Realising the potential of MILK PHOSPHOLIPIDS as an ingredient to improve cognitive function

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1 Realising the potential of MILK PHOSPHOLIPIDS as an ingredient to improve cognitive function Professor Louise Dye Human Appetite Research Unit, Institute of Psychological Sciences Leeds University

2 NUTRITION & MENTAL performance A clear but complex link Nutriton impacts cognition PROMOTION of optimal brain development PREVENTION of neurodegeneration and cognitive decline

Phospholipids (PL) - bioactive and fundamental for life Phospholipids

ALL biological membranes STRUCTURAL and FUNTIONAL There are five major

sources of PL include meat, egg, soy and MILK (bovine/human) Dietary

3 Phospholipids (PL) - bioactive and fundamental for life Phospholipids (PL) are bioactive lipids which play various important functions in ALL biological membranes STRUCTURAL and FUNTIONAL There are five major PLs characterized by different head units (PC, PE, PI, PS PG) Dietary sources of PL include meat, egg, soy and MILK (bovine/human) Dietary PL has good oral bioavailability and readily crosses the blood brain barrier.

BRAIN PL- content (Arb Units) Phospholipids - from a BRAIN

abundant phospholipids of brain cell membrane Phospholipids

are incorporated in the membrane system PC PE PS PI SM

block of membrane bilayers and provides choline for

[36% brain PL] key building block of membrane bilayers

in biosynthesis and release of neurotransmitters.

neurons Phospatidyl Inositol (PI) [2-5% brain PL] key membrane

processes Sphingomyelin (SM) [11% brain PL] contributes to

number of membrane-bound proteins and is also a source of

4 BRAIN PL- content (Arb Units) Phospholipids - from a BRAIN perspective PC, PE, PS, PI, SM represent FIVE of the most abundant phospholipids of brain cell membrane Phospholipids constitute more than 60% of total brain lipid, most of which are incorporated in the membrane system PC PE PS PI SM Phosphatidyl choline (PC) [33-37% brain PL] ] key building block of membrane bilayers and provides choline for Acetycholine (Ach) synthesis Phosphatidyl ethanolamine (PE) [36% brain PL] key building block of membrane bilayers Phosphatyidyl serine (PS) [10-20% brain PL] - plays a key role in biosynthesis and release of neurotransmitters. PS is neurotrophic, increasing total number and size of neurons Phospatidyl Inositol (PI) [2-5% brain PL] key membrane constituent and as a participant in essential metabolic processes Sphingomyelin (SM) [11% brain PL] contributes to myelination of neurons, is required for the activity of a number of membrane-bound proteins and is also a source of choline. SM not found in plants. PC PE PS PI SM Svennerholm et al 1994, Parletta et al Kwee IL & Nakada T, AGE

% phospholipid of total PL content The potential of MILK phospholipids to improve

Phosphatidylserines (PS) Phosphatidylethanolamines (PE) 10 Others 0 Brain tissue

5 % phospholipid of total PL content The potential of MILK phospholipids to improve cognitive function Bovine MILK PHOSPHOLIPIDS A natural source of bioactive lipids with a SIMILAR profile as found in human BRAIN Phosphatidylcholines (PC) Phosphatidylinositoles (PI) Sphingomyelins (SM) Phosphatidylserines (PS) Phosphatidylethanolamines (PE) 10 Others 0 Brain tissue (Human) Bovine MILK Human MILK Egg Soy * Cerebral cortex 16 year male from Svennerholm et al Burling & Graverholt 2008.

Brain development and cognitive functioning - Lifelong process - from conception to adulthood Infants experience the most rapid periods of postnatal brain growth and development A vast range of

6 Brain development and cognitive functioning - Lifelong process - from conception to adulthood Infants experience the most rapid periods of postnatal brain growth and development A vast range of nutrients are critically needed for optimal BRAIN development in this period Composition of MILK has adapted to fulfill the needs Recent research on brain neurogenesis and plasticity confirms that good nutrition is important for optimal brain function throughout our lifecycle Tau et al 2010, Andersen et al 2003

7 The potential of MILK phospholipids - as ingredients to improve cognitive function BOVINE MILK phospholipids have been documented to IMPROVE BRAIN development & COGNITION in infants POTENTIAL for PROMOTING optimal brain development during childhood? POTENTIAL for PREVENTING neurodegeneration and cognitive decline?

Realising the potential for MILK PHOSPHOLIPIDS.

phospholipids improved behavioral regulation in healthy pre-school CHILDREN (Vereman-Weuters et al.

Supplementation to infant formulas of MILK derived PLs versus Egg-Yolk derived PLs was found positively associated

al. 2013) Tanaka et al. 2012 2013 2014 2015 Liu et al. Gurnida et al.

8 Realising the potential for MILK PHOSPHOLIPIDS. - Results from RECENT HUMAN clinical trials & PIGLET trials Functional milk drink enriched with bovine MILK phospholipids improved behavioral regulation in healthy pre-school CHILDREN (Vereman-Weuters et al. 2012) Vereman- Weuters et al. Supplementation to infant formulas of MILK derived PLs versus Egg-Yolk derived PLs was found positively associated with neurobehavioral development of pre-term infants and subscribed to its higher content of SPHINGOMYELIN (Tanaka et al. 2013) Tanaka et al Liu et al. Gurnida et al. Supplementation of MILK derived complex lipids to infant formulas was are associated with beneficial effects on cognitive development in healthy INFANTS (Gurnida et al. 2012, Timby et al, 2014) Timby et al. Supplementation of MILK derived phospholipids improved spatial learning and increased brain growth and composition in neonatal PIGLETS - (Liu et al. 2014)

Exploring the POTENTIAL for MILK phospholipids to IMPROVE cognitive performance in school children AIM: To explore the effects of a daily supplement of MILK phospholipids on cognitive performance- &

Strategic collaboration between The University of Leeds, UK and Arla Foods Ingredients, Denmark Randomized, 6 week, parallel groups, double blind, placebo controlled trial Participants: n= 84, 6-8

9 Exploring the POTENTIAL for MILK phospholipids to IMPROVE cognitive performance in school children AIM: To explore the effects of a daily supplement of MILK phospholipids on cognitive performance- & subjective state in school children. Strategic collaboration between The University of Leeds, UK and Arla Foods Ingredients, Denmark Randomized, 6 week, parallel groups, double blind, placebo controlled trial Participants: n= 84, 6-8 year old school children 3 cohorts from 2 primary schools in UK Supplement: MILK phospholipid (Lacprodan PL20) enriched milk or non-enriched milk. 3 Assessments baseline (Week 0), mid-intervention (Week 3) & postintervention (Week 6) Measures of cognitive performance, related to learning (CANTAB) i.e. improvement in performance from baseline to week 6 Subjective state measures (Visual Analogue Scales ratings) Delivered as a school-based intervention (Monday Friday)

10 CANTAB Cognitive Tests and Brain Regions Delayed Matching to Sample Reaction Time Rapid Visual Information Processing Emotion Recognition Test Affective Go/No-go Spatial Working Memory Stockings of Cambridge Attention Switching Task Stop Signal Task Paired Associates Learning Verbal Recall / Recognition Memory Pattern or Spatial Recognition Memory

Phospholipid Intervention for Cognitive Ageing Reversal (PLICAR)

seniors AIM: To investigate neurocognitive effects of daily

University of Technology The trial protocol has been published:

Trials, 14:404 Is registered on the Australia and New Zealand

recruiting AGE Human clinical trial to evaluate whether chronic

12 Phospholipid Intervention for Cognitive Ageing Reversal (PLICAR) CLINICAL TRIAL exploring the POTENTIAL for MILK phospholipids in seniors AIM: To investigate neurocognitive effects of daily supplementation with MILK phospholipids, in elderly participants with age-associated memory impairment. Jointly funded by Arla Foods Ingredient, Denmark and Swinburne University of Technology The trial protocol has been published: Scholey et al Trials, 14:404 Is registered on the Australia and New Zealand Clinical Trials Registry as ACTRN Is currently recruiting AGE Human clinical trial to evaluate whether chronic (daily) supplementation with MILK phospholipid over a 6-month period improves cognitive functioning and mood in healthy older adults (>55 years) with age-associated memory impairment (AAMI).

Brain composition and functioning alters as we age - decline in cognitive and mental functioning AAMI, AD Estimated prevalence of AAMI diagnosis 40 % of people age 50-59 > 50 % of people age 60-69 Up

13 Brain composition and functioning alters as we age - decline in cognitive and mental functioning AAMI, AD Estimated prevalence of AAMI diagnosis 40 % of people age > 50 % of people age Up to 80 % of people age >80 AAMI, Age associated memory impairment, i.e., normal decline in mental functioning MCI, mild cognitive impairment AD, Alzheimers disease Concentration of most lipids in the human DECREASE after age of 20 PL decreases 18-31% and the volume of the brain declines with age at a rate of around 5% per decade after the age of 40 To date Nutritional supplements with PL s like PC and PS in ISOLATION have shown beneficial effects for treating or slowing the progression of mental decline/aami Svennerholm et al Ledesma et al Parletta et al

Phospholipid Intervention for Cognitive Ageing Reversal (PLICAR) CLINICAL TRIAL exploring the POTENTIAL for MILK phospholipids in seniors Neuroimaging MRI, fmri (subset of participants)

PL-20) or one of two placebos (phospholipid-free milk protein concentrate or inert rice starch) 6-month intervention with testing at baseline, 90 days and 180 days PRIMARY outcome:

14 Phospholipid Intervention for Cognitive Ageing Reversal (PLICAR) CLINICAL TRIAL exploring the POTENTIAL for MILK phospholipids in seniors Neuroimaging MRI, fmri (subset of participants) Randomized, double-blind, placebocontrolled parallel groups N= 150 (N = 50/group) AAMI participants aged > 55 years randomized to receive daily supplement of MILK phospholipids (Lacprodan PL-20) or one of two placebos (phospholipid-free milk protein concentrate or inert rice starch) 6-month intervention with testing at baseline, 90 days and 180 days PRIMARY outcome: composite memory score from the Rey Auditory Verbal Learning Test SECONDARY outcome: include cognitive, cardiovascular, gastrointestinal, brain imaging and biochemical measures Scholey et al. 2013

years to manifest Cognitive tests need to be carefully selected Appropriate samples children, middle aged (40-65yrs -pre AAMI) Consider

15 Conclusions Good & growing evidence for role of Milk PL in cognition early in development & later in life Challenging to measure the effects of nutrition on cognitive function Effects - subtle Nutritional interventions with enduring effects on cognition may take months or even years to manifest Cognitive tests need to be carefully selected Appropriate samples children, middle aged (40-65yrs -pre AAMI) Consider additive/synergistic effects of other behaviour e.g. physical activity, body weight change by Talitha Best & Louise Dye (Eds.) Hardcover 1 Jun 2015

16 Future Directions Changing nature of diet, health & population Understand effects of altered eating patterns Effects of under & over-nutrition Cognitive benefits could be conferred directly specific nutrients or overall intake Or via other effects on health e.g. better glucoregulation, reduced triglycerides or other markers Important to preserve cognitive capacity in ageing Need functional foods to help maintain brain function

17 THANK YOU for your ATTENTION!

18 References Andersen Trajectories of brain development: point of vulnerability or window of opportunity? Neuroscience and Biobehavioral Reviews 27;3-18 Svennerholm Distribution and fatty acid composition of phosphoglycerides in normal human brain J Lip Res 9, Svennerholm et al Membrane lipids of adult human brain lipid composition of frontal and temporal lobe in subjects of age 20 to 100 years. J Neurochem, 63.(5). Ledesma MD et al Lipid changes in the aged brain: effect on synaptic function and neuronal survival. Prog Lipid Res. 51(1): Parletta et al Nutritional modulation of cognitive function and mental health. The Journal of Nutritional Biochemistry. 24 (5): Kwee IL & Nakada T (1988). Phospholipid profile of the Human Brain: 31P NMR Spectroscopic Study, Magnetic Resonance. Medicine 6, Tau et al Normal Development of Brain Circuits. Neuropsychopharmacology REVIEWS 35, Scholey et al. (2013). Trials, 14:404 Liu et al J. nutr. (X)xx-xx Burling & Graverholt Milk - A new source for bioactive phospholipids for use in food formulations. Lipid technology 10: Gurnida et al Association of complex lipids containing gangliosides with cognitive development of 6-month-old infants. Early Hum Dev Timby et al 2014 Neurodevelopment, nutrtiton, and growth until 12 mo of age in infants fed a low-energy, low-protein formula supplemented with bovine milk fat globule membranes: a randomized controlled trial. Am J Clin Nutr Tanaka et al Sphingomyelin-fortidiedmilk has a positive association with neurobehavioural development of very low brith weight infants during infancy, randomized control trial. Brain Dev 35;45-52 Vereman-Weuters et al Milk fat globule membrane (INPULSE) enriched formula milk decreases febrile episodes and may improve behavioral regulation in young children. Nutrition. 28(7-8):749-52

Developing and marketing cognitive products: ranging from life style and prevention to medical nutrition

Developing and marketing cognitive products: ranging from life style and prevention to medical nutrition Juliane Hellhammer, PhD daacro Full Service CRO booth 146 Nutrient biological effects marketing