Ageing in Indonesia Dementia and Memory - ILSI...

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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:

-If your total cholesterol is high:

-If you smoke:

Kivipleto Arch Neurol. 2005;62:1556-1560.

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.

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

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

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’

Smith & Jobst, 1996 Br Med Bull 0

z-score

memory

z-score

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!

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

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

Baseline1

Baseline2

2 weeks 5 weeks 8 weeks

Tempe Flour

Tahu Flour

Estradiol

Casein

NON OVX

Beta amyloid and treatments after OVX

Sidang Terbuka, 20 Agustus 2013 36

Baseline 1Baseline 2 2 minggu 5 minggu 8 minggu

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)

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?

Ageing in Indonesia Dementia and Memory - ILSI...

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