Molecular Nutrition Group
School of Chemistry, Food and Pharmacy
The acute and chronic effects of flavanol/
anthocyanin intervention on human
cognitive function
Professor Jeremy P E Spencer
Centre for Integrative Neuroscience and Neurodynamics
Institute for Cardiovascular and Metabolic Research
May 5, 2016
© University of Reading 2008
www.reading.ac.uk
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)
The physiological actions of dietary
flavonoids
Enhancement human memory and
cognition by dietary flavonoids
BBSRC grant (Grant ref. BB/F008953/1): Enhancement of learning and memory by flavonoids
[Start date: 01-04-08, end date: 31-03-11]: £485,357
Measurement of multiple
cognitive domains
Primary domains of human cognition
Impact of cocoa flavanol supplementation
on cognitive performance
63 healthy 65-80 yrs
Acute intervention:
0-2 h
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
High CF product
252
30
494
89
21
384
113
1
1
5
197
16
3
10
9
15
185
507
243
2
272
82
1
0
0
BBSRC grant (Grant ref. BB/F008953/1): Enhancement of learning and memory by flavonoids
[Start date: 01-04-08, end date: 31-03-11]: £485,357
Low CF Product
639
30
29
3
3
20
112
1
1
5
204
16
4
9
9
17
176
573
225
4
247
74
1
0
0
Cocoa flavanol intervention acutely (2h)
improves executive function and episodic memory
Executive Function
Episodic memory
z-score from 5 tests
z-score from 4 tests
p < 0.05
Executive Function
(Z Score)
0.25
0.20
0.0
Episodic Memory
(Z-Score)
-0.5
0.15
p < 0.001
-1.0
0.10
-1.5
0.05
-2.0
0.00
BBSRC grant (Grant ref. BB/F008953/1): Enhancement of learning and memory by flavonoids
[Start date: 01-04-08, end date: 31-03-11]: £485,357
Fl
av
an
ol
H
ig
h
Fl
av
an
ol
Lo
w
Fl
av
an
ol
H
ig
h
Lo
w
Fl
av
an
ol
-2.5
Cocoa (flavanol) and berry (anthocyanin)
intervention acutely improves human
executive function and episodic memory
-1.5
LFC"
HFC"
***"
-2.0
Executive Function Episodic memory
52
50
48
46
1
-0.5
***"
54
0
0.0
-1.0
p=0.09"
56
Time (h)
BBSRC grant (Grant ref. BB/F008953/1): Enhancement of learning and memory by flavonoids
[Start date: 01-04-08, end date: 31-03-11]: £485,357
5
*"
Executive function
(GoNoGo task correct responses)
Cognitive function (z score)
0.5
Difference in correct responses
(Pre to post)
Chronic improvements in cognitive function
following OJ (250 ml/day for 8 weeks)
4
Control
OJ
2
Executive Function/Attention
p = 0.049
Control
OJ
2
0
3
Control
OJ
2
1
J
O
C
on
tro
l
O
J
C
on
tro
l
0
Serial 7s
ses
p = 0.034
4
Difference in correct responses
(Pre to post)
Difference in correct responses
(Pre to post)
Serial 7s
4
4
O
Working memory
DSST
6
J
C
on
tro
l
0
How do they exert such actions
in the brain?
Flavonoids
Cell Signalling and Gene Expression
Changes in
cerebrovascular
blood flow
Modulation of
synaptic plasticity
Inhibition of
Neuroinflammation
Blueberry?)
Cocoa))
Tea)
R1
Flavanols(
HO
R2
O
R3
OH
OH
Lower)
Blood)Pressure)
Improved)Vascular)Func8on)
Decreased))
Blood)Clo=ng)
Reduced)Risk)of)Cardiovascular)Disease)
Flavanols and anthocyanins induce
peripheral blood flow
C"
10
Control
Flavanols (495 mg; cocoa)
Anthocyanins (766 mg; BB)
***"
% FMD
9
*"
***"
8
7
6
0
2
4
Time (h)
6
Time-series analysis on resting state ASL data
- cocoa vs. control intervention (axial slices)
Middle frontal
gyrus
Pre-central
gyrus
Lateral occipital
cortex
!
Flavonoids/
phenolicacids
metabolites
Mechanisms of
action
ERK1/2,Akt/PKB
eNOS
NO
Vascular
endothelium
Increasedmeancerebralblood
perfusion
BBB
Periphery
Brain
Neuron
Akt/ERK
CREB
BDNF,
NRF,Arc
NeuronalMorphology
DendriEcspinegrowth
NeuronalcommunicaEon
SynapEcplasEcity
Neuralac6vitytriggers
neuro-vascularcoupling
nNOS
NO
Region
specific
blood flow
Oxygen/
nutrient
delivery
EnhancementofMemoryandCogniEon
Benefits and novelty
•  Will yield mechanistic insights into flavonoidinduced improvements on cognition.
•  Will yield a mechanistic understanding of both
short- and longer-term effects of flavonoids on
cognition.
•  Will fulfil the Bradford-Hill criteria for causation,
satisfying consistency, specificity, temporality, and
plausibility (mechanistic) factors, necessary to
provide adequate evidence of a causal relationship
between intervention.
Industry relevance
•  Flavanols and anthocyanins are found in a wide
array of sustainable, UK based crops, notably
apples, pears, blackcurrants, raspberries and juices
derived from these.
•  Requirement for novel approaches designed to
improve cognitive health has never been greater
given the increased incidence of age-related
cognitive decline and concomitant
neuropsychological disorders.