DEMENTIA PREVENTIONDEBORAH COLSON MSC DIPION

Guildford GP Education – Update WeekRoyal Surrey County Hospital, 6 November 2014

BACKGROUND

Deborah Colson MSc DipION MBANT CNHCNutritional Therapist

• Specialist in nutrition / lifestyle for disorders of nervous system• Institute for Optimum Nutrition (DipION, 2002)• MSc Nutritional Therapy (University of Westminster, 2014)• Author of Optimum Nutrition for Your Child and Optimum

Nutrition for your Child's Mind, Alzheimer's Prevention Plan • Professional Association: British

Association for Applied Nutrition and Nutritional Therapy (BANT)

• Regulator: Complementary and Natural Healthcare Council (CNHC)Professional Standards Authority Accredited Voluntary Register (AVR)

Clinical Practice

• Brain Bio Centre • Clinic for nutritional treatment of mental health

and neurological disorders (since 2003)• Wholly owned by charity Food for the Brain

whose aim is to raise awareness of the link between nutrition and mental health

• Re:Cognition Health• Multi-disciplinary cognitive health clinic

• The Insight Network• Network of therapists and psychiatrists

What is Nutritional Therapy?

• The application of nutrition and health science to enable individuals to maximise their health potential

• Holistic therapy, complementary to medicine• Manages biochemical / nutritional

imbalances which impact health• Genetic, environmental and psychosocial

factors considered

How does Nutritional Therapy work?

• Full case history• Biochemical / nutritional tests recommended• Practical dietary, lifestyle and supplement advice

given, tailored to the individual• Optimise biochemistry• Address risk factors• Manage drug-nutrient interactions• Informed by evidence base• Favourable risk:benefit ratio• ‘Wholistic’ – benefits are broad

Nutrition and lifestyle-related factors

• blood glucose control• essential fatty acids• minerals • Mg, Se, Zn, Cr, Mn, I, Cu, Ca

• vitamins• D, Bs, C, E, A, K

• amino acids• phytonutrients• Mediterranean diet• microbiome

• homocysteine• drug-nutrient interactions• food intolerances• oxidative stress• environmental toxins• stress• sleep• exercise• social activity

Risk Factor Modifiable?

Age XType II Diabetes √Overweight √Hypertension (mid-life) √Dyslipidaemia (mid-life) √Smoking, ↓physical activity √↓Education, mental/social stimulation √Genetics – ApoE et al ?

Well-established dementia risk factors

Other nutrition & lifestyle risk factorsRisk Factor Modifiable?

↑ HbA1c (w/out diabetes) √↓ Adherence to Mediterranean diet √↓Omega-3 / fish consumption √↑Homocysteine / ↓B vitamins √↓Vitamin D √↑Oxidative stress / ↓antioxidant nutrients √↑Alcohol √↓Polyphenols (curcumin et al) √↑Stress √

Reversal of cognitive decline: A novel therapeutic program

• Personalised intensive diet, lifestyle, supplement programme• 10 pts (Alzheimer's, amnestic mild cognitive impairment

(aMCI), or subjective cognitive impairment (SCI))• 9/10 showed subjective or objective improvement in cognition

from 3-6 months (1/10 = very late stage AD). • 6/10 had had to discontinue working or were struggling with their

jobs at the time of presentation, and all were able to return to work or continue working with improved performance.

• Improvements sustained. Longest follow-up is 2.5 years from initial treatment, with sustained and marked improvement.

Bredesen DE (2104) Reversal of cognitive decline: A novel therapeutic program. Aging (Albany NY) 6(9):707-17.

Evidence base

• Limited due to:• Lack of pharmaceutical interest and

non-pharmaceutical funding• Challenge of studying nutrients/diet

in RCT setting• Synergy of nutrients often ignored

Evidence-based practice

“the conscientious, explicit and judicious use of current best evidence in making decisions about the care of the individual patient. It

means integrating individual clinical expertise with the best available external clinical

evidence from systematic research.”

Sackett D, 1996

Evidence-based practice

EBP: Hierarchy of evidence

BMJ Clinical Evidence

DEMENTIA

Blood glucose

• Diabetes is a known risk factor• n = 2 067, mean age 76 yrs• In subjects without diabetes, higher glucose levels

(6.4 vs 5.5 mmol/l) in preceding 5 years associated with increased risk of dementia HR 1.18 (95% CI 1.04 - 1.33) p=0.01

• In subjects with diabetes, higher glucose levels were also related to an increased risk of dementia (p=0.002)• glucose level 10.5 mmol/l vs 8.9 mmol/l, HR 1.40 (95% CI, 1.12 -

1.76)

Crane et al (2013) Higher glucose levels may be risk factor for dementia (even in absence of diabetes). NEJM 369(6):540-8

2008, 5:51

Genetic factorsApoE ε4 PSEN-1, -2,

othersEnvironmental factors

Trauma, toxins, diet

Biological factorsHTN, CVD, DMhypoperfusion

Vascular compromise

Oxidative stress

Neuroinflammation

βAmyloidTau (hyperphosphorylation

Carbs vs protein

• n = 24, obese, premenopausal women (20-50yrs) no diabetes or prediabetes randomised to:• 6 months, 500 kcal/day• HP (30% protein, 40% carbohydrates, 30% fat), or• HC (15% protein, 55% carbohydrates, 30% fat)

Kitabchi AE et al, (2013 ) Effects of high-protein versus high-carbohydrate diets on markers of β-cell function, oxidative stress, lipid peroxidation, proinflammatory cytokines, and adipokines in obese, premenopausal women without diabetes: a randomized controlled trial. Diabetes Care 36(7):1919-25

Kitabchi AE et al (2013 ) Diabetes Care 36(7):1919-25

High protein (HP) vs high carbohydrate (HC)

CRP ( -2.1 vs. -0.8 mg/L, P = 0.0003) inflammation √TNFα (-1.8 vs. -0.9 pg/mL, P < 0.0001) inflammation √IL-6 (-1.3 vs. -0.4 pg/mL, P < 0.0001) inflammation √E-selectin (-8.6 vs. -3.7 ng/mL, P = 0.0007) inflammation √

β-cell function (7.4 vs. 2.1, P < 0.0001) metabolic/obesity/DM √

insulin sensitivity (4 vs. 0.9, P < 0.0001) metabolic/obesity/DM √adiponectin (1,284 vs. 504 ng/mL, P = 0.0011) metabolic/obesity/DM √free fatty acid (-0.12 vs. 0.16 mmol/L, P = 0.0002) dyslipideamia √REE (259 vs. 26 kcal, P < 0.0001) metabolism √dichlorofluorescein (-0.8 vs. -0.3 µmol/L, P < 0.0001) cellular oxidative stress √

malondialdehyde (-0.4 vs. -0.2 μmol/L, P = 0.0004) lipid peroxidation √

Omega-3 Omega-6ALA

18:3 ω−3

EPA20:5 ω-3

DHA22:6 ω-3

LA18:2 ω−6

eicosanoids, resolvins(anti-inflammatory)

AA20:4 ω-6

GLA18:3 ω−6

DGLA20:3 ω−6

eicosanoids(anti-inflammatory)

eicosanoids(pro-inflammatory)

oily fish

linseeds, walnuts

and their oils,

green veg

nuts, seedsseed oil

Evening Primrose Oil / borage oil

meatdairy

∆6 desaturaseMg, Zn, B3, B6, C

trans fats, alcohol, stress, sat fats

∆5 desaturaseMg, Biotin

trans fats, alcohol, stress, sat fats

resolvins, protectins(anti-inflammatory)

RBC omega-3 and brain ageing

Lower RBC DHA levels are associated with smaller brain volumes and a “vascular” pattern of cognitive impairment even in

persons free of clinical dementia

Tan Z.S. et al., 2012 Red blood cell omega-3 fatty acid levels and markers of accelerated brain aging. Neurology, 78(9):658-664

Omega-3 and fish

• Prospective study, Chicago Health and Aging Project (CHAP), 1993-2000, followed up 3.9 years for development of AD

• n = 815 community-dwelling, 65-94 years, free from AD• 131 developed AD• Fish ≥ 1/week: 60% less risk of AD vs non-consumers (RR, 0.4;

95% CI, 0.2-0.9)• Total intake of omega-3, and DHA intake associated with

reduced risk of AD. EPA not associated with AD• Conclusion: Dietary intake of n-3 fatty acids and weekly

consumption of fish may reduce risk of incident Alzheimer disease.

M. Morris, et al.. (2003) Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol, 60:940-946

Omega-3 and fish• Prospective cohort, 210 elderly• Fish consumers had significantly less 5-y subsequent

cognitive decline than nonconsumers (p = 0.01)• Linear trend for relation between the intake of EPA+DHA

and cognitive decline (p = 0.01)• An average difference of 380 mg/d in EPA+DHA intake

was associated with a 1.1-point difference in cognitive decline (p = 0.01).

van Gelder et al., (2007) Fish consumption, n-3 fatty acids, and subsequent 5-y cognitive decline in elderly men: the Zutphen Elderly Study, Am J Clin Nutr. 85(4):1142-7

Cochrane Review: Omega-3

“Direct evidence on the effect of omega-3 PUFA on incident dementia is lacking”

Sydenham E et al., (2012) Cochrane Database Syst Rev. Omega 3 fatty acid for the prevention of cognitive decline and dementia. 13;6:CD005379.

BDNF

• Brain-derived neurotrophic factors• Neurogenesis occurs throughout life• New neurons are fragile and survival is uncertain• BDNF supports survival of these neurons and

synaptic connections• Exercise, vitamin D, omega-3 promote BDNF

Vitamin D

• Higher serum vitamin D3 levels are associated with better cognitive test performance in patients with Alzheimer's diseaseOudshoorn et al, Dement Geriatr Cogn Disord. (2008)

• Vitamin D deficiency is associated with low mood and worse cognitive performance in older adultsWilkins et al, Am J Geriatr Psychiatry (2006)

• Vitamin D inversely associated with increased odds of cognitive impairment (p for linear trend = .001)Llewellyn et al, (2009) Serum 25-Hydroxyvitamin D Concentration and Cognitive Impairment. J Geriatr Psychiatry Neurol.

Vitamin D

• Hypovitaminosis D is prevalent among older adults

• Stimulates neurotrophin release (BDNF)• Protects the brain by buffering antioxidant and

anti-inflammatory defences against vascular injury and improving metabolic and cardiovascular function

Cherniack EP et al., (2009) Some new food for thought: the role of vitamin D in the mental health of older adults. Curr Psychiatry Rep. 11:12-9

Sources of vitamin DFull-body exposure to UVB 10,000 iu D3

(15 to 20 minutes at midday in summer, fair skin, no sun-block)

Cooked tuna sardines, mackerel 200 – 360 iu D3

or salmon (3-3.5 oz)

Shitake mushrooms 100 iu D2

(fresh 3.5 oz)

Egg yolk 20 iu D2 or D3

Cod liver oil (1 tbspn) 1,360 iu D3

200 iu = 5µg 10,000 iu = 250µg

Vitamin D – how much?

• 5000 iu/day vitamin D3 for 12 months increased serum D to > 74 nmol/l for 92% of 45 nursing home residents.

• Average level 125 nmol/l. • No adverse effects seen

Mocanu V et al., (2009) Long-term effects of giving nursing home residents bread fortified with 125 µg(5000 IU) vitamin D(3) per daily serving. Am J Clin Nutr. 89(4):1132-7

Homocysteine

“77 cross-sectional studies on >34,000 subjects and 33 prospective studies on

>12,000 subjects have shown associations between cognitive deficit or dementia and

homocysteine and/or B vitamins”

Smith AD (2008) The worldwide challenge of the dementias: a role for B vitamins and homocysteine? Food Nutr Bull. 29(2 Suppl):S143-72

35

Homocysteine

• Treatment with B vitamins (FA, B6, B12) for 24 months significantly slowed the rate of brain atrophy in elderly subjects with MCI

• Rate of atrophy per year (p =0.001)• B vitamins = 0.76% [95% CI, 0.63–0.90]• placebo = 1.08% [0.94–1.22]

• Greater rate of atrophy was associated with lower final cognitive test scores

Smith AD et al. (2010) Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial. PLoS ONE

Homocysteine-lowering nutrients

• Folic acid 400µg Green, leafy veg, pulses• Vitamin B12 100µg Animal products (eggs, meat,

dairy etc)• Vitamin B6 20mg Eggs, cheese, fish, mushrooms,

broccoli, lentils, yoghurt, nuts• Vitamin B2 10mg Wholemeal bread, oily fish,

walnuts, lentils, bananas, chicken• Zinc 5 mg Sardines, eggs, tofu, oysters,

lamb, seeds, nuts

• These levels may be found in a good multi or B-complex

How much B12?

• 50µg/day effective in restoring normal B12 status in people over the age of 50

• 10µg/day no more effective than placebo• UK RDA = 1.5µg/day

Seal et al., (2002) A Randomized, Double-Blind, Placebo-Controlled study of Oral Vitamin B12 Supplementation in Older Patients with Subnormal or Borderline Serum Vitamin B12 Concentrations Journal of the American Geriatric Society, vol 50, pp. 146-151

How much B12 ?• Dose-finding RCT to determine lowest oral dose of cyanocobalamin to

normalize biochemical markers of vitamin B12 deficiency in older people with mild vitamin B12 deficiency• defined as a serum vitamin B12 level of 100 to 300 pmol/L (135-406

pg/mL) and a methylmalonic acid (MMA) level of 0.26 µmol/L or greater.

• n = 120, 16 weeks, daily oral doses used: 2.5, 100, 250, 500, and 1000 µg

• Mean reductions in MMA: 16%, 16%, 23%, 33%, and 33%, respectively• 647 - 1032 µg/d cyanocobalamin associated with 80% - 90% of

estimated maximum reduction in MMA• Conclusion: Lowest dose of oral cyanocobalamin required to

normalize mild vitamin B12 deficiency is more than 200 times greater than the Dutch RDA, which is approximately 3 µg daily.

Eussen et al., (2005) Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dose-finding trial, Arch Intern Med

Mediterranean diet

Published studies suggest that greater adherence to Mediterranean diet is associated with slower cognitive decline and lower risk of

developing Alzheimer disease.

Lourida et al, (2013) Mediterranean diet, cognitive function, and dementia: a systematic review. Epidemiology

Vitamin E

• n = 5395, 55+ years, free of dementia, provided dietary information at baseline

• mean follow-up period of 9.6 years• higher intake of vitamin E at study baseline was associated

with lower long-term risk of dementia (P = .02 for trend). • Lowest tertile of vitamin E intake vs highest tertile were 25%

less likely to develop dementia (HR 0.75; 95% CI 0.59-0.95)• Dietary intake of vitamin C, beta carotene, and flavonoids were

not associated with dementia risk (P > .99 for trend for vitamin C and beta carotene and P = .60 for trend for flavonoids)

Devore EE et al, (2010) Dietary antioxidants and long-term risk of dementia. Arch Neurol. 67:819-25.

Superfoods??

• Turmeric (curcumin) • Berries (flavonoids, anthocyanidins)• Brassicas (sulphoraphane)• Green tea (catechins, L-theanine)• Grapes / wine (resveratrol)• ..........

Polyphenols

• Produced by plant as defence mechanism• UV radiation, browsing animals, infection• Hormetic response to stress

• Not part of our biochemistry• Not used for structure or to activate enzymes• Affect quality of our biochemistry• Regulators of our microbiome

Polyphenols

• Potential role as neuroprotective agents. • Curcumin, catechins, and resveratrol (beyond their

antioxidant activity) are involved in anti-amyloidogenic and anti-inflammatory mechanisms.

• Correlations between neuroprotective functions and potential therapeutic value in AD.

Davinelli S et al., (2012) Pleiotropic Protective Effects of Phytochemicals in Alzheimer's Disease Oxid Med Cell Longev. doi: 10.1155/2012/386527

Polyphenols

• Food sources:

• Colourful fruits, vegetables, herbs, spices, seeds, nuts

Cochrane: Exercise and dementia

...promising evidence that exercise programs can have a significant impact in improving

ability to perform activities of daily living and possibly in improving cognition in people with

dementia

Forbes D et al, (2013) Exercise programs for people with dementia. Cochrane Database Syst Rev 12:CD006489.

Alcohol• A J-shaped relationship may exist between alcohol consumption and

cognitive decline in MCI patients

Xu G et al., (2009) Alcohol consumption and transition of mild cognitive impairment to dementia. Psychiatry Clin Neurosci. 63:43-9

• In MCI pts, up to 1 drink/day of alcohol or wine may decrease the rate of progression to dementia.

Solfrizzi V et al., (2007) Alcohol consumption, mild cognitive impairment, and progression to dementia.; Italian Longitudinal Study on Aging Working Group. Neurology 68:1790-1799

• Some evidence to suggest that limited alcohol intake in earlier adult life may be protective against incident dementia later

Peters R et al., (2008) Alcohol, dementia and cognitive decline in the elderly: a systematic review. Age and Ageing 37:505-512

Drug-nutrient interactionsDrug Effect

PPIH-2 receptor antagonists

↓ B12, minerals

Metformin ↓ B12

Statins ↓ Co-enzyme Q10

Advice for the patientDo:• Eat low-carb Mediterranean

style• ↑ vegetables, fresh fruit, seeds,

nuts, legumes, cereals, oils, fish, eggs

• X trans fats, refined carbs, sugar

• Engage in physical, mental and social activity

• Consider supplementing fish oil, multi / B-complex, vitamin D

• Drink water

Don’t:• Eat BAD

• British Average Diet

• Eat sugar or refined carbohydrates

• Drink juice• Smoke• Over consume alcohol or

caffeine• Be chronically stressed

What can you do?

• Test homocysteine• B vitamin supplementation to bring down to 8µmol/l

• Test B12• B12 supplementation (100µg/day) to maintain in top

half of range• Test red cell folate• Folate supplementation to maintain in range

• Test vitamin D3• D3 supplementation to maintain above 125 nmol/l

Deborah Colson MSc DipION e deborah@thinkingnutrition.co.uk w www.thinkingnutrition.co.uk

@thinkinutrition 07957 277 811