cognitive decline and alzheimer’s disease: the influence of...

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Cognitive Decline and Alzheimer’s Disease:

The Influence of Nutrition

Cynthia Lieu, Pharm.D., BCNSP

Naomi Quint, Melody Armiteh, Kelly Tran

University of Southern California, School of Pharmacy

April 13, 2018

Objectives

• Describe nutrients and foods that negatively affect cognitive function or increase the risk for Alzheimer’s Disease (AD)

• Describe nutrients and foods that positively affect cognitive function or reduce the risk for AD

• Design a nutritional plan to reduce the risk of cognitive decline and AD

Dementia: decline in mental ability severe enough to interfere with daily life

• Alzheimer’s disease (AD): most common type

– Brain changes may begin 20 years before symptoms begin

• Other types of dementia:

– Vascular dementia

– Frontal-temporal dementia

– Parkinson's dementia

– Lewy-Body dementia

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• Subjective cognitive decline (SCD)

– Subjectively perceived subtle cognitive deficits

– Neuropsychological testing: normal performance

• Mild cognitive impairment (MCI)

– Neuropsychological test results: mildly reduced

• Neuropsychological tests

– Memory, visuoconstruction, attention/processing speed, executive functioning

• Pathophysiological processes take place years before AD manifestation

Eliassen, et al. Brain Behav. 2017;7(9): e00776.

Subjective Cognitive Decline (SCD)

Mild Cognitive Impairment

(MCI)Dementia

Warning signs of Alzheimer’s• Memory loss that disrupts daily life

• Challenges in planning or solving problems

• Difficulty completing familiar tasks at home, at work or at leisure

• Confusion with time or place

• Trouble understanding visual images & spatial relationships

• New problems with words in speaking or writing

• Misplacing things & losing the ability to retrace steps

• Decreased or poor judgment

• Withdrawal from work or social activities

• Changes in mood & personality

https://www.alz.org/alzheimers_disease_10_signs_of_alzheimers.asp. Accessed March 31, 2018.

Tests used for AD & cognitive impairment• Mini-Mental State Examination (MMSE)

– Overall measure of cognitive impairment

– 30 point questionnaire

– 20-24 = mild dementia; 13-20 = moderate dementia; <12 = severe dementia.

• Alzheimer Disease Assessment Scale (ADAS-cog)1

– Evaluates memory, attention, language, orientation, and praxis

– 70-point scale

– Higher scores indicate greater impairment1Aisen, et al. JAMA. 2008;300(15):1774-1783.

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• Alzheimer’s Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory1

– Assesses functional ability to perform activities of daily living in patients with AD

– Scores range from 0 to 78

– Lower scores indicate worse function

• Neuropsychiatric Inventory (NPI)2

– Assessment of severity and frequency of psychological and behavioral disturbances in patients with dementia

• Delusions, hallucinations, dysphoria, anxiety, agitation, euphoria, disinhibition, irritability, apathy, and aberrant motor activity

– Provides scores for 10 subscales1Dysken, et al. JAMA. 2014;311(1):33-44.

2Cummings, et

al. Neurology. 1994;44(12):2308-14.

Alzheimer's Disease Facts & Figures, U.S.• 2018:

– 5.7 million Americans• 2025, estimated: 7.1 million• 2050, projected: nearly 14 million

– Projected health & long-term care, individual with AD: $424,000

– Alzheimer’s & other dementias, cost of care: $277 billion• 2050, projected: $1.1 trillion

• Leading cause of disability & poor health• 6th leading cause of death in US

– 5th leading cause of death, 65 & older• 1 in 3 seniors dies with Alzheimer’s or another dementia

https://www.alz.org/documents_custom/2018-Facts-and-Figures-Press-Release.pdf. Accessed March 31, 2018.

Risk Factors • Apolipoprotein E (ApoE) ɛ4 allele1

• Oxidative stress2

– Transition metal accumulation

– Mitochondrial dysfunction

– Amyloid-β

• Diabetes3

• Elevated blood homocysteine (Hcy) levels4

1Liu, et al.Nat Rev Neurol 2013; 9(2): 106-118. 2Smith, et al. Biochim Biophys Acta. 2000;1502:139-144. 3Arvanitakis, et al. Arch Neurol. 2004;61(5):661-6. 4Smith, et al. J Alzheimers Dis 2018; 62(2): 561-570.

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Risk Factors – Nutrition-Related

• Significantly low protein intake1

• Very low sodium diets2

• Calcium supplementation3

• Aluminum-containing additives in food/water4

• Dietary patterns associated with mild cognitive impairment5

– Lower consumption of fish & more red meat– Low plasma concentration of HDL cholesterol– Low total antioxidant capacity & alpha-tocopherol

1Koh, et al. Nurtients 2015;7(4):2415-2439. 2Rush, et al. J Nutri Health Aging 2017;21(3):276-283. 3Kern, et al. Neurology 2016;87:1674–1680. 4Solfrizzi, et al. J Alzheimers Dis 2006;10(2-3):303-30. 5Yuan, et al. Nutrition. 2016;32(2):193-8.

Risk Factors – Nutrition-Related

• Increased cerebral amyloid plaque burden1

– High glycemic load diet

– High carbohydrate intake

– High sugar intake

• Reduced cognitive performance

1Taylor, et al. Am J Clin Nutr. 2017;106(6):1463-1470.

Nutritional Interventions:Dietary Supplements• Vitamin B12 & B6

• Folic acid

• Antioxidants

• Vitamin D

• Omega 3

• Herbs

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Elevated Homocysteine

• Risk factor for cognitive impairment, dementia1

– Vascular mechanisms

– Regional brain atrophy

– Neurofibrillary tangle & amyloid plaque formation

– Neuronal death

– Epigenetic mechanisms

• Studies: variety of cut-offs

• 2018 international consensus: suggested threshold, 10-11 umol/L1

1Smith, et al. J Alzheimers Dis 2018; 62(2): 561-570.

Folic Acid (FA, Vitamin B9)

Dose/Duration Participants Results

Folic acid 15 mg/d x 60 days1

N = 30Age = 65+Cognitive declineFolate levels < 3 ng/ml (low)

FA vs placebo: Attention efficiency score significantly improved

FA 800 mcg/d x 3 years2

N = 818Age = 50-70From NetherlandsHcy levels > 13 μmol/L (elevated)

FA vs placebo: Plasma Hcy decreased by 26%Global cognitive function improved (based on 5 cognitive tests)

1Fioravanti, et al. Arch Gerontol Geriatr 1998;26(1):1-13. 2Durga, et al. Lancet 2007;369(9557):208-216.

Combination Supplements


Vit B12 1 mg/d & FA 5 mg/dx 2 months1

N = 28: mean age = 74Mild to moderate dementia (VaD, FTD, AD, mixed dementia, or other dementia)

High Hcy at baseline: Improved MMSE & memory &attention scoresNormal baseline Hcy: No changes

Vit B12 1000 mcg/d alone or with FA 400 mcg/d x 24 weeks2

N = 195: age = 70+No to moderate cognitive impairmentFrom NetherlandsMild vit B12 deficiencyMean plasma Hcy 14.5-15.8 (high)

Supplement (vit B12 or vit B12 + FA) vs placebo: vit B12 levels corrected & Hcy levels reduced by 16% (vit B12 group) & 37% (vit B12 + FA)No improvement in cognitive function vs placeboImproved memory in placebo group vs vit B12 group

1Nilsson, et al. Int J Geriatr Psychiatry. 2001;16(6):609-14.

2Eussen, et al. Am J Clin Nutr. 2006;84(2):361-70.

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Vit B12 1 mg/d, FA 5 mg/d & vit B6 25 mg/d, x 18 months1

N = 344Age = 50+ yrsProbable ADNormal vit B12 & folate levelsMean plasma Hcy= 9.2 (SD = 3.2)

Supplement vs placebo: Hcy levels decreased by -2.4 vs -0.9No improvement in cognitive function

Vit B12 0.5 mg/d, FA 0.8 mg/d & vit B6 20 mg/dvs placebo, x 2 yrs

N = 223Age = 70+ yrsMCI

Supplement vs placebo:Hcy decreased (increased with placebo)High Hcy: Decline in rate of brain atrophySlowed cognitive decline (significant decline with placebo)

1Aisen, et al. JAMA. 2008;300(15):1774-1783;

2de Jager, et al.

Int J Geriatr Psychiatry 2012; 27: 592-600

Antioxidants

Oxidative Stress in AD

• Cellular respiration generates free radical intermediates (ROS formation)

• Sequestration mechanisms unable to capture all ROS

• Cellular respiration generates free radical intermediates (ROS formation)

• Sequestration mechanisms unable to capture all ROS

Reactive Oxygen Species

• Neurons vulnerable to oxidative damage

• Lipid peroxidation• Reactive carbonyls• Nitration• Nucleic acid

oxidation

• Neurons vulnerable to oxidative damage

• Lipid peroxidation• Reactive carbonyls• Nitration• Nucleic acid

oxidation

Oxidative Damage

• Formation of Aβ in neurons

• Compensatory mechanism: partial protection against oxidative damage in neurons

• Formation of Aβ in neurons

• Compensatory mechanism: partial protection against oxidative damage in neurons

Amyloid-β

Bonda, et al. Neuropharmacology. 2010;59(4-5):290-4.

AntioxidantsProtection against neurotoxicity

due to oxidative stress

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Vit E 2000 IU/day in 2 divided doses, vs memantine 20 mg/day, vs vit E + memantine, vs placebo,x 6 months-4 years1

N = 613Mean age 78.897% men (veterans)Possible or probably ADMMSE = 21

Delayed decline in ADCS-ADL & reduced caregiver time in vit E groupEffect not seen in other treatment groups No statistically significant differences in MMSE, ADAS-cog, or NPI

Vitamin E

1Dysken, et al. JAMA. 2014;311(1):33-44


Acetyl-L-carnitine (ALCAR) 1 g TID x 1 year1

N = 229Age = 45-65Probable AD (young-onset)

ALCAR vs placebo: No significant difference in the rate of decline in ADAS-cog scoreLess decline in MMSE

Alpha-lipoic acid (ALA) 600 mg/dx 16 months2

N = 126AD with T2DM (Group A) & without T2DM (Group B)

Group A vs Group B:Significant improvements in MMSE, ADAS-cog, CIBIC scores

N-Acetylcysteine (NAC) 50 mg/kg/day in 3 divided doses x 6 months3

N= 43Probable ADMMSE scores between 12 & 26

NAC vs placebo: Trend to perform better on MMSE & the Wechsler Memory Scale Performed significantly better on letter fluency task

Antioxidants

1Thal, et al. Neurology 2000;55:805–10. 2Fava, et al. J Neurodegener Dis. 2013;2013:454253. 3Adair, et al. Neurology. 2001;57(8):1515-7.


ALCAR 500 mg, NAC 600 mg, S-adenosylmethionine (SAM) 400 mg (200 mg active ion), vit E 30 IU, FA 400 mcg & vitB12 6 mcg x 3-6 months2

N= 106Probable AD &/or senile dementia of the Alzheimer type

Supplement vs placebo: Cognitive performance (Clox-1 & DRS) improvedNo statistical change in BPSD

Combination Supplements

2Remington, et al. J Alzheimers Dis. 2015;45(2):395-405.

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Vitamin D deficiencyVitamin D deficiency

• Serum 25-hydroxyvitamin D concentrations ≤ 20 ng/mL (50 nmol/L)

• 41.6% deficient in the US general population• 82.1% blacks, 69.2% Hispanics• No college education, obese, poor health status, HTN,

no daily milk consumption, high cholesterol

Forrest, et al. Nutr Res.2011;31(1):48-54.

Vitamin D

Amyloid-B

TAU

Inflammatory stressOxidative stress

Vascular stress

Neuronal death Decline in Memory & learning

• Role of vitamin D mediated by VDRs• Clearance of AB peptide• Anti-inflammatory action• Antioxidant action• Primary prevention and reduction of ischemic zone size

Annweiler, et al.Front.Pharmacol.2014;5:6

Vitamin D

1Zhao, et al. Nutrition 2013;29(6):828-32.

2Afzal, et al. Alzheimer's

& Dementia 2014;10:296–302.3Olsson, et al. Am J Clin Nutr.

2017;105(4):936-943.

Dose/Duration Participants ResultsVit D1 6 studies on AD patients

319 patients, 573 controlsAge 65+

AD patients: Either vit D deficient or had insufficient plasma vit D levels(Insufficient <20 ng/ml; Deficient<10 ng/ml)

Vit D2 N = 10,186White Danish individuals30 years follow up

Lower plasma vit D levels:Increase risk of AD & vascular dementia

Vit D3 N = 1182 Swedish menMean age 7118 years follow up(<20ng/mL, 20-30ng/mL, >30ng/mL)

No association between baseline vit D status & long term risk of dementia or cognitive decline

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Vitamin D Combination


Memantine 20 mg, vs vit D 400-1000 IU, vs Memantine + vit D, x 6 mo.

43 white patientsNew diagnosis of ADNo anti-dementia drug or vit D supplementation before

Memantine + vit D group:Increased MMSE score by 4 pointsNo test score changes for the other two groups

Annweiler, et al. Cogn Behav Neurol 2012;25(3):121-127.

Omega 3 PUFAs: DHA & EPA

• Brain requires DHA1

– Production and clearance of ß-amyloid– Maintenance of neuronal membranes – Modulation of inflammation – Improvement of vascular health

• Dementia2

– Decreased DHA– Decreased EPA– Decreased total n-3 PUFAs

• Predementia2

– Decreased EPA

1Yassine, et al. JAMA neurology. 2017;74(3):339-347. 2Lin, et al. J Clin Psychiatry 2012; 73(9): 1245-1254.


4 capsules 1.6 g EPA & 0.8 g DHA/day1

Healthy older adults Age = 62-80Subjective memory impairment (not meeting criteria for MCI or AD)

Red blood cell omega 3 content, working memory performance & blood oxygen level dependent (BOLD) signal increased

High dose DHA/EPA ranging from 150-2200 mg/d2

Mice: APOE4 carriers & non-carrier with or without AD

Incidence of AD was reduced significantly in APOE4 carriers

1.7 g of DHA + 0.6 g of EPA, vs. placebo, x 6 mo3

N = 204Mean age = 74ADMMST score of 15

No delay in rate of cognitivedecline in patient with mild-moderate ADPositive effect on patient with very mild AD

Omega 3

1Boespflug, et al.J Nutr Health Aging 2016; 20(2):161-9 2Yassine, et al. JAMA Neurology. 2017;74(3):339-3473Freund-Levi, et al. Neurol 2006 ;63:1402–8.

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N-3 PUFAs on dementia• Observational studies1

– Beneficial in 17 studies

• Higher level of ALA: decreased risk

• Higher level of DHA: decreased risk

• Fatty fish > 2/wk vs < 1/month: decreased risk

– No benefit in 3 studies

• Intervention studies1

– Beneficial in 8 studies

– No benefit in 5 studies

• APOE e4 carriers2

– More vulnerable to dietary n-3 deficits

– Supplementation with DHA as early as possible might help to prevent onset of AD

1Yanai, J Clin Med Res 2017; 9(1): 1-9; 2Nock, et al. Biochem Biophys Acta 2017; 1862(10 Pt A): 1068-1078.

Dementia can be improved or prevented by n-3 PUFA• Mild memory &/or cognitive impairment

– Subjective memory impairment

– Mild cognitive impairment

– Cognitive impairment no dementia

– Mild Alzheimer’s disease

• Higher intake of fish

• Additional daily n-3 PUFA intake > 2 g

• Additional daily DHA intake > 900 mg

• Duration of treatment > 6 mos

1Yanai, J Clin Med Res 2017; 9(1): 1-9.

Herbs

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Curcumin

• Compound in turmeric– Herb in the ginger family– Curcuma longa L.

• Spice in curry powder• Anti-inflammatory1

• Powerful antioxidant2

• Inhibits amyloid β formation2

1Srimal, et al. J Pharm Pharmacol. 1973;25:447-452. 2Mirmosayyeb, et al. Int J Prev Med. 2017;8:5.

CurcuminDose/Duration Participants ResultsCurcumin 80 mg single dose1

N = 60Healthy adultsAge 60-85

Acute curcumin vs placebo: Significantly improved sustained attention & working memory tasks 1 hour post dose

Curcumin 80 mg/d x 4 weeks1

Chronic curcumin vs placebo: Significantly improved working memory & mood

Curcumin 1500 mg capsules/d x 12 months2

N = 160Age 40-90No cognitive impairments

Curcumin vs placebo: Improved cognitive performance at 6 monthsNo differences between groups at 12 months

Theracurmin: curcumin 90 mg twice/d x 18 months3

N = 40Age = 51-84Non-demented

Curcumin vs placebo: Improved memory & attention Benefit associated with decreases in amyloid & tau accumulation

1Cox, et al. J Psychopharmacol. 2015;29(5):642-51. 2Rainey-Smith, et al. Br J Nutr. 2016;115(12):2106-13. 3Small, et al. Am J GeriatrPsychiatry. 2018;26(3):266-277

Sage

• Herbal supplement

• Antioxidant and anti-inflammatory

• Inhibits acetylcholinesterase (AChE)1,2

• CNS depressant

• Salvia officinalis

• S. lavandulaefolia

1Perry, et al. Pharmacol Biochem Behav 2003;75(3):651-9. 2Kennedy, et al. J Psychopharmacol 2011;25(8):1088-100.

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Sage ExtractDose/Duration Participants ResultsS. lavandulaefoliaessential oil50 mcg capsules QD x 1 week, then BID x 1 week, then TID x 4 weeks1

N = 11Age = 76-95Mild to moderate probable ADMMSE = 10-26

After 6 weeks of treatment: 14.4% decrease in AChE activity Improvements in Neuropsychiatric Inventory (NPI) measurementsMMSE scores stayed the same

S. lavandulaefoliaessential oil50 uL single dose2

N = 36Mean age = 23Healthy participants

S. lavandulaefolia vs placebo:Improved cognitive performance & moodImproved attention & memory performance 1-h post doseReduced mental fatigue & increased alertness more prominent 4-h post-dose

1Perry, et al. Pharmacol Biochem Behav 2003;75(3):651-9. 2Kennedy, et al. J Psychopharmacol 2011;25(8):1088-100.

Sage ExtractDose/Duration Participants Results

S. officinalisextract60 drops(~4 mL)/day x 4 months

N = 42Age = 65-80Mild to moderate ADScore > 12 on the ADAS-cog

S. officinalis vs placebo:Improved cognitive functions (ADAS-cog & CDR-SB scores)May reduce agitation

Akhondzadeh, et al. J Clin Pharm Ther. 2003;28(1):53-9.

Foods/Diet Plans

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Specific Foods/Fluids

Nutrients Food Sources

DHA, vitamin D Fatty fish

Monounsaturated fat Olive oil

Tocopherols (vitamin E) Leafy green vegetables

Flavonoids Berries

Polyphenols Red wine, green tea

Studies on Specific FoodsFoods Participants Results Fish1 N = 2233

Age = 65+ yrsLean fried fish: no effectFatty fish:APOE e4: no protective effectAPOE e4 negative: reduced risk of dementia & AD

Fish2 N = 5395Age = 55+ yrs

No association between fish intake & dementia risk

Olive oil3

N = 6947Age = 65+ yrs

High or moderate consumption of olive oil: Lower odds of cognitive deficit in visual memory & verbal fluency

1Huang TL, et al. Neurology 2005;65(9):1409-14.

2Devore EE, et al.

Am J Clin Nutr 2009;90(1):170-176.3Berr C, et al. Dement Geriatr

Cogn Disord 2009;28(4):357-364.

Foods Participants ResultsLeafy green vegetables1

N = 3,718Age = 65-102 yrsChicago60% Black, 62% FFood frequencyquestionnaireFollow-up: 3 & 6 yrs

Greater consumption of leafy green vegetables:Slower rate of cognitive decline> 2 vegetable servings/day = cognition 5 yrs younger Fruit consumption:No cognition benefit

Leafy green vegetables2

N = 960Age = 58-99 yrsFood frequency questionnaire & cognitive assessmentsMean 4.7 yrs (2-10)

Green leafy vegetable consumption (highest quintile: mean 1.3 servings/d; higher intakes of folate, phylloquinone& lutein):Slower cognitive declineEquivalent to 11 yrs younger vs rarely or never consumed green leafy vegetables

1Morris MC, et al. Neurology 2006;67(8):1370-1376.

2Morris MC, et al.

Neurology 2018; 90:e1-9.

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Foods Participants ResultsBerries1 N = 16,010 women

Age = 70+ yrsNurses’ Health StudyFood frequency questionnaire

Higher total flavonoidintake: Slower rates of cognitive declineBlueberries & strawberries (2+ servings/wk):Delayed cognitive aging by up to 2.5 yrs

Berries2 N = 9Age = 76.2 +/- 5.2 yrsEarly memory changesWild blueberry juice daily vs grape juice vs placebo, x 12 wks

Blueberry juice: Improved paired associate learning, word list recall

1Devore EE, et al. Ann Neurol 2012;72(1):135-43.

2Krikorian R, et

al. J Argic Food Chem 2010;58(7):3996-4000.

Foods Participants ResultsWine1 N = 980

Age = 65 yrsUp to 3 servings of wine daily: lower risk of AD

Green tea2

N = 1003Age = 70+ yrs

Green tea (> 3 cups/week):Lower prevalence of cognitive impairment

Tea3 N = 490Age = 60+ yrs

Green tea every day vs none:Cognitive decline (dementia or MCI): OR 0.32 (P=0.001)Dementia: OR 0.26 (P=0.06)

Black tea or coffee: no association for dementia or cognitive decline

1Luchsinger JA, et al. J Am Geriatr Soc 2004;52(4):540-6.

2Kuriyama

S, et al. Am J Clin Nutr 2006;83(2):355:61. 3Noguchi-Shinohara M, et

al. PLoS One 2014;9(5): e96013.

Foods Participants Results

Coffee1 N = 1409Age: 65-79 yrsAvg follow-up21 yrs

Coffee consumption at midlife vs no/little coffee: Lower risk of dementia & ADlater in lifeLowest risk (65% decrease): 3-5 cups/day

Coffee2 N = 676 men10-yr prospective cohort studyFinland, Italy, Netherlands

Coffee consumption vs non-consumers:Smaller cognitive declineInverse & J-shaped associationLeast cognitive decline: 3 cups of coffee/day

1Eskelinen MH, et al. J Alzheimers Dis 2009;16(1):85-91.

2Van Gelder

BM, et al. Eur J Clin Nutr 2007;61(2):226-32.

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DASH (Dietary Approaches to Stop Hypertension)

• Emphasis on:– Vegetables– Fruits– Whole grains– Low-fat or fat-free

dairy products– Lean meat, poultry, &

fish– Nuts, seeds, legumes

• Increased amounts: – Potassium– Calcium– Magnesium– Fiber

• Limit:– Saturated fat– Sugar-sweetened

beverages & sweets– Sodium

DASH Diet Participants Study Design Results

N = 16,144Age = 70+ yrsWomen1

Prospective cohort studyNurses’ Health Study

Long-term adherence: Better average cognitive function

N = 124Middle ageElevated BPSedentary & overweight or obese (BMI 25-40)2

Randomized control trialDASH alonevs DASH + weight management vs usual diet control group

DASH + weight managementand DASH alone: Greater neurocognitive improvements

1 Berendsen AAM, et al. J Am Med Dir Assoc 2017;18(5):427:432; 2Smith

PJ, et al. Curr Alzheimer Res 2012;8(5):510-519.

Mediterranean Diet

• High intake of:

– Extra virgin olive oil

– Vegetables, including leafy green vegetables

– Fruits

– Cereals

– Nuts & pulses/legumes

• Moderate intake of:

– Fish & poultry

– Dairy products

– Red wine

• Low intake of:

– Red meat

– Eggs

– Sweets

Davis, et al. Nutrients 2015; 7(11): 9139-9153.

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Mediterranean Diet Participants Study Design Results

N = 22581

No dementiaProspective study, NYFood frequency questionnaireEvaluated Q 1.5 yrsAdherence: 0-9 pts

262 cases of AD4 yr (0.2-13.9) follow-upFor AD vs lowest tertile:Highest tertile: HR 0.60 Middle tertile: HR 0.85

N = 5222

Age 55-80 yrs(74.6 +/- 5.7)High vascular risk

Randomized control trial, SpainMedDiet+EVOOvs MedDiet+Nutsvs low-fat diet (control)Mean follow-up: 6.5 yrs

MedDiet enhanced with EVOO or nuts: Better cognitive performanceMCI (60): 18 vs 19 vs 23Dementia (35): 12 vs 6 vs 17

1Scarmeas N, et al. Ann Neurol 2006;59(6):912-21.

2Martinez-Lapiscina EH, et al. J Neurol Neurosurg Psychiatry

2013;84(12):1318-25.

Dietary Plans

DASH DASH MedDietMedDiet MIND MIND

Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND)

Whole grains 3/d

Green leafy vegetables 1/d

Other vegetables 1/d

Berries 2/wk

Fish 1/wk

Poultry 2/wk

Beans >3/wk

Nuts 5/wk

Alcohol/wine 1/d

Olive oil = primary oil

Fast/fried food <1/wk

Butter, margarine <1T/d

Cheese <1/wk

Red meats and products <4/wk

Pastries, sweets <5/wk

Morris MC, et al. Alzheimers Dement 2015;11(9):1007-1014.

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Rush Memory and Aging Project

• Prospective study, 2004-2013

• N = 923, 58-98 years old

• Evaluated 3 dietary patterns to incidence of AD

• Food frequency questionnaire

– Usual frequency of intake over previous 12 mos

– 144 items

• Mean of 4.5 years follow-up

– 151 AD cases developed


DASH (max total score 10)

Components Max score Components Max score

Total grains ≥ 7/d 1 Total fat ≤ 27% of kcal

1

Vegetables ≥ 4/d 1 Saturated fat ≤ 6% of kcal

1

Fruits ≥ 4/d 1 Sweets ≤ 5/wk 1

Dairy ≥ 2/d 1 Sodium ≤ 2400 mg/d 1

Meat, poultry & fish ≤ 2/d

1

Nuts, seeds & legumes ≥ 4/wk

1


MedDiet (max total score 55)

Components Max score Components Max score

Nonrefined Grains > 4/d

5 Legumes, nuts & beans > 6/wk

5

Vegetables > 4/d 5

Potatoes > 2/d 5 Olive oil ≥ 1/d 5

Fruits > 3/d 5

Full-fat Dairy ≤ 10/wk 5 Alcohol < 300 mL/d but > 0

5

Red meat ≤ 1/wk 5

Fish > 6/wk 5

Poultry ≤ 3/wk 5


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MIND (max total score 15)Components Max score Components Max score

Whole grains ≥ 3/d 1 Nuts ≥ 5/wk 1

Green leafy ≥ 6/wk 1 Fast/fried food < 1/wk

1

Other Vegetables ≥ 1/d

1 Olive Oil primary oil 1

Berries ≥ 2/wk 1 Butter, margarine < 1 T/d

1

Red Meats & products < 4/wk

1 Cheese < 1/wk 1

Fish ≥ 1/wk 1 Pastries, sweets < 5/wk

1

Poultry ≥ 2/wk 1 Alcohol/wine 1/d 1

Beans ≥ 3/wk 1Morris MC, et al. Alzheimers Dement 2015;11(9):1007-1014.

Diet Scores


Tertile 1 Tertile 2 Tertile 3 P for Linear Trend

DASHScore range 1.0 - 3.5 4.0 - 4.5 5.0 - 8.5HR 1.0 0.98 0.6195% CI Referent 0.66, 1.46 0.38, 0.97 0.07

MediterraneanScore range 18 - 29 30 - 34 35 - 46 HR 1.0 0.81 0.4695% CI Referent 0.54, 1.24 0.27, 0.79 0.006

MINDScore range 2.5 - 6.5 7 - 8 8.5 - 12.5HR 1.0 0.65 0.4795% CI Referent 0.44, 0.98 0.29, 0.76 0.002

CerefolinNAC: L-methylfolate 6 mg, methyl-cobalamin 2 mg, N-acetylcysteine 600 mg

Participants ResultsHHcy+CFLN (N=34) vs NoHHcy+NoCFLN(N=82)2

No B vit supp

AD, VD, mixed dementia

Slower rate of cognitivedeclineRelated to: Hcy reduction from baseline, duration of CFLN, milder baseline severity

HHcy+CFLN (N=30) vs NoHHcy+NoCFLN(N=37)2

No B vit suppHHcy: Hcy ≥ 12 umol/L

AD or cognitive impairment due to cerebrovascular disease

CFLN for 2 or more yrs: Delayed hippocampal & cortical atrophy rateRelated to: greater Hcylowering, longer CFLN duration, milder baseline severity

1Henderson ST, et al. Nutr Metab 2009;6(31).

2Shankle WR, et

al. J Alzheimers Dis 2016;54(3):1073-1084.

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Medical FoodsMedical Foods Participants ResultsSouvenaid1,2

Contains DHA 1200 mg & EPA 300 mg, B vitamins 1 mg, uridinemonophosphate 625 mg, choline 400 mg, & phospholipids 106 mg

N = 26Age = 50-65 yrsBehavioral variant of frontotemporal dementia

Treatment vs placebo: Significant reduction of behavioral symptomsIncrease in Theory of Mind skillNo effect on executive functions

N = 259Age = 50+ yrs

Drug-naïve pts with mild AD: Improved memory performance

1Pardini M, et al. Neurodegener Dis 2014;15(1):58-62.

2Scheltens P, et al. J Alzheimers Dis 2012;31(1):225-36.

Reversal of cognitive decline

• 10 patients, memory loss: Alzheimer’s disease (AD), amnestic mild cognitive impairment (aMCI), or subjective cognitive impairment (SCI)

• Nine of 10: subjective or objective improvement in cognition beginning within 3-6 months; one failure: very late stage AD

• Six patients: – Discontinued working or were struggling with their jobs

at time of presentation– All able to return to work or continue working with

improved performance• Longest patient f/u: 2½ years from initial treatment, with

sustained & marked improvement

Aging 2014; 6: 707-717

Metabolic enhancement for neurodegeneration (MEND) protocol

Goal Approach

Optimize diet: minimize simple CHO, minimize inflammation

Choice of several low glycemic, low inflammatory, low grain diets

Enhance autophagy, ketogenesis

Fast 12 hr each night, including 3 hr prior to bedtime

Reduce stress Yoga or meditation or music, etc

Optimize sleep 8 hr sleep per night, melatonin 0.5 mg po qhs; Tryptophan 500 mg po 3x/wk if awakening. Exclude sleep apnea.

Brain stimulation Posit or related

Aging 2014; 6: 707-717

4/3/2018

20


Goal Approach

Homocysteine < 7 Me-B12, MTHF, P5P, TMG if necessary

Serum B12 > 500 Me-B12

CRP < 1.0, A/G > 1.5 Anti-inflammatory diet; curcumin; DHA/EPA; optimize hygiene

Fasting insulin < 7; HgA1C < 5.5

Diet as above

Hormone balance Optimize fT3, fT5, E2, T, progesterone, pregnenolone, cortisol

GI health Repair if needed; prebiotics & probiotics

Aging 2014; 6: 707-717


Goal Approach

Reduction of A-beta Curcumin, Ashwagandha

Cognitive enhancement Bacopa monniera, Mg Threonate

25(OH)D3 = 50-100 ng/mL Vitamins D3, K2

Increase NGF H. erinaceus or ALCAR

Provide synaptic structuralcomponents

Citicoline, DHA

Optimize antioxidants Mixed tocopherols & tocotrienols, Se, blueberries, NAC, ascorbate, α-lipoic acid

Aging 2014; 6: 707-717


Goal Approach

Optimize Zn:fCu ratio Depends on values obtained

Ensure noctural oxygenation Exclude or treat sleep apnea

Optimize mitochondrial function

CoQ or ubiquinol, α-lipoic acid, PQQ, NAC, ALCAR, Se, Zn, resveratrol, ascorbate, thiamine

Increase focus Pantothenic acid

Exclude heavy metal toxicity Evaluate Hg, Pb, Cd; chelate if indicated

MCT effects Coconut oil or Axona

Aging 2014; 6: 707-717

4/3/2018

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Metabolic enhancement for neurodegeneration (MEND) protocol• Decrease in:

– hs-CRP– Fasting insulin– HbA1c– Homocysteine

• Increase in:– 25OH vitamin D– MMSE– MoCA– Hippocampal volume

• Improvement in:– Memory– Recall– Processing speed– Executive function

Aging 2016; 8: 1250-1258

ConclusionNutritional Intervention

Result

Folic acid Lowered Hcy and improved cognition

Vitamin E Improvement in cognition

Alpha-lipoic acid Improved cognition in patients with diabetes

Omega 3 Reduced incidence of dementia; improvements in cognition in healthy adults and in very mild dementia

Curcumin Improved cognition in healthy adults

Sage Decreased AChE activity and improvements in cognition in patients with dementia

DASH and MeDidiets

Only high adherence was associated with cognitive improvement

MIND diet Even moderate adherence reduced risk of AD

Thank You!

Speaker Contact Information:

Melody ArmitehUSC School of PharmacyEmail: [email protected]

Naomi QuintUSC School of PharmacyEmail: [email protected]

Kelly TranUSC School of PharmacyEmail: [email protected]

Cynthia Lieu, Pharm.D., BCNSPUSC School of PharmacyOffice: (323) 442-1472Email: [email protected]

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