Exercise - Diet and Dementia Prevention NIKOS SCARMEAS

Exercise - Diet and Dementia Prevention NIKOS SCARMEAS

Exercise - Diet and Dementia Prevention NIKOS SCARMEAS MD, MSc Associate Professor of Neurology Columbia University Medical Center, New York, NY, USA Disclosures: None Research Support: NIA RO1: AG028506, / Alzheimers Association IIRG-04-1353 26th International Conference of Alzheimers Disease International

Toronto, March 2011 Lower risk of AD or slower cognitive decline Vitamin C Masaki, Losonczy et al. 2000; Engelhart, Geerlings et al. 2002; Zandi, Anthony et al. 2004; Morris, Beckett et al. 1998 Vitamin E

Masaki, Losonczy et al. 2000; Engelhart, Geerlings et al. 2002; Morris, Beckett et al. 1998; Morris, Evans et al. 2002; Morris, Evans et al. 2002; Zandi, Anthony et al. 2004; Corrada, Kawas et al. 2005 Vitamin B12

La Rue, Koehler et al. 1997; Clarke, Smith et al. 1998; Wang, Wahlin et al. 2001; Haan et al. 2007; Tangney 2009 Vitamin B6 Corrada, Kawas et al. 2005 Folate

Clarke, Smith et al. 1998; Wang, Wahlin et al. 2001; Ravaglia 2005; Corrada, Kawas et al. 2005; Balk 2007 (metaanal-interv). Modest to Moderate ETOH Orgogozo, Dartigues et al. 1997; Ruitenberg, van Swieten et al. 2002; Truelsen, Thudium et al. 2002; Mukamal, Kuller et al. 2003; Luchsinger, Tang et al. 2004; Ganguli , Vander Bilt et al. 2005;

Espeland, Gu et al. 2004; Stampfer Kang et al 2005 Flavonoids Commenges, Scotet et al. 2000 Caroten Barberger-Gateau et al 2007;

Fish Barberger-Gateau, Letenneur et al. 2002; Morris, Evans et al. 2003; Morris, Evans et al. 2005; Huang, Zandi et al; 2005; Barberger-Gateau et al 2007; Unsaturated fatty acids Kalmijn, Feskens et al. 1997; Morris, Evans et al. 2003; Morris, Evans et al.

2003; Schaefer, Bongard et al. 2006; Laitinen et al. 2006; Barberger-Gateau et al 2007; Lower total fats, cholesterol, saturated fats Kalmijn, Launer et al. 1997; Kalmijn, vanBoxtel et al. 2004; Morris, Evans et al. 2003; Luchsinger, Tang et al. 2002; Laitinen et al. 2006

Coffee Maia, de Mendonca 2002 Fruits Dai, Borenstein et al 2006; Barberger-Gateau et al 2007; Vegetables (polyphenol antioxidants?) Dai, Borenstein et al 2006, Kang, Grodstein; Research-Practice AD 2007,

Barberger-Gateau et al 2007; Curry (curcumin - antiinflammatory? antioxidant?) Tze-Pin Ng et al 2006 Risk for AD or cognitive decline not associated with Vitamin C Luchsinger, Tang et al. 2003, Masaki, Losonczy et al. 2000, Heart Protection Study 2002; Laurin,

Masaki et al. 2004; Dai, Borenstein et al 2006; Yaffe 2004 Vitamin E Sano 1997; Luchsinger, Tang et al. 2003, Masaki, Losonczy et al. 2000; Heart Protection Study 2002; Laurin, Masaki et al. 2004; Yaffe 2004; Dai, Borenstein et al 2006; Kang 2006 Vitamin B12

Crystal, Ortof et al. 1994, Seshadri, Baser et al. 2002; Morris 2006; Ravaglia 2005; Balk 2007 (metaanal-interv); Aisen 2008 Vitamin B6 Seshadri, Baser et al. 2002; Morris 2006; Balk 2007 (metaanal-interv); Aisen 2008 Folate Seshadri, Baser et al. 2002; Balk 2007 (metaanalinterv); Haan 2007; Middleton 2007; Morris 2006;

Aisen 2008 Fish Schaefer, Bongard et al. 2006; Fats Engelhart, Geerlings et al. 2002 Omega-3 O.van de Rest et al. 2008

Carotenes Heart Protection Study 2002; Luchsinger, Tang et al. 2003; Laurin, Masaki et al. 2004; Yaffe 2004. Calcium (high worse) Van Vliet 2004. Wine Dai, Borenstein et al 2006; Barberger-Gateau et al 2007;

Flavonoids Laurin, Masaki et al. 2004. Tea Forster, Newens et al. 1995; Rogers, Simon et al. 1999 Fruits Kang, Grodstein; Research-Practice AD 2007

Diet and AD One of the reasons for discrepancies between studies: we look at isolated-individual food or nutrients and not composite dietary patterns. Individuals do not consume foods or nutrients in isolation but rather as components of their overall daily diet. Growing attention in dietary pattern analysis (Jacobson, Stanton 1986) in relation to Cirrhosis Corrao, Zambon et al. 2004

Various cancers McCann, Weiner et al. 2001; Rouillier, Senesse et al. 2004; Cottet, Bonithon-Kopp et al. 2005 Cardiovascular disease Dietary patterns not explored in the neurological literature Individual dietary components Unadjusted

Mild-Moderate alcohol consumption 0.61 [0.45-0.82]; p = 0.001 Higher vegetable consumption 0.76 [0.60-0.97]; p = 0.030 Adjusted for cohort, age, gender, ethnicity, education, APOE genotype, caloric intake, smoking, comorbidity index and body

mass index. None of the individual components was a significant AD predictor. Baseline non-MCI Incident MCI MeDi Incident MCI N = 275

Baseline Non MCI N = 1393 Follow-up 4.5 (0.9 16.4)years Annual Incidence: ~ 5% Baseline MCI Incident AD: MeDi Incident AD

N = 106 Baseline MCI N = 482 Follow-up 4.3 (1 13.8) years Annual incidence 5% Biological Mechanism

Nutrients: SFA, MUFA, -3 PUFA, -6 PUFA, Vit E, Vit B12, Folate 30 Food groups: Fruits, Fish,

Nuts, Red Meat, etc. 30 Food groups: Fruits, Fish, Nuts, Red Meat, etc. 30 Food

groups: Fruits, Fish, Nuts, Red Meat, etc. Response variables (Nutrient Factors)

Nutrients: SFA, MUFA, -3 PUFA, -6 PUFA, Vit E, Vit B12, Folate Alzheimers Disease/ Cognitive

Performance Factor Scores (Dietary Patterns) Response variables (Nutrient

factors) Nutrients: SFA, MUFA, -3 PUFA, -6 PUFA, Vit E, Vit B12, Folate Alzheimers

Disease/ Cognitive Performance Outcome Risk Estimation Model Nutrients: Factor Scores (Dietary Patterns)

Response variables (Nutrient factors) SFA, MUFA, -3 PUFA, -6 PUFA, Vit E, Vit B12,

Folate Latent variables used in current step of analysis Observed variables not used in current step of analysis

Regression RRR Step 3 30 Food groups: Fruits, Fish, Nuts, Red Meat, etc.

Observed variables used in current step of analysis Principal Components Analysis RRR Step 1 RRR Step 2

Alzheimers Disease/ Cognitive Performance Alzheimers Disease/ Cognitive Performance

Latent variables not used in current step of analysis New latent variables developed from current step of analysis Dietary Pattern

higher intakes salad dressing nuts fish tomatoes poultry cruciferous vegetables fruits dark and green leafy vegetables

lower intake high-fat dairy red meat organ meat butter NUTRIENTS SFA, B12

3 PUFAPUFA 6 PUFAPUFA Vit PUFAE PUFA Folate PUFA Survival curves based on Cox analysis comparing cumulative Alzheimer disease incidence in

subjects belonging to each dietary pattern (DP) score 2 tertile (P for trend <.001) Gu, Y. et al. Arch Neurol 2010;67:699-706. Copyright restrictions may apply. Vascular Clinical, Homocysteine MRI SCI, WMH

Oxidative Isoprostanes Diet Inflammatory IL-6 IL-1 CRP Metabolic

Insulin Adiponectin Alzheimers disease Vascular Clinical, Homocysteine MRI SCI, WMH

Oxidative Isoprostanes Diet Inflammatory IL-6 IL-1 CRP Metabolic

Insulin Adiponectin Alzheimers disease 1219 non demented subjects hsCRP, Insulin, Adiponectin measured at baseline 118 incident AD cases after 4 years of follow-up

Initial Simple Model Alzheimers disease MeDi Inflammatory / Metabolic Mediation Model MeDi

Mediating Variables hs CRP Insulin Adiponectin Alzheimers disease Vascular Clinical

Homocysteine MRI SCI, WMH Oxidative Isoprostanes Diet Inflammatory IL-6 IL-1

CRP Metabolic Insulin Adiponectin Alzheimers disease Simple Model Alzheimers

disease MeDi Vascular Mediation Model Vascular Variables MeDi Heart disease,

Stroke, Diabetes, Hypertension HDL, TG, LDL Alzheimers disease Odds Ratios for Subjects With Alzheimer Disease vs, Nondemented Subjects by Mediterranean Diet Score in Continuous and Tertile Form

Scarmeas, N. et al. Arch Neurol 2006;63:1709-1717. Copyright restrictions may apply. WHICAP imaging sub-sample Those in current analyses more likely African Americans or Whites Similar in all other aspects

(age, gender, education, BMI, 4, smoking, diabetes, hypertension, heart disease) 707 current analyses 62 Missing Diet or

Missing Stroke assessments Small infarct (<1cm) Large infarct (>1cm) Scarmeas et al. Annals of Neurology, 2010 Mean survival: Lower adherence:

6.6 years Middle adherence: 7.9 years Higher adherence: 10.5 years Scarmeas N., Luchsinger J., Mayeux R., Stern Y. Mediterranean diet and Alzheimers disease mortality. Neurology, Neurology 2007; 69: 1084 - 1093. Alzheimer Disease (AD) Incidence in Individuals by No, Some, or Much Physical Activity and

Low, Middle, and High Mediterranean-Type Diet Adherence Scores Unadjusted HR: 0.78 (0.53-1.14) 0.63 (0.43-0.92) 0.46 (0.31-0.69) 0.33 (0.19-0.57) Trend: 0.77 (0.69-0.85) p<0.001 Adjusted HR: 0.96 (0.60-1.55)

0.92 (0.59-1.43) 0.58 (0.36-0.95) 0.39 (0.20-0.76) Trend: 0.80 (0.71-0.90) p<0.001 Scarmeas, N. et al. JAMA 2009;302:627-637. Copyright restrictions may apply. Concerns - Limitations Replication

Healthy Person Bias Residual Confounding Observation vs. Randomization ?

Physical Activity and Cognition: Potential Mechanisms Barnes et al. 2006 15 prospective studies (not cross-sectional, not interventional) 33816 non-demented subjects 1-12 years of follow-up

3210 subjects had cognitive decline (not dementia) during follow-up (Colcombe and Kramer 2003) meta-analysis 18 fitness training intervention studies in cognitively normal adults 55 Maximum benefit included combined strength and aerobic training, sessions of moderate duration (no shorter than 30 minutes), overall training program of long duration (6 months or more),

higher percentage of female participants, and mid-old participants (not younger than 65, not older than 70) 170 subjects with memory problems but not dementia. 6 month home based physical activity intervention 1.5 years of follow-up

Table 2. Effects of the Intervention and Time on Cognitive Outcomes, Mood, and Quality of Life of Participants (Intention-to-Treat Method Using Multiply Imputed Data) Copyright restrictions may apply. Lautenschlager, N. T. et al. JAMA 2008;300:1027-1037 2020 participants 30 randomized trials between 1970 and 2003

Adults 65 and older with cognitive impairment or dementia (MMSE <26; mean ~16) 12 studies looking into cognitive outcomes enrolling ~900 subjects (Heyn, Beatriz et al 2004) meta-analysis Overall Conclusions Conflicting literature on diet and dementia-cognitive decline There may exist a value in considering dietary patterns rather than

single foods or nutrients. A Mediterranean-type diet may be beneficial for cognition. Possible biological mechanisms still unexplored but vascular pathways may be important Physical activity may be also beneficial for cognition, possibly over and above dietary habits. Confidence in the diet-exercise / cognition associations is relatively limited because most studies have been observational and there is limited clinical trial confirmation. But, there are confirmed benefits of a healthy diet and exercise on a

series of other diseases (i.e. mostly cardiovascular); therefore, it makes sense to follow them anyway.

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