Nutrients that Affect Early Brain Development

Michael K. Georgieff, M.D.Professor of Pediatrics and Child Psychology

Division of Neonatology

Institute of Child Development

Director, Center for Neurobehavioral Development

University of Minnesota

Objectives• Recognize the major nutrients that are most

needed by the developing brain

• Identify the perinatal brain processes that are at risk in nutrient deficient infants

• Recognize the association between those brain regions and behaviors dependent on those regions

• Recognize the different roles for nutrients and growth factors in determining brain growth rates

I have nothing to disclose

Overview of Talk

• Basic Principles of Nutrient/Brain Interactions– Timing, Dose and Duration– Ascribing Behavioral Effects to Nutrients– Nutrients of Particular Importance to Early Brain

Development• Protein, fats, iron, zinc, iodine, choline

• Are Nutrients Sufficient? The Role of Growth Factors– Integration through neuronal mTOR signaling

Basic Principles of Nutrient/Brain Interactions

Early Nutrition and Brain Development:General Principles

Positive or negative nutrient effects on brain development

Based on…

Timing, Dose and Duration of ExposureKretchmer, Beard, Carlson

(1996)

Nutrient-Brain-Behavior Relationships

• Brain regions/processes have different developmental trajectories

• The vulnerability of a brain region to a nutrient deficit is based on – When nutrient deficit is likely to occur in a lifetime– Brain’s requirement for that nutrient at that time

• Behavioral changes must map onto those brain structures altered by the nutrient deficit

Nutrients and Brain Development: Processes Affected

• NEUROANATOMY– Neurons

• Division (numbers of neurons)• Growth (size of neurons)• Development (complexity of neurons, synaptogenesis, dendritic

arborization)– Supporting cells

• Oligodendrocytes=> myelination • Astrocytes=>nutrient delivery• Microglia=>trafficking

Nutrient examples include protein, energy, iron, zinc, & LC-PUFAs (“fish oils”)

Nutrients and Brain Development: Processes Affected

• NEUROCHEMISTRY• Neurotransmitter concentration • Receptor numbers• Neurotransmitter uptake transporter numbers

Nutrient examples include protein, iron, zinc, choline

• NEUROPHYSIOLOGY• Neuronal metabolism• Efficiency of electrical activity of brain

Nutrient examples include glucose, protein, iron, zinc, choline

What is happening in the brain during fetal and early postnatal life?

Fetus Late Infancy/Toddler Pubertal

Thompson & Nelson, 2001

Nutrients with Particularly Large Effects on Early Brain Development and Behavior

• Macronutrients– Protein– Specific fats (e.g. LC-PUFAs)– Glucose

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

• Vitamins/Cofactors – B vitamins (B6, B12)– Vitamin A– Vitamin K– Folate– Choline (example of potential enhancement)

Protein-Energy Malnutrition

Why does the brain need protein and energy?

Effects of early protein-energy malnutrition

What the Brain Does with Protein

• DNA, RNA synthesis and maintenance• Neurotransmitter production (synaptic efficacy)• Growth factor synthesis• Structural proteins

– Neurite extension (axons, dendrites)– Synapse formation (connectivity)

Evidence From Animal Models

• Deleterious effect of early life PEM on brain development– Reduced cell number– Reduced cell protein synthesis– Reduced brain size– Ultrastructural changes in synapses– Reduced neurotransmitter production– Altered myelination– Reduced growth factor concentrations

Protein-Energy Malnutrition Clinical conditions early in life

– Intrauterine growth restriction (IUGR)• Likely occurred in significant number of orphaned children (untreated

maternal diseases)

– Postnatal Growth Failure• Starvation/poor food access during childhood

– Chronic illness• prematurity/neonatal illness

• chronic renal, hepatic, cardiac, pulmonary, infectious diseases (CHF, cystic fibrosis, HIV)

Protein-Energy Malnutrition

None of the clinical conditions are pure PEMo Unethical to randomize to malnutrition or not

PEM in a population is associated witho Multiple other nutrient deficiencies (e.g. protein

is major zinc source)o Environmental stressors that affect behavioral

outcomes

IUGR: Evidence from Clinical Studies

• IUGR=>Poor developmental outcome– Verbal outcome

– Visual recognition memory

– 6.8 point IQ deficit at 7 years (Strauss & Dietz, 1998)

– Dose responsive 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)

Previous Research: Growth Failure in International Adoptees

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core

Eastern Europe

• Children adopted from Eastern Europe• N=57• Age range: 9-46 months (M=19, SD=9)• Baseline & six month follow-up• Macronutrient & iron status

Fuglestad et al., J Pediatrics, 2009

Macronutrient StatusConfirmed Previous Data

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Fats

Why the brain needs fats

• Cell membranes• Synapse formation• Myelin

Long Chain Polyunsaturated Fatty Acids

Aka “Fish oils”

Docosohexaenoic Acid (DHA)

Neurobiological Effects of LC-PUFAs• Essentiality of LC-PUFAs derived from studies of severe

essential fatty acid deficiency– Hypomyelination– Altered fatty acid profile– Abnormal behavior including visual speed of processing– Findings in mice, rats, non-human primates

• Proposed effects on – Myelin – Neuronal membranes– Synaptogenesis– Cell Signaling

• Unknown: how much deficiency gives behavioral effects

LC-PUFAs and Mental Development

• More consistent effect seen newborns (premies > terms)

• Outcome measurements are short-term and generally gross (MDI) and not generally predictive of later function

• Long term studies unavailable- early acceleration may result in– No long term advantage (most likely)– Permanent advantage (not shown)

• Studies are underpowered to draw conclusions about long-term efficacy

Micronutrients

Iron

Zinc

Iodine

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!

Nutritional Status in Internationally Adopted Children

• Macronutrient status– Anthropometry– Serum proteins [albumin, Retinol Binding Protein (RBP)]

• Micronutrients– Iron – Zinc– Vitamin D– Vitamin A– Folic acid– Vitamin B12– Iodine & Selenium (TSH)

PopulationRegion Age

at Arrival (months)

Sex(%)

Clinic Visitn

(days after arrival)

Research Visitn

(days after arrival)

Eastern Europe

8.1 — 18.5 (M=13.9; SD=2.8)

M:81F:19

n=1613—38 (M=17;

SD=7)

n=1317—49

(M=30;SD=9)

Ethiopia

8.3 — 18.1(M=11.0; SD=2.7)

M:46F:54

n=264– 40 (M=21;

SD=10)

n=225—69 (M=31;

SD=16)

China8.8 – 17.2(M=12.2; SD=2.3)

M:11F:89

n=1812—40 (M=22;

SD=7)

n=1525—54 (M=34;

SD=9)

All Regions

8.1 — 18.5 (M=12.1; SD=

2.9)

M:45F:55

n=604—40 (M=20;

SD=8)

n=505 – 69 (M=32;

SD=12)

Baseline Micronutrient/Vitamin Status: 58% with at Least 1 Abnormality

Nutrient Definition Deficient

Retinol Binding Protein

< 3 mg/dL 38%

Iron 2 abnormal indices 17%

Zinc <60 µg/dL 29%

Vitamin D Deficient: <20 ng/mLInsufficient: <30 ng/mL

21%

Vitamin A Retinol: <13-50 µg/dL 0%

Folic Acid RBC:< 280 ng/mLSerum: 5.4 ng/mL

3%

Vitamin B12 <200 pg/mL 0%

TSH >5.0 mU/L 15% (elevated)

Baseline Nutritional Deficiencies by Region

Follow-up Nutritional Status: Better Zn, No Change in Iron, Worse Vit DNutrient Definition Deficient

Retinol Binding Protein

< 3 mg/dL 53%

Iron 2 abnormal indices 10%

Zinc <60 µg/dL 11%*

Vitamin D Deficient: <20 ng/mLInsufficient: <30 ng/mL

35%*

Vitamin A Retinol: <13-50 µg/dL 0%

Folic Acid RBC:< 280 ng/mLSerum: 5.4 ng/mL

0%

Vitamin B12 <200 pg/mL 0%

TSH >5.0 mU/L NA

Iron Deficiency

Why does the developing brain need iron?

Effects of early ID

Iron: A Critical Nutrient for the Developing Brain

– Delta 9-desaturase, glial cytochromes control oligodendrocyte production of myelin

• Iron Deficiency=> Hypomyelination

– Cytochromes mediate oxidative phosphorylation and determine neuronal and glial energy status

• Iron Deficiency=> Impaired neuronal growth, differentiation, electrophysiology

– Tyrosine Hydroxylase involved in monamine neurotransmitter and receptor synthesis (dopamine, serotonin, norepi)

• Iron Deficiency=> Altered neurotransmitter regulation

Fetus Late Infancy/Toddler Pubertal

Typical Time Periods of Iron Deficiency

ID in Infancy: Who is at risk?

Most postnatal ID is due to inadequate dietary intake ± low stores at birth ± blood loss

– Low stores at birth• Maternal anemia, hypertension, smoking, diabetes

mellitus

– Inadequate dietary intake• Low iron formula• Early change to cow milk

– Blood loss• Hemorrhage at birth (anemia)• Parasitic infection, food intolerance (GI loss)

Catch-up Growth & ID at 6 MonthsC

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Fuglestad et al., 2009

Neurobehavioral Sequelae of Early Iron Deficiency in Humans

Over 40 studies demonstrate dietary ID between 6 and 24 months leads to:– Behavioral abnormalities (Lozoff et al, 2000)

• Motor and cognitive delays while iron deficient

• Profound affective symptoms

• Cognitive delays 19-23 years after iron repletion– Arithmetic, writing, school progress, anxiety/depression, social

problems and inattention (Lozoff et al, 2000)

– Electrophysiologic abnormalities (delayed EP latencies)• At 6 months while iron deficient (Roncagliolo et al, 1998)

• At 2-4 years after iron repletion (Algarin et al, 2003)

• Characteristic of impaired myelination

Courtesy of B. Lozoff

Effect of Iron Deficiency in Infancy on Affect and Engagement

Courtesy of B. Lozoff

Effect of Iron Deficiency in Infancy on Affect and Engagement

Iron Status: Cognitive & Motor Outcomes

Cognitive Motor

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Iron Status: Speed of Neural Processing (VEP)

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p < 0.10

Iron Status: Socio-emotional & Exploratory Behavior

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Zinc Deficiency

Why does the brain need zinc?

Effects of early zinc deficiency

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 IGF-I and GH receptor 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

Zinc Deficiency: Human Evidence for Neurobehavioral Effects on Brain

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

• Postnatally, 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

Zinc Status: Cognitive & Motor Outcomes

Cognitive Motor

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Zinc: Socio-Emotional & Exploratory Behavior

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Iodine Deficiency

Why does the brain need iodine?

Effects of perinatal iodine deficiency

Iodine Deficiency and Brain Biology

• Iodine’s primary role is in thyroid hormone

• Low iodine levels lead to hypothyroidism– 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

• Timing of deficiency is critical• Fetal effects are much more profound

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

• Childhood: due to lack of iodine in diet– Reduced verbal IQ– Decreased reaction time (motor effect)– Older children=> effects reversible, suggests metabolic

effect (slower processing) rather than anatomic effect

Baseline Micronutrient/Vitamin Status: 58% with at Least 1 Abnormality

Nutrient Definition Deficient

Retinol Binding Protein < 3 mg/dL 38%

Iron 2 abnormal indices 17%

Zinc <60 µg/dL 29%

Vitamin D Deficient: <20 ng/mLInsufficient: <30 ng/mL

21%

Vitamin A Retinol: <13-50 µg/dL 0%

Folic Acid RBC:< 280 ng/mLSerum: 5.4 ng/mL

3%

Vitamin B12 <200 pg/mL 0%

TSH >5.0 mU/L 15% (elevated)

Principles of Enhancement Therapies for the Central Nervous System

If some is good, is more better?

Candidates for “Brain Enhancement”

• Choline• Oligosaccharides• Neurotrophic factors (growth factors)

– Brain Derived Neurotrophic Factor• Docosohexaenoic acid

– As supplementation rather than repletion of deficit

Pre- or Early Postnatal Choline Supplementation

• Improved performance in cognitive or behavioral tests that involve memory (Meck et al., 1988; Meck et al., 1989; Williams et al., 1998; Tees, 1999b; Brandner, 2002; Schenk and Brandner, 1995; Tees and Mohammadi, 1999; Meck and Williams, 1997a; Meck and Williams, 1997b)

• Improved electrophysiological, biochemical, and morphological endpoints (Mellott et al., 2004; 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

• Modification in the expression of genes that influence cell cycle, differentiation, learning and memory (Zeisel et al, 2006; Mellott et al.,2007)

Is Nutrient Supply (i.e., Fuel) Sufficient?

The Role of Growth Factors

Growth Factors

• Small proteins– Promote cellular growth and differentiation through

efficient utilization of nutrients– They “transmit” fuel (nutrients) into structure and

function• General vs organ-specific

– Insulin, Insulin-like Growth Factor (IGF), Growth Hormone

– Brain Derived Neurotrophic Factor (BDNF)– Nerve Growth Factor (NGF)– Erythropoietin (Epo)– Fibroblast Growth Factor (FGF)

Growth Factors: The Cell’s Transmission

• Without GFs, cells will not differentiate in spite of adequate nutrients

• Without nutrients, GF cannot mediate growth• Growth factors regulate neuronal growth and

complexity– Dependent on nutrients

• Oxygen, glucose, amino acids, iron– Independent of nutrients

• Infection• Physiologic Stress

Nutrition and Stress: 2-Way Model

NUTRIENTS STRESS

IRON Poor White Cell Function/Cytokine Response

Blunted Response

ZINCPROTEIN

Reduced GF synthesisReduced synaptic efficacy

Cortisol activation

Cytokine production

Diversion of amino acidsTissue (protein) breakdown

Hepcidin Activation

Amino acids & growth factors

= Brain Protein Malnutrition

Poor Brain Growth

Brain Iron Deficiency

Summary: Nutrition 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 as well as the brain’s need for the particular nutrient

• Some nutrients have “signature” effects on the brain, but there is overlap among nutrients

Summary: Nutrition and the Brain

• Nutrient availability only represents “supply side” economics; one has to think about “demand” and “processing” as well

• Consider growth factors as well; the two work together to stimulate normal neuronal growth and development