ILSI Europe Satellite Workshop on
‘Nutrition for the Ageing Brain: Towards
Evidence for an Optimal Diet’
03-04 July 2014, Milan, Italy
Organised by
The ILSI Europe Nutrition and Mental Performance Task Force
What is the potential role of exercise and
nutrition (and stress) in cognitive ageing? can exercise enhance micronutrient effects?
Eef Hogervorst
Ageing in Indonesia Study of Elderly’s Memory impairment and
Associated Risk factors (SEMAR)
• N=719 participants from rural and urban
Java (Jakarta, Citengah and Yogyakarta)
• Aged 52 to 99 years of age, 68% women
Similar cohort studies now in China
Shanghai (n=800) (Singapore, India)
-Diagnoses (screening)
-Risk factors
-Treatment
Dementia
diagnostics
The clinical diagnosis is based on history of cognitive decline,
in particular of memory, which can not be explained by other
disorders and which interferes with activities of daily life.
Most common clinical diagnosis Alzheimer’s disease
Risk factors Things we
cannot change:
Getting older, gender, having little education,
genetics
Things we can change:
smoking, diet, exercise
Midlife
Being obese, high blood pressure/cholesterol/diabetic
Increased risk for cardiovascular disease
=increased risk for dementia
Midlife disease risk factors
for dementia risk in later life:
-If you are obese (BMI>30 kg/m2) :
you double your risk
-If you have high blood pressure:
you double your risk
-If your total cholesterol is high:
you double your risk
-If you smoke:
you double your risk
Kivipleto Arch Neurol. 2005;62:1556-1560.
0
1
2
3
4
5
6
7
0 risk
factors
1 risk
factor
2 risk
factors
3 risk
factors
O.R. for
dementia
Exercise
• Can lower blood pressure, total cholesterol,
abdominal fat (cytokines?), glucose (DM)
• Can improve blood flow to the brain, improve
vascular function (hypoxia), immune system
• By acting directly: decreasing toxicity beta-
amyloid, increasing neurotransmitter synthesis
• Increasing neurogenesis in hippocampus,
improving synaptogenesis etc.
Liu-Ambrose et al, 2008, van Praag, 1999
Exercise in old rats improves
dendritic sprouting
Study of Elderly, Memory impairment and
Associated Risk Factors Clifford, 2010; Stock, in press
Engaging in sport is associated with better memory (HVLT)
and global cognition (MMSE) in elderly
Engaging in sport halves dementia risk
Stand.
Beta
t p R2
change
p Exp(B) p
HVLT .136 3.308 .001 .012 .001
.449 .076
MMSE .174 4.248 .000 .020 .000
Can exercise prevent long term cognitive decline ? Angela Clifford (2009); Hogervorst (2012)
*Clifford, A., Bandelow, S. & Hogervorst, E. The effects of physical exercise on cognitive function in the elderly: a review. In: Q. Gariépy & R.
Ménard (2009). Handbook of Cognitive Aging: Causes, Processes and Effects (pp. 109-150). New York: Nova Science Publishers
* Yes, but:
i) Exercise may affect simple (memory) abilities
(span) ii) Women may benefit more than men
iii) not all types of exercise (yoga is not effective
for memory but may help with balance and flexibility)
iv) Effects of exercise may depend on type
-50% of aerobic exercise studies (running/cycling/swimming)
-most of resistance (anaerobic) training RCT!
Exercise program cross-over RCT (n=21)
Progressive resistance training:
Programme of 6 exercises using
resistance bands
3x week 20-30 min
home-based
Flexibility training:
Programme of 7 yoga exercises
*Team Colours
Cognitive testing
Mini Mental State Examination (MMSE) Hopkins Verbal Learning Task (HVLT) Verbal Fluency (VF) � Trail Making Test (TMT) Stroop Colour-Word Test Flanker Task Corsi Blocks Task Visual Search Task
Other measures include diet, mood, social support, height, weight, BMI, blood pressure, resting heart rate, waist:hip ratio, timed up-and-go test
Aim: To investigate if 12 weeks of resistance training can lead to improvements in cognitive performance in a middle-aged, sedentary healthy sample
Training made no difference to global or complex cognition
(MMSE/TMT)
Resistance training led to improvements on memory (HVLT and VF)
in women
strength strength
yoga yoga
Exercise can also help in dementia: Mixed stretching/strength (60% VO2max)
Global cognitive (MMSE) performance in 60+ elderly with dementia
Kwak 2008
Not all studies found positive effects of
exercise when pts have dementia
• Aroverde (2008): AD no effect of mixed exercise
on MMSE (very low intensity)
• Van Uffelen (2008): walking no effect in MCI (but
people did not do exercise well: range 2-81%)
• Kwak (2005) and Scherder (2008) both included
mainly older women, similar to effects of
observational studies and exercise treatment for
elderly without dementia
(Clifford, 2009a,b; Hogervorst, 2012 JADP)
Exercise is good
but
Diet is also important
Sir Ran Fiennes, Photo: MARTIN HARTLEY from Telegraph website
Micro-nutrients and cognition
• Anti-oxidant vitamins (vit E, C, A, (D))
Levels are lower in AD ,may protect against cognitive
decline=controversial (Dangour,2004; Lopes da Silva 2013)
Whole foods vs supplements ?
Berries, apples , soy etc. are better if they are stressed!
• Increasing levels of B vitamins (folate, vit B12, vit B6) to reduce homocysteine
What about exercising and
eating fruit?
ANOVA: Tests of Between-Subjects Effects
Dependent Variable: total immediate recall HVLT (memory)
Source df F Sig.
Corrected Model 6 72.636 .000
Intercept 1 74.835 .000
SPORT * FRUIT 1 5.415 .020
FRUIT 1 2.837 .093
SPORT 1 13.283 .000
AGE 1 47.800 .000
SEX 1 4.431 .036
EDUC 1 120.165 .000
Error 664 36.479
Total 671
Corrected Total 670
R Squared = .396 (Adjusted R Squared = .391)
Serum folate in Alzheimer’s disease
0
20
40
60
80
100
Cumulative
frequency
(%)
0 5 10 15 20
Serum folate (mg/l)
Controls
Clinical DAT
p < 0.0001
AD histopath. p < 0.0001
OPTIMA, Arch. Neurol. (1998) 55: 1449
Wang et al. Neurology (2001) 56, 1188
Dementia O.R. 1.8 [1.1-2.8]
Alzheimer’s O.R. 2.1 [1.2-3.5]
Low folate levels or low vitamin B12 levels were associated with an increased risk of developing:
Prospective Kungsholmen Study
over a three year period
B vitamins and cognitive dysfunction
- Review of 19 treatment studies (Ford, 2012 JAD):
no effect of B vitamins on improving cognition
- Similar findings in earlier review (Malouf, 2003 Cochrane):
4 randomized controlled trials provide no evidence for improvement in people with CI/dementia
of folic acid with or without vitamin B12 or B6
- Later Cochrane update incl. 8 studies (2008):
There is some effect: e.g. better response to cholinesterase treatment OR if without dementia AND if tHcy are high (De Jager, 2013)
B vitamines help stop brain shrinkage by 30% in
those with memory problems, but not dementia
Folic acid (0.8 mg/d), vitamin B12 (0.5 mg/d) and
vitamin B6 (20 mg/d), over a 2 year period in n=168
elderly with memory problems (Smith, 2010) (http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0012244)
This part of
the brain is
50% smaller
in people with
Alzheimer’s
and losses
mass 10
times faster
over a years’
time
Smith & Jobst, 1996 Br Med Bull 0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
z-score
memory
z-score
speed
Difference in
cognitive
performance
with folic acid
compared with
placebo
3 year period folic acid (0.8 mg/d)
FACIT n=818, normal 50-70 yr
Durga (2007) Lancet
Souvenaid: combination (Choline,phospholipids, folic acid, vit B12, vit B6, C, E, selenium, uridine docosahexaenoic acid, EPA/DHA
Lopes da Silva: 2013 Vitamin A, folate, B12. C (D) E and zinc are lower in
AD (many studies in this review, however, showed no difference)
Scheltens, 2010; 2012: 12 weeks: positive effect on delayed recall (n=225)
24 weeks, idem positive effect on memory and EEG in AD, not ADAS-Cog
Shah 2013: n=527 24 weeks: no difference between groups on ADAS-Cog
Mild to moderate AD -- > NEEDS MORE WORK! (e.g. with exercise)
Barnard 2014 Neurobiology of Aging
Guidelines from meeting Nutrition and Brain Washington 2013
Cut down on trans and saturated fat, eat more veg and fruits
BUT do not take vitamin E suppl.-> from food (risk folic acid)
Be careful with iron and copper supplements (Squiti 2014 etc.
Vitamin B12 (absorption) and may need supplements/inject
What about the Indian diet?
Previous data show:
Reduced risk dementia India
Lentils
-decreased cholesterol (fiber)
-low GI: better for blood sugar
39% iron intake with 1 cup
90% folate intake!!
What about dahl? Tumeric: curcumin
-decreased beta-amyloid plaques,
-delayed degradation of neurons,
-anti-inflammatory/antioxidant
etc.(but low bioavailability?)
-> No pos effect of ‘jamu’ in Indonesia,
only when tumeric was eaten fresh!
But
Case studies show positive effects
in reducing Alzheimer’s symptoms
Mediterranean diet
reduces dementia risk (Lorida 2013)
Olive oil
fights amyloid plaques (oleocanthal)
improves immune system
better vascular health
Reduced risk of dementia (Berr, 2009; Lourida, 2013)
Fewest dementia cases after
nuts (vit E!) + MED diet 6 years (compared to olive oil or low fat)
in n>500 elderly at risk for CVD
(Martinez-Gonzales, 2013 JNNP)
Combinations?:
olive oil+ green vegetables=> nitro fatty acids: lowers blood pressure (by blocking epoxide hydrolase).
Charles et al (2014 Proc Natl Aca Sci)
Superfoods
Folate:
beans, citrus
Green leafy
vegetables:
Broccoli, kale
Spinach also E
For vit B12
Red meat,
Eggs (for B12)
Hard if you are
Vegan!!
Soy products
In those over 68 years of age in rural Borobudur :
• Tofu intake (total/wk) increased risk by 30%
• Tempe intake (total/wk) reduced risk by 20%
Controlled for age, sex, and education, and, in
separate analyses, other foods (fruit intake)
(Hogervorst, 2007; 2011)
Same found in Shanghai: Tofu increased risk of
dementia in old, but eating meat, green veg and
exercising halved risk (Xu in press JAD)
Soy products
Tofu or tahu is made of soybean curd
Tempe is made of the fermented
whole soybean
Could folate protect against high
levels of estrogenic compounds ?
RATIO TE2 / (TE2 + TE1)
0.600.500.400.300.200.1000.00
Min
i-Men
tal S
tatu
s E
xam
inat
ion
(0-3
0)
30
25
20
15
10
5
0
High serum folate
Rsq = 0.0718
Low serum folate
Rsq = 0.1565
Source: Hogervorst, 2002 Neuro Endocrinol Lett.; 23(2):155-60.
Data from OPTIMA
showed that women
with high estrogen levels
who also had high levels
of serum folate did not
perform below the cut-off
of 25 on the MMSE
Atik Kridawati (2010)
Bogor: OVX rats
Tempe improved
brain volume and memory
Memory function
after treatments + OVX
Sidang Terbuka, 20 Agustus 2013 35
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Baseline1
Baseline2
2 weeks 5 weeks 8 weeks
Co
gn
itiv
e f
un
cti
on
sco
re
Tempe Flour
Tahu Flour
Estradiol
Casein
NON OVX
Beta amyloid and treatments after OVX
Sidang Terbuka, 20 Agustus 2013 36
70
90
110
130
150
170
190
Baseline 1Baseline 2 2 minggu 5 minggu 8 minggu
Beta
Am
ilo
id (
pg
/ml)
Tempe
Tahu
Estradiol
Kasein
NON OVX
Oral health and dementia
Several studies found doubled risk for dementia and having <10 teeth (Okamoto, 2010; Stein, 2007; Kim, 2007; Setyawan, 2009)
Why ?
Because of forgetfulness: poor oral hygiene
Because of oral disease, chronic inflammation: increase cytokines/CVD
Because of oral disease: smoking/poor nutrition?
Protein
• Tyrosine (AA): precursor dopamine important in
cognitive ageing (Backman)
• In protein (from phenylalanine: chicken, turkey, fish,
diary, seeds, beans, soy)
• Fiatatrona 1994: resistance exercise+ suppl (soy
protein e.o.) for frail (87 years): better muscle
function+ carry-over effect: diet/spont activity >
exercise or nutrient supplement 10 wk RCT
• Vd Rest 2014: same: resistance exercise+
protein (2x15 g/day): improved info processing
exercise alone: attention/WM 24 wk RCT n=127)
Conclusion
• Risk factors for Alzheimer’s disease are the same as those for cardiovascular disease, e.g. high blood pressure, smoking, high cholesterol, obesity, lack of folate/vit B12
(vOsch, 2004 Neurol; Hogervorst 2002b Arch Neurol, Kivipleto, 2005)
• These cardiovascular risk factors (obesity, smoking, high cholesterol/blood pressure etc) need to be treated in midlife/before sympt to reduce risk of dementia in later life
• Supplements other than vitamin B12 are not needed when a varied diet is followed with sufficient vegetables/fruit, beans, legumes and nuts/seeds, whole grains but little meat /fatty fish/olive oil, diary (yogurt). Role of sugars and stress/sleep/siesta!! needs more attention (OPTIMA)
Acknowledgements
• University of Indonesia
(Prof Tri Budi Rahardjo)
Shanghai (Prof Xiao Shifu)
• OPTIMA
University of Oxford (Professor A. D. Smith)
• MRC CFAS
University of Cambridge
(Prof C. Brayne) • This work was supported
with grants from MRC Wellcome Trust, RIA, NDA
Treatment for cardiovascular disease risk factors
in old age probably will not affect dementia risk
• Treating blood pressure in AD can lead to hypotension(falls
• Not much effect statins (to lower cholesterol) to reduce
dementia symptoms (=too late) see Cochrane reviews
• Giving sex steroids (estrogens) to elderly increases risk
dementia, is only effective in midlife (Hogervorst, 2013)
• Reducing body weight in older age may not b good (Morley)
• Feeding helps to reduce cachexia in dementia (forget)
Better to improve fitness and muscle mass (frailty) by using
exercise to prevent falls. Also positive effects in dementia
Prevention of dementia:
a lifelong approach
Increasing risk for dementia
and dependence
Decreasing risk: building up reserve capacity
When to intervene?
In mid-life: as ‘risk’ factors change later
• High blood pressure is seen 15 years before onset of the actual
disease (in midlife), but we see a decrease in blood pressure 1-2
years before the onset of dementia (Skoog, 2003)
• Patients with Alzheimer’s disease often have lower blood pressure
(Hogervorst, 2002). Must be treated as early as possible in midlife
• Same for high total cholesterol and obesity!
The Swedish prospective
population study of women Mielke, 2010, Neurology
decline in cholesterol
predicts dementia
risk OR=2.35
Mental Activity and
physical eXercise trial (MAX) (Barnes, 2013. JAMA)
- Inactive older adults (n=126, 73 yrs)+ cognitive complaints
- 12 weeks of 60 min x 3 day/wk physical (aerobic/strength vs stretch)
- with/without mental activity (computer games or educational DVD) :
better global cognitive function BUT
NO difference between intervention and active control groups.
AMOUNT but not type of activity? Practice effects?
