Nutrition and the Brain: Nutrient Priorities and Measurement

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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

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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, 85614S-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.

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I have nothing to disclose and no conflicts of
interest
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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

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Early Nutrition and Brain DevelopmentGeneral
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)

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Early Nutrition and Brain DevelopmentGeneral
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)

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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

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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)gt acute
  dysfunction
• Long-term (beyond time of deficiency)gtaltered
  developmental trajectory

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What is happening in the brain during this time
period?
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Fetus
Late Infancy/Toddler
Pubertal
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Protein
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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)

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IUGR Outcomes Human Studies(Reviewed in
Fuglestad et al, 2008 Handbook of Developmental
Cognitive Neuroscience MIT Press)

• IUGRgtPoor 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)

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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)

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Neuroimaging Volumetrics
Cerebral Cortex (Protein)
Cerebral White Matter (Fat Iron)
Caudate
Putamen
Subcortical Nuclei
Thalamus
Psychiatry Iowa Neuroimaging Consortium
Courtesy of P. Nopoulos
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Fats
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Why the brain needs fats

• Cell membranes
• Synapse formation
• Myelin

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Long Chain Polyunsaturated Fatty Acids
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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

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LC-PUFAs and Mental Development

• Effect size preterms gt 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

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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

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Iron
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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

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Iron What Can Negatively Affect Neonatal Brain
Iron Status?

• Maternal Anemia
• Fetus with very iron deficient mother (Hgblt8.5)
• Common (gt30) 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

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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).

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Mom Hi Baby
Stranger Hi Baby
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Event Related Potentials (ERPs) in Newborns
Iron Sufficient
Iron Deficient
Siddappa et al., 2004, Pediatr. Res.
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Assessment of Iron Status(For review, see JL
Beard et al, Lab Med, 38103-108, 2007)

• Brain Iron
• No direct measures
• Newborn Serum Ferritin lt 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!

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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)

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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

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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

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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 (lt70
  mcg/dL)
• Most accurate approach is serum or RBC
  metallothionein concentrations

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Can we see nutrient effects on the brain?

• Sensitivity- yes
• Specificity- not really!

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Nutrients and Perinatal Brain Circuitry
Nutrient Brain Requirement for Nutrient Circuitry/Process Affected
Protein-Energy Cell Proliferation Cell Differentiation Synaptogenesis Growth Factors Global Cortex Hippocampus
Iron Myelin Dopamine Energy White Matter Striatal-Frontal Hippocampal-Frontal
Zinc DNA Neurotransmitter release ANS Hippocampus Cerebellum
LC-PUFAs Synaptogenesis Myelin Eye Cortex?
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Circuit Specific Assessment of Nutrient Effects
on the Premature Brain
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Limitations to Neurologic Assessment
Developmental Prediction in the Premature

• Limited cortical expression
• gt poor direct prediction of later functioning
• Ongoing illness confound
• gt not at their best
• Later plasticity/catch-up
• gt it is not as bad as it might seem

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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)

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Assessments and At Risk Nutrients What can you
diagnose with what you can measure?
ASSESSMENT BRAIN AREA RISK NUTRIENT(S)
OFC Global Protein-energy
Reflexes Global Myelination Iron ?Protein-energy
Neurologic Exam Global Protein-energy
EEG maturity Cortex Protein-energy ?LC-PUFA
Stimulated HR, BP, salivary cortisol response Autonomic Nervous System Zinc
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Assessments and At Risk Nutrients What can you
diagnose with what you can measure?
ASSESSMENT BRAIN AREA RISK NUTRIENT(S)
ABR/ERG Myelination synaptic efficacy (processing speed) Iron LC-PUFA
Auditory Event Related Potentials Hippocampus (recognition memory) Protein Iron Zinc
MRI Global Regional Volumetrics Protein Fat
MR-Diffusion Tensor Imaging Myelin Tract Integrity Fat Iron
MR-Spectroscopy Neurochemistry Iron
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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

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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 brains need for the
  nutrient
• Some nutrients have signature effects on the
  brain

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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!

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Enhancement Therapies for the Central Nervous
System

• If some is good, is more better?

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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)

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Choline
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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)

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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)

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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

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Neurobehavioral Domain Assessments General
DOMAIN RISK NUTRIENT TEST Age Neuroimaging Age
Global Protein/EnergyFe, Zn, LC-PUFA OFC 1-2.5 y lt2.5 y gt2.5 y MR-Volumetrics NB gt6 y
Myelin Fe LC-PUFA? Speed of Processing 4m ABR, VEP ERP DTI NB-gt NB-gt NB gt6y
ANS Zinc PDI (Bayley) Spontaneous activity Bimanual Coordination 1-2.5y Regional MR Volume (sensory-motor) NB gt6y
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Cognitive Domain Assessments
Domain Nutrient Behavior Age Neuroimaging Age
Cognition -Recognition (HC) Protein/Energy Fe, Zn, VPC Elicited Imitation DNMS gt4m gt12m gt6m ERP (auditory) ERP (visual) ERP (cross-modal) HC Volume NB 4m 8m NB/gt6y
Cognition -Working (PFC) Fe Elicited Imitation CANTAB gt12m gt4y MR PFC volume fMRI NB gt6y gt6y
Cognition -Procedural (striatum) Fe IVH Implicit memory- priming gt4m MR Caudate volume NB gt6y
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Affective Domain Assessments
Domain Nutrient Behavior Age Neuroimaging Age
Affect -Attention Fe, Zn Bayley rating CANTAB Flanker task gt12m gt5y gt5y MR Frontal volume ?Dopamine challenge NB gt6y
Affect -Reactivity (HPA ANS) Fe, Zn Restraint Separation Immunization NB-gt HR response vagal tone NB-gt
Affect -Social Interaction Fe Spontaneous movement (actigraph) Bayley rating NB-gt gt12m None
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Testing Beyond Year 2

• By age 5, frontal lobes become more testable
  using CANTAB Neuropsych Battery
• Strategy switching
• Executive function planning
• Working memory
• By age 6-8, children can be imaged without
  sedation allowing fMRI
• Working memory (back4)
• Attention (Flanker task)
• Implicit memory (Priming tasks)

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Mom Hi Baby
Stranger Hi Baby
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Neonatal ERPs to Auditory Recognition Task
deRegnier et al, 2000