Transcript JointCouncilNYCmkg

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 Exposure
Kretchmer, 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 PEM
o Unethical to randomize to malnutrition or not
 PEM in a population is associated with
o 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
–
–
–
–
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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)
z score
Previous Research: Growth
Failure in International Adoptees
Eastern Europe
• Children adopted from Eastern Europe
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•
•
•
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
z scores
Macronutrient Status
Confirmed Previous Data
***
***
***
***
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
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–
–
–
–
Iron
Zinc
Vitamin D
Vitamin A
Folic acid
Vitamin B12
Iodine & Selenium (TSH)
Population
Region
Age
at Arrival
(months)
Sex
(%)
Clinic Visit
Research Visit
n
n
(days after arrival)
(days after arrival)
Eastern
Europe
8.1 — 18.5
(M=13.9; SD=2.8)
M:81
F:19
n=16
13—38 (M=17; SD=7)
n=13
17—49 (M=30;SD=9)
Ethiopia
8.3 — 18.1
(M=11.0; SD=2.7)
M:46
F:54
n=26
4– 40 (M=21; SD=10)
n=22
5—69 (M=31; SD=16)
China
8.8 – 17.2
(M=12.2; SD=2.3)
M:11
F:89
n=18
12—40 (M=22; SD=7)
n=15
25—54 (M=34; SD=9)
All
Regions
8.1 — 18.5
(M=12.1; SD= 2.9)
M:45
F:55
n=60
4—40 (M=20; SD=8)
n=50
5 – 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/mL
Insufficient: <30 ng/mL
21%
Vitamin A
Retinol: <13-50 µg/dL
0%
Folic Acid
RBC:< 280 ng/mL
Serum: 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 D
Nutrient
Definition
Deficient
Retinol Binding Protein
< 3 mg/dL
53%
Iron
2 abnormal indices
10%
Zinc
<60 µg/dL
11%*
Vitamin D
Deficient: <20 ng/mL
Insufficient: <30 ng/mL
35%*
Vitamin A
Retinol: <13-50 µg/dL
0%
Folic Acid
RBC:< 280 ng/mL
Serum: 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
Typical Time Periods of Iron Deficiency
Fetus
Late Infancy/Toddler
Pubertal
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 atFuglestad
6 Months
et al., 2009
Change in z scores
*
*
*
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
Effect of Iron Deficiency in Infancy on Affect and Engagement
Courtesy of B. Lozoff
Effect of Iron Deficiency in Infancy on Affect and Engagement
Courtesy of B. Lozoff
BSID III Standardized Score
Iron Status: Cognitive & Motor
Outcomes
130
Cognitive
***
***
115
*
100
Motor
Non-adopted
Controls
IA Iron Sufficient
IA Iron Deficient
85
70
Iron Status: Speed of Neural
Processing (VEP)
Milliseconds
p < 0.10
Behavior Rating
Iron Status: Socio-emotional &
Exploratory Behavior
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
BSID III Standardized Score
Zinc Status: Cognitive & Motor
Outcomes
130
Cognitive
***
115
100
Motor
***
Non-adopted
Controls
IA Zinc Sufficient
IA Zinc Deficient
85
70
Behavior Rating
Zinc: Socio-Emotional &
Exploratory Behavior
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/mL
Insufficient: <30 ng/mL
21%
Vitamin A
Retinol: <13-50 µg/dL
0%
Folic Acid
RBC:< 280 ng/mL
Serum: 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
Amino acids & growth factors
= Brain Protein Malnutrition
Diversion of amino acids
Tissue (protein) breakdown
Cortisol activation
Poor Brain Growth
Hepcidin Activation
Cytokine production
Brain Iron Deficiency
NUTRIENTS
IRON
ZINC
PROTEIN
STRESS
Poor White Cell Function/Cytokine
Response
Reduced GF synthesis
Reduced synaptic efficacy
Blunted Response
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