedded within a normal Bayley derived DQ • Specific nutritionally at-risk brain functions that can be assessed in year 1: • Recognition memory (Hippocampus): Preferential Looking (Fagan); Visual ERPs, Elicited Imitation • Speed of Processing (Myelin; synaptic efficacy): ABR; ERPs • Affect; Distractability (striatum; monoamine): Direct scoring • Procedural Memory (striatum): Visual priming studies

42. Summary Nutrients and the Brain • Malnutrition can have global or circuit specific effects on the developing brain • Effects are based on timing and magnitude of nutrient deficit + the brain’s need for the nutrient • Some nutrients have “signature” effects on the brain

43. Summary Assessing Nutritional Effects on Brain • Key Point: Match nutrient with specific developing brain region that is dependent on the nutrient • Use specific brain assessments that are sensitive to the nutrient deficiency • Testing of specific brain areas can be done at a very young age, but becomes more reliable as the child ages And, remember, nutrition is the one thing in the NICU you can do something about!

45. Enhancement Therapies for the Central Nervous System If some is good, is more better?

46. Candidates for “Brain Enhancement” • Choline • Oligosaccharides • Neurotrophic factors (growth factors) • Brain Derived Neurotrophic Factor • Docosohexaenoic acid (an LC-PUFA) • As supplementation rather than repletion of deficit (current formulas)

47. Choline

48. Role of Choline in the Brain • Essential nutrient for humans • Substrate for neurotransmitter (acetylcholine) • Likely has epigenetic effect (methyl donor) • Promotes larger neuronal size, more dendritic arborization and greater neuronal signaling • Especially in hippocampus (learning and memory)

49. Effects of Maternal Choline Supplementation • Only studies are in animals • Supplementation of choline sufficient rat dams results in • More advanced hippocampal structural maturation • Better performance than controls on memory function • Rare example for “if some is good, more is better” • Human studies have started (For recent reviews, see supplemental issue of Brain Research, October 2008)

50. Does “Enhancement” Last? Caveats! • Many “enrichment” studies are actually “less deficit” studies • LC-PUFA • Early environmental enrichment studies in at-risk humans (e.g. Head Start; IHDP) show wash-out over time