Upload
others
View
11
Download
0
Embed Size (px)
Citation preview
02.09.2014
1
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
02.09.2014
2
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)
02.09.2014
3
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
02.09.2014
4
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
02.09.2014
5
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
02.09.2014
6
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
02.09.2014
7
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
02.09.2014
8
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
02.09.2014
9
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)
02.09.2014
10
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
02.09.2014
11
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
02.09.2014
12
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]
02.09.2014
13
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
02.09.2014
14
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
02.09.2014
15
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
02.09.2014
16
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
02.09.2014
17
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
02.09.2014
18
Is this our goal?