NGx for Studying Cognitive Function

Transcription

1 NGx for Studying Cognitive Function Carol L Cheatham, PhD Associate Professor of Psychology & Neuroscience University of North Carolina at Chapel Hill

2 Cheatham Nutrition & Cognition Laboratory Developmental cognitive neuroscientist (developmental psychologist) Studying how nutrition affects cognition From preconception to birth to old age nutrition is central to brain function.

3 What is cognition? Sigelman & Rider: the activity of knowing and the process through which knowledge is acquired and problems are solved. Components of cognition Perception Attention Memory Reasoning Problem-solving What do they have in common? Rely on the brain

4 Maternal Nutrition and Brain Development Iodine - #1 cause of mental retardation worldwide 1924 added to salt in US Iron #1 deficiency worldwide 1941 first iron-fortified cereal Folate needed before conception 1998 folate added to food supply Fatty acids important for brain in 3rd trimester 2008 added to infant formula BUT requirement is genetically determined

5 Docosahexaenoic Acid (DHA) Part of the omega-3 family of fatty acids Found in eggs, oily fish, and meat from grass-fed animals Makes up 17% by weight total brain fatty acids Signal processing (Yehuda et al, 2002; Crawford et al., 2013) Fluidity of the neuronal membranes Integral to long term potentiation (LTP) in the hippocampus (Fujita et al., 2001; Kavraal et al., 2012) Important for visual development Carol L. Cheatham, Ph.D.

6 DHA in Neural Membranes DHA Cartoon courtesy of Mihai Niculescu, MD, PhD

7 n-3 LCPUFA mol/fb DHA Accumulation in the Brain DHA DPA EPA Post menstrual age, wk Martinez 1992

8 DHA and Cognitive Development Fewer than 40% of RCTs find effects in fullterms Only 22% find effects in global development

9 DIAMOND Trial Cheatham, Colombo, & Carlson 2008 Bayley Scales of Infant Development - MDI No DHA.33% FA.67% FA 1.0% FA

10 DHA and Cognitive Development Fewer than 40% of RCTs find effects in fullterms Only 22% find effects in global development Why are effects elusive? Need to test specific cognitive abilities. There are uncontrolled confounds. Approach Use well-targeted assessments

11 DHA and Imitation Tasks 10m Cheatham & Carlson * No DHA *.33% DHA 0.67% DHA % DHA Baseline Recall * p < 0.005

12 DHA and Cognitive Development Fewer than 40% of RCTs find effects in fullterms Only 22% find effects in global development Why are effects elusive? Need to test specific cognitive abilities. There are uncontrolled confounds. Approach Use well-targeted assessments Type genes involved in fatty acid metabolic pathway

13 Genetic Influence on DHA Levels Humans can convert LNA to DHA (using plant source to metabolize same fatty acid found in animal sources). FADS genes code for the desaturase involved. Endogenous synthesis of DHA does not begin until after birth. Fetus and neonate rely on maternal DHA Alpha-linolenic acid (18:3 n-3) is essential

14 Metabolic Pathway n-6 and n-3

15 Genetics, Breastmilk, & IQ Genotype = Infant FADS2 rs Caspi et al. 2007

16 Genetics, Breastmilk, & IQ Genotype = Parent Genotype = Infant FADS2 rs CC CG CC CG GG Elementary School IQ Caspi et al GG

17 Fatty Acids, Genetics, & Breastmilk CC 0.2 GG DHA EPA ARA Genotype = Parent rs on FADS2 gene Xie & Innis, 2008 DPA n-3 DPA n-6

18 Study Design Enroll 16-month-old toddlers (n= 65); randomize to flax or corn oil group Baseline declarative memory Immediate, 20 minute delay, 1 week delay Blood sample from mother and toddler Determine rs genotype Analyze fatty acid levels Assess methylation & CNV 1200 mg flaxseed oil per day for 120 days Outcome declarative memory at 4 months Immediate, 20 minute delay, 1 week delay Carol L Cheatham, Ph.D.

19 2 Step Sequence

20 2 Step Sequence

21 Intervention Results No differences between groups at baseline on events tested immediately. No differences between groups at baseline on events tested after a 20-minute delay. No differences between groups at 7-day delay test or relearning. No differences between groups at outcome on new events. Moreover, old events were recalled better by the control group.

22 Intervention Results Old Events 1.4 p < Ordered Recall p <.05 Control Oil 0.6 Flaxseed Oil m Delay Relearning

23 16-month-old Imitation Cheatham, Niculescu, & Lupu 2012 Ordered Recall Immediate Test GG CG Maternal FADS2 rs Genotype CC

24 Genotype X Group Old Events 0.7 Ordered Recall of Old Events after a 4m Delay Control 0.3 Flaxseed 0.2 p< GG CG CC Maternal FADS2 rs Genotype

25 Genotype X Group New Events Ordered Recall of New Events after a 7-day Delay Control 1 Flaxseed p< GG CG Maternal FADS2 rs Genotype CC

26 Breastfeeding Study Enrolled 200 breastfeeding 3 months Incidence of GG at rs = 7% Breastmilk samples taken at 3 months to relate to maternal genotype A subset 6 months GGs ~14 and random selection of CCs and CGs ERP protocol to explore recognition memory abilities and relate them to genotypes and fatty acid content

27 Human Milk Fatty Acids * * *

28 Electrophysiology: Event Related Potentials Electrical activity measured at the scalp EEG (electroencephalogram) Pattern of variation in voltage over time ERP (event related potentials) EEG that is time-locked to an event High-density systems provide good coverage Sensor nets lend themselves to infant work

29 First Cheatham Lab Participant Photo courtesy of Salisbury Post 2/21/2010

30 Recognition Memory Oddball Paradigm 2012 Carol L Cheatham,

31 Carol L. Cheatham, Ph.D.

32 Extracting the Signal ERP generation is based on differences in voltage between electrodes and a reference. EEG background noise should average to zero The residual activity represents brain activity to the event Limitation: can t assess individual trials Compare grand means of conditions

33 ERP Waveform: Novel vs. Familiar

34 Carol L. Cheatham, Ph.D.

35 ERP Waveforms Novel vs. Familiar

36 Novel vs. Familiar GG Maternal Genotype Carol L. Cheatham, Ph.D.

37 Recognition Memory ERP Cheatham, * Familiar Novel Maternal CC Maternal GG

38 Summary Nutrition does not generally affect the brain globally, but rather has specific effects. Thus, targeted assessments of specific cognitive abilities should be utilized. Results in a need for trans-disciplinary work Maternal nutrition is integral to infant and toddler cognition. Maternal genetics may be proxy for placental transfer of fatty acids. Future work - Is the effect of maternal genotype permanent? If we identify early, will intervention help?

39 Thank you. All families that participate in research around the world Stevie Ray Wunder Patricia J. Bauer, Ph.D. Megan R. Gunnar, Ph.D. Michael K. Georgieff, M.D., Ph.D. Charles A. Nelson, Ph.D. Sandra Wiebe, Ph.D. Steven Zeisel, M.D., Ph.D. J. Steven Reznick, Ph.D. A myriad of undergrads and grad students The Cheatham Nutrition & Cognition Team Funding agencies: NSF, NIH, CNBD, URC, CNRU, NRI, Pfizer, Wyeth (Nestle) Carol L Cheatham, Ph.D.