5/11/2019

Nutrition and the Brain: What is the Connection?

Wisconsin Dells, Wisconsin May 21th,2019 # 206 Room F 2.00p-3.00p Prof. Piero Antuono MD Research Center Department of Neurology and Biophysics The Medical College of Wisconsin

Conflict of Interest Statement

• I am not an epidemiologist • I am not a or nutritionist • I like to eat • I like to cook

What you will hear today

• Oxidation aging, disease and • Metabolic risk factors for Alzheimer disease and brain reserve • How diet can change the brain (basic science evidence) • How diet can change brain function (clinical evidence)

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The picture above shows iron rust. Oxygen reacts with steel, in a process called oxidation. It gives a grey and red color, and soon, steel d Oxidation can also been seen in food, turning rancid cooking oils or transforming nice apples into sad brown food. This process of oxidat

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Mid Life Risk and Protective Factors

• Leisure time (Helms 2010,Aliskog 2011) • Lipids (Kivipelto 2010,Hysagama 2011) • Hypertension (Sprint study, 2018) • Physical activity (Erickson 2011, Liang 2010) • Wine (Arntzen 2010) • Retirement time (Lupton 2010) • (Xu 2010, Gustafson 2011) • (Scarmeas, 2010)

Nutrition, obesity and dementia

Overweight Children, 1965-2005

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Obesity and AD

Gustafson D et al, Arch Intern Med, 163: 1524-1528, 2003

Possible mechanisms that may explain the association between vascular risk factors and an increased risk of developing dementia

Middleton, L. E. et al. Arch Neurol 2009;66:1210-1215.

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•Risk factors

Brain Reserve Memory loss and Alzheimer

Aging

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The combined relationships of sitting and physical activity with all-cause mortality

All participants No health issues Subjects at baseline with CVD DM

van der Ploeg, H. P. et al. Arch Intern Med 2012;172:494-500.

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•Xu Chen, Li Gan : An exercise-induced messenger boosts memory in Alzheimer’s disease • Nature Medicine volume 25, pages20–21 Published: 07 January 2019

HIPPOCAMPUS 19:1030–1039 (2009) Aerobic Fitness is Associated With Hippocampal Volume in Elderly Humans

Kirk I. Erickson,1* Ruchika S. Prakash,2,3 Michelle W. Voss,2,3 Laura Chaddock,2,3 Liang Hu,4 Katherine S. Morris,4 Siobhan M. White,4 Thomas R. Wo´jcicki,4 Edward McAuley,2,4 and Arthur F. Kramer2,3

Scatterplots showing that with an increase in fitness (VO2 peak) there is an increase in hippocampal volume (cm3). Correlations for both the left and right hippocampus with fitness remained significant even after including age, sex, and years of education as covariates. HIPPOCAMPUS 19:1030–1039 (2009)

Nutrition

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Dementia: Neuropathology

Fruit Polyphenolics

Phenolics

Simple Phenolics

Flavonoids Hydroxycinnamates

 Anthocyanins  Flavonols Blueberries are rich in these  Proanthocyanidi ns  Courtesy of W. Kalt, Ph.D. Catechins

Possible Mechanisms in the Beneficial Effects of the Polyphenolics

• Functional antioxidant effects/anti-inflammatory effects –Decreased sensitivity to oxidative stress –Decreased sensitivity to neurotoxins and inflammatory agents –Increased calcium clearance –Membrane effects. –Alterations in signaling • Decreased inflammatory signaling • Decreased oxidative stress signaling • Increased protective signaling • Signaling in learning and memory

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ORAC (1 g fresh wt μmol trolox equiv/g)

Fresh Fruit Veggies and Legumes Blueberries 2400 Kale 1770 Blackberries 2036 1260 Cranberries 1750 Brussels 980 Strawberries 1540 sprouts Raspberries 1220 Alfalfa 930 Plums 949 sprouts Avocado 782 Broccoli 890 Oranges 750 florets Red grapes 739 Beets 840 Cherries 670 Red bell p. 460 Kidney b. 460

ORAC=oxygen radical absorbance capacity. Onions 450 Courtesy of , Ron Prior Ph.D. Corn 402

Effects of Irradiation and Diet on Survival Time a* b b 400 Non-irradiated Radiated 350

300

250

200

Survival(Days Postirradiation) Control Blueberry Strawberry Diet *Means not sharing a common letter are significantly different from one another (P<.05). Courtesy of J. Joseph, PhD.

Fruits and Veggies That Alter Behavioral Deficits in Aging

James A. Joseph PhD • Memory Neuroscience Laboratory – Spinach USDA – Strawberries – Cranberries Research Center on Aging – Black currant Tufts University – Purple Grape Juice Boston, Massachusetts – Plum Juice – Blueberries – Walnuts • Motor: – Cranberries – Purple Grape Juice – Blueberries – Strawberries – Walnuts

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Calorie restriction and Ab (APP 670/671/717 &APP/PS1 mice)

Patel NV et al, Neurobiol Aging 26: 995-1000, 2005

Calorie restriction, but not reduces A and tau pathology

Total (mAb HT7) and p-tau, (mAb At8) s Hippocampus, , * p<0.05

Kumar et al, Neurobiol Disease 26: 212-220, 2007

DHA decreases insoluble A and lowers plaque burden

Lim GP et al, Neurobiol Disease, 25: 3032-3040, 2005

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Lipid diets and dementia (APPswe/PS1dE9)

Typical Western diet is with 40% saturated fatty acids!

FO fish-oil based diet (n-3 PUFAs) SO soy oil-based standard diet (n-6) CO corn oil-based diet (n-6) DHA supplemented diet also decreases A and activated microglia Effect of various lipid diets on hippocampal A42 Concentrations (a) and A42 surface area (b) Oksman et al, Neurobiol Dis, 23: 563-572, 2006

Curcumin (Tumeric) • Antioxidant and antiinflammatory properties • Inhibits in vitro lipid peroxidation of the brain • Scavenges NO-based radicals • More potent than vit E as a free scavenger • Antiatherogenic agent

Curcumin and Ab aggregation

A40 A 6 days incubation

A40 3 days incubation

Curcumin - 0.125M 2M

Yang F et al,J Biol Chem 280: 5892-5901, 2004

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Curcumin and Ab

Yang F et al,J Biol Chem 280: 5892-5901, 2004

Pomegranate juice and Ab

Brain A load in APPswe. Mice treated with PJ have less A and fibrillar (thioflavine-S+) A in the hippocampus, no statistically significant reductions in the dorsal cortex.

Hartman RE et al, Neurobiol Dis 24: 506-515, 2006

Rhubarb and A

Normal +A

IMR-32 cells after 48 h in medium (A), treated with 10 mM Ab (B), incubated with Ab in simultaneous presence of 30 m M rhaponticin (C) or rhapontigenin (D). Misiti F et al, Brain Res Bull 71: 29-36, 2006

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Clinical studies

Micronutrients/ Macronutrients/ Antioxidants: Lipid metabolism: Vitamine A, C, E ApoE Flavanoids PUFA Folic acid Caloric HomocysteineRestriction B6/B12 BMI

CHAP: Chicago Health and Aging Project

Map of Chicago CHAP: Chicago Health and Aging Project L a •Door-to-door census k e •Home interviews: 6,158 persons 65+yrs (79% of all eligible residents)

Successive Cohorts and expansion of study community to 9,000+

Clinical Evaluations for AD on stratified random samples

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CHAP: Fish Intake and 4-Year Incidence of AD FISH INTAKE Never 1-3/month 1/week 2+/week

RR 1.0 0.6 0.4* 0.4*

(95% CI) (0.3-1.3) (0.2-0.9) (0.2-0.9)

* adjusted for age, sex, race, education, total energy intake, APOE4

Morris, MC. Arch Neurol 2003

Epidemiologic Studies of AD

Rotterdam Study 2-year follow-up RR=0.3 (0.1-0.9) fish intake 18 g/d vs. <3 g/d 6-year follow-up RR=1.07 (0.9-1.3) per SD n-3 fatty acid intake PAQUID Study 7-year follow-up RR=0.7 (0.5-1.0) 1 fish /week vs never Cardiovascular Health Study RR=0.7 (not significant) 2+ fish/wk vs. <1/mo Framingham Study RR=0.67 (p<0.05) DHA PC in upper half

Mediterranean diet and risk for dementia

• Mediterranean diet related to lower risk for cardiovascular disease, cancer and overall mortality • 2,258 elderly followed up for 4y, every 1.5y • 262 incident AD over 4y • High adherence to MeDi is linked to lower risk for AD (OR 0.76-0.91). • This association is not mediated by vascular comorbidity. Scarmeas N et al, Arch Neurol 63: 1709-1717, 2006 Scarmeas N et al, Ann Neurol 59: 912-921, 2006

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Scarmeas N. Neurology,Sept 11 2007

MCI

Scarmeas et al Arch Neurol 2009 66 (2:216-225)

Alzheimer Disease (AD) Incidence in Individuals by No, Some, or Much Physical Activity and Low, Middle, and High Mediterranean-Type Diet Adherence Scores

Scarmeas, N. et al. JAMA 2009;302:627-637.

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Why Mediterranean diet is associated with lower risk of AD?

• Major components of the diet (high intake of monounsaturated fatty acids, fish, cereals, vegetables, and red wine) protect against age-associated cognitive decline (Panza et al, 2006) • The high antioxidant content of the foods combined with reduced caloric intake (characteristic of the diet) may explain the lower risk for AD (?)

FDA Class Comparison

Food/nutrition Medical Nutrition Pharma products

• Normal food • Nutrients – Medical Food • Chemical entities

• In general NOT tested • In general combination • In general 1 compound in clinical trials of nutrients tested in tested in clinical trials clinical trials (phase I-IV: safety, (tolerance, efficacy) efficacy

• No registration • National registration / • National registration notification (FDA)

• For (healthy) consumer • For patients use • For patients use use (medical supervision) (medical supervision)

•Not reimbursed • Frequently reimbursed • Usually reimbursed

Souvenaid®, a multi-nutrient drink containing FortasynTM Connect

•UMP • Improve the formation of synapses • Increase precursor supply •Omega-3 FAs • Increase phosphatide synthesis • Increase neurite outgrowth • Choline • Increase dendritic spine density • Increase formation of synapses (markers) • Phospholipids • Increase cholinergic neurotransmission • Synergy between nutrients • B • Improve learning & memory • Antioxidants • Decrease Abeta and amyloid toxicity

Broersen et al. (2008) ICAD; Cansev (2006) Brain Res Rev 52: 389-97; Cansev et al. (2005) Brain Res 1058: 101-8; Cansev and Wurtman (2007) Neuroscience 148: 421-31; Cansev et al. (2008) Alzheimer's & Dementia 4: S153-S168; De Bruin et al. (2003) Neurobiol Learn Mem 80: 63-79; de Wilde et al. (2002) Brain Res 947: 166-73; de Wilde et al. (2003) Brain Res 988: 9-19; Farkas et al. (2002) Brain Res 954: 32-41; Groenendijk et al. (2008) ICAD; Holguin et al. (2008) Behav Brain Res 191: 11-6; Holguin et al. (2008); Kamphuis et al. (2008) ICAD; Knapp and Wurtman (1999) Brain Res 822: 52-9; Pooler et al. (2005) Neuroscience 134: 207-14; Richardson et al. (2003) Brain Res 971: 161-7; Richardson and Wurtman (2007) Biochim Biophys Acta 1771: 558-63; Sakamoto et al. (2007) Brain Res 1182: 50-9; Teather and Wurtman (2003) Prog NeuropsychopharmacolBiol Psychiatry 27: 711-7; Teather and Wurtman (2005) Learn Mem 12: 39-43; Teather and Wurtman (2006) J Nutr 136: 2834-7; Ulus et al. (2006) Cell Mol Neurobiol; Ulus et al. (1989) Brain Res 484: 217-27; van der Beek et al. (2006) Society for Neuroscience; Wang et al. (2007) Brain Res 1133: 42-8; Wang et al. (2005) J Mol Neurosci 27: 137-45; Wurtman et al. (2000) Biochem Pharmacol 60: 989-92; Wurtman et al. (2006) Brain Res 1088: 83-92

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Cannot be met by normal diet…

Clinical studies on Diet interventions

French Multidomain Alzheimer’s Prevention Trial (MAPT)

Dutch Prevention of Dementia by Intensive Vascular Care (PreDIVA)

Original FINGER (Finland-1260, MCI+NL-60,75-NTB- 2014) •Researchers point to interventions that improve heart health as a possible reason the study is showing positive results •The study relied on a diet researchers dubbed the ‘healthy Nordic diet’: fish, fruits, vegetables and oils •Brain training that was individualized and challenging had a positive effect

World Wide FINGER studies

Nutrition guidance, exercise, cognition, and vascular risk Management vs Individual Counseling Group based activities Similar clinical outcomes Local adaptation of diets -US POINTER (Kaiser P and Wake Forest -$20M by AA-2 yr- 2500 people – 60,79-Aerobic exercise x 3 q wk)

MIND-China (2500 people Shandong Pr.) SINGER (Singapore-6 mo-MCI-150) UK FINGER CND Germany Spain Japan Australia AUSTRALIA: Maintain your brain (MYB) 16,000-net- 55,75- Criteria :2 dem risk fact. 3-4 q week contacts

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MIND Diet Associated with Reduced Incidence of Alzheimer’s Disease.

- Prospective study - 923 participants - Ages 58 to 98 years - Followed 4.5 yrs - Semi-quantitative food frequency questionnaire

Martha Clare Morris, S.D., Christy C. Tangney, Ph.D., Yamin Wang, Ph.D, Frank M. Sacks, M.D., David A Bennett, M.D., and Neelum T. Aggarwal, M.D. MIND Diet Associated with Reduced Incidence of Alzheimer’s Disease. Alzheimers Dement. 2015 September ; 11(9): 1007–1014. doi:10.1016/j.jalz.2014.11.009.

MIND diet, a hybrid of the Mediterranean and the Dietary Approaches to Stop Hypertension (DASH) diets, both of which reduce risk for hypertension, diabetes, heart attack, and stroke by limiting , and , , pastries, and sweets, and fried or fast foods, and by incorporating vegetables, especially leafy greens, along with nuts, berries, beans, whole grains, fish, poultry, olive oil, and wine.

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Alzheimer Risk Reduction in the MIND Diet

Participants: 953 Age 58-98 Follow up : 4.5 Yrs 53% 35%

Morris MC et al. 2015

AlzheimerMed Diet Risk Reduction in the MIND Diet

Med Diet

54%

DASH

39%

Here are the 10 foods the MIND diet encourages:

• Green, leafy vegetables: Aim for six or more servings per week. This includes kale, spinach, cooked greens and salads. • All other vegetables: Try to eat another vegetable in addition to the green leafy vegetables at least once a day. It is best to choose non-starchy vegetables because they have a lot of nutrients with a low number of calories. • Berries: Eat berries at least twice a week. Although the published research only includes strawberries, you should also consume other berries like blueberries, raspberries and blackberries for their antioxidant benefits . • Nuts: Try to get five servings of nuts or more each week. The creators of the MIND diet don’t specify what kind of nuts to consume, but it is probably best to vary the type of nuts you eat to obtain a variety of nutrients. • Olive oil: Use olive oil as your main cooking oil.

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Here are the 10 foods the MIND diet encourages:

• Whole grains: Aim for at least three servings daily. Choose whole grains like oatmeal, quinoa, brown rice, whole-wheat pasta and 100% whole-wheat bread. • Fish: Eat fish at least once a week. It is best to choose fatty fish like salmon, sardines, trout, tuna and mackerel for their high amounts of omega-3 fatty acids. • Beans: Include beans in at least four every week. This includes all beans, lentils and soybeans. • Poultry: Try to eat chicken or turkey at least twice a week. Note that fried chicken is not encouraged on the MIND diet. • Wine: Aim for no more than one glass daily. Both red and white wine may benefit the brain. However, much research has focused on the red wine compound resveratrol, which may help protect against Alzheimer’s disease.

5 Foods to Avoid on the MIND Diet

• Butter and margarine: Try to eat less than 1 tablespoon (about 14 grams) daily. Instead, try using olive oil as your primary cooking fat, and dipping your bread in olive oil with herbs. • Cheese: The MIND diet recommends limiting your cheese consumption to less than once per week. • Red meat: Aim for no more than three servings each week. This includes all beef, pork, lamb and products made from these meats. • Fried food: The MIND diet highly discourages fried food, especially the kind from fast-food restaurants. Limit your consumption to less than once per week. • Pastries and sweets: This includes most of the processed and desserts you can think of. Ice cream, cookies, brownies, snack cakes, donuts, candy and more. Try to limit these to no more than four times a week.

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Conclusions Development of dementia

Tau Neurotrophins Inflammation A Neuronal Genes loss MCI DEMENTIA

0204060>80

Diet for prevention and ? treatment of dementia

The Paleolithic Lifestyle, Compared to the present More Less

, calcium, • Dietary salt, calories, vitamins, antioxidants saturated fat, sugar (*domesticated animals have ~ 5 times more fat than game)  physical and mental activity

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Aging is Modifiable…

• “…after eighty, the percentage of the remaining life span in twin pairs that is attributable to heredity is almost zero”

Finch CE, Aging , inflammation and the body electric. Daedalus, Winter 2006

Aging is Relative Concept

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The largest Last Supper: depictions of food portions and plate size increased over the Millennium; B Wansink and C S Wansink

Last Supper: Leonardo da Vinci

International Journal of Obesity , (23 March 2010) |doi:10.1038/ijo.2010.37

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Food 69% Bread 63% Plate size 33%

28%

…Homo sedentarius

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Evolution and diseases of modern culture

• Diabetes mellitus • Atherosclerosis • Hypertension • Some forms of cancer • Arthritis • Alzheimer’s disease

Dietary recommendations to lower AD risk • High intake of antioxidants (fruits and vegetables) and fish

• Avoid high or very low fat diet

• Avoid obesity

• Avoid high salt intake

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Non-Dietary recommendations to lower AD risk (cont)

•Exercise • Socialization and cognitive stimulation • Blood pressure management • Smoking cessation • Management of Depression

Health Maintenance

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