Role of DHA in Cognitive Aging and Alzheimer s Disease

January 14, 2019 | Author: Phoebe McLaughlin | Category: N/A
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1 Role of DHA in Cognitive Aging and Alzheimer s Disease Michelle Keske PhD 10 November, 20082 Conflict of Interest Mart...

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Role of DHA in Cognitive Aging and Alzheimer’s Disease Michelle Keske PhD 10 November, 2008

Conflict of Interest

Martek Biosciences Corporation

Microalgae versus Fish Oil Fish oil with DHA+EPA

Algal DHA Oil

Fish eat algae

Fermentation Process

Algae make DHA

Docosahexaenoic acid (DHA) • Omega-3 fatty acid • Important component of all cell membranes

DHA

• Found in all tissues; most abundant in neural and retinal tissue  Brain: 97% of n-3 is DHA  Retina: 93% of n-3 is DHA

22:6 3

• Important in infant visual and mental development • Maintains cardiovascular, visual and neural function throughout the lifespan

Long-chain Omega-3 Intakes

LCPUFA’s in various tissues Brain

20 15 10 5 0

ALA

EPA

DHA

LA

Retina 20 15 10 5 0

ARA

ALA

25

EPA

DHA

LA

ARA

EPA

DHA

LA

ARA

25

Adipose 20

weight % total fatty acids

weight % total fatty acids

n-3 n-6

25

weight % total fatty acids

weight % total fatty acids

25

15 10 5 0

ALA

EPA

DHA

LA

Lauritzen et al (2001) Prog Lipid Res

ARA

20

Liver

15 10 5

0

ALA

DHA Distribution in the Brain • DHA represents 10 to 15% of brain total fatty acids – Of brain n-3 fatty acids, DHA represents 97%

• DHA preferentially represented in cell membranes frontal cortex executive function working memory - sustained attention, - problem solving hippocampus spatial learning declarative memory formation (ability to recall facts and events)

Role of DHA in Brain Structure and Function Structural Role – Integrated into brain phospholipids – Modulates function of signal transduction molecules, G-protein coupled receptors (e.g. rhodopsin)

Functional Roles • Converted to anti-inflammatory docosanoids – recently, neuroprotectin D1 (protection from stroke)

• • • •

Serves as second messenger in synaptic signal transduction and synaptic function Neuronal differentiation Myelination Synaptogenesis

Human Studies on Aging and Dementia Epidemiology • Risk of Dementia: – Fish consumption > 1x/week or higher serum DHA, 40-60% risk reduction of dementia (Kalmijn, 1997; Barberger-Gateau, 2002, 2007; Morris, 2003; Schaefer, 2006; ) – Greater proportion of RBC membrane or plasma n-3 Fatty Acids are significantly associated with lower risk of cognitive decline (Heude, 2003; Beydoun, 2007) • Cognitive Performance in Elderly: – Greater fish consumption better cognitive scores (Nurk, 2007); or less cognitive decline (van Gelder, 2007; Dullemeijer, 2007) • Brain MRI scan: – greater Omega-3 intake associated with greater grey matter volume in the anterior cingulate cortex, hippocampus and amygdala (Conklin, 2007)

DHA Deficiency • Brain phospholipid fatty acids are significantly reduced in AD frontal cortex & hippocampus vs. age-matched controls (Soderburg, 1991) • Plasma levels n-3 fatty acids are significantly lower in AD (Conquer, 2000)

Evidence Reviews • Several evidence reviews have been conducted – – – –

AHRQ Report, 2005 Cochrane Report, 2006 ISSA, A. 2006 Noel,K et al Research & Practice in Alzheimer’s Disease, 2006

• AHRQ Report, March 2005 states “Total omega-3 fatty acid consumption and consumption of DHA (but not ALA or EPA) were associated with a significant reduction in the incidence of Alzheimer’s”… “ however due to small number of studies…further research is necessary before a strong conclusion can be drawn.”

Omega-3 Centre Consensus Report Oct 08 Level of Evidence: Cognition : - Ranking +1 - Weak evidence to date, important to follow up - Dose difficult to define Dementia, Alzheimer’s disease: - Ranking +1 - Weak evidence to date, important to follow up - Dose difficult to define

Pathology of Alzheimer’s Disease Amyloid Plaques: • Deposits of beta-amyloid.

• Plaques found in the spaces between the brain’s nerve cells. Neurofibrillary Tangles:

• Twisted threads of a protein called tau. • Tau is a protein found inside nerve cells. • In AD, Tau changes so that it becomes threads wound around each other.

In vitro studies • DHA Neuroprotective effects in aging human neural cells (Lukiw, 2005) –DHA attenuates Amyloid Beta secretion –↑biosynthesis of neuroprotectin D1 –↑ neuroprotective gene expression • DHA increases neuron survival (Florent, 2006) − DHA prevents neuronal apoptosis induced by soluble amyloid-β oligomers.

Pre-clinical Studies (Aged mice) • Dietary supplementation of DHA in mice (Lim et al., 2002)

– supplemented 0. 5 – 2 g DHA / 100g diet – increased brain DHA content by 4 wt. % (absolute) – Improved maze-learning ability after 4 months • decreased latency and reduced errors • Chronic DHA (300mg/kg/d, 10 wks) decreased reference and working spatial memory errors in Aged rats (Gamoh, 2001)

Pre-clinical Studies (AD models) Chronic Administration of DHA in Amyloid β-infused Rats (Hashimoto, 2002; 2005)

•Dietary DHA (300mg/kg/d) supplementation of β-amyloid infused rats for 12 weeks

•DHA group had greater avoidance responses (conditioned avoidance task) vs. control or Aβ groups

•DHA group had reduced reference and working memory errors (8-arm radial maze) vs. control or Aβ groups

Pre-clinical Studies (AD models) (Calon, et al. Neuron, 2004; Lim et al. J. Neuroscience, 2005)

Martek DHA supplementation of transgenic Alzheimer’s mice: – 70% reduction in insoluble total amyloid Beta – 40% reduction in amyloid plaque burden – improvement in learning and memory task

Pre-clinical Studies (AD models) (Green, et al, Journal of Neuroscience, 2007)

Martek DHA supplementation of triple transgenic Alzheimer’s mice: – significantly reduced soluble Ab (amyloid plaque precursor) – reduced tau protein (neurofibrillary tangle precursor) and phosphorylated tau – significantly decreased presenilin PS1 (catalytic core of γ-secretase) levels – no effect on Amyloid Precursor processing

Soluble Ab / 9 Months 1200

Ab40

Ab42

800 600

200

*

0

control DHA-T DHA-S DHA-T + ARA

400

control DHA-T DHA-S DHA-T + ARA

pg/ml

1000

Control

DHA-T

DHA-S

DHA-T+ARA

Clinical Studies The OmegaAD study

•204 subjects with AD and MMSE>15 •Randomized to omega 3’s vs placebo •Dose:1.7 g DHA and 0.6 g EPA per day •Placebo-controlled for 6 months

Results In all subjects at 6 months or 12 months (open-label of omega-3s) (n=91 omega-3; n=87 placebo) • • • •

No difference in ADAS-cog No difference in MMSE No difference in CDR Global or CDR-SOB Benefit was reported in a post hoc analysis of subjects with MMSE>27 (n=32)

MIDAS (Memory Improvement with Docosahexaenoic Acid Study) Goal: Evaluate the effects of Martek DHA on cognitive outcomes in healthy elderly (>55 yrs.) with a mild memory complaint (Martek-sponsored study) Trial Design: •Randomized, double-blind, placebo-controlled, parallel, multi-center •Oral Dose: 900 mg DHA/day or placebo (corn/soy) •Study treatment: 6 mos. •Sample size: 465 subjects •Primary Endpoint: cognitive test of memory, attention & learning (CANTAB)

•Secondary Endpoints: cognitive tests of executive function, Activity of Daily Living skills, visual acuity, plasma phospholipid fatty acid levels, safety and tolerability Registered on www.clinicaltrials.gov

NIH trial: Effect of DHA in Alzheimer’s Disease Hypothesis: DHA supplementation will slow the rate of cognitive decline in patients with mild-to-moderate Alzheimer’s Disease (AD) by a combination of antioxidant, anti-amyloid, and neuroprotectant effects.

Trial Design: • Randomized, double-blind, placebo-controlled, parallel, multi-center study • Doses: 2,000 mg DHA/day vs. placebo • Study treatment: 18 months • Sample size: 400 patients • Sites: 50 (U.S.) ADCS centers •Primary Endpoints: changes in Cognitive measures: ADAS-Cog and CDR-SOB • Secondary Endpoints: biomarkers, fatty acid levels, MRI, safety measures Registered on www.clinicaltrials.gov

Other Clinical Trials In-progress • OPAL Study -Older people and n-3 PUFAs (UK), RCT, n=798, 24 mths,700mg/d (500mgDHA, 200mgEPA), 70-79 yrs old, Results projected in 2008 • MEMO Study -Omega-3 and mental health in elderly (Netherlands), RCT, n=300, 6 mths, 3 arms: 400mg, 1.8 mg/d (EPA/DHA), placebo; 65+ yrs, Results recently published in Neurology, 2008, 71:430-438 • Older People, Omega-3 and Cognitive Health (Australia), RCT, n=400, 18 mths, 585mg/d (450mgDHA, 135mg EPA), 65-90 yrs, ongoing • Montauban Study -Omega-3 prevention of dementia study (long-term) (France), RCT, n=1200, 3 yrs, 800mg/d, >70 yrs

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