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Energy regula+on, dietary pa2erns and brain health in the Taiwanese
popula+on
Meei-‐Shyuan Lee DrPH1, Mark L Wahlqvist MD1,2
1School of Public Health, Na3onal Defense Medical Center, Taipei, Taiwan, ROC
2 Ins3tute of Popula3on Health Sciences, Na3onal Health Research Ins3tutes, Miaoli County, Taiwan, ROC
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“Of all the things I’ve lost, I miss my mind the most.”
-‐ Mark Twain
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The Present and Future Burden of Disease • Located in the brain • Factors affecCng brain funcCon • our habitat • personal behavior • life expectancy BUT neurodegeneraCon is not inevitable with age
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Origins of Brain DysfuncBon • Our environmental interface, • The intergeneraConal expression of our genome, • The risk profile of diet and physical acCvity, substance abuse (alcohol, tobacco), • Associated morbidity and medicaCon (esp. body composiConal disorders, diabetes and cardiovascular disease), • NeurodegeneraCon (cogniCve impairment and extrapyramidal disorders like Parkinson’s disease) and affecCve disorders (anxiety and depression). 4
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Rapid growth of diabetes -‐ The 4th or 5th leading cause of death in most high-‐ income countries -‐ Epidemic in many economically developing and newly industrialized countries
(hWp://www.idf.org/diabetesatlas/5e/the-‐global-‐burden)
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Prevalence of DM in Taiwan
(Jiang YD et al., 2012)
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Global prevalence of demenBa
• Age-‐standardized prevalence for those aged ≥ 60 yrs 5%-‐7% in most world regions 8.5% in LaCn America 2%-‐4% in sub-‐Saharan African regions
• EsCmated 35.6 million people lived with demenCa worldwide in 2010 • Expected to double every 20 years
(Prince M et al., 2013)
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Chinese demenBa prevalence • Meta-‐analysis based on mainland China, Hong Kong and Taiwan during 1980-‐2012 • DSM-‐IV diagnosCc criteria (Wu YT et al., 2013)
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The metabolic syndrome is characterized as abdominal fatness (energy stores), fasCng hypertriglyceridemia and impaired fasCng glucose (both energy transport systems). Its core is impaired energy regula1on.
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Diabetes and DemenBa
Taiwan cohort study
Meta-‐analysis
U.S. cohort study
Compared with non-‐DM people, demenCa incidence was 2.6 Cmes higher in the diabeCc paCents without medicaCon
(Hsu CC et al., 2011)
Presently 1 in 10-‐15 cases of demenCa are aWributable to diabetes.
(Reijmer YD et al., 2010)
CogniCve decrements may also develop in the early stages of glucose dysmetabolism.
(Young SE et al., 2006)
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Glycemic Status and DemenBa
Risk of incident demenCa associated with the average glucose level during the preceding 5 years
Crane PK et al. New Engl J Med, 2013
1.18
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Diabetes DemenBa • Vascular • Alzheimer’s type neurodegeneraCon • Brain diabetes-‐insulin deficiency & resistance (?Type 3) • Pre-‐DM as manifest in the metabolic syndrome is in large measure a problem of energy regulaCon
therefore • We studied the development of neurodegeneraCve disorders.
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Our Approach in Taiwan -‐ Epidemiological & IntervenBon • Epidemiological • PopulaCon-‐based cohorts • NutriCon surveys linked to the NaConal Health Insurance datasets
• IntervenBon • Candidate foods & Working Memory
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NHI Cohort of 800,000 in Taiwan • General Hypotheses • Diabetes increases the incidence of neurodegeneraCve diseases in Taiwan • It is possible to minimize the risk of cogniCve impairment by pharmacotherapy of low risk
• Study design • Diabetes & neurodegeneraCon-‐free • matching protocol (simulate a clinical trial) to deal with immortal Cme bias • studies of demenCa, Parkinsonism & depression preceded by DM (incidence & RR)
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Risk (Hazard RaBos, 95% CI) of NeurodegeneraBon with Diabetes, NHI-‐Taiwan (1996-‐2007)
Subjects were matched by year and month of birth & gender matched.
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2.21 2.24
3.5
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1.68 1.54
2.5
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1.93 1.86
2.96
0.5
1
1.5
2
2.5
3
3.5
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Diabetes free Dementia inDiabetes without
OAAs
Parkinsonism inDiabetes without
OAAs
AffectiveDisorder in
Diabetes withoutOAAs
Hazard Ratio
(ref)
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Effect of OAAs on Risk of NeurodegeneraBon (12 y), NHI-‐Taiwan (1996-‐2007)
DemenBa Parkinson Depression
Descriptor HR (95%CI) HR (95%CI) HR (95%CI) DM without OAAs ref. ref. ref. Me]ormin only 0.94 (0.63-‐1.40) 1.28 (0.69-‐2.37) 0.92 (0.59-‐1.45)
DM without OAAs ref. ref. ref. Sulfonylureas only 1.11 (0.88-‐1.39) 1.63 (1.19-‐2.22)** 1.08 (0.84-‐1.38)
DM without OAAs ref. ref. ref. Sulfonylureas+Me]ormin 0.67 (0.56-‐0.81)*** 0.84 (0.66-‐1.08) 0.40 (0.32-‐0.50)***
Fully Adjusted models
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Hsu, Wahlqvist, Lee, & Tsai, 2011; Wahlqvist, Lee, Chuang, et al., 2012; Wahlqvist, Lee, Hsu, et al., 2012
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AMP Kinase
hWp://themedicalbiochemistrypage.org/ampk.html 17
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AMPK in muscle
Ouyang J et al. J. Biol. Chem. 2011;286:1-‐11
©2011 by American Society for Biochemistry and Molecular Biology 18
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What connects demenBa, Parkinsonism & depression? • Macrovascular disease an insufficient explanaCon • Insulin resistance ? Maybe • Hyperglycemia? Inconsistencies • Energy dysregulaCon? Possible through AMP kinase • Microglial disorders • Lipoprotein Disorders (ApoE4; Perilipin or PAT family proteins, also involved in energy regulaCon through TG droplets) • CombinaCon of these
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Food, CogniBon & Mortality
• Design: Cohort, 10 yrs follow-‐up • ParBcipants: PopulaCon representaCve sample of free-‐living older adults in Taiwan from the NAHSIT Elderly Cohort of 1999-‐2000 • Measures: • CogniCve funcCon: SPMSQ • Dietary diversity score (DDS) • Physical acCvity • All-‐cause mortality
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Figure 3. Joint hazard raCos (HRs) for developing diabetes in elder Taiwanese aqer an 8-‐year follow-‐up in accordance with cogniCve funcCon and in relaCon to dietary diversity scores (DDS), physical funcCon.
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Joint hazard raCos (HRs) for all cause mortality in elder Taiwanese aqer 10-‐year follow-‐up in accordance with cogniCve funcCon and in relaCon to DDS.
Chen et al, Food Nutr Res, 2011
Dietary Diversity, CogniBon & Mortality
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Survival curves Alzheimer’s disease incidence and the Mediterranean diet (MeDi) terBle (p for trend 0.007).
Scarmeas N et al., Ann Neurol 2006;59:912-‐21.
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Dairy and Mortality
J Am Coll Nutr 2014;33(6):426-‐36.
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0.660.5
0.58
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0.48
0.15 0.1
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0.770.86
0.54
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0.5
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1.5
0 0.1-‐3.0 3.1-‐7.0 >7.0
Weekly dairy consumption frequency
HR (9
5% CI)
Al l -‐cause
CVD
Cancer
p for trend 0.009 0.404 0.002
Adults aged 40-‐64 yrs (n=2275), fully adjusted models
Dairy intake vs. MortaliBes
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IntervenBon: Turmeric & Working Memory
• Older adults with pre-‐diabetes • Inclusion criteria
• A fasCng blood glucose regarded as impaired (100-‐126 mg/dL) • Aged 60 years or over • Never used any anC-‐hyperglycemic medicaCon
• Exclusion criteria • Congenital diseases, cancer, heart failure, renal failure or dialysis • BMI> 35 or BMI< 18.5 • ContraindicaCon to the use of turmeric • Any medicaCon which might affect metabolic status or interact with the intervenCon
Lee MS et al. Asia Pac J Clin Nutr 2014
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29 Working memory (WM) model
Baddeley A, Trends in CogniCve Sciences (2000)
• Short-‐term memory (STM) ‒ Assumed to comprise a unitary temporary
storage system
• Unshaded systems are assumed to be “fluid” capaciCes ‒ AWenCon & temporary storage ‒ Unchanged by learning
• Shaded areas represent “crystallized” cogniCve systems ‒ AccumulaCng long-‐term knowledge ‒ Language & semanCc knowledge
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Working memory responses to 1 gm turmeric before and 6 hr aier intervenBon
0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
User Nonuser
* 2.61 2.91
2.59 2.55
Lee MS et al. Asia Pac J Clin Nutr 2014
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Conclusions
• The strategic use of large, representaCve data bases linked to a naConal health insurance system has allowed new insights and approaches to brain health in Taiwan. • IER is contributory to neurodegeneraCon and may be a route by which it may be minimized.
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Our Team (alphabe+cal order)
• Dr. Hsing-‐Yi Chang • Dr. Yu-‐Hung Chang • Ms. Rosalind C-‐Y Chen • Dr. Yu-‐Ching Chou • Dr. Shao-‐Yuan Chuang • Dr. Wen-‐Hui Fang • Dr. Chih-‐Cheng Hsu • Ms. Lin-‐Yuan Huang
• Mr. Jen-‐Chun Kuan • Dr. Jiunn-‐Tay Lee • Ms. Hsiao-‐Yu Liu • Ms. Ting-‐Mei Lu • Dr. Wen-‐Harn Pan • Ms. Hsin-‐Ni Tsa • Dr. Lili Xiu
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“When grace is joined with wrinkles, it is adorable. There is an unspeakable dawn in happy old age.”
-‐ Victor Hugo Thank You!
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