02.09.2014 1 Early Nutrition and the Brain: Should We Be Concerned? (Yes) Michael K. Georgieff, M.D. Professor of Pediatrics and Child Development Director, 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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02.09.2014
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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
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)
• 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
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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