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Early Nutrition and the Brain: Should We Be Concerned?

(Yes)Michael K. Georgieff, M.D.

Professor of Pediatrics and Child DevelopmentDirector, Center for Neurobehavioral Development

University of Minnesota School of Medicine

Overview of Talk• Brain Development in late fetal and early

neonatal life

• Early nutrition and brain development– Basic Principles of nutrient-brain interactions– Neurodevelopmental assessment tools

• Macronutrient undernutrition and risks to the developing brain – In utero malnutrition (IUGR)– Early postnatal nutrition (EUGR)

• Micronutrients and the developing brain– Iron, zinc, copper, iodine, folate, choline

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Principles of Nutrient-Brain Interactions

Early Nutrition and Brain Development:General Principles

• Nutrients regulate brain development during prenatal and postnatal life

• Rapidly growing brain in neonate – More vulnerable to damage – More amenable to repair

“Vulnerability outweighs Plasticity”(National Institutes of Health)

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Early Nutrition and Brain Development:General Principles

Positive or negative nutrient effects on brain are based on:

Timing, Dose and Duration of ExposureKretchmer, Beard, Carlson

(Am J Clin Nutr, 1996)

Nutrients->Brain• Brain is not a homogenous organ

– Regions (cortex, hippocampus, striatum, cerebellum)

– Processes (myelin, neurotransmitters)

• All have different developmental trajectories• Vulnerability to a nutrient deficit is based on

– When a nutrient deficit occurs

– Region’s requirement for that nutrient at that time

Thompson & Nelson, Am Psychol, 2001

Hippocampus

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Nutrients that Particularly Affect Early Brain Development

• Macronutrients– Protein*– Specific fats (e.g.

LC-PUFAs*)– Glucose*

• Micronutrients– Iron*– Zinc*– Copper*– Iodine (Thyroid)*

• Vitamins/Cofactors – B vitamins (B6, B12*)– Vitamin A– Vitamin K– Folate*– Choline*

*Exhibits critical/sensitive period for

neurodevelopment

Nutrients and Brain Development: Processes Affected

• NEUROANATOMY– Neurons

• Division (numbers)• Growth (size)• Development (complexity)

– Supporting Cells • Oligos=> Myelin • Astrocytes=>Nutrient Delivery; Repair• Microglia=>Trafficking

Nutrient examples: protein, fats, energy, iron, zinc , choline

Nutrients and Brain Development: Processes Affected

• NEUROCHEMISTRY (Neurotransmitters)• Concentration • Receptors• Re-Uptake

Nutrient examples: protein, iron, zinc, choline

• NEUROPHYSIOLOGY• Neuronal metabolism => Electrical activity of brain

Nutrient examples: glucose, protein, iron, zinc, cho line

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Examples of Nutrients and Regional vs Global Perinatal Brain Effects

Nutrient Brain Requirement for Nutrient

Affected Areas

Protein-Energy Cell Proliferation, Cell Differentiation

Synaptogenesis,Growth Factors

GlobalCortex

Hippocampus

Iron MyelinDopamine

Energy

White MatterStriatal-Frontal

Hippocampal-Frontal

Zinc DNANeurotransmitter release

Autonomic NSHippocampus

Cerebellum

LC-PUFAs SynaptogenesisMyelin

EyeCortex

Fundamental Questions

• Does a nutrient that alters neonatal brain development result in abnormal brain function (behavior)?

• Is the effect transient or long-term?– Only during deficiency=> Acute dysfunction– Beyond time of deficiency=> Altered development & adult

dysfunction

Early MALnutrition

Undernutrition-IUGR-EUGR

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Do each of these babies have different cognitive outcomes?

Neurodevelopmental Risk in Growth Restricted Babies

Prenatal Malnutrition: IUGR

� IUGR is a good model for fetal undernutrition effects on brain

– Brain is in rapid growth phase during last trimester=> more vulnerable

– Not just protein-energy malnutrition

• 50% of IUGRs are iron deficient

• Likely to have other micronutrient deficiencies

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IUGR: Clinical Studies� Poor prenatal head growth=>Poor developmental

outcome– Lower IQ at 7 years– Impaired verbal skills in childhood– Worse recognition memory– 15% with mild neurodevelopmental

abnormalities

� Cognitive rather than motor disabilities– Consistent with global insults

• PEM, iron deficiency, hypoxia

What Happens When Postnatal Growth Failure Follows IUGR in Term Infants?

• Collaborative Perinatal Project in US– 45,000 children in National Collaborative

Perinatal Project (1959-1976)– 464 infants <2.2 kg at 37 weeks or greater

• Outcome at 7 years– Slow postnatal growth increases

developmental risk

1000 2000 3000 4000 5000

6070

8090

100

Weight gain at 16 weeks of age (grams)

Ful

l Sco

re

IQ

Pylipow et al, 2009

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IUGR: Conclusions

� Fetal PEM can reduce head size at birth– Lack of head sparing => severe IQ loss– Head sparing => variable neurobehavioral risk

� Reduced head size represents reduced cell number, size, myelination, synaptogenesis

� Behavioral effects include reduced cognitive ability

Postnatal Malnutrition: Prematurity & “EUGR”

� Premature infants have significant nutrient deficits

� We are not particularly good at growing preterm infants to match expected intrauterine growth rates

� Many infants <1000 g birthweight become “microcephalic” during hospitalization

� Catch-up head growth to original percentiles may take years

Q: Is there a relationship between poor growth and developmental outcome in preterm infants?

Ehrenkranz et al. Reproduced with permission from Pediatrics, Vol 104:280-289, Copyright 1999 by the AAP

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1.Transition

2. Catch-up

3. Post-discharge

CPS phase 1:“Transition”0-10 daysSickCatabolic

CPS Phase 2:“Catch-up”10d-34 wks PCAWellAnabolicImmature Physio

CPS Phase 3: “Post-discharge”WellAnabolicMature Physio

Nutritional Status at Discharge

• Protein-energy malnutrition

– Cumulative energy deficit: 1000 kcal/kg

- Cumulative protein deficit: 25 grams/kg

- 2000 grams at 37 weeks = “EUGR”

• Iron Deficiency (or overload)

• Other nutrients that affect brain development?

Contributors to EUGR• Lack of knowledge of current nutritional

recommendations– Survey (Hans et al, Pediatrics 2009)

• Failure to prescribe what is known– “NEC-ophobia” (Joe Neu)

• Failure to deliver what is prescribed– Current NIH sponsored trial (Patti Thureen, PI)

• Failure to grow in spite of adequate delivery– Can sick babies grow?

• Failure to assimilate (absorb, traffic)• Failure to translate (growth factors)

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Outcome of 500-1000g Infants: Relationship to Weight Gain

Ehrenkranz et al, Pediatrics, 2005

• NICHD Network: 495 infants divided into 4 quartiles of mean weight gain

• Neurodevelopment at 18-22 monthsOutcome Quartile 1 Quartile 2 Quartile 3 Quartile 4 P value

Weight gain(g/kg-d)

12.0 (2.1) 15.6 (0.8) 17.8 (0.8) 21.2 (2.0)

MDI 75.7 (18) 77.7 (18) 79.7 (18) 80.9 (15) 0.32

PDI 74.8 (19) 77.5 (19) 81.5 (17) 83.3 (14) <0.01

Weight or Length?• Protein accretion parallels organ growth including

brain– Mediated by mTOR signaling pathway

• Linear growth closely related to protein accretion, but not fat mass gain

• Protein accretion/linear growth is a function of– Protein intake – Non-nutritional factors (protein breakdown)

• Infections• Steroids• Chronic Disease

Linear Growth and NeurodevelopmentRamel et al, Neonatology, 2011

• 62 AGA infants (27 weeks EGA)

• Weight Z-score at discharge or during follow-up not associated with 24 month outcome

• Linear growth (controlling for weight)– Each 1SD greater linear growth at discharge, 4

mos or 12 mos of age improved Cognitive (4.5 points) and Speech (7.9 points) Bayley Index at 24 months

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Speed of Processing in Premies: High vs Low Fat Free Mass (Pfister et al, 2013)

Micronutrients and Early Brain Development

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

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Iron: A Critical Nutrient for theDeveloping Brain

Iron containing enzymes and hemo-proteins are involved in important cellular processes in developing brain– Delta 9-desaturase, glial cytochromes control

oligodendrocyte production of myelin– Cytochromes mediate oxidative phosphorylation and

determine neuronal and glial energy status– Tyrosine Hydroxylase involved in monoamine

neurotransmitter and receptor synthesis (dopamine, serotonin, norepi)

– New evidence that ID affects genome while ID and long after ID is treated

Hippocampal Effects (Rodent Models)

• Short and long-term genomic changes (ES Carlson et al, 2007)

– Dendrite structure, synaptic efficacy, oxidative metabolism • Altered dendrite morphology (ES Carlson et al, 2009)*

• Long-term suppression of BDNF and its receptor (P Tran et al, 2009)

• Reduced learning and memory (B Felt and B Lozoff, 1996; AT Schmidt et al, 2007)

Sufficient Deficient

What Can Negatively Affect Neonatal Brain Iron Status?

• Maternal Anemia– Fetus with very iron deficient mother (Hgb<8.5)

• Intrauterine Growth Restriction– Usually due to maternal hypertension

• Diabetes Mellitus in Pregnancy– Pre-existing or Gestational

• Maternal Smoking in Pregnancy

• Prematurity– [Reduced iron accretion + phlebotomy ]- [transfusion + intake]

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Factors that Determine Preterm Infant

Iron Balance in the NICU

Negative Iron Balance• Low Endowment (IUGR)• Phlebotomy Losses• Iron Rx at 2 months• Iron Rx < 2mg/kg/d• rhEpo Rx• Rapid Postnatal Growth

Positive Iron Balance• Older gestation & AGA• RBC Transfusion• Iron Rx at 2 weeks• Iron Rx @ 2-4 mg/kg/d• Iron Rx @ 6mg/kd/d c rhEpo• Parenteral Iron• Slow Postnatal Growth Rate

Neurodevelopmental Sequelae of Perinatal ID

• Term infants– GENERAL: Low neonatal iron stores (<76mcg/L) => poorer school

age neurodevelopment (Tamura et al, 2002)

– HIPPOCAMPUS: Cord ferritin <40 mcg/L => impaired recognition memory (Siddappa et al, 2004)

– DOPAMINE: Iron deficient infants born to IDA mothers => altered temperament (Wachs et al, 2005)

• Preterm infants– GENERAL: Early iron supplementation => higher mental

processing composite score at 5.3 years (Steinmacher et al, 2007)

– MYELIN; SYNAPTOGENESIS: Ferritin <76 mcg/L at discharge => abnormal reflexes (Armony-Sivan et al, 2004)

– MYELIN: Cord ferritin <76 mcg/L => slower central nerve conduction speeds (Amin et al, 2010)

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 Growth Factor (IGF-I) 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

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Zinc Deficiency: Neurobehavioral Effects on Late Fetal Brain

• Fetuses of zinc deficient mothers demonstrate:– Decreased movement– Decreased heart rate variability– Altered Autonomic Nervous System stability

• Postnatally, fetal 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

No studies of neurodevelopmental outcomes of preterm infants as a function of Zn status

Copper: Brain Biology

• Dopamine mono-oxygenase activity

• ROS scavenger (Cu-Zn SOD)

• Iron transport (multi-copper oxidase)– Cu deficiency => Fe deficiency

• Neuronal energy metabolism (rodents)

– Cytochrome c oxidase activity– Particular effects on developing cerebellum,

hippocampus– Perinatal deficiency effects are long-lasting

Copper: Populations at Risk

• Increased Cu need during pregnancy and lactation

• Preterms and IUGRs born with low stores

• Preterms given excessive Zn or Fe– Competition among divalent metals for transporters

No neurodevelopmental outcome studies of pretermsas a function of perinatal Cu status

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IodineWhy does the brain need iodine?

Effects of fetal-neonatal iodine deficiency

Iodine Deficiency and Brain Biology

• Iodine’s primary role is in thyroid hormone– No direct role of I in brain development

• Lower brain weight and brain DNA• Thyroid sensitive promoter regions• Reduced dendritic arborization• Reduced myelination (fatty acid synthesis effect)• Reduced synaptic counts

Iodine Deficiency: Behavioral Effects• Fetal effects are much more profound

– Greatest effect is I deficiency during first 12 weeks– Reduced head size– Global mental deficits/not reversible

• Postnatal effects– Reduced verbal IQ=> global effect on cell

division?– Decreased reaction time (motor effect)=> due to

delayed myelination or reduced synaptogenesis?

No studies of neurodevelopment in preterm infants as a function of iodine status

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Folate• Co-factor in numerous enzyme pathways• Most important during periconceptional period• Neuroanatomy (first 8 weeks) • Neuronal migration (6-24 weeks)• Premature infants (24-36 weeks)

– Immature enzyme systems

Folate and the Developing Brain

• Folate is critical for neural tube development and closure– Meningomyelocele, encephalocele, 2*Arnold-Chiari malformation

• Folate deficiency in infancy are primarily motor, but some cognitive effects

• Status is not typically monitored in NICU• No neurodevelopmental outcome studies of preterms as a

function of folate

Choline: What is the Biology?• Neurotransmitter component

– Acetylcholine

• Myelin component– Phosphotidylcholine (Rao et al, 2003)

• Methyl Donor– Potential epigenetic modification (Zeisel, et al, 2010)

– Brain Derived Neurotrophic Factor (BDNF) III• Synaptic plasticity

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Prenatal Choline Supplementation (Rodent Models)

• No studies of deficiency or supplementation in preterm infants

• Apparent critical period during mid-late gestation

• Improved electrophysiology, biochemistry, brain morphology, learning and memory (Mellott et al., 2004; Meck et al., 1988; Meck et al., 1989; Williams et al., 1998; Ricceri and Berger-Sweeney, 1998)

–Normal rats–Rats with fetal alcohol exposure–Rett’s Syndrome mice–Down’s Syndrome mice–Iron deficient rat

P65 BDNF3 mRNA expression

0.00

0.25

0.50

0.75

1.00

1.25

What about LC-PUFAs?(How much time do I have to speak?)

• Critical nutrient for eye and brain development– Mechanisms of action not completely understood

• Maturation of synthesis is developmentally modulated– <33 week EGA at high risk for rapid negative balance

• Supplementation of preterms – Improves ERG– Improves short-term neurodevelopment

Summary• Nutrient effects depend on timing, dose and duration

– Timing in terms of brain development process– Timing in terms of prevalence of nutrient deficit in population

• Certain nutrients have high impact on early brain development– Effects can be global or circuit specific

• Earlier identification and correction is essential

• Nutrition is something that affects the neonatal brain that we (neonatologists) can control

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Is this our goal?