Testing the effects of diet on neuro-cognitive performance: Human, animal and cellular models

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Molecular Nutrition Group School of Chemistry, Food and Pharmacy Testing the effects of diet on neuro-cognitive performance: Human, animal and cellular models Professor Jeremy

1 Molecular Nutrition Group School of Chemistry, Food and Pharmacy Testing the effects of diet on neuro-cognitive performance: Human, animal and cellular models Professor Jeremy P E Spencer Centre for Integrative Neuroscience and Neurodynamics Institute for Cardiovascular and Metabolic Research 07 July 2014 University of Reading

2 Dietary Flavonoids A wide array of Fruits and vegetables Green & Black Tea: (Flavanols) Citrus: (Flavanone) Red wine: (Flavanol, Flavonols) Cocoa: (Flavanols and procyanidins) Berries: (Anthocyanins)

3 The actions of flavonoids

4 Effect of flavonoids on memory and cognition

5 Measurement of multiple Cognitive domains Primary domains of human cognition

6 Measurement of multiple Cognitive domains Cognitive Test Construct Brain Region MMSE (screening >25) Everyday awareness Frontal xxx Hipp l x Go-NoGo task Stroop task Category shift task Attention/Exec Func/inhibition Exec Func/inhibition Exec Func/inhibition xxx xxx xxx Xx xx xx Memory: DSST (screening) RVIP Implicit memory Explicit memory Spatial memory Prospective memory Working memory Working memory/attention Priming/preference judgement Verbal recall/recognition Spatial working memory Remembering to do things x x xx x xx xx xxx xxx xx xxx xxx xxx

7 Impact of cocoa flavanol supplementation on cognitive performance 63 healthy yrs Acute intervention: 0-2 h Chronic intervention: 12 weeks Packet code Packet size, g mg Cocoa Flavanols (DP 1-10) epicatechin, mg catechin, mg dimers-decamers, mg Calories Total fat, g Saturated fat, g Cholesterol, mg Sodium, mg Total Carbohydrates, g Dietary Fiber, g Sugars, g Protein, g Caffeine, mg Theobromine, mg Potassium, mg Calcium, mg Iron, mg Phosphorus, mg Magnesium, mg Zinc, mg Copper, mg Manganese, mg

8 Executive Function (Z Score) Episodic Memory (Z-Score) Cocoa flavanol intervention acutely (2h) improves executive function and episodic memory Executive Function z-score from 5 tests Episodic memory z-score from 4 tests 0.25 p < p < Low Flavanol High Flavanol -2.5 Low Flavanol High Flavanol

9 Flavanone-rich OJ/cognition study 42 healthy adults aged years (fasted) Standardised evening meal the night before Cognitive performance at: baseline, 2 h, 6 h Protein (g) Fat (g) Sugars (g) Fiber (g) Calcium (mg) Potassium (mg) Orange juice (8floz) BQL Control (8floz) BQL Vitamin C (mg) Folate (mg) BQL Flavonoids (mg) 240 BQL

Global cognitive performance Change from baseline Z- score Global cognitive score as change from baseline 0.20 0.15 0.10 0.05 0.00-0.05-0.10-0.15-0.20-0.

10 Global cognitive performance Change from baseline Z- score Global cognitive score as change from baseline *** 2 hour 6 hour *p = AControl Orange juice C Global cognitive performance is improving following orange intervention, relative to control. 10

11 ses Difference in correct responses (Pre to post) Difference in correct responses (Pre to post) Difference in correct responses (Pre to post) Chronic improvements in cognitive function following OJ (250 ml/day for 8 weeks) 4 2 Control OJ Executive Function/Attention 0 Working memory Control OJ 6 DSST p = Serial 7s p = Control OJ 3 2 Control OJ Control OJ 0 Control OJ Serial 7s 4

12 Mean no. of correctly detected targets Mean no. of correctly detected targets Improvements in human executive function (attention) following blueberry (160g) intervention Go-NoGo task: Executive function/attention Subjects : yrs Subjects: yrs * BB (160 g) Control * BB (160 g) Control Pre-drink 1h post 5h post 36 Pre-drink 1h post 5h post Sustained ability to correctly detect target stimuli following flavonoid supplementation compared to the control (* p < 0.05; n=48).

13 How are these effects mediated?

14 How do they exert such actions in the brain? Cocoa Flavanols Cell Signalling and Gene Expression Changes in cerebrovascular blood flow Modulation of synaptic plasticity Inhibition of Neuroinflammation

15 Cocoa Blueberry? Tea R 1 HO Flavanols R 2 O R 3 OH OH Lower Blood Pressure Improved Vascular Func on Reduced Risk of Cardiovascular Disease Decreased Blood Clo ng

16 Enhanced vascular function induced by blueberry consumption dose dependency Rodriguez-Mateos et al, AJCN, 2013

17 Time-dependent effects Rodriguez-Mateos et al, AJCN, 2013

18 % FMD mean CBF (ml/100g/min) BP (mm Hg) Acute cognitive improvements induced by flavanols may be linked to changes in blood flow Low Flavanol High Flavanol Flavanol effects of peripheral vascular response 10 p = Control High Flavanol *** 5 0 p = L R Control High Flavanol p = 0.04; n =6 8 6 *** -5 Systolic BP Diastolic BP Baseline 2h 4h h 4h

19 Brain imaging using fmri ASL: arterial spin labelling - measuring cerebral blood flow (CBF) in vivo fmri: functional MRI - haemodynamic response (change in blood flow) related to neural activity in the brain

20 Time-series analysis on resting state ASL data - Cocoa intervention: baseline to 2h

21 Time-series analysis on resting state ASL data - cocoa vs. control intervention (axial slices) Middle frontal gyrus Pre-central gyrus Lateral occipital cortex

with the control drink at 2 hrs post consumption (p<0.

22 MRI following Orange intervention Axial slices: sig. greater perfusion flow after grapefruit and orange juice drink compared with the control drink at 2 hrs post consumption (p<0.05) Orange 2hrs>Control 2hrs No of voxels X Y Z Stat threshold Frontal Gyrus Z =3.69, p< 0.001

Blood Flow and Cognition Flavonoids/ phenolic acids metabolites ERK1/2, Akt/PKB enos NO Vascular endothelium BBB Peripheral & Cerebrovascular blood flow Increased brain blood perfusion Periphery

23 Blood Flow and Cognition Flavonoids/ phenolic acids metabolites ERK1/2, Akt/PKB enos NO Vascular endothelium BBB Peripheral & Cerebrovascular blood flow Increased brain blood perfusion Periphery Brain Neuron BDNF, NRF, Arc Akt/ERK CREB VEGF-B, nnos Neuronal Morphology Dendri c spine growth Neuronal communica on Synap c plas city Angiogenesis/ Neurogenesis Oxygen/ nutrient delivery Enhancement of Memory and Cogni on

24 How do they exert such actions in the brain? Cocoa Flavanols Cell Signalling and Gene Expression Changes in cerebrovascular blood flow Modulation of synaptic plasticity Inhibition of Neuroinflammation

25 Rodent model - spatial working memory - non-invasive screening for behavioural activity Younger animals Old animals 8-arm radial maze T-maze alternation task Memory Paradigm Learning Paradigm Phase Acclimatization Task learning ( aquisition ) Retention ( consolidation ) Testing ( Retrival )

26 Effect of a 2% w/w blueberry supplementation on spatial working memory in old animals Paradigm Phase 2 weeks Acclimatization 6 weeks 12 weeks Task learning Retention ( aquisition ) ( consolidation ) Correct Choices (max 8) month old 18 month old 18 month + 2% BB Time required for Correct Choice (Seconds) Time (weeks) Williams et al, FRBM, 2008 Time (weeks)

27 Hippocampal signalling underlying behavioural effects 60 (1) BDNF (2) AMPA-R NMDA-R TrkB Hippocampal BDNF (pg/mg protein) PKC BDNF CREB PKA CaMK ERK PI3K Akt (3) Postsynaptic Correct Choices (max 8) Arc/Arg3.1 mtor Homer2 Hippocampal CREB activation (pcreb/total CREB) Enhancement of Protein Synthesis and synapse growth/expansion Williams et al, FRBM, 2008 Spencer et al, Chem Soc Rev, 2009 Correct Choices (max 8)

28 Pure flavonoid supplementation and spatial memory Correct choices (max 8) Placebo Number of correct choices (out of 8) Control Blueberry Flavanol 7.0 Blueberry Anthocyanins Flavanols * * Time (weeks) Days of Diet Repeated Measures ANOVA revealed a main effect of Diet [F(6,144) = 7.24, p<0.01] on correct choices. Further post hoc tests show a significant effect of BB (p=0.001), Flavanols (p=0.001) and Anthocyanins (p=0.004) Rendeiro et al., Plos One, in press

29 BB and pure flavonoids induce BDNF expression in the hippocampus Control BDNF mrna Hippocampal BDNF protein CA1 region of hippocampus Blueberry 1.6 ** Relative Band Intensity * * BDNF Pro-BDNF Anthocyanin Flavanol C BB Anthocyanin Flavanol RNase (control) Rendeiro et al., Plos One, in press

Increases in PSA-NCAM in the dentate gyrus of flavanol supplemented animals NCAM PSA-NCAM positive cells (per unit area) 80 70 60 Control Flavanol ** Blueberry (4%)

30 Increases in PSA-NCAM in the dentate gyrus of flavanol supplemented animals NCAM PSA-NCAM positive cells (per unit area) Control Flavanol ** Blueberry (4%) PSA-NCAM Control PSA-NCAM levels in the dentate gyrus were highly correlated with acquisition and recall of the spatial memory task (R= ; p<0.05)

Flavanol-induced hippocampal NMDA receptor

Control Relative Band Intensit y 0.18 0.16 0.14 0.

02 Control 2%BB 4%BB NR2B subunit levels in NMDA

31 Flavanol-induced hippocampal NMDA receptor phosphorylation NMDA-R2B Hippocampus CA3 NMDAR2B GAPDH Control Relative Band Intensit y * ** Flavanol Control 2%BB 4%BB NR2B subunit levels in NMDA receptors are significantly increased in Flavanol-supplemented animals. No changes in NMDA-R1 or R2 RNase

32 Flavonoids Pro-BDNF BDNF? TrKB AMPA Fyn NCAM Polysialylation by ST8SiaII and IV PSA-NCAM NMDAR Increase in glutamate signalling FAK Raf / Ras Ca 2+ PKB/ Akt ERK1/2 mtor TrKB CREB AMPA BDNF Arc / Arg 3.1 NR2B Changes in Structural and Functional Plasticity Learning and Memory Improvements

Cellular and molecular effects underpin multiple physiological activities Flavonoids/ metabolites Inhibition

Arc mtor, VEGF-B, TGF-b Neuroinflammation Neuronal Viability Neuronal Morphology Vascular Effects Suppression

of survival proteins Dendritic spine growth Neuronal communication Synaptic plasticity Increased blood flow

33 Cellular and molecular effects underpin multiple physiological activities Flavonoids/ metabolites Inhibition JNK1/2/3, p38, ASK1 Activation ERK1/2, Akt/PKB STAT-1, c-jun CREB inos, NO Bad, Bcl xl, Caspases BDNF, NRF, Arc mtor, VEGF-B, TGF-b Neuroinflammation Neuronal Viability Neuronal Morphology Vascular Effects Suppression of microglia Reduction in NO production TNF-alpha reduced Inhibition of apoptosis Neuronal survival Expression of survival proteins Dendritic spine growth Neuronal communication Synaptic plasticity Increased blood flow Angiogenesis New nerve cell growth Prevention of Neurodegeneration & Brain Ageing Enhancement of Memory and Cognition

Acknowledgements Dr. Manal Abd El Mohsen Dr. Giulia Corona Dr. Ana Rodriquez-Mateos Dr. Maria-Jose Oruna-Concha Dr. Katerina Vafeiadou Dr. David Vauzour Prof. Judi Ellis Dr.

34 Acknowledgements Dr. Manal Abd El Mohsen Dr. Giulia Corona Dr. Ana Rodriquez-Mateos Dr. Maria-Jose Oruna-Concha Dr. Katerina Vafeiadou Dr. David Vauzour Prof. Judi Ellis Dr. Laurie Butler Dr. Claire Williams Vanessa Collins Georgina Dodd Eva Hernandez Pauline How Susie Jennings Sara Neshatdoust Catarina Rendeiro Caroline Saunders Setarah Tabatabaee Xenofon Tzounis

Editors-in-Chief Prof. Jeremy P.E. Spencer University of Reading Email: j.p.e.spencer@reading.ac.uk Prof. Britt Burton-Freeman, PhD, MS Illinois Institute of Technology Email: bburton@iit.

35 Editors-in-Chief Prof. Jeremy P.E. Spencer University of Reading Prof. Britt Burton-Freeman, PhD, MS Illinois Institute of Technology Nutrition and Aging is an international journal directed to the study of the effects of diets and dietary components on aging and age-related diseases. It is particularly concerned with experimental results emanating from biochemical and pharmacological studies, neuroscience, cardiovascular medicine, and nutritional sciences that demonstrate the effects of dietary constituents on the adverse effects of aging.

Reviewing novel dietary strategies to delay or prevent Alzheimer s disease. Dr David Vauzour

Reviewing novel dietary strategies to delay or prevent Alzheimer s disease Dr David Vauzour Populations are getting older x 2.5 United Nations 2012 Ageing and dementia Global impact of dementia World Alzheimer