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Conflict of Interest Statement What You Will Hear Today 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 Dementia 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 dietitian or nutritionist • I like to eat • I like to cook What you will hear today • Oxidation aging, disease and diet • 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) 1 5/11/2019 2 5/11/2019 3 5/11/2019 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 4 5/11/2019 5 5/11/2019 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) • Obesity (Xu 2010, Gustafson 2011) • Mediterranean Diet (Scarmeas, 2010) Nutrition, obesity and dementia Overweight Children, 1965-2005 6 5/11/2019 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. Copyright restrictions may apply. •Risk factors Brain Reserve Memory loss and Alzheimer Aging 7 5/11/2019 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. Copyright restrictions may apply. 8 5/11/2019 •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 9 5/11/2019 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 10 5/11/2019 ORAC (1 g fresh wt μmol trolox equiv/g) Fresh Fruit Veggies and Legumes Blueberries 2400 Kale 1770 Blackberries 2036 Spinach 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 Human Nutrition – 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 11 5/11/2019 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 intermittent fasting 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 12 5/11/2019 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 A42 Concentrations (a) and A42 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 A40 A 6 days incubation A40 3 days incubation Curcumin - 0.125M 2M Yang F et al,J Biol Chem 280: 5892-5901, 2004 13 5/11/2019 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 14 5/11/2019 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 15 5/11/2019 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 meal/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 16 5/11/2019 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. Copyright restrictions may apply. 17 5/11/2019 Why Mediterranean diet is associated with lower risk of AD? • Major components of the diet (high intake of monounsaturated fatty acids, fish, cereals, vegetables, olive oil 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 vitamins • 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.
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